The spinal cord, vertebral bodies, both neural foramina, and anterior paravertebral soft tissue were significantly more visible with MAVRIC SL T2 than with T2WI (p < 0.05). MAVRIC SL T2 might be a useful technique for the evaluation of postoperative cervical spine with ADR and complements T2WI in the evaluation of the spinal cord and nerve roots which were important structures for post-operative recurrent neck/radicular pain.Anterior cervical discectomy with artificial disc replacement (ADR) is an effective treatment of cervical degenerative disc disease. However, postoperative MRI due to recurrent neck/radicular pain is limited due to severe metallic artifacts of artificial disc instrument. Multiacquisition with variable resonance image combination selective T2 (MAVRIC SL T2) has been developed as an MRI technique for metal artifact reduction but has not been evaluated for the postoperative cervical spine with ADR. In our study, we compared MAVRIC SL T2 with the fast spin echo (FSE) T2-weighted sequence (T2WI), which was an essential MR sequence for evaluation of the cervical neural structure, for metallic artifact reduction in the post-operative cervical spine with ADR. Our study revealed MAVRIC SL T2 showed smaller signal void areas, less distortion and signal pile-up, and was more clinically useful than T2WI ( However, when it comes to post-operative MR imaging, the ADR has a great challenge in post-operative radiological diagnosis, comparing with ACDF2. The artificial disc instrument which used in ADR distorts the magnetic field severely resulting in severe metallic artifacts and making it difficult to assess bony and neurologic structures at the implanted and adjacent levels, regardless of the metal property3. Multiacquisition with variable resonance image combination selective (MAVRIC SL) have been developed for metallic artifact reduction. Our previous study demonstrated short tau inversion recovery (STIR) using MAVRIC SL technique is significantly decreased metallic artifact of the artificial disc instrument comparing with STIR without MAVRIC SL4. Therefore, we wondered whether fast spin echo T2 weighted sequence combined with MAVRIC SL (MAVRIC SL T2) can also replace fast spin echo T2 weighted sequence with superior metallic artifact reduction for the postoperative cervical spine with ADR4. The purpose of our study was to evaluate MAVRIC SL T2 for metallic artifact reduction in MRI in the postoperative assessment of the cervical spine with ADR compared with the fast spin echo (FSE) T2-weighted sequence (T2WI).Anterior cervical discectomy with artificial disc replacement (ADR) is an effective treatment of cervical degenerative disc disease with less loss of segment motion and less risk of adjacent level degeneration than anterior cervical discectomy and fusion (ACDF)p = 0.018 for axial plane, 0.012 for sagittal plane, Table The areas of signal voids of MAVRIC SL T2 in both the axial and sagittal planes were significantly smaller than those of T2WI  in the sagittal plane  results in the slower signal decay along the echo train because smaller refocusing flip angles allow more transverse magnetization to be restored to the longitudinal axis, where the signal decays at a much slower T1 relaxation time as shown in Busse et al.8 Therefore, the overall T2-contrast of MAVRIC SL T2 was not as strong as that of T2WI. This might cause an undesirable impact on the evaluation of spinal cord signal change. In axial plane, the spinal cord compression in operated level was also show poor performance in MAVRIC SL T2. MAVRIC SL T2 is not equipped with gradient-moment nulling, which mitigate the CSF flow artifact in T2WI and gradient echo sequences. Therefore, MAVRIC SL T2 showed strong CSF pulsation artifacts, showing dark signal intensity of the CSF within the anterior subarachnoid space, which limits evaluation of any compressive lesion to the spinal cord, especially in the axial plane. A long scan time is also thought to contribute to strong CSF pulsation artifact. MAVRIC SL obtains images using 3D-FSE acquisition with an increased number of excitations to acquire the data for each excited slabs, resulting in long scan times compared to 2D-FSE techniques9. A long scan time is a significant drawback of MAVRIC SL T2 because patients with severe pain may not be able to complete the MRI scan or have severe motion artifacts.However, in terms of the clinical usefulness, the spinal cord signal change was insufficiently visualized in MAVRIC SL T2 due to blurring and decreased T2 contrast. MAVRIC SL utilizes a longer ETL of 32 and 3D-FSE acquisition, which can result in increased blurring compared to 2D-FSE (ETL = 16)11. Although T1WI is excellent for evaluating bone marrow abnormalities, it is less sensitive for evaluating of spinal cord and nerve root abnormalities that are important for postoperative neck pain. Therefore, we focused on effectiveness of MAVRIC SL T2 compared to T2WI, which was an essential MR sequence for evaluation of the cervical neural structure in the post-operative cervical spine. Second, the number of volunteers included in this study was too small. Third, the diagnostic performance of post-operative complication or recurrent disc pathology among sequences was not conducted because we did not include patients with symptoms. However, considering the long scan time of MAVRIC SL T2, which may be difficult for patients to bear, our preliminary study may be meaningful in verifying the effect of the metallic artifact reduction of MAVRIC SL prior to a large-scale clinical study. Forth, we analyzed most of the artifacts semi-qualitatively, except for the area of the signal void. Therefore, we performed independent analysis and calculated inter-reader reproducibility for the reliability of the semi-qualitative analysis. Fifth, the inter-reader agreement of axial images in clinical usefulness was relatively lower than that of sagittal images. We assumed that strong CSF pulsation artifacts in axial images might affect image interpretation among readers about spinal cord and nerve root compression. Due to the small number of volunteers, even a slight difference in agreement can significantly change the kappa value, so verification with a large population study is required in the future.There are several limitations in our study. First, we did not analyze T1 weighted image (T1WI) which is a routine sequence for evaluation of cervical spineIn conclusion, MAVRIC SL T2 might be useful for the reduction of metallic artifacts in the postoperative cervical spine with ADR, especially for the reduction of signal loss and distortion, and may complement