Noninvasive electronic bone growth stimulators (EBGSs) have been in clinical use for decades. However, systematic reviews show inconsistent and limited clinical efficacy. Further, noninvasive EBGS studies in small animals, where the stimulation electrode is closer to the fracture site, have shown promising efficacy, which has not translated to large animals or humans. We propose that this is due to the weaker electric fields reaching the fracture site when scaling from small animals to large animals and humans. To address this gap, we measured the electric field strength reaching the bone during noninvasive EBGS therapy in human and sheep cadaver legs and in finite element method (FEM) models of human and sheep legs. During application of 1100 V/m with an external EBGS, only 21 V/m reached the fracture site in humans. Substantially weaker electric fields reached the fracture site during the later stages of healing and at increased bone depths. To augment the electric field strength reaching the fracture site during noninvasive EBGS therapy, we introduced the Injectrode, an injectable electrode that spans the distance between the bone and subcutaneous tissue. Our study lays the groundwork to improve the efficacy of noninvasive EBGSs by increasing the electric field strength reaching the fracture site. These huge costs have driven efforts to augment the well-studied process of fracture healing. Electrical stimulation is one method that has been explored to improve fracture healing. Fukada and Yusada discovered the piezoelectric property of bone—that bone generates endogenous electrical fields when put under mechanical stress—and its relationship to bone formation in 19532. Since then, there have been multiple studies in in vitro, small animal, and large-animal models, as well as clinical studies, to explore the effects of electrical stimulation on an array of osseous injuries3. These studies have led to the approval of nine electronic bone growth stimulators (EBGSs) by the Food and Drug Administration (FDA) for use in the treatment of osseous nonunion4.Orthopedic trauma causes $256.4 billion per year of economic loss in the form of healthcare costs and time lost from work in the United States5. Direct current electrical stimulation (DCES) and capacitive coupling (CC) electrical stimulation are two popular forms of EBGSs. The clinical data suggest that direct current electrical stimulation methods appear to work better to promote bone healing than noninvasive stimulation methods but increase risk of infection6 and require a costly and complex invasive device that has a high rate of failure due to device-related complications. Capacitive coupling is typically a noninvasive method of electrical stimulation that involves electrodes placed on the skin on opposite sides of the osseous injury. Alternating current generates an electric field between the electrodes, but the penetration of this field into tissues is poor7, making this modality applicable to only superficial bones like the distal radius or tarsal bones.A recent survey study reported that only 32% of orthopedic traumatologists have ever used an EBGS, and the main reasons given were high costs and inconsistent clinical efficacy8 reported that improvements in healing after fracture caused by the application of an electric field are believed to be due to the activation of voltage-gated calcium channels. The report summarized that the electric field causes voltage-gated Ca2+ channels in the cell walls of osteocytes to open, changing intercellular and cytosolic Ca2+ levels9. The change in intercellular and cytosolic Ca2+ levels triggers signaling molecules to promote osteoblastic differentiation and formation, thereby upregulating bone formation activity10. The putative mechanism of action depends critically on getting sufficient electric field strengths at the fracture site to open voltage-gated calcium channels and trigger the biological cascade leading to bone healing. The proposed mechanism of action is supported by clinical data suggesting that direct current electrical stimulation methods, where strong electric fields are applied directly to the fracture, appear to work better to promote bone healing than noninvasive stimulation methods6.The FDA Bone Stimulation workshop report11 and in rodents suggest that noninvasive stimulation from the surface of the skin can work nearly or as effectively as invasive stimulation to promote bone growth, yet the positive results from these models have yet to be born out in clinically translatable large-animal models or clinical studies. One underappreciated factor that may explain this disconnect is the difference in scale between noninvasive stimulation in a rodent versus a human. Electric potential falls off from a bipolar electrode pair proportional to ~ 1/r27, where r is the distance of the tissue from the electrode. In a rodent this distance is often 1 mm or less, whereas in a human the distance to the apex of the fracture can be 1 cm or more, meaning the same voltage applied externally may yield more than two orders of magnitude less electric potential at the site of fracture in humans than in rodents. However, there are no reports in the literature of measurements of electric field strength reaching the fracture site during noninvasive EBGS therapy. This is despite the criticality of the electric field strength at the fracture site to activating voltage-gated calcium channels—central to the proposed mechanism of action of EBGSs.Furthermore, early data in vitroIn this study, we—for the first time—use computational modeling and direct measurements from sheep cadaver metatarsus and tibia and human cadaver tibia cortex to create a framework for estimating the electric field strength reaching the fracture site during noninvasive EBGS therapy. We demonstrate that noninvasive stimulation at the skin in a large-animal model only generates a weak electric field at the deep bone fracture. We show that the electric field reaching the fracture site is highly dependent on the depth of the fracture and the electrode configuration. To address these limitations, we introduce a strategy using a novel electrode, the Injectrode, which can be simply injected into the bone fracture in a minimally invasive fashion, to increase the electric field strength reaching the deep fracture site during noninvasive EBGS therapy. Finally, we discuss the changing impedance of tissue at the fracture site during healing and its impact on the electric field reaching the fracture site during noninvasive EBGS therapy. This study lays the groundwork for a future in vivo large-animal sheep study planned by our group to test Injectrode-augmented EBGSs versus standard noninvasive EBGSs.First, we made direct measurements of the electric field strength reaching the fracture site in human tibia cadavers, and FEM computer models, to study the limitations of conventional noninvasive EBGSs. We then created another FEM model for a sheep leg in the metatarsus region based on dimensions from literature and measured in sheep cadavers and tissue conductivity values from literature  were made 2 mm and 5 mm from the defect along the longitudinal axis of the tibia for the recording electrode pair. The soft tissue flap was then closed in layers using 5–0 permanent suture to obliterate dead space. The recording electrodes were inserted percutaneously through the flap into the 0.5-mm diameter holes made previously in the cortical bone. The noninvasive stimulation electrode pair, separated by 2 cm, was placed across the 5.5 mm osseous defect on the skin overlying the defect.To create the fracture model, we drilled a unicortical 5.5-mm diameter defect14. Further work is needed to identify optimal stimulation parameters.Electrical stimulation was delivered to the cadaver legs with a TDT electrical stimulator . Pulses at 5 mA with a pulse width of 300 mentclass2pt{minimMeasurements of electric potentials at the fracture were performed using a pair of shank-insulated microneurography electrodes, with exposed recording tips, inserted into the two 0.5-mm diameter holes, separated by 3 mm, adjacent to the osseous defect. An electrically conductive gel  was placed inside the two 0.5-mm recording electrode holes before recording electrode placement to ensure good electrical contact of the recording electrode with bone. 3 mm was selected as the minimum distance we could reliably drill the second hole without concern of drill bit slippage and damage to the first hole. A smaller distance would give a better estimate of electric field at a point but could also introduce excessive electric field distortion, which occurs from the placement of the conductive measurement probe into less conductive tissue. We used an oscilloscope with differential probes to record the voltage  waveform across the two recording electrodes inserted in the bone Fig. C to alloElectric potential values between the measurement electrode pair were reported throughout this manuscript. To convert to electric field magnitude values (V/m), the electric potential (V) was divided by the distance between the measurement electrode pair (3 mm). Results were reported in electric potential to allow for more intuitive contextualization by EBGS therapy practitioners who typically program EBGSs in the units of ‘Volts’ or ‘mA’.FEM models were set up in COMSOL Multiphysics  representing simplified adult human legs  analysis of the steady-state electric potentials in the modeled volume when a constant electrical stimulation is delivered. A ‘fine’ mesh was used in both models with 312,438 tetrahedral elements in the human model, and 67,100 tetrahedral elements in the sheep model. Use of the ‘fine’ mesh setting was determined through a mesh convergence analysisOhm’s law in vector form was used to calculate the spread of current from the surface stimulation electrodes and the corresponding electrical potentials (voltages) throughout the modeled volume. Electric potential at the drill hole fracture site was reported between five paired points (3 mm pair length) around the fracture hole in the model Fig. E becauseSeveral combinations of different monopolar and bipolar stimulation electrode configurations were tested in the FEM model Fig. B–F. EachIn the cadaver work, we used a bipolar stimulation electrode configuration with both electrodes over the defect Fig. F and rec8 and aid bone healing. Injectrode begins as an uncured, free-flowing prepolymer20. This prepolymer sets into a solid in the body and forms a conductive interface with the target tissue. In principle, the benefit of this minimally invasive electrode is that it offers increased stimulation strength by targeting the fracture site directly, similar to direct current electrical stimulation (DCES), by routing current from the EBGS TENS electrodes to the fracture site18. An Injectrode ‘collector’ can be added subcutaneously and routed to the bone defect in cases of a deeper fracture  with metallic silver particles  were mixed and loaded into a 5 mL syringe.A silver-particle-based Injectrode prototype, formulated for preclinical studies, was used in this study to demonstrate proof of concept. Injectrode material used in this study was manufactured by Neuronoff, Inc.  using a polymer-conductor variant of the Injectrode as described previouslyAfter data collection was performed without the Injectrode, the sutures were released, and the flap was re-elevated. The Injectrode was administered in its elastomer state into the 5.5 mm osseous defect until the surface of the elastomer was flush with the surrounding cortical bone Fig. A,B. The We directly compared measurements of the electric potential at the fracture site between the Injectrode and non-Injectrode states measured in cadavers to the values predicted by the computational FEM models. The Injectrode material was modeled to completely fill the bone defect and have the conductivity of a conductive metal 4e7 S/m)  against the alternate hypothesis (H1: gain > 1) for human and sheep cadavers. One-sample t-tests were selected over paired t-tests as the hypothesis was that Injectrode would augment the electric potential reaching the fracture. The one-sample one-tail t-test offered the simplest method to test this hypothesis, while the calculation of the gain value  further collapsed the variability in electric potential values between cadaver legs. One-sample t-tests and correlation analysis were run in Microsoft Excel 2018. The Shapiro–Wilk test was used to verify the normality assumption of the student t-tests. Type II error tolerance was set at 5% . The electric potential falls off from a bipolar electrode proportional to ~ 1/rTo investigate our hypothesis, we made direct measurements of the electric potential at the fracture site during EBGS therapy in human cadavers. During 5 mA of externally applied stimulation through 1 × 1 inch square TENS electrodes, generating a voltage of ~ 15–30 V, only 64 mV (45 mV standard deviation (SD)) reached the fracture site on average , we measured an average voltage of 680 mV (SD 550 mV) at the fracture site  and 22.0 mV  reaching the fracture site during 5 mA of stimulation delivered noninvasively Table . The cadWe computed the ratio of electric field applied externally to the electric field at the fracture site to compare to the average 1.9% ratio measured in the human leg cadaver. The human FEM model predicted a ratio of 1.9% for late-stage healing and 2.6% for early-stage healing compared to the 1.9% measured in the cadaver. This improved agreement of electric field ratios between model and cadaver suggested that the model captured the spread of electric field in tissue accurately, even when the absolute electric field values were inaccurate. Therefore, trends in the FEM model may be accurate even when absolute values were not.17 during healing leads to different tissue electrical conductivities at the fracture site over the course of the healing process. In general, the conductivity at the fracture site decreases during healing, starting with a conductivity similar to extracellular fluid or hematoma and ending with the conductivity of cortical bone. This influences the electric field reaching the fracture site during use of an EBGS. More electric current reaches the fracture site in the acute stage of healing as the fracture is filled with higher conductivity material and represents a preferential, lower resistance, path for current to travel. For this reason, we computed model values for both early-stage and late-stage healing  to 4.34e-1 S/m (dermis22) to model skin with the outermost epidermis layer compromised by the extended application of Nair™. The updated FEM model calculated 536 mV reached the fracture site during 5 mA of noninvasive stimulation—comparable with the cadaver measurements of 680 mV (SD 550 mV). However, for the remaining study, we used the original conductance of skin (8.0e−4 S/m) in the sheep model. We did this to retain the relevance of the sheep model findings to the planned in vivo Injectrode-augmented EBGS sheep study, where the skin preparation will be more conservative and should not damage the epidermis.We created a FEM model for a sheep leg in the metatarsus region based on dimensions from literature and measured in sheep cadavers. The model calculated 5385 mV reached the fracture site during 5 mA of noninvasive stimulation, while sheep cadaver (n = 5) measurements averaged 680 mV (SD 550 mV) at the fracture site Table . The modSeveral electrode configurations were explored in the FEM model to identify suitable configurations for an upcoming sheep EBGS study planned by our group. Stimulation electrode configuration Fig. B–F and mThe Injectrode, a minimally invasive conductive electrode, may be injected under image guidance to the fracture site to guide current delivered noninvasively towards the fracture site. We hypothesize that utilizing Injectrode at the fracture site will augment the electric field reaching the bone during noninvasive EBGS therapy. To investigate the efficacy of the Injectrode to augment the electric field reaching the fracture site, we modified the previous sheep and human computation models to include the Injectrode. We also made measurements in the same cadaver models with the addition of Injectrode in the fracture. We report on the ‘gain’ in electric field at the fracture site . There was an error of 11–17% between FEM model early- and late-stage healing and human cadaver measurements. Note that we consider these findings exploratory and not confirmatory because the measurement and statistical analysis methods were not pre-registered but determined post-hoc instead.Computational modeling for the human tibia in the late-stage healing state (low conductivity tissue at fracture site) resulted in a 37% gain in electric field at the fracture site with the addition of the Injectrode , shown in Fig. FEM modeling for the sheep metatarsus predicted a 69% gain in electric field at the fracture site with the addition of the Injectrode in the late-stage healing state (low conductivity tissue at fracture site) Table . In the 0: gain = 1, H1: gain > 1, one-tail) compared with the superficial metatarsus bone, which showed a gain of only 22% , shown in Fig. We found that the Injectrode provided more benefit over conventional EBGSs at greater depths of the fractured bone from the surface of the skin. With increased pretibial fat thickness in humans (distance between fracture site and surface EBGS electrodes), the ‘gain’ in electric field at the fracture site with the Injectrode compared to without increased R = 0.54), shown in Fig. 4, shown Data in Tables 8. We investigated the electric field strengths reaching the fracture site during noninvasive EBGS therapy in sheep and human cadavers and computational models. We observed minute electric fields reaching the fracture site. On average, only ~ 1.9% of the externally applied electric field reached the fracture site in human cadavers. We reported on the effects of fracture depth and healing stage on the electric field strength reaching the fracture site. We then proposed and investigated the use of a minimally invasive injectable electrode, the Injectrode, to augment the electric field reaching the deep fracture site. The computational and cadaver models in this study lay the groundwork for a preclinical sheep study planned by our group to investigate the use of the Injectrode in vivo to augment electric field strength reaching the fracture site—and consequently improving time to fracture healing—during EBGS therapy.In this study, we reported on electric fields measured at the fracture site during noninvasive EBGS therapy. Strength of the electric field at the fracture site is believed to be critical to the proposed mechanism of action of EBGSs—the activation of voltage-gated calcium ion channels23. Neural activation is predicated on voltage-gated sodium channel activation while bone healing is putatively based on voltage-gated calcium channel activation, so differences in activation threshold are expected between sodium and calcium channels. However, the known neural activation thresholds contextualize the weak electric field strengths reaching the fracture site during noninvasive EBGS therapy in humans—even on the most superficial of bones. There are notable parallels between bone stimulation and neurostimulation and both fields may benefit from adopting techniques used in the other11.To our knowledge, this is the first study to characterize electric field strengths at the fracture site during noninvasive EBGS therapy. This marks a critical step towards building consistent efficacy of EBGSs in human patients. We measured only ~ 1.9% of the externally applied electric field reaching the fracture site in human cadavers. This translates to an electric field strength of 21 V/m at the fracture site during 5 mA of noninvasive stimulation. The 21 V/m electric field strength is low compared to neural activation thresholds, which are reported to be > 100 V/m3. Moreover, many of these studies do not measure the electric field strength reaching the fracture site3. Directly measuring electric field in the cortex of the bone is critical to understand the field strengths required for a therapeutic effect and is also critical to scale from culture and small animal studies to large animal and humans24. The authors recommend future studies in the bone stimulation field employ direct measurement strategies.Though there are many promising preclinical studies examining the effects of electrical stimulation for a wide array of osseous insults, many use custom stimulators and provide incomplete device specifications, making it difficult to repeat the experiment or translate the findings18, the Injectrode was shown to improve neural activation by more than an order of magnitude over conventional noninvasive stimulation, while in the current study, the Injectrode is showing a more limited benefit of a 37% increase in electric field at the fracture site. The current work is studying the tibial bone, where the fracture is at a depth of only a few mm from the stimulation electrodes, while in the previous neural study, the nerve of interest was at a depth of ~ 2 cm from the stimulation electrodes. Overall, this makes deeper bones, such as the femur, more ideal to show the benefit of Injectrode-augmented EBGSs over conventional EBGSs. For fractures at the depth of the femur, the optional Injectrode ‘collector’  conventional EBGSs deliver lower electric fields to deeper fracture sites Fig. A and thaor’ Fig. C may be The two findings highlighted in the previous paragraph also explain why the Injectrode was shown to have a statistically significant benefit in augmenting electric field at the fracture site in human but not sheep cadavers. The depth of the fracture was deeper on average in humans, due to pretibial fat, compared to sheep. This resulted in weaker electric fields at the fracture site with conventional EBGS therapy and more of a ‘gain’ with the Injectrode. The larger effect size contributes greatly to establishing statistical significance at small sample sizes.Our findings also characterize the effect of the stage of bone healing on efficacy of conventional noninvasive EBGSs. With a conventional EBGS, the electric field reaching the fracture is higher during the acute stages of healing, when high conductivity tissue fills the fracture—acting to route current to the deep fracture site. However, with an Injectrode-augmented EBGS, the ‘gain’ in electric field at the fracture is higher during the later stages of healing—when low conductivity tissue fills the fracture. The higher ‘gain’ of the Injectrode at later stages of healing has positive implications towards the delivery of Injectrode after a fracture. The Injectrode does not need to be administered immediately in the acute stages of healing, but rather can be administered even in the later stages of healing—widening the therapeutic time window available for its application.24. PEMF devices would benefit from a similar study as reported in this paper with direct measures of the electric field reaching the bone.Inductive coupling is another noninvasive EBGS modality that exists in the form of pulsed electromagnetic field (PEMF) therapy, which uses pulsed currents through solenoids arranged parallel to the skin to generate an alternating magnetic field. The alternating magnetic field induces an alternating electric field in tissue. PEMF therapy suffers reliability issues with electric field strength variation due to variation in the placement of the device and the thickness of enveloping soft tissue layersThere were discrepancies between the computational model and cadaver measurements in absolute electric field value, especially in the sheep model. This was explained by the differences in tissue conductivity—especially the skin layer, after freezing and thawing in the cadaver and the application of Nair™ for hair removal—compared to tissue conductivity values from literature performed in living subjects or fresh tissue samples used in the FEM model. Although these differences in tissue conductivity make absolute electric field results from the model less predictive, relative results and trends still hold. An example of a relative result is the ‘gain’ value calculated for the model, which was the ratio of electric field at the fracture site with Injectrode compared to without. A better agreement was seen between cadaver and computational models in these gain values for both the human and sheep model.Also due to differences in tissue conductivities, the cadaver measurements are likely reflective of values between early-stage and late-stage healing. The cadavers were frozen and then thawed, which created accumulation of high conductivity fluid in the leg. At the same time, due to the lengthy duration since the death of the subject, some tissue had congealed, forming lower conductivity spaces. Overall, the cadaver is likely more reflective of early-stage healing due to the accumulated fluid in the fracture drill hole from thawing of