T2WI in the evaluation of spinal cord and nerve root compression at the operated level.GE Healthcare  provided research support for the implantation and application of MAVRIC SL. This study was prospectively designed and approved by the institutional review board of Inha University Hospital, in accordance with the Declaration of Helsinki. Informed consent was obtained from all participating volunteers.Eight volunteers  who underwent ADR using Prodisc C  and without recurrent neck and radicular pain in our hospital would like to participate our study. Written informed consent was obtained for all volunteer in accordance with the institutional review board. Table After the MRI scan, the axial and sagittal image datasets from each sequence were re-labeled to remove the original sequence name and randomize. Among the eight volunteers, the axial images of T2 and MAVRIC SL T2 of one volunteer (V5) were excluded from image analysis due to image quality.A musculoskeletal radiologist measured the area of signal loss around the prosthesis in all axial and sagittal sequences using the Maroview PACS system  for quantitative analysis of the area of the signal void. An ROI was drawn around the artifact encompassing the signal void (including the implant) image by image in all axial and sagittal T2WI and MAVRIC SL T2 and the areas of signal voids were summed.Three musculoskeletal radiologists (one had 3 years and the others had 13 years of experience) independently evaluated the image datasets for geometric distortion, signal pile-up, visualization of anatomic structures, and clinical usefulness.4. Distortion was defined as changed or impaired anatomic allocation around the prosthesis4. Signal pile-up were defined as a peripheral rim of high signal intensity around the prosthesis4.A 4-point scoring system was used for evaluation of geometric distortion and signal pile-up Table 4. Distor4.A 5-point scoring system was used for the assessment of visualization of anatomic structure for the following structures: the anterior subarachnoid space, spinal cord, both neural foramina and anterior paravertebral soft tissue for the axial and sagittal planes; and apposing upper and lower vertebral bodies at the operated site in the sagittal plane  was calculated to determine the interobserver agreement. The strength of agreement quantified by a kappa statistic was graded as follows: < 0, poor; 0.01–0.20, slight; 0.21–0.40, fair; 0.41–0.60, moderate; 0.61–0.80, substantial; and 0.81–1, almost perfect13. For comparison between the sequences, the average scores from the consensus reading of the qualitative analysis were compared using the Wilcoxon log-rank test.The sum of the areas of the signal void for each sequence in the axial and sagittal planes was tested using the Wilcoxon log-rank test. To evaluate the reliability of qualitative analysis of geometric distortion, signal pile-up, visualization of anatomic structure, and clinical usefulness among three readers, weighted Cohen’s kappa statistic . Statistical significance was established at


Adjusting for demographics and standard drinking measures, High Intensity Drinking (HID), indexed by the maximum quantity consumed in a single day in the past 12 months, may be valuable in predicting alcohol dependence other harms across high and low income societies. The data consisted of 17 surveys of adult  in Europe (3), the Americas (8), Africa (2), and Asia/Australia (4). Gender-disaggregated country analyses used Poison regression to investigate whether HID  was incrementally influential, beyond log drinking volume and HED , in predicting drinking problems, adjusting for age and marital status. In adjusted models predicting AUDIT-5 for men, adding HID improved the overall model fit for 11 of 15 countries. For women, 12 of 14 countries with available data showed an improved fit with HID included. The results for the five Life-Area Harms were similar for men. Considering the results by gender, each country showing improvements in model fit by adding HID had larger values of the average difference between high intensity and usual consumption, implying variations in amounts consumed on any given day. The amount consumed/day often greatly exceeded HED levels. In many societies of varying income levels, as hypothesized, HID provided important added information on drinking patterns for predicting harms, beyond the standard volume and binging indicators. Improving alcohol intake pattern measurements is vital for epidemiological studies ,2,3,4 inThere has recently been an upwelling of attention to High Intensity Drinking, with calls for more HID research ,19. A cohttps://med.und.edu/genacis/ (accessed on 28 December 2022) and Wilsnack et al. [The survey samples were collected under the multi-country GENACIS  project ,30,31,32k et al. ). A totan of male and especially of female current drinkers varied greatly and were small in some cases. Although women’s full samples were adequate  was randomly or systematically selected per enumerated or selected household. The analyses that follow used current  drinkers only, with an average sample size across countries of 916 for men and 909 for women. Per the GENACIS study objectives, nearly all datasets, with the exception of Brazil and Isle of Man, included a minimum sample size of approximately 1000. The datasets from the United States and especially Canada were substantially larger. Because of gender differences in abstention, actual adequate , there wLife-Area Harms and AUDIT Dependence Subscale: The two alcohol-related outcomes considered in these analyses are Life Area Harms [ea Harms ,34 and Aea Harms ,36, eachea Harms : “Acute ea Harms .Alcohol Consumption Measures : For each country included in the analysis, at least one of the two above problem variables were required as well as a measure of the overall yearly volume of consumption (recoded to number of 12 g drinks/year), frequency of binge drinking (defined below), and maximum quantity consumed in a single occasion. Volume was constructed across countries, typically using one of two sets of questions, and was based on recommendations proposed in the GENACIS dataset distribution. The first method was based on sums of beverage-specific volume measures [measures , and theall kinds of alcoholic beverages combined, that is, any combination of cans, bottles or glasses of beer; glasses of wine; or drinks containing liquor of any kind (OR THE CULTURAL EQUIVALENT). During the last 12 months, what is the largest number of drinks you had on any single day? Was it: (7) 240 g or more of ethanol in a single day (20 or more drinks), (6) at least 144 g but less than 240 g (at least 12 but less than 20 drinks), (5) at least 96 g but less than 144 g (at least 8 but less than 12 drinks), (4) at least 60 g but less than 96 g (at least 5 but less than 8 drinks), (3) at least 36 g but less than 60 g (at least 3 but less than 5 drinks), (2) at least 12 g but less than 36 g (at least 1 but less than 3 drinks), (1) at least 1 g but less than 12 g (at least a sip but less than one full drink)”. This was the format of the item, for example, in Nigeria and in approximately 10 other countries. However, there were several permutations of this question format. Some countries did not include gram equivalents and only asked about the number of ‘drinks’  with reference tables provided for drink size equivalents for the interviewer to assist the respondent. Other countries had slightly different ranges for the number of drinks for each category . Sweden had a single question “What is the largest number of drinks you drank on any one day?” and respondents provided a continuous number of drinks, and the question was only asked of a random half of the full sample. The US maximum item differed in that (a) it did not include the last category  and (b) the drink ranges instead were about 1–2, 3–4, 5–7, 8–11, 12–23, and 24+ drinks/day instead of the ranges shown above [The maximum quantity consumed in a single occasion, obtained from the initial maximum question preceding a Graduated Frequencies-type measure , was typdrinks),  at leastwn above . Each ofIn the analyses, the frequency of binge drinking (HED) was compared to the maximum quantity, considered to be a measure of HID drinking patterns. A ‘continuous’ covariate with more possible response categories  may outperform (in terms of variance explained) a similar covariate with fewer possible response categories simply due to its scale of measurement. Therefore, to make the two variables more equivalent in number of categories, we categorized HED binge frequency into seven binned values across countries defined as: (1) never, (2) 1–12 times per year, (3) 1–2 times per month, (4) 3–4 times per month, (5) 1–3 times per week, (6) every other day, and (7) every day.A measure of usual quantity per drinking occasion was also constructed for each country using a frequency-weighted beverage-specific usual quantity. For each beverage consumed, the beverage frequency was multiplied by the beverage usual quantity. This product was summed across beverages and divided by the sum of the frequencies across beverages. This quantity could be computed for all countries except for Sweden, as beverage-specific and the maximum question were in different subsamples. The resulting usual quantity will be referred to subsequently as either usual quantity or a frequency-weighted beverage-specific usual quantity. This measure of usual quantity was constructed to be more consistent with maximum quantity than the single measure of usual quantity in a day, because the single usual quantity item was asked in varying formats across countries.Individual Level Control Variables: Age and marital status were taken from responses to the GENACIS surveys in each country. Across countries, age was asked as a continuous variable. Marital status, although asked with slightly different possible categories across country, was coded as 1 if the respondent was married or living with a partner and 0 otherwise (mostly single but including some others). All analyses were performed disaggregated by gender.2 value as well as the increase in the model pseudo R2 estimate from including the maximum quantity consumed . The two primary outcomes under consideration were the five Life-Area Harms and the five Audit dependence items. Prior work [The primary goal of the present analyses is to examine whether the maximum quantity consumed in a day, considered to index HID, contributes to the prediction of alcohol-related problems across countries, above and beyond that of other typically used measures of overall intake (here log volume + 1) and HED (frequency of binge drinking). As only a relatively small number of countries were available, often 15 or fewer, multilevel models were not implemented due to the lack of available power for estimation of level 2 effects. In addition, due to the correlation of the various consumption measures, the focus was not primarily on the significance of the coefficient for the maximum but on the significance of the reduction in the model’s χior work  examined2 estimate for the model was recorded. Second, ln volume was added as a covariate and the coefficient of ln volume and the increase in the model’s pseudo R2 estimate was noted. Third, frequency of binge drinking was included in the model along with age, marital status, and ln volume, and its coefficient and increase in the model pseudo R2 estimate was noted. Fourth, the maximum quantity consumed as the HID indicator was included in the model along with age, marital status, and ln volume, and its coefficient and increase in the model’s pseudo R2 estimate was noted. Finally, the maximum quantity consumed was included with age, marital status, ln volume, and frequency of binge drinking, and its coefficient and increase in the model’s pseudo R2 estimate was noted. The significance in each instance was determined by the reduction in the model’s χ2 value.For the AUDIT-5 and Harms-5 outcome variables, separate models were estimated for each country as well as overall across countries. For each outcome, a total of five models were estimated. First, a base model was estimated which controlled only for age and marital status, and the pseudo Rλ, serving as both the mean and variance of the distribution) was estimated for each country as well as overall across countries. This was appropriate as the outcome variable took on only non-negative integer values (0 to 5) with a strong concentration of values at 0 and with higher values represented with relatively low frequencies. Such a distribution closely resembles that of a Poisson distribution with a mean not far above zero. Although technically, a Poisson distribution has non-zero probability on all non-zero integers  and our outcome mass function only has support for the integers from 0 to 5, we considered the departure of our empirical distribution from that of the theoretical Poisson, i.e., that the probability that a Poisson distribution takes on integer values of 6 or larger when the mean is as large as λ = 1 is only 0.0006. Even mean values as large as λ = 2 have less than 2% of their mass on integers above 5. From empirical plots of the Poisson probability mass function, overall