the cadaver limbs. For these reasons, we compared cadaver measurements to both early-stage and late-stage results from the FEM model. Opening and then suturing of the soft tissue flap in the cadaver legs could also have changed the conductivity of the thin fascial tissue layers compared to the intact state. Performing a similar protocol in a live anesthetized animal, or in a chronic experiment where scar formation occurs, would provide a more accurate picture of the electric fields reaching the fracture site during noninvasive EBGS therapy.2 relationship, where ‘r’ is distance)7. To this end, in the FEM model, we had a single distance between the defect and the stimulation electrodes, representing the average distance in cadavers. In each cadaver, this distance varied and may have contributed greatly to the subject-to-subject variation observed in the cadaver results.Further limitations of the experimental and modeling set-up may also explain the differences between the computational model and cadaver results. Firstly, the computational model assumed uniform thickness of fat and skin across the tibia. The human cadaver model in comparison is not a uniform cylinder and was subjected to wider variations. Secondly, the depth of the defect from the stimulation electrode has a profound effect on the electric potential reaching the fracture , as previously described, poses a significant infection risk and requires surgeries to implant and remove the device. Noninvasive stimulation (capacitive coupling) is an attractive option as it is noninvasive, thereby minimizing infection risk, and easy to use. However, the penetration of the electrical field into tissue is proportional to ~ 1/r25. While there are significant differences between the conductivity of bone and nerve tissue, Injectrode-augmented noninvasive EBGS therapy may offer a promising solution for the treatment of osseous nonunion and acute fractures prone to nonunion.The Injectrode has the potential to provide reliable stimulation strength similar to DCES without the need of open surgeries for implantation and removal, which lead to increased risk of infection. To this end, the Injectrode has already been validated to produce neural effects at similar levels as conventional electrodes for dorsal root ganglion stimulation in a cat model26.The Injectrode formulation used in this study was an early silver-particle-based prototype—only for use in cadaver and acute preclinical studies due to the toxicity of silver. It was used in this study to demonstrate proof of concept of electric field increase at the fracture site with Injectrode-augmented noninvasive EBGS. Other electrically conductive materials would have a similar effect of increasing electric field at the fracture site. Future versions of the Injectrode under development are based on gold or platinum microwires. Future work will need to investigate biocompatibility of the Injectrode, degradation kinetics, and its suitability to be injected at the fracture site. Past work includes testing the biocompatibility of the Injectrode in humans28, rabbit30, and sheep31 have been used as animal models in published fracture healing studies investigating electrical stimulation to improve osteogenesis. We intend to use the large-animal sheep model in our study and so focused on studying sheep alongside humans in this study.This computational study lays the groundwork for a future preclinical study planned by our group to investigate augmenting conventional EBGSs with Injectrode to increase the electric field strength reaching the fracture site. While the Injectrode prototypes used in this study were used for proof-of-concept testing, newer generations of the microwire-based devices have higher translational potential. In the later stages of healing, we showed in sheep computational models and cadavers that the Injectrode-augmented EBGS therapy increased electric field strength at the fracture site by ~ 70% and 60% respectively compared to conventional EBGS therapy. RatsIn a large-animal fracture model, sheep, and human, both modeling and cadaver measurements demonstrate that noninvasive EBGS therapy applied transcutaneously generates weak electric fields at the fracture site. These data suggest it is critical to consider how the electric fields applied by stimulation electrodes change at a distant portion of tissue when scaling from culture or small animals to large animals or humans. Our findings (1) help explain the inconsistency in translating promising EBGS results showing improved fracture healing in small animal studies to clinical use and (2) lay the groundwork for a future large-animal study to test the use of Injectrode-augmented EBGSs to further aid bone healing by increasing electric field strengths reaching the deep fracture site.Supplementary Information.


Background: Excessive fluoride consumption affects reproductive and child health. We examined the association between levels of fluoride in drinking water and birth weight, in the National Health and Nutrition Examination Survey 2013–2016, after adjusting for known risk factors Low Birth Weight (LBW) including age, smoking, and socio-demographic variables including education, food security, health care access, and health status. Methods: The study included 7147 and 6858 women with complete birth weight and water fluoride data, respectively. Linear regression models evaluated the association between water fluoride and birth weight across racial/ethnic groups. The odds of delivering an LBW infant (<2500 g) compared to an infant weighing ≥ 2500 g, as well as the odds of delivering a Very Low Birth Weight  infant compared to an LBW infant were explored in separate logistic regression models. Results: Women with LBW infants were exposed to significantly higher levels of water fluoride compared to those with normal birth weight infants. Our findings suggest a significant association between excess water fluoride exposure (>0.7 ppm) and LBW weight in Hispanic women, independent of established LBW risk factors. In logistic regression models, Hispanic women exposed to increased levels of water fluoride were 1.5 times more likely to give birth to an LBW infant and 3.5 more likely to give birth to a VLBW infant. Conclusion: Taken together, these findings can inform public health education strategies that highlight water fluoride as a potential risk factor during pregnancy in Hispanic women. More research is needed to confirm these findings. Low Birth Weight (LBW) and Very Low Birth Weight (VLBW) describe infants weighing less than 2500 g and less than 1500 g, at birth, respectively. Both LBW and VLBW . FurtherAdequate amounts of fluoride are required to mineralize bones and teeth, which is needed to make them strong . Over thStudies have demonstrated that fluoride accumulates primarily in the bone and teeth . High leNature discusses the benefits and possible harm caused by fluoride exposure, especially in newborns [A recent commentary in the journal newborns . Studiesnewborns .The relationship between maternal fluoride exposure and adverse pregnancy outcomes, including the risk of miscarriage, stillbirth, and preterm and LBW infants, has been explored before in areas with excessive water fluoride levels (>1.5 mg/L) ,18,19. AA recent study suggested that the benchmark threshold levels for fluoride in the urine of pregnant women should be around 0.2 mg/L . This hiAdditionally, the motivation to explore the association between water fluoride exposure across racial/ethnic groups stemmed from findings we obtained from a Geographic Information System (GIS) analysis conducted to examine the relationship between low birth weight and fluoride level across areas with the heaviest Hispanic population density in Texas. The GIS maps showed that most Hispanics (>50%) reside in areas with the highest concentration of fluoride in drinking water (1.21–5.10 ppm), in particular, the Northwest regions of Texas. Similarly, the greatest prevalence of LBW (8.7–21.7%) in Texas is observed in areas with the greatest concentration of fluoride in water (unpublished).Study design and research population: The National Health and Nutrition Examination Survey (NHANES) is a cross-sectional survey designed and administered by the National Center for Health Statistics (NCHS). Starting in 1999, NHANES is conducted annually and employs a stratified multistage probability design to obtain a nationally representative sample of the civilian, non-institutionalized US population [pulation . The surpulation . This stOut of a combined 20,146 participants who participated in NHANES between 2013 and 2016, a total of 7147 women had complete infant birth weight data, data on age, education, access to health care, food security, and smoking. From this subgroup, 6858 participants had complete data on water fluoride. Thus, 12,999 subjects were excluded out of a total of 20,146 subjects in the NHANES study (2013–2016) for lack of birth weight data. Furthermore, among, 7147 subjects who had birth weight data, 289 subjects did not have data on fluoride and were hence excluded. Thus, the analytic sample included 6858 subjects.In the NHANES dataset, all measures included in analysis were obtained using interviewer-administered questionnaires. To conduct subgroup analyses, we combined Mexican American and other Hispanic groups in NHANES into an overall Hispanic category. The age at delivery was used in all the analyses. Low Birth Weight (LBW) and Very Low Birth Weight (VLBW) describe infants weighing less than 2500 g and less than 1500 g, at birth, respectively.“When you drink tap water, what is the main source of the tap water? Is it the city water supply; a well or rain cistern; spring water; or something else?” The tap water source variable was then coded as “community water supply,” “well or rain cistern,” “spring,” and “don’t drink tap water.” The 24 h recall also included a question on participants’ total plain water consumption the day before the MEC interview. The total plain water variable included consumption of tap water and bottled water.Water consumption and source of water supply in NHANES were collected using 24 h recalls with participants. The source of tap water was ascertained with the question, Water fluoride levels in NHANES were measured in drinking water . Water fluoride samples were then shipped overnight on ice to Georgia Regents University  so that fluoride concentration could be measured electrometrically using an ion-specific electrode. Two samples from tap water were obtained from each participant’s residence and were measured for their fluoride levels. The average of these measures was used for the analysis. More details on water fluoride collection methodology can be found in the NHANES laboratory procedure manual .Independent variables were chosen based on established risk factors for LBW documented in the literature and socio-demographic factors . These fwhat is the highest grade or level of school you completed or the highest degree you received? Responses included, “less than 9th grade,” 9–11th grade,” “high school grad/GED or equivalent,” “some college or AA degree,” and “college graduate or above.” For the analysis, the Education level “less than 9th grade,” was grouped, and the rest were combined into a common group.Education level was obtained with the following question: Health status was derived by asking participants whether they could classify their general health condition as: “excellent,” “very good,” “good,” “fair,” or “poor.” For the analyses, we coded the “excellent” and “very good” responses into a “good/excellent” category, and the “fair” and “poor” responses into the “fair/good” category. The “poor” category was used as such.Is there a place that you usually go to when you are sick or when you need health advice? Responses were coded as “yes,” “there is no place,” and “there is more than one place.” For the analyses, we combined the responses “yes” and “there is more than one place” into an overall “yes” response, and coded the response ‘there is no place” as “no.”Having a routine place for seeking health care was asked with the following question: Food security was ascertained by asking respondents to characterize their overall food security status. Responses were coded as a four-level categorical variable: 1 = full food security; 2 = marginal food security; 3 = low food security; and 4 = very low food security. For the analyses, we combined levels 1 and 2 into a “secure” category, and levels 3 and 4 into a “low food security” category.did you smoke at any time while pregnant? Responses were coded as “yes” or “no” and used as such.Maternal tobacco use was assessed with the question: Statistical Analysis: SPSS software was used to merge, clean, and recode NHANES variables in preparation for statistical analysis. To achieve adequate sample sizes for subgroup analyses, data from four years of NHANES was combined (2013–2016). NHANES data files are made available to the public in cycles of two years. Two 2-year sample weights were divided by 2 to get the total 4-year sample weight used in analyses (ref). The weights were adjusted for: (1) the different sampling rates for Mexican Americans, African Americans; (2) non-coverage; and (3) non-response bias.p ≤ 0.05.The main objective of the analysis was to explore the association between fluoride levels in drinking water (measured in mg/L) and birth weight (measured in grams) across racial/ethnic groups. Categorical variables were summarized as frequencies and percentages by racial/ethnic groups, and statistically significant differences in proportions were determined using Chi-square tests. Dummy variables were created for all categorical variables  and entered as such as independent variables in linear and logistic regression analyses. Continuous variables were summarized by means and standard errors, and statistically significant differences were determined using analysis of variance (ANOVA). Statistical significance was set at a two-sided significance level of Due to the skewed distribution of birth weight and water fluoride, we log-transformed these values before inclusion in the linear regression models. Birth weight was considered as an outcome variable in univariate and multivariate regression analyses, and water fluoride was used as the main independent variable. Water fluoride and maternal age at delivery were also entered in all models as continuous variables. Potential confounders were selected and included in regression models based on previous literature, including age, education, overall health status, a routine place for receiving health care, food security, and smoking status. In addition, we explored the association between an interaction term between water fluoride and food security and birth weight in regression models. A categorical birth weight variable was created to include normal birthweight (>2500 g), moderate birth weight (1500–2499 g), and VLBW (<1500 g).We fit five models to the data: Model 1 presented a univariate linear regression analysis in which water fluoride was entered as the sole independent variable, Model 2 adjusted for maternal age at delivery, Model 3 adjusted Model 2 for education, health status, and routine place for receiving health care, Model 4 adjusted Model 3 for food security, and Model 5 adjusted Model 4 for maternal smoking during pregnancy. Results were expressed as standardized beta coefficients, standard errors, and 95% confidence intervals.In addition, we also conducted two separate logistic regression analyses to explore the association between water fluoride exposure at >0.7 ppm and birth weight, controlling for age, education, and maternal smoking. In one multivariable logistic regression model, LBW was included as the dependent variable and in the second model, VLBW was the dependent variable .Descriptive Statistics : Overallp <0.001). Significant racial/ethnic disparities were observed in education, access to health care, and food security. Almost 21.9% of Hispanic women did not complete high school education, compared to NHWs, NHBs, and women belonging to other racial/ethnic groups . Similarly, Hispanic women were more likely to report not having a regular place to obtain health care than NHWs, NHBs, and women belonging to other racial/ethnic groups . Nevertheless, there was no significant difference in self-reported health status (fair to excellent) across racial/ethnic groups. Hispanics and NHBs were more likely to report food insecurity  compared to 17.4% for NHWs and 16.1% for women belonging to other racial/ethnic groups. Smoking prevalence during pregnancy was also significantly lower among Hispanics, compared to NHW, NHB, and women belonging to other racial/ethnic groups . As expected, the overall prevalence of LBW (very LBW to moderate LBW combined), was significantly greater for NHB (14.9%) and women belonging to other racial/ethnic groups (11.6%), compared to Hispanic women (8.6%) and NHW .NHW and women belonging to other racial/ethnic groups were significantly older than NHB, and Hispanic women . Women who gave birth to LBW babies were exposed to comparable mean levels of water fluoride across racial/ethnic groups. However, a significantly higher mean level of water fluoride exposure was observed among Hispanics and other races/ethnic group who gave birth to VLBW babies   .p = 0.03, p < 0.001; Hispanic, standardized beta coefficient 0.08, SE 0.62, p < 0.001; and women belonging to other racial/ethnic groups, standardized beta coefficient 0.07, SE 0.67, p = 0.03). In only NHW but not in the other groups, both education and place to receive health care were significantly associated with LBW  after adjusting for mother’s age at delivery, education < 9th grade and smoking during pregnancy. Since published data describe the increasing severity of chronic disease in children who have very low birth weight , we examined if exposure to fluoride during pregnancy results in VLBW infants compared to both normal birth weight and LBW infants. In these comparisons (Models 2 and 3), Hispanic women exposed to fluoride levels > 0.7 ppm were 3.5 times more likely to deliver VLBW  [Our findings, using population-based data from NHANES, suggest a significant association between excess water fluoride exposure (>0.7 ppm) and LBW weight, independent of established LBW risk factors. Our results concur with findings from Ortíz-García and colleagues, who examined the impact of fluoride exposure in pregnancy and birth weight, in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort study. The ELEMENT study is a prospective cohort study designed to examine the impact of environmental toxicants on maternal and child health in Mexico. The authors concluded that prenatal fluoride exposure was significantly associated with a decrease in birth weight starting with incremental levels of fluoride exposure in the second and third trimesters  . In the  = 0.03) . The NHAThe observed significant association between excess fluoride and LBW in Hispanic women contrasts with existing epidemiological evidence, suggesting that Hispanic women are more likely to give birth to normal-weight babies, as described in the literature as the Latina epidemiologic paradox . The LatChildren who weigh < 2500 g at birth are known to be predisposed to several chronic diseases, including diabetes, cognitive impairments, cardiovascular, metabolic disorders, and even mortality, either during childhood or early in their adult life, with the severity of the condition predicted to be more pronounced for VLBW babies . In the Evidence suggests that inadequate maternal nutrition during pregnancy contributes to LBW and intrauterine growth restriction ,47. We eInterestingly, although the mean fluoride levels were comparable across racial/ethnic groups, we observed a significantly higher mean for water fluoride in Hispanic women who gave birth to VLBW babies. Furthermore, water fluoride exposure at 0.7 ppm in a multivariable logistic regression analysis showed a 3.5 times higher likelihood of Hispanic women giving birth to VLBW babies . The oddUnlike many publicly available datasets, the demographic distribution of the NHANES data represents the US population, and therefore findings are more likely to be generalizable. Several limitations for this study are worth mentioning. Due to the study’s cross-sectional nature, the temporal relationship between water fluoride exposure and LBW cannot be conclusively established. It is unclear whether the women included in this study resided in the same areas with the same water fluoride levels during pregnancy and childbirth as when they participated in the NHANES study. Furthermore, as described in our results, community water was the main source of tap water for all racial/ethnic groups. The limitation, however, is that the water variable included both tap water and bottled water. Therefore, it is difficult to tease out participants who drank only bottled water from those who drank only tap water, because those who drank bottled water may also have drunk tap water. Additionally, no fluoride measures were obtained from bottled water. Nevertheless, in our analysis, the total plain water variable was added as a continuous variable in the univariate model and was not significant across the racial/ethnic groups. We, therefore, did not include it in multivariable models.We also appreciate that other risk factors in addition to fluoride exposed before and during pregnancy could be related to infants’ birth weights. However, to our knowledge, a systematic study measuring these risk factors and environmental exposures such as water fluoride levels before pregnancy and following it up during pregnancy, has not been undertaken. Specifically, we believe that a study measuring fluoride levels before pregnancy and during pregnancy (preferably every trimester) compared to a control group where fluoride levels in water are kept within acceptable limits both before pregnancy and during pregnancy, may provide useful insights into the direct effect of fluoride in pregnancy outcomes.In our analysis, we adjusted for a limited set of important variables that we understand is not all-encompassing due to lack of available data points in NHANES. Given this, we included variables that have been consistently collected for the time frame for which LBW data was available. Since all the variables included in the analysis were collected uniformly across all years (2013–2016), we do not believe the pooling could have introduced a bias in our analysis. Importantly, our analysis took into consideration all the samples that had complete data on birth weight and water fluoride levels without any preferential bias to any specific racial/ethnic groups. A follow-up to our original observation showing a significant association between water fluoride and LBW across the entire study population led to additional subset analysis examining race/ethnic groups. Such an analysis revealed that the association between water fluoride and LBW was more pronounced in Hispanic populations.We also must take into consideration that social desirability bias related to smoking and pregnancy may have resulted in under reporting smoking prevalence during pregnancy. While NHANES collects detailed data on dental practices and fluoride exposure, birth weight data is unavailable for the same years. Therefore, the study could not examine the impact of dental practices, including fluoride exposure from dental sealants and fluoride supplementation. Furthermore, the NHANES was not methodologically designed to examine the association between fluoride exposure and birth weight.Nevertheless, keeping all these limitations in context, our findings form the steppingstone for longitudinal studies in the future to examine the association of fluoride with LBW across racial/ethnic groups in the US. It is also important to note that in no way do the findings in this study minimize the significant burden of LBW among NHBs, which was observed by us in the context of socio-economic variables.What is already known on this topicExcess exposure to fluoride in drinking water significantly affects reproductive outcomes in animal models and human subjects. What this study addsThis study shows an association between fluoride exposure in drinking water and the likelihood of having a low birth weight baby among Hispanic women.How this study might affect research, practice, or policyFindings from this research highlight the need for increased attention to the contribution of fluoride as a potential environmental toxicant in fetal development.Exposure to high fluoride concentrations in water changes the previously observed favorable pregnancy outcome in Hispanic women. Results from this study suggest that exposure to the high concentration of fluoride in drinking water puts Hispanic women at increased risk of delivering an LBW infant. These findings highlight the need for increased attention to the potential contribution of fluoride as an environmental toxicant in fetal development. More research is needed to confirm these findings.