mean parameter values were expected to be in the range of approximately 0.3. The preliminary results from base Poisson models indicated that the conditional mean values for those with higher problem levels could be as large as 1 but no larger than 2.Considering the strong skewness in the raw outcome distribution for Life-Area Harms and AUDIT dependence items, each with response categories as integers ranging from 0 to 5, a Poisson regression model with a canonical log link function for the single parameter of the distribution (λ) is modeled as a function of individual level characteristics. For example, the specification for the final model including all covariates and using AUDIT-5 as the outcome variable was:iλc, is the average of the Poisson distributed number of AUDIT items endorsed for the ith respondent in the cth country, iAc, is their age, iMSc, is their marital status, Ln is their log volume of consumption, iBingec, is their frequency of binge drinking, and iMaxc, is their maximum quantity consumed in a day.In a Poisson regression model, the natural log of the mean parameter  to somewhat higher (0.11 in Sweden and the USA).2 and increasing the pseudo R2 from 0.05 to 0.20. The results from Models 3 and 4 compare the relative improvement in the model fit from including HED frequency of binge drinking (Model 3) as opposed to instead adding the maximum quantity consumed (Model 4). For 8 of the 15 countries, the Model 3 results indicated that frequency of binge drinking was a significant predictor of the log Poisson mean AUDIT-5 score. Comparatively, the results from Model 4 indicated that using the maximum quantity consumed instead of frequency of binge drinking gave significant results for 11 of the 15 countries/societies, including 4 countries for which binge drinking was not significant ; the coefficients for all 4 countries were significant for the maximum quantity consumed (p < 0.001) in addition to 1 country for which binge was significant but the maximum quantity was not . Including the maximum quantity consumed as a covariate above and beyond age, marital status, ln volume, and frequency of binge drinking (in Model 5) significantly improved the overall model fit for the same 11 countries for which the maximum alone had improved the model fit in Model 4 . Note that although the direct interpretation of the coefficient for maximum may be problematic due to high correlations between volume, binge frequency, and maximum quantity consumed, a significant improvement to the model’s χ2 fit from including the maximum quantity consumed as a single variable covariate block indicates that significant additional information was added by the maximum measure.For all countries, the beta coefficient for ln volume in the second model was highly significant, i.e., by reducing the model’s χInterpretation of the significant result for these 11 countries as well as for the 4 countries for which the maximum quantity consumed was not significant  can be partially informed by considering the relationship between the maximum quantity and usual quantity of consumption. For male drinkers in each country see  for eachIn predicting the HARM-5 life-area harms for men, very similar results were found to those for predicting the AUDIT-5. Here, the five countries for which the maximum did not significantly improve the model fit were Brazil, India, Nicaragua, Sri Lanka, and Uganda. For example, in In predicting the AUDIT-5 scale for women . This remains true when controlling for HED (here defined as 5+ drinks/day).Thus, among current drinkers in many countries, both in the developed and developing world, the maximum on any day, especially when including HID levels such as 8–11 and 12+ drinks, is a sensitive measure that adds to the prediction of alcohol dependence and tangible harms in the lives of drinkers and their families. For a substantial number of people across the world, the quantities consumed at least sometimes exceeded the hazardous level of 5 or more drinks, indicating patterns with high intensity drinking. Assessing the maximum quantity consumed on any given day in the prior year is relatively easy , and is Recently, a US study found that quality screening, defined as health care practitioners asking about quantity of alcohol consumed, was more likely for those with HID rather than just HED , This isAmong the limitations of this study are its reliance on self-reported cross-sectional data and a limited set of countries with available data for analysis. In addition, the surveys were conducted at varying times from 1998 (Mexico) to 2007 —mostly between 2000 and 2003. The surveys, though based on a common instrument, used differing modalities of data collection see . The fraAfter accounting for age, marital status, binge drinking (5+) rate, and average alcohol intake, across a broad range of high and low income societies located in multiple continents, the results support the importance of measures of high intensity drinking (far beyond 5+) for enhancing associations to both alcohol dependence symptoms and negative effects on health, marital, or friendship relationships, work or study, and finances. In 75–85 percent of the included countries, high intensity drinking was incrementally significant in relation to dependence symptoms (more so for women than men). In relation to life areas harmed, from about two thirds to two fifths of the included countries (favoring men) showed an incremental relationship owing to high intensity drinking. These gender differences, especially for Life-Area Harms, deserve further study. Given the broad findings of the advantage of adding an indicator of high intensity drinking in models predicting alcohol-related problems, we recommend adding the maximum quantity consumed on any day to the more typical average volume and 5+ binge drinking measures in future multinational epidemiological surveys of alcohol use patterns and related harms. More fully capturing variation in drinking amounts over time, as indicated by high intensity drinking for any given volume of consumption, is vital for understanding how both chronic and acute alcohol problems accrue. As we have shown, in many parts of the world, alcohol dependence, health harms, and hurtful effects on people and families are all exacerbated by the scourge of high intensity drinking. Our results support policy makers in adopting both evidence-informed population-wide alcohol control measures and more targeted interventions aimed at curbing extremely heavy drinking levels, shown here to be widely linked to alcohol dependence symptoms and other medical and social harms.


Studies universally find early age of drinking onset is linked to lifelong risks of alcohol problems and alcohol use disorder (AUD). Assessment of the lasting effect of drinking during adolescent development in humans is confounded by the diversity of environmental and genetic factors that affect adolescent development, including emerging personality disorders and progressive increases in drinking trajectories into adulthood. Preclinical studies using an adolescent intermittent ethanol (AIE) exposure rat model of underage binge drinking avoid the human confounds and support lifelong changes that increase risks. AIE increases adult alcohol drinking, risky decision-making, reward-seeking, and anxiety as well as reductions in executive function that all increase risks for the development of an AUD. AIE causes persistent increases in brain neuroimmune signaling high-mobility group box 1 (HMGB1), Toll-like receptor, receptor for advanced glycation end products, and innate immune genes that are also found to be increased in human AUD brain. HMGB1 is released from cells by ethanol, both free and within extracellular vesicles, that act on neurons and glia, shifting transcription and cellular phenotype. AIE-induced decreases in adult hippocampal neurogenesis and loss of basal forebrain cholinergic neurons are reviewed as examples of persistent AIE-induced pathology. Both are prevented and reversed by anti-inflammatory and epigenetic drugs. Findings suggest AIE-increased HMGB1 signaling induces the RE-1 silencing transcript blunting cholinergic gene expression, shifting neuronal phenotype. Inhibition of HMGB1 neuroimmune signaling, histone methylation enzymes, and galantamine, the cholinesterase inhibitor, both prevent and reverse AIE pathology. These findings provide new targets that may reverse AUD neuropathology as well as other brain diseases linked to neuroimmune signaling.Adolescent underage binge drinking studies find that earlier adolescent drinking is associated with lifelong alcohol problems including high levels of lifetime alcohol use disorder (AUD). Preclinical studies find the underage binge drinking adolescent intermittent ethanol (AIE) model causes lasting changes in adults that increase risks of developing adult alcohol problems. Loss of hippocampal neurogenesis and loss of basal forebrain cholinergic neurons provide examples of how AIE-induced epigenetic and neuroimmune signaling provide novel therapeutic targets for adult AUD. I.Adolescent alcohol drinking contributes to long-lasting changes in adults that increase risks for adult problem drinking and alcohol use disorder (AUD). AUD has behavioral, cognitive, and physiologic symptoms related to repeated heavy alcohol use, a strong desire to consume alcohol, and difficulties in controlling its use despite problems that can include withdrawal symptoms and blackouts . AdolescII.Studies universally agree that an early adolescent age of drinking onset or initiation leads to increased adolescent and lifelong alcohol drinking, alcohol-related problems, and risks for development of an AUD . AlthougThe effect of adolescent drinking in many adult studies is confounded by variations in human genes, diet, adolescent onset of mental disease, and family environment as well as the common trajectory of increased drinking with age from adolescence to adult heavy drinking and development of AUD. Since initiation of alcohol drinking in early adolescence typically continues into adulthood, adult drinking confounds a clear understanding of the effect of an early age of drinking onset. To understand the effect of an early age of drinking onset, it is important to distinguish the effects of adolescent alcohol exposure on maturation of adult neurobiology and behavior from the effect of AUD and heavy drinking in adults. If adolescent drinking creates unique lifelong risks as studies suggest, this supports focused prevention efforts in early adolescence. Interestingly, studies in rats find early adolescence is a more sensitive period , similarIII.Adolescent alcohol drinking is characterized as binge and extreme drinking, typically occurring during social events and vacations, that differs from the daily heavy drinking in adults with alcohol dependence. In 2007, Maria Pascual and Consuelo Guerri recognized the need to develop a preclinical underage binge drinking model in Wistar rats and designed the adolescent intermittent ethanol (AIE) procedure involving eight ethanol treatments  across puberty [postnatal days (P) 25–40], with determinations in late adolescence just after the last ethanol treatment, as well as weeks later in adulthood, to test hypotheses on the lasting effect of adolescent binge drinking on adult brain. They discovered increased levels of proinflammatory iNOS and COX2 just after AIE treatment as well as following 3 weeks of abstinent maturation to adulthood . AIE alsA.Multiple studies, including those from the NADIA consortium, report that AIE promotes adult alcohol drinking . Adult dPrevious reviews have covered the effect of AIE exposure on adult alcohol responses; increases in alcohol drinking, risky behaviors, and anxiety; and loss of behavioral flexibility . A recenIV.The hippocampal subgranular zone is a unique neurogenic niche, which allows continuing new neuron birth and functional integration into local circuitry throughout adolescence and adulthood . HoweverThe finding that adolescent alcohol exposure increased HMGB1 proinflammatory signaling in adult brain led to studies that inhibit HMGB1 proinflammatory signaling to determine how it affects neurogenesis and loss of cognitive flexibility. Wheel running voluntary exercise and pharmacological treatments  have been found to prevent and restore the AIE-induced hippocampal loss of neurogenesis and behavioral pathology, further indicating that AIE-induced loss of neurogenesis and cognitive-behavioral impairments are linked . While AV.α and IL1β, HMGB1, and cyclooxygenase-2 as well as expression of a spectrum of innate immune signaling Toll-like receptors  and the receptor for advanced glycation end products (RAGE) , which is increased in brain by AIE, consistent with induction of proinflammatory gene transcription  . An intes (RAGE) . HMGB1 hs (RAGE) . For exarferon-β . HMGB1 crferon-β . For exarferon-β . EV contcription . CollectκB p65 activation positively correlates with activation of the executioner caspase-3 within neuroprogenitors, highlighting doublecortin+ (DCX+) neuroprogenitor proinflammatory signaling and loss of neurogenesis in the hippocampus after AIE , and transfer protein, nucleic acid, and lipid cargo  that binds the transcriptional repressor RE1-silencing transcription factor   . REST is factor) . REST re factor) , and met factor) . AIE incpromoter , consistf others . AlthougVIII.