Low birth weight (LBW) infants are at increased risk of morbidity and mortality. Identification of LBW may not occur in settings where access to reliable scales is limited. Mid–upper arm circumference (MUAC) may be an accessible, low-cost measure to identify LBW and vulnerable infants.We explored the validity of newborn MUAC in identifying LBW and vulnerable newborns in rural Sierra Leone.z-score (WLZ) <−2, length-for-age z-score (LAZ) <−2, neonatal mortality, and mortality within the first 6 mo of life.This study was a secondary analysis of infant data from a randomized controlled clinical trial of supplementary food and anti-infective therapies compared with standard care for undernourished pregnant women. Data for singleton liveborn infants with birth measurement and 6-mo survival data were included in this analysis. The primary outcome was validity of MUAC in identifying low–birth weight (LBW) neonates. Secondary outcomes included validity of MUAC and head circumference (HC) in identifying weight-for-length r = 0.817) and HC (r = 0.752) were highly correlated with birth weight. MUAC  performed superiorly to HC  in identifying LBW. The MUAC for identifying LBW was 9.6 cm . Neither MUAC nor HC reliably identified newborns with WLZ <−2 or LAZ <−2. MUAC ≤9.0 cm was the ideal cutoff for neonatal mortality . Birth anthropometrics did not reliably identify infants at risk of death in the first 6 mo of life.The study population included 1167 infants, 229 (19.6%) with LBW. Birth MUAC  can be used to identify infants with low birth weight and infants at risk for neonatal mortality, with an MUAC ≤9.0 cm indicating the highest risk. MUAC (mid–upper arm circumference) can be used to identify infants with low birth weight and infants at risk for neonatal mortality, with an MUAC ≤9.0 cm conferring the highest risk. Despite reductions in infant mortality rates over the last 30 y, neonatal mortality, especially in Sub-Saharan Africa, remains unacceptably high , underscMid–upper arm circumference (MUAC) is a routinely used measurement to assess nutritional status in children aged 6–59 mo, often by community health workers in regions where undernutrition is prevalent . TherefoIn this study, we analyzed data from a birth cohort in rural Sierra Leone to evaluate the validity of MUAC in the identification of newborn nutritional status and infants at high risk for neonatal mortality and mortality during the first 6 mo of life.This study was a secondary analysis of data from a prospective, randomized, controlled clinical effectiveness trial in which we compared the impact of a package of nutritional and anti-inflammatory interventions with the standard of care in undernourished pregnant women in Sierra Leone. Full details of the study design and interventions administered have been described previously , 27. TheA total of 1489 women were enrolled in the primary clinical trial, and pregnancy outcomes were obtained from 1417 women. Women were enrolled at an average of 24 wk gestation, as assessed by fundal height, and randomly assigned to the intervention package or standard of care. Standard of care included corn-soy flour and intermittent preventative treatment for malaria. The intervention included replacing the flour with ready-to-use supplementary food and added azithromycin as well as testing and treatment for vaginal dysbiosis.Clinic staff and participants notified the study coordinator at the time of delivery. A birth measurement team was dispatched to measure infants within 48 h of delivery. Birth measurements were taken as soon as was feasible, with a goal of within 72 h after birth. Infant weight, length, HC, MUAC, and morbidity were assessed at birth, 6 wk, 3 mo, and 6 mo of life. Nude weight was obtained using a Seca 334 infant digital scale accurate to 5 g. Recumbent length was measured in triplicate using a Seca 417 rigid height board; if the measurements differed by >2 mm, a fourth measurement was taken, and the 3 closest measurements were recorded and averaged. HC and MUAC of the left arm were obtained using a standard insertion tape accurate to the nearest 0.1 cm. Subsequently, if an infant was identified as deceased, the age at time of death was recorded.Pregnant women with undernutrition defined by an MUAC ≤23 cm and a fundal height <35 cm as a proxy for length of gestation were enrolled from 43 government antenatal clinics in Pujehun and the Western Rural Area Districts of Sierra Leone , 27. ExcAll singleton live births born to mothers enrolled in the described clinical trial with complete birth measurements and follow-up survival data to 6 mo of life were included in the current analysis.Data were collected directly on clinic cards and then double entered into a spreadsheet database (Microsoft Access) and cross-checked for discrepancies. All discrepancies were resolved by examination of the original data card. No imputations or estimations were performed for missing data. Data were then anonymized. Once the content of the database was determined, it was locked for analyses.z-scores using the 2006 WHO growth standards (Descriptive statistics were used to characterize the study population. Anthropometric parameters were converted to tandards . WLZ canJ statistic (J = sensitivity + specificity − 1), which assumes false positives and false negatives to be equally undesirable, was calculated to evaluate effectiveness and identify the optimal anthropometric cutoff  curves were used to calculate 95% CIs of AUCs, as this allowed for the assessment of the performance of MUAC and HC to identify LBW, wasted, stunted, and underweight infants over a range of possible values . The Youc cutoff .Time-to-event values for mortality stratified by the identified anthropometric cutoffs were analyzed using both the Kaplan–Meier method with log-rank test and Cox proportional hazards regression, with the latter adjusted for maternal intervention received in the primary clinical trial and infant sex.Statistical analysis was performed using IBM SPSS Statistics version 25 and GraphPad Prism version 8.3.0.clinicaltrials.gov (NCT03079388).This study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving research study participants were approved by the Sierra Leone Ethics and Scientific Review Committee (SLESRC) and from the Human Research Protection Office at Washington University in St. Louis(ID# 201611119). Informed consent for participation in the primary clinical trial and secondary use of data was obtained for eligible and interested women by a signature or thumbprint if the participant was unable to write. Participants received nutritional supplementation for the duration of pregnancy and incentives for postpartum followup visits. Participants directly benefited from the clinical trial in receiving nutritional supplementation and quality antenatal care. Results of the primary clinical trial were disseminated to local communities. The primary clinical trial was registered at Supplemental Figure S1). Birth measurements were obtained at a median of 1 d of life (IQR: 2 d). Among this cohort, 229 (19.6%) were LBW. Descriptive statistics of birth anthropometrics are presented in In total, 1167 infants were included in this analysis  (z-score (WAZ)    (MUAC was strongly correlated with birth weight (< 0.001) . The pre< 0.001)  with a p <0.001) .z-score (WLZ) < −2, and length-for-age (LAZ) < −2 at birth . Use of a MUAC cutoff of ≤9.6 cm demonstrated a sensitivity of 73.3%, a specificity of 66.3% and a Youden J of 0.40. Birth HC also demonstrated moderate diagnostic validity in identifying neonates at-risk for neonatal mortality  with a cutoff of ≤32.2 cm . Using a birth HC of ≤33.5 cm, which identified LBW infants, resulted in a sensitivity of 73.3%, specificity of 64.3%, and a Youden J of 0.38.During the neonatal period, 15/1167  infants died. Neonatal deaths occurred at a median of 15 d (IQR: 18) with 3 deaths (20%) occurring in the first 3 d of life. Four (26.7%) of the infants that died had birth weights <1.500 kg. Birth MUAC demonstrated moderate diagnostic validity for identifying neonates at risk of neonatal mortality . A birth MUAC ≤9.0 cm was identified as the optimal cutoff  . An MUAC of 9.0 cm was the best cutoff for neonatal mortality, resulting in an HR of 9.57  (P = 0.017) (P = < 0.001) (P = < 0.001)  . An MUAC= 0.006) . An MUAC= 0.006) . An MUAC= 0.006) . An MUACSupplemental Table S2, Supplemental Figure S2). Neither birth MUAC  nor birth HC  demonstrated diagnostic validity in identifying infants at risk for mortality in the first 6 mo of life. Birth length demonstrated the best diagnostic validity for identifying infants at risk of mortality in the first 6 mo of life  with a cutoff of 48.2 cm , followed by birth weight  with a cutoff of 2.965 kg .During the 6-mo period, a total of 63/1167  died. Among infants born LBW, there were 18/229  deaths in the first 6 mo of life, accounting for 28.6%  of deaths in the cohort. All birth anthropometrics demonstrated AUCs of >0.5 for identifying infants at risk of mortality in the first 6 mo of life; however, all performed relatively poorly , followed by birth HC-for-age z-score <−3  and mother support groups be trained in its use to identify malnutrition in children . The typAdditionally, most studies investigating proxy measurements for LBW have collected data in hospital settings . PopulatStrengths of this study include a large study population, standardized collection of all anthropometric measurements taken within 72 h of birth by a specifically trained technician, and the taking of all measurements in the participant's home community or peripheral health unit. Limitations of this study are that the study population was taken from undernourished pregnant women, which may not reflect the population of all pregnant women. The rate of LBW (14%) in our study is higher than that reported in Sierra Leone (∼6%) . An addiGiven the effectiveness of MUAC as a screening tool for LBW and neonatal mortality in rural Sierra Leone and the existing widespread use of MUAC screening, future research should investigate the feasibility and effectiveness of using MUAC to identify LBW in other high-risk populations in resource constrained environments. MUAC can be quickly obtained, is simple to perform, and does not require calibration or sophisticated equipment. If data continue to show MUAC to be a sensitive and specific marker for LBW and vulnerable neonates, the introduction of large-scale screening programs for neonates in areas of the world where mortality is high could decrease the number of unrecognized and inadequately supported neonates, helping to achieve UN Sustainable Development Goal 3.2 .nzac138_Supplemental_FileClick here for additional data file.