α7 nicotinic agonists, and modifiers of histone methylation-acetylation.The finding that AUD cortical and hippocampal brain regions have increased expression of HMGB1, TLR receptors, and other proinflammatory molecules overlaps with other mental and neurodegeneration-related diseases, many of which are comorbid with AUD. Not surprisingly, there is an increasing number of preclinical and clinical trials under way investigating anti-inflammatory immune therapies for AUD. Anti-inflammatory targets discussed next include HMGB1 and TLR receptors, phosphodiesterase (PDE) inhibitors; inhibition of microglial proinflammatory priming, anti-inflammatory acetylcholine/A.κB transcription of proinflammatory, innate immune, and many other genes. NFκB has many target genes but is most commonly linked to proinflammatory gene induction. TLR and other proinflammatory signaling regulate immune cell phenotype in part through formation of polychrome complexes that recruit histone-modifying polychrome or other complexes that enhance or repress specific genes. Microglia are well known to have multiple phenotypes that change during development and with drug treatment. The findings that exercise (running wheel), indomethacin (a direct anti-inflammatory drug), and galantamine and donepezil (anti-cholinesterase drugs) block the AIE-induced increases in proinflammatory HMGB1-TLR-RAGE signaling and loss of neurogenesis and cholinergic neurons as well as cognitive deficits, supporting HMGB1-TLR-RAGE signaling as a mechanism of AIE-induced AUD-like pathology. AUD is treated with opiate antagonists, and both human and preclinical studies support an off-target TLR4 blockade by opiate antagonists naltrexone, naloxone, and nalmefene as the mechanism of reduced heavy drinking in human AUD trials using these drugs  to HMGB1 and TLR4, the HMGB1 neutralizing antibody naltrexone, and the TLR4 antagonist LPS-Rs, as well as minocycline, the microglial activation inhibitor, blocked both ethanol and exogenous HMGB1 proinflammatory gene induction  gene expression and enhanced anti-inflammatory  gene expression during acute binge ethanol withdrawal  on microglia (α7nAChR nicotinic receptor agonist that may enhance anti-inflammatory activity. Interestingly, varenicline, a smoking cessation medication with partial nicotinic α4β2 agonist activity, has full α7nAChR agonist activity and has shown efficacy in reducing craving for alcohol and heavy drinking in patients with AUD (α7nAChR nicotinic agonists as anti-inflammatory treatments.The anti-inflammatory actions of acetylcholine are well known from systemic and central nervous system studies . Immune icroglia . The anticroglia . Galantawith AUD . AdditioIX.Adolescent alcohol drinking is common, and studies of early adolescent age of drinking onset or initiation universally agree that early adolescent drinking increases adolescent and lifelong alcohol drinking and alcohol-related problems, as well as risks for AUD. Multiple complex risk factors for AUD include altered reward-seeking, impulse inhibition, risky decision-making, and perseveration involving complex neurocircuits. Proinflammatory signaling including HMGB1/TLR and other innate immune genes are increased in multiple brain regions that contribute to the development of AUD .κB transcription. Each of these HMGB1 signals is a drug target for AUD. PDE inhibitors also show promise as a treatment of AUD due to PDE inhibition blocking NFκB while enhancing CREB transcription, reversing proinflammatory phenotypes. Loss of hippocampal neurogenesis is related to changes in proliferation, maturation, and survival of progenitors that are altered by a proinflammatory shift in the neurogenic milieu. AIE causes a loss and shrinkage of forebrain cholinergic neurons due to increased REST repressing cholinergic genes. Treatments that restore the fully differentiated cholinergic phenotype may benefit AUD and many other brain pathologies. The brain regional changes in phenotypes related to innate immune and trophic factor gene expression induced by adolescent alcohol exposure are known to persist long after exposure has ended but are poorly understood and need additional study. Multiple new targets, including inhibitors of HMGB1 and other innate immune receptors, need to be explored to extend the anti-inflammatory indomethacin, acetylcholinesterase inhibitors, and histone deacetylase inhibitors shown to be potential therapeutic targets for AUD. Further, these mechanisms overlap with neurodegenerative disorders and may be targets for neurodegeneration diseases as well. Studies identifying EVs as contributors to innate immune signaling indicate our understanding of signals is incomplete since EV signaling is poorly understood and may mediate components of responses to ethanol. The reversal of loss of basal forebrain cholinergic neurons suggests previous studies of cholinergic degeneration need to be reassessed. The persistence of epigenetic changes in gene expression supports the hypothesis that adolescent drinking, independent of adult drinking, can increase risks for adult heavy drinking and AUD. The discovery that anti-inflammatory/epigenetic drugs can reverse AIE-induced changes at the molecular and behavioral levels provides promise for new therapies.Preclinical studies of adolescent alcohol exposure such as the NADIA AIE model find unique and persistent changes in neurobiology and behavior lasting into adulthood and often not found with comparable adult exposure. For example, AIE causes long-lasting adult increases in alcohol drinking, risky decisions, reward-seeking, and anxiety as well as reduced executive functions that are paralleled by increased HMGB1-TLR brain neuroimmune signaling , 2017. H


Respiratory infectious disease outbreaks such as those caused by coronaviruses and influenza, necessitate the use of specialized aerosol test chambers to study aspects of these causative agents including detection, efficacy of countermeasures, and aerosol survivability. The anthrax attacks from 2001 and earlier biowarfare and biodefense also influenced the study of biological aerosols to learn about how certain pathogens transmit either naturally or through artificial means. Some high containment biological laboratories, which work with Risk Group 3 and 4 agents in biosafety level -3, biosafety level-4 containment, are equipped with aerosol test chambers to enable the study of high-risk organisms in aerosolized form. Consequently, the biomedical, military and environmental sectors have specific applications when studying bioaerosols which may overlap while being different. There are countless aerosol test chambers worldwide and this number along with numerous high containment biological laboratories underscores the need for technical standards, regulatory and dual-use compliance. Here we survey common aerosol test chambers and their history, current use, and practice. Our findings reinforce the importance and need for continued collaboration among the multi-disciplinary fields studying aerobiology and biological aerosols. Aerosol test chambers (ATC) are specialized facilities used to house studies for detection, animal models, and related efforts involving dispersal of biological aerosols (bioaerosols). ATCs are common among academic, commercial, government, and non-profit research organizations where they often employ researchers who perform studies involving these facilities and maintaining such equipment. For example, ATCs are used to study aerosols containing biological material and minimize the physical loss of particles to isolate key variables and study specific aerosol parameters over time or to infect animal subjects to a relevant dose . These fAlthough the World Health Organization designates SARS-CoV-2 as a Risk Group 3 biological agent, it can be handled at the BSL-2 level for routine diagnostic analysis ABSA, . HoweverNational state programs became active in biodefense in the first half of the 20th century, as consequence of World War II (WWII), and during the Cold War. The Geneva and Biological Weapons Conventions banned offensive use of biowarfare agents (BWA) thus reinforcing biodefense measures for studying detection, survivability and dispersal. Biodefense studies involving BWA may include actual pathogens or simulants and dispersals occurring indoors such as aerosol chamber and outdoors such as field test . The ForIn general, aerosol work would be difficult to detect, monitor, and verify. This is especially true for indoor aerosol studies using ATCs where it is hard to discern dual-use equipment. Aerobiology study methods are often straight-forward but descriptions for equipment set up, agent dispersion, sampling, collection, and detection are lengthy due to the inherent physical and biological nature. Frameworks such as the Australia Group were established to maintain an export control list of dual-use equipment . TrackinAlthough there is no standard biosafety oversight, WHO and CDC provide widely accepted biosafety guidelines which aid at the national level . WHO andIn addition to bioaerosol research aspects and dual-use applications, recent publications also address the need for standardized methods, harmonized regulations, and increased multi-disciplinary initiatives . AlthougGenerally, an aerosol particle per volume (liter or cubic meter of air) does not indicate that particle contains the target agent. A simple particle counter like an Aerodynamic Particle Sizer® would measure particle per liter (P/L) of air. For culturing bacteria and viruses, biologists commonly use colony forming unit (CFU) and plaque forming unit (pfu) which can also be used to measure bacteria (i.e. CFU/liter of air) or viruses  in the air from liquid or solid collection. The US Department of Defense (DOD) has historically used the term Agent Containing Particles of liter of air (ACPLA) to describe a particle that has a detected target organism within it; to differentiate it from simply a particle per liter of air which provides comparable data when evaluating detectors but little operational utility . FurtherDue to their broad and multi-disciplinary use, aerosol chambers generally exist as one of three categories, Static Chambers, Flow-Through Chambers, and Rotating Chambers . Static Flow-Through Chambers, also referred to as Dynamic or Wind-Tunnel Chambers, are more complex and incorporate air that is continuously introduced into the chamber using airflow velocity to counteract the loss of aerosol due to gravity over the course of an experiment. This enables researchers and testers to mimic a realistic airflow environment, however they require continuous aerosol dissemination to maintain aerosol concentration over time. Rotating Chambers, which are also referred to as Goldberg Drum or Rotating Drum Chambers, are typically constructed as a cylinder that rotates over time to reduce the effects of gravity and to maintain aerosol aloft for longer time when compared to a static chamber . The rot• Suspected use of chemical and biological weapons during the two Gulf Wars in 1991 and 2003.• The terrorist attacks on New York City and Washington DC on 11 September 2001.B. anthracis attacks in the United States in October 2001.• The 2001 • Outbreaks of SARS, MERS-CoV, ebolaviruses in 2000s.• Outbreak of SARS-CoV-2 in 2019 and COVID-19 pandemic.As mentioned previously, biodefense programs in the US, United Kingdom, and Canada have continued bioaerosol work domestically and jointly since WWII. In the US, academic, industry, and Government organizations with ATC capabilities have performed research and related activities in their respective niche market that have traditionally experienced low demand. Some of these markets included industrial hygiene applications such as monitoring exposure to environmental chemicals and molds. Nonprofit research organizations have also historically provided related biotech research services for translational sciences including diagnostics, therapeutics, and vaccines . The conThere are numerous aerosol test chambers worldwide represented across academia, industry and government. A few examples of each category are shown . For theAnother example of an entity repurposing their expertise to study SARS-CoV-2 is the US Army Dugway Proving Ground (DPG). In addition to biodefense, DPG provides testing and support for counter CBRE hazards , and theSimilar to the United States, foreign governments have entities that focus on infectious disease, to include BWA. An allied counterpart in the United Kingdom is their Defence Science