Pnonlinearity < 0.01) indicated that age at first birth older than 32 (P < 0.05) increases the risk of urinary incontinence. First birth before age 32 make decrease the risk of urinary incontinence after delivery.Studies investigating the impact of age at first birth on urinary incontinence after delivery have reached inconsistent conclusions. We performed this systematic review and meta-analysis of studies assessing the risk of urinary incontinence after delivery, regardless of the type, with age at first birth. MEDLINE via PubMed and Web of science databases were searched up to March 13, 2021. Restricted cubic splines were used to model the dose–response association. Twelve publications were included in this meta-analysis. The summary odds ratio (OR) and 95% confidence interval (CI) per 1-year increase in age at first birth were 1.01 ) for urinary incontinence ; Europe: 1.03 ; Asian: 0.99 ). A non-linear dose–response ( It is not only an organic lesion, but also causes psychological problems such as depression and reduced self-esteem4, which can seriously affect a woman’s quality of life5.Urinary incontinence (UI), is one of the problems during pregnancy and the postnatal period, with a prevalence ranging from 5 to 70%8. Age at first birth is associated with mortality9, BMI10, and cancer11. However, studies investigating the effect of age at first birth on UI have reached inconsistent conclusions. A retrospective cohort study shows that younger age at first birth is associated with a higher risk of UI in later life12, while another study shows that age at first birth over 25 years is associated with UI13. Furthermore, no study has been reported so far on quantitative and comprehensive evaluation of the dose–response association between incidence of UI after delivery and age at first birth. In this study, we performed a dose–response meta-analysis of risk of UI after delivery and age at first birth to provide an evaluation of the existing data. Limited by the number of articles, we did not classify the types of UI after delivery in this meta-analysis. Our aim is to elucidate the shape and strength of the dose–response association between UI after delivery and age at first birth, and to determine the potentially optimal age at first birth for protection against UI after delivery.Recent evidence suggests that advanced maternal age at pregnancy, timing of delivery, pregnancy, obstetric trauma and mode of delivery, infant birthweight, infant head circumference, obesity and ageing, and bladder neck hypermobility are the risk factors for UI25 and previous reviews29 were manually searched for additional relevant studies.PubMed and Web of Science databases were searched from their inception until March 13, 2021. The search terms used for the PubMed and Web of science search, including medical subject heading (MeSH) terms and free texts, are provided in Supplemental Table 30 . A two-tailed P < 0.05 was considered statistically significant.For studies reporting HRs, RR, or ORs for UI after delivery, we assumed the HRs and RRs were approximately equal to ORs36. The DerSimonian and Laird random-effects model35 was used to pool the study-specific dose–response OR estimates. Study-specific OR estimates were calculated for each 1-year increase in age at first birth and then pooled for a linear association. Potential nonlinear dose–response relationships between age at first birth and UI after delivery were assessed by using restricted cubic splines, with three knots located at the 25th, 50th, and 75th percentiles of the distribution37. The P-value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to zero according to a likelihood ratio test38.Generalized least-squares regression was used to estimate the study-specific dose–response association239. A P < 0.10 was considered statistically significant for the Q-statistic. Subgroup analyses were stratified by geographic locations. We performed a sensitivity analysis by excluding one study at a time to assess the stability of the results and potential sources of heterogeneity. Publication bias was evaluated by Begg’s test40 and funnel plot examination, and publication bias was indicated at P < 0.10. Stata v12.1  was used for analyses.Heterogeneity was statistically tested by Cochran Q and I16. The review included 120,290 participants and all studies involved adult women (≥ 18 years old). Three publications were from America23, six from Europe22, and three from Asia25. The features of the included studies were summarized in Supplemental Table There were 169 records identified during our literature search: 119 were evaluated in detail and 17 were considered potentially eligible for inclusion. A total of 12 publications were included in the meta-analysis; Two of these studies reported the risk estimate for UI after delivery of age at first birth on a continuous scalePheterogeneity < 0.01) . In the sensitivity analysis, the direction and size of the pooled estimates for all results have no change when one single study got removed at a time. . No unhealthy effect were found in Asia  and America .A total of twelve publications have been analyzed. The ORs for UI after delivery per 1-year increase of age at first birth ranges from 0.87 to 1.32, and the summary OR is 1.01 , showing a U-shaped curve  and significantly increased with the age at first birth (range of age at first birth: 13–42 years)  increase the risk of UI after delivery. These results may help identify women at increased UI after delivery risk who would benefit from early prevention strategies.Supplementary Information 1.Supplementary Information 2.


Sa surface roughness parameter was obtained below 0.6 µm in the whole range of used feed rates. The surface roughness parameter Sa measured on the surface after machining by special insert depends on the cutting conditions (wet and dry machining). After, the dry machining parameter Sa, similar to the Wiper insert, was below 0.6 µm in the whole range of used feed rates. Unfortunately, cutting Inconel 718 using special insert with feed rate f = 0.25 mm/rev and cooling generated a surface with Sa parameter over 2 times higher than for the same feed rate without cooling, while this parameter, after turning by conventional insert, increases over 4 times using feed rate f = 0.25 mm/rev compared to feed rate f = 0.05 mm/rev during machining with cooling. This ratio is lower for conventional insert in dry machining because of sticking, which arises at the smallest feed rate according to previous research.This paper presents a comparison of surface morphology obtained after machining Inconel 718 by the conventional insert, by Wiper insert and by using the cutting insert made by Spark Plasma Sintering (SPS). The shape of the special insert was obtained by employing Wire Electrical Discharge Machining (WEDM). The paper focuses on the description of surface topography after turning in dry and wet conditions. The performed investigation included longitudinal turning tests of Inconel 718 performed in a range of variable feeds. Surface topography measurements have been performed with the application of Nanoscan 855. The performed analysis includes a parametric evaluation of the obtained surfaces. With the Wiper insert, the  Inconel 718 belongs to the group of superalloys on the nickel matrix. This material, due to its properties, such as susceptibility to hardening, low heat conductivity, high hardness and susceptibility to reaction with the tool, is difficult to machine. Due to its properties, it is widely applied in the aircraft industry ,3.The cutting inserts offered by the tool producers are made by the conventional technique of metal powders sintering . Spark PToday, higher productivity in the manufacturing processes is required. This in turn necessitates the use of adequate cutting tools, allowing its performance to meet the quality criteria. Simultaneously, investigations are ongoing into the tool materials that will be price competitive without deterioration of the products manufactured. One of the proposals of many tool manufacturers is the application of Wiper-type cutting inserts.Many papers show the results of investigations of the influence of cutting parameters on surface quality.Elbah et al.  have notWiper cutting insert geometry has also been discussed, with most studies showing that the feed rate has the greatest influence on the surface quality . StachurThere are also researchers who have tried to improve the surface roughness with different methods. Özbek et al.  investigPeng and Shareef  have alsBased on the results of the previous investigation, the authors of the work have decided to design the shape of the cutting insert, based on the shape of insert type WNMG. The designed cutting insert has been made by the Spark Plasma Sintering technique (SPS). The insert has been subjected to comparative tests with the commercial inserts with applied anti-wear coatings.f = 0.25 mm/rev, obtained surface roughness will be similar to that which can be obtained when turning with a conventional insert with a corner radius of 0.8 mm, using feed rate f = 0.05 mm/rev.All the tests on the influence of the Wiper type cutting inserts on the surface quality concern 2D roughness parameters. The authors have decided to compare the conventional cutting insert to the Wiper type cutting inserts and the designed special cutting insert. The aim of the research was to check whether, when machining inserts with a large value of the corner radius  with a feed rate of εr = 0.8 mm and special insert with ISO type of WNMG size 080,408 SPS sintered binderless tungsten carbine were used in the tests . The Hommel Map Premium 6.2.6409 software version was used to collect and present the measurement data. Topography parameters were measured on a surface dimensioned 5.21 mm and 4.95 mm in accordance with ISO 25178 standard.The length of the active cutting edge for the individual cutting inserts used in the investigation has been graphically determined with the use of the Catia V5R20 application.Sp, and maximum heights of the surface pits, Sv, both for tests performed with the use of cooling and lubrication liquid and in dry conditions are presented in the form of diagrams in Sp parameter is not so clear, it is significant for the Sv parameter. However, this is not a principle because, for a conventional insert after machining without coolant with the smallest tested value of the feed, f = 0.05 mm/rev, the average value of the Sp parameter amounts to 25.5 µm and the results of the individual measurements vary from 19.8 to 32.9 µm. On the other hand, the highest value of the height of the surface pit, Sv = 4.677 µm, has been recorded after machining with the special insert, with the application of emulsion for the highest value of the feed, f = 0.25 mm/rev. It has been observed that the Sp parameter reaches the highest values for almost all feed values under examination for the surface machined with a conventional insert without the use of emulsion, while the Sv parameter reaches the highest values for surfaces machined with the special insert with the application of coolant. The special insert, in machining with the use of coolant, makes it possible to obtain Sp parameters comparable to those obtained after machining with the Wiper insert. However, there are clear differences between the Sv parameters for those two cases of machining. The Sv parameters after machining with the special insert are about two times greater than those after machining with the Wiper cutting insert.The measurement results of maximum heights of the surface peaks, Sp and Sv parameters. The statement is confirmed in tests performed without the application of coolant. The difference between the highest and the lowest values of those parameters was as great as 13.1 µm. On the other hand, for the surfaces after machining with emulsion, the difference was up to 0.45 µm, i.e., it was almost 30 times smaller. This means that cutting Inconel 718 alloy without the application of emulsion is less stable and can generate peaks identified in [Krolczyk et al.  state thified in  as stickified in . They foSz parameter, which is the sum of Sp and Sv parameters, shows that the smallest values have been obtained after machining with the Wiper insert with the application of coolant for all the tested values of feed  stainless steel and observed that the variation in these parameters due to the feed increase takes place