and Technology Laboratory (Dstl) which the Ministry of Defense operates at Porton Down. Prior to the COVID 19 outbreak, Dstl conducted numerous studies using a Rotating Drum to study the stability and viability of aerosolized infectious diseases, including Lake Victoria Marburgvirus, Zaire ebolavirus, and Reston ebolavirus . FollowiB. anthracis and bioterrorism was high. However, ATCs and related bioaerosol efforts have historically been a niche and service-oriented market resulting in a lack of standardized methods for ATC use and measuring bioaerosols.Recent descriptions of high containment biological laboratories that demonstrated their utility and lessons learned during COVID-19 pandemic offer unique capability that has become essential during the recent outbreaks of respiratory infectious disease . BesidesOften the use of ATCs does not accommodate the different kinds of research being conducted. As described, the basic types of ATCs are inherently inflexible. For example, if a researcher is studying infection pathways or infectious dose, they are primarily limited to ABSL Flowthrough chambers, or if studying aerosol survivability in the environment, researchers will primarily use Rotating Chambers or Static Chambers. Another consideration is the artificiality inherent in using ATCs such as the inability to replicate the relevant real-world environment including UV radiation and pollutants. Researchers have attempted to address this artificiality over time by enhancing capabilities, but it is important that researchers consider these parameters when analyzing results.While the number of HCBLs continues to increase for many reasons as countries and states will choose to prioritize and build them, the number of ATCs will likely increase since the small, portable facilities have lower startup cost. In addition, ATCs are often not under governmental oversight, which make it difficult to estimate their exact numbers. Further work is needed to define methods according to perspectives of health-risk to humans, product-performance of detectors and efficacy of treatments. While challenging, the multi-disciplinary nature of the work offers potential opportunities for greater collaboration among respective communities, which encourages greater transparency through trust building.Responsible development of bioaerosol capabilities should also be considered in the future as related to maintaining resilient biotech industrial base. As demonstrated in the COVID-19 pandemic, the so-called “warm-base” model is essential for preparedness for supplementing manufacture of disposable consumables such as swabs and personal protective equipment. In addition, biomanufacturing of commonly used reagents such as viral transport medium and vaccines require specific materials and scale-up process which are difficult and expensive to have on-demand. These capabilities and associated markets support the bioeconomy ecosystem as a whole.


Only intravenous (IV) formulation is available, however the off-label oral use is frequent in surgical and medical patients. There is no data on the actual in-hospital prescription preferences in French physicians regarding nefopam. We wish to identify nefopam prescription habits for acute and chronic pain among hospital physicians.an online survey was sent to physicians via professional emails. Frequency of prescription, indication, preferred and prescribed administration route, dose regimen, and personal perception of the nefopam tolerance and efficiency were examined.a total of 527 responses were analysed. Nefopam was mostly prescribed by senior hospital physicians, for acute pain, orally (85%), 20 mg/6h with 120 mg maximal daily dose. For chronic pain, the oral administration was more frequent. More than half of prescribers considered the efficacy of the oral route was similar to intravenous, and better tolerated compared to intravenous administration. Forty-eight percent of responders would change their prescription attitude in case of oral route approval of nefopam.oral prescription of intravenous formulation of nefopam is frequent, especially for acute pain, and has the same dose and regimen pattern as for intravenous route. Prescribers consider oral nefopam efficient and safe for patients. Regulatory actions regarding the oral nefopam prescription authorization and duration of such prescription are needed. Nefopam hydrochloride is a tricyclic compound derived from diphenhydramine and developed in the early 1970s firstly as an antidepressant . Nefopam“néfopam - ampoule pour préparation injectable - versé sur un morceau de sucre” - “nefopam - vial for injection - give on a piece of sugar” [Annex 1 - Section 1).In the context of surgery, nefopam is used as a part of multimodal analgesia not only perioperatively, but also after the patient´s discharge from the hospital . Off-labf sugar” , both inIn case of outpatient surgery, particularly orthopaedics - one of the most common functional procedures, nefopam is commonly used as complementary postoperative analgesic. It is prescribed at hospital before discharge, with continuous injection of 120 mg of nefopam using an elastomeric pump at the patient´s home, or as a single intravenous perfusion in the evening after discharge, made by visiting nurses , 12. TheDespite the increasing prescription rate of intravenous formulation of nefopam given orally, there are no guidelines to formalize such attitude. Frequent off-label use leads to heterogeneous practices between physicians, however, there are no data available on physicians´ attitude concerning doses, regimen, duration, security and safety of oral prescription of this intravenous formulation. The aim of this study was to identify nefopam prescription preference patterns for acute and chronic pain management in hospital physicians.The study was exempted from the Ethical approval committee of our institution (Hospices Civils de Lyon); as no patients were involved, no written consent was necessary from the participating practitioners.Annex 1 Section 2). Data collected were: practice type, professional status, age, frequency of prescription of nefopam, indication for prescription, preferred (single choice) and prescribed (multiple choice questions) administration route, dose regimen prescribed intravenously and orally, and personal perception of the nefopam tolerance and efficiency (Likert-type questions). It was an anonymous online questionnaire generated using