evenly, i.e., the values of both parameters increase in an even way. εr = 0.8 mm corner radius), especially without coolant, has generated Sp and Sv values which are inconsistent with this hypothesis. Sp and Sv parameters increase or decrease depending on the cutting conditions (dry and wet machining) and feed rate value.According to Królczyk , the cutSa  and for the Wiper insert with the feed rate, f = 0.25 mm/rev.A negative value of the Ssk-Sku maps, one can notice that both for dry machining and machining with cooling, only for the special insert the Ssk values are located near the axis and parameter Sku < 3. However, the lowest values of parameter Sku were observed for the Wiper insert at the feed rates of f = 0.15 mm/rev and f = 0.25 mm/rev in the case of machining with cooling.Looking at the f = 0.05 mm/rev) and intermediate (f = 0.15 mm/rev) values of the feed rate. Of course, isometric maps for all the conditions under investigation; however, for the highest applied feed rate (f = 0.25 mm/rev), most obtained isometric images had analogous characteristics. An exception was the isometric map obtained for the surface dry machined with the special insert. For those conditions, many high peaks were observed; the peaks are an effect of sticking appearing on the machined surface.The study presents isometric maps for the lowest  on the surfaces mating other elements, designers very often determine the required roughness at the level of Ra lower or equal to 0.4 µmAn analysis of the usability of the surfaces under investigation was performed based on the obtained Abbot-Firestone curves (AFC) . The stuSa parameter was lower or equal to 0.4 µm was the one obtained in dry turning by a special insert at the feed rate of 0.05 mm/rev , while for a conventional insert, the lowest Sq = 0.359 µm was obtained with coolant.The lowest values of the roughness parameter, f = 0.15 mm/rev. On the surface machined by the Wiper insert, sticking appeared when using the feed of 0.15 mm/rev. When machining with the special insert, the highest frequency of the occurrence of sticking was observed at the feed of f = 0.25 mm/rev. This means that the frequency of the occurrence of sticking is related to the active cutting edge entering the machined material.Sticking appears on the machined surface only during dry machining and the frequency of their occurrence depends on the type of inserts and the feed value. In machining with the use of the conventional insert, sticking appeared at the lowest feed used in the investigation Ssk = 6.530 and Sku = 53.533. Machining with the use of a Wiper insert has generated sticking at the feed of 0.15 mm/rev, the kurtosis parameter, Sku = 16.170. A surface composed of many high peaks will degrade quickly when matching another surface, causing the formation of backlash . Thus, dry cutting of Inconel 718 does not provide the desired functional properties. The roughness parameter, Ssk, is positive with three exceptions: after wet and dry machining at the lowest feed used for the special insert and after dry machining with the highest feed used for the Wiper insert.The sticking caused a significant increase in the parameters, Ra parameter. In the aircraft industry, general roughness is often defined by the value of Ra = 1.6 µm. If we assume that Ra is equivalent to Sa, all the surfaces under investigation are in accordance with the requirements with the exception of one case .In design drawings, roughness is often determined by the The occurrence of sticking on the machined surface after dry turning is dependent on the feed and the length of the active cutting edge. For a conventional insert with an active cutting-edge length of 0.65 mm, sticking appeared on the machined surface at the feed rate of 0.05 mm/rev. In the case of the Wiper insert with an active cutting edge length of 0.93 mm, sticking appeared on the machined surface at the feed rate of 0.15 mm/rev. In the case of the special insert with an active cutting edge length of 0.99 mm/rev, sticking appeared at all applied values of the feed; however, the largest quantity was observed at the feed rate of 0.25 mm/rev.Based on the investigation performed, the following conclusions have been formulated:


The American Academy of Pediatrics describes late preterm infants, born at 34 to 36 completed weeks' gestation, as at‐risk for rehospitalization and severe morbidity as compared to term infants. While there are prediction models that focus on specific morbidities, there is limited research on risk prediction for early readmission in late preterm infants. The aim of this study is to derive and validate a model to predict 7‐day readmission.This is a population‐based retrospective cohort study of liveborn infants in California between January 2007 to December 2011. Birth certificates, maintained by California Vital Statistics, were linked to a hospital discharge, emergency department, and ambulatory surgery records maintained by the California Office of Statewide Health Planning and Development. Random forest and logistic regression were used to identify maternal and infant variables of importance, test for association, and develop and validate a predictive model. The predictive model was evaluated for discrimination and calibration.n = 122,014), of which 4.1% were readmitted to hospital within 7‐day after birth discharge. The random forest model with 24 variables had better predictive ability than the 8 variable logistic model with c‐statistic of 0.644  in the validation data set and Brier score of 0.0408. The eight predictors of importance length of stay, delivery method, parity, gestational age, birthweight, race/ethnicity, phototherapy at birth hospitalization, and pre‐existing or gestational diabetes were used to drive individual risk scores. The risk stratification had the ability to identify an estimated 19% of infants at greatest risk of readmission.We restricted the sample to healthy late preterm infants (Our 7‐day readmission predictive model had moderate performance in differentiating at risk late preterm infants. Future studies might benefit from inclusion of more variables and focus on hospital practices that minimize risk. Birth certificates, maintained by California Vital Statistics, were linked to a hospital discharge, emergency department, and ambulatory surgery records maintained by the California Office of Statewide Health Planning and Development. The linkage algorithm included variables such as birth hospital, date of birth, sex, zip code, race/ethnicity, and hospital discharge records that are also recorded on the birth certificates. Of the 3,448,707 infants recorded in the birth certificate file, 91.3% had hospital discharge records linked to both mother and infant. Infants who had a birth admission discharge status indicating a transfer to another hospital were identified as “transferred” and those whose birth admission discharge status indicated death as “died during birth hospitalization.” California birth certificates include a variable that indicates if an infant was admitted to a neonatal intensive care unit (NICU). By excluding LPTs who were transferred, died, admitted to a NICU during birth hospitalization, or had major congenital anomalies,2.2The outcome of interest, readmission within 7‐day, was defined as any LPTs readmitted to hospital within 7‐day after birth hospitalization.2.3a priori based on literature) to 24 ; and (3) model 3 ‐ a 7‐predictor logistic regression model‐based on the 8‐predictor model but excluding race/ethnicity as a variable. We then developed a risk score by assigning points proportional to the β‐coefficient values of the eight predictors in model 2, and three risk categories  were created.A four‐step approach was used to develop and validate the predictive models. First, the cohort was randomly divided into a training/derivation sample including 80% of infants, and a validation sample including 20% of infants. Random forests, a supervised machine learning technique, was then applied to the derivation sample to rank candidate variables of importance.The predictive model was evaluated using the c‐statistic, performance parameters of sensitivity, specificity, positive predictive value, and negative predictive value, Brier score,2.5The study was approved by the Committee for the Protection of Human Subjects of the California Health and Human Services Agency. The manuscript adheres to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statements and explanations.3n = 5017) were readmitted within 7‐day from birth hospitalization. The derivation  and validation  samples had comparable characteristics including similar readmission (4.1% vs. 4.3%), mean length of stay, gestational age breakdown, maternal morbidity, and infant morbidity  and cesarean delivery  were protective. Assisted vaginal delivery , primiparity , and receiving phototherapy  were risk factors , followed by 0.613  for the 8‐predictor logistic model  and a Brier score of 0.0408; and the calibration plot indicated performance comparable to the derivation sample  in the validation sample. The risk stratification strategy exhibited some capacity for predicting risk of readmission.4.2Our predictive model is novel due to its focus on LPTs, early readmission, and use of routinely collected variables. Limitations were unavailability of potentially important candidate predictor variables such as breastfeeding, weight loss, bilirubin screening, dehydration, respiratory complications, and sepsis. While several morbidities that are more prevalent in very early preterm infants population were available in the database and have been found to increase risk of readmission, hence included in Table 4.3LPTs, though more vulnerable to morbidity, mortality, and readmission, often receive similar care to term infants at birth hospitalization. The risk classification strategy developed in our study provides a promising start for future predictive studies and the ability to differentiate LPTs at risk of early readmission. LPTs that had short length of stay, born via assisted vaginal birth, to primipara women, and those who have diabetes need extra attention at predischarge care including assessing parental readiness, screening for hyperbilirubinemia, feeding support, and early follow‐up. The protective effect of cesarean delivery is possibly mediated by prolonged birth hospitalization of mother‐baby dyad and management of complications such as temperature instability, feeding difficulties, sepsis, and hyperbilirubinemia predischarge.Earlier studies have found that infants ≥36 weeks' gestation who had excess weight loss (≥10% of birthweight) tended to have increased outpatient and inpatient health care utilization in the first month of life as compared to those who had <8% of birthweight loss,Aside from the debate whether readmission is appropriate or not to measure neonatal quality of care or to compare hospital performances, it is critical that we identify hospital, physician, and parental practices that have minimized risk of readmission, and the extent of preventability of readmissions in the neonatal period.5Early readmission after birth is costly, disruptive to the family, and places preterm infants at risk of nosocomial infections. Our 7‐day readmission predictive model had moderate performance in differentiating at risk LPTs. Predischarge care practices and transition plan need to be informed by maternal and infant variables that are protective or risk factors for readmission. Our study provides the basis for future prospective research and predictive models where more clinical variables could be included in model.Ribka Amsalu: Conceptualization; data curation; methodology; validation; visualization; writing – original draft. Scott P. Oltman and Rebecca J. Baer: Conceptualization; data curation; formal analysis; methodology; writing – review & editing. Melissa M. Medvedev: Conceptualization; methodology; writing – review & editing. Elizabeth E. Rogers, Stephen C. Shiboski, and Laura Jelliffe‐Pawlowski: Conceptualization; methodology; writing – review & editing.The authors declare no conflict of interest.The lead author Ribka Amsalu affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.Supplementary information.Click here for additional data file.Supplementary information.Click here for additional data file.Supplementary information.Click here for additional data file.Supplementary information.Click here for additional data file.


To explore the frequency and predictors of flares over 2 years during a treat-to-target strategy with urate-lowering therapy (ULT) in patients with gout.In the treat-to-target, tight control NOR-Gout study patients started ULT with escalating doses of allopurinol. Flares were recorded over 2 years. Baseline predictors of flares during months 9–12 in year 1 and during year 2 were analyzed by multivariable logistic regression.Of 211 patients included , 81% (150/186) of patients experienced at least one gout flare during the first year and 26% (45/173) during the second year. The highest frequency of flares in the first year was seen during months 3–6 (46.8% of patients).Baseline crystal depositions detected by ultrasound and by dual-energy computed tomography (DECT) were the only variables which predicted flares both during the first period of interest at months 9–12  and also in year 2. Baseline subcutaneous tophi  and prior use of colchicine at baseline  were independent predictors of flares during months 9–12, whereas self-efficacy for pain was a protective predictor .In patients with gout, flares remain frequent during the first year of a treat-to-target ULT strategy, especially during months 3–6, but are much less frequent during year 2. Baseline crystal depositions predict flares over 2 years, supporting ULT early during disease course.ACTRN12618001372279 Gout is the most prevalent inflammatory arthritis . The disRecurrent gout flares are associated with reduced health-related quality of life (HRQoL) and work participation , 6, and Higher serum urate (SUA) levels and longer disease duration of gout have been considered to carry an elevated risk for acute gout flares, but there is variability with other factors involved, leaving us with limited knowledge on prognostic factors for recurrent gout flares .Long-term use of urate-lowering therapy (ULT) leads to crystal dissolution, reduces the risk of flare , and preGiven sparse evidence regarding factors associated with gout flare during initiation and escalation of ULT in patients, we studied the incidence of gout flares over 2 years follow-up during ULT and examined predictors of flares in gout.NOR-Gout (Gout in Norway) is a prospective, observational single-center study in a hospital-based rheumatology unit. Patients were eligible if having a gout attack within the last month, had increased SUA (> 360 μmol/L), and no contraindication for ULT. Other severe co-morbidities including chronic kidney disease stage 3b and higher were exclusion criteria. Patients were consecutively included according to the protocol (ACTRN12618001372279). In all patients, a diagnosis of gout was based on identification of monosodium urate crystals in polarized microscopy after arthrocentesis  performePatients received at baseline individual information by trained research nurses on gout, including non-pharmacological and pharmacological management. Drug use was recorded for NSAID, colchicine, prednisolone, and for ULT  at every visit which also included registration of drug dosage and adverse events. All patients not already on ULT started as recommended , 20 withA study nurse and a rheumatologist   assessed patients at baseline as well as after 3, 6, 12, and 24 months. Additional scheduled visits with only the study nurse were at 1, 2, and 9 months, and if necessary monthly, until the treatment target was reached. Telephone contact with review of the SUA result could substitute for face-to-face visits. During the second year, patients were followed by their general practitioners as needed.A gout flare during months 9–12 in year 1 was the primary clinical outcome. At every clinical visit during the 2-year study, the patient self-reported gout flares since the last visit during a structured interview with the study nurse who recorded the flares. If in doubt, the patient and study nurse discussed whether an experienced episode with pain or swelling was to be defined as a gout flare or not.At baseline, self-reported information on number of flares ever and during the last year before study entry was collected by questionnaire as well as pain severity during the most recent and the strongest attack , with 0 = no pain and 10 = unbearable pain. Flares were reported as the frequency of patients having had ≥ 1 flare as well as the total number of flares, at all study time points, as recommended . The numAt baseline, patients reported age, gender, ethnicity, marital status, family history of for gout, disease duration, highest level of education, comorbidities, and working status. For comorbidities, the Self-Administered Comorbidity Questionnaire (SCQ) was used (range 0–36) ; it inclDaily and previous smoking, consumption of alcohol and sugar sweetened drinks, and the frequency of physical activity were reported by patients.Questionnaires at each visit recorded present joint pain due to gout, general pain, fatigue, and patient global assessment of disease activity, all on 0–10 numerical rating scales.Physical function was measured with the Health Assessment Questionnaire (HAQ) without adjustment for help or devices . Health Self-efficacy with subscales for pain (5 items) and symptoms (6 items) was measured with the Arthritis Self-Efficacy Scales . This inThe Beliefs about Medicines Questionnaire (BMQ)  exploresClinical assessments included weight and height for calculation of body mass index (BMI) and 44-swollen and tender joint counts and clinical examination for subcutaneous tophi.To assess the level of crystal deposition, all patients were examined by ultrasound and DECT. Ultrasound was at baseline scored as previously described  (score 0DECT baseline scoring of feet and ankles applied the semiquantitative Bayat method (scores 0–3) , 29, and2, CKD-EPI formula) at baseline and follow-up visits.SUA was analyzed at each study visit and is presented both as a dichotomous (cutoff 360 μmol/L) and continuous variable, as recommended . LaboratT-test and by the χ2 test or Fisher’s exact, as appropriate. A cumulative probability plot shows flares in the first year, where every patient is one observation, and flares are ordered from 0 to maximum flare number.Descriptive measures of baseline variables are presented using frequency, mean, and standard deviation. Differences between groups with and without flares during defined time periods were explored using independent sample p < 0.10) then entered in stepwise backwards multivariable logistic regression analyses, adjusting for age and gender and disease duration and retained if statistically significant (p < 0.05). Analyses were performed with IBM SPSS statistics (version 27).Odds ratio (OR) with 95% confidence intervals (95% CI) were calculated by logistic regression analyses after performing bivariate analyses with baseline candidate predictor variables of flares at 9–12 months and during the second year. These variables were selected from baseline data, based on their potential clinical relevance, and were in case of possible statistical relevance   and 173 SUA decreased from mean 500 μmol/L at baseline to 311 μmol at 1 year and 324 μmol/L at year 2, and 85.5% of patients were at target < 360 μmol at year 1 and 78.6% at year 2. Demographics and baseline characteristics are shown in Table All patients initiated or escalated ULT. Only 14.7% (31/211) of patients had ever used ULT with allopurinol and none had used febuxostat, while 78% had experience ever with NSAID, and about half with each colchicine and prednisolone. During the first year, prescription of allopurinol decreased from 95.0% to 87.6% due to switch to febuxostat and increased for febuxostat from 3.5 to 12.4%. Mean doses for allopurinol remained just below 300 mg and below 60 mg for febuxostat. Flare prophylaxis with colchicine was used by 76.3% (161/211) of patients from baseline, with 72.3% (146/202) using colchicine at 1 month, 75.6% (146/193) at 2 months, 42.8% (80/189) at 3 months, and 14.5% (27/187) at 6 months follow-up. NSAIDs and prednisolone were not used as prophylaxis for flares.In the first year, 80.6% 150/186) of patients experienced at least one gout flare and 26.0% (45/173) during the second year. The cumulative incidence of flares during the study is shown in Fig. 50/186 ofTable Characteristics for SUA, drug use, and flare history are displayed in Table The distribution of flares during year 1 among patients is presented as a cumulative probability plot in Fig. Measures for baseline urate deposition  were all bivariately related to flares in year 1 (months 9–12), but baseline ultrasound and DECT sum scores were the only variables which were associated with flares in year 2. There was no consistent relationship between other variables and flares at year 2, including SUA levels or allopurinol dose. For months 9–12, some other baseline factors were significantly associated with flares in bivariate analyses: more co-morbidities, more frequently experience with NSAID and colchicine ever, more flares before study entry, higher pain during the worst flare ever, worse physical function , and lower self-efficacy , but not for flares in year 2. Prophylaxis status at month 6 was not related to flares during months 9–12 or year 2.In sensitivity analyses, we examined the relationship between previous ULT and flares and stratified also for patients who still used prophylaxis after 3 and 6 months. No relationship for previous ULT and flares was observed. There was a higher frequency of flares during months 9–12 in patients using prophylaxis at months 3 versus not .Importantly, crystal depositions at baseline were evaluated by three methods , and all three methods could predict flares at months 9–12 and ultrasound and DECT also at year 2. This is a novel finding, and determination of the crystal load by three methods and over 2 years in this study strengthens the validity of findings. Crystal depositions are only slowly resolved during therapy, and therefore, flares must be expected in patients with a high crystal burden.We also found that patients with high self-efficacy for gout pain independently had a lower risk for flares during months 9–12, whereas patients with previous experience with colchicine at baseline had an increased risk of flares. We have earlier shown in NOR-Gout that high self-efficacy contributes to achieving the target SUA level at 1 year .Patients with frequent flares may have used colchicine more frequently both before and during the first months of the study. It could thus be that colchicine use in this study is more an indicator of frequent flares and disease severity, and our non-randomized design does not allow to study the prevention of flares with colchicine.Interestingly, no other demographic, life-style factors, SUA, or medication predicted flares in our study. While high SUA does increase gout incidence and flare recurrence , no releOther studies find frequent flares early after initiating ULT , 34 or oAbsence of consistent clinical predictors of flares was also observed in a long-term evaluation after the incidence of gout . Other sThe reporting of flares in clinical studies of gout has not been standardized and various methods have been used. Flare in gout shows a high variation , and theOur study is large and with frequent follow-up visits, showing that while the promoted urate target is realistic in daily clinical practice, gout flares must be expected.Limitations in our study include the single-center design. Secondly, flare assessment was mainly self-reported, and the study was initiated before publication of validated self-reported flare criteria . ThirdlyOur study finds frequent flares with increasing cumulative incidence during the first year, even though ULT lead to low SUA levels already after 3–4 months . Four ouIn conclusion, patients with gout frequently flare during the whole first year, especially during months 3–6, but flares are much less frequent during year 2 when treated with ULT. Baseline crystal depositions predict flares over 2 years, supporting ULT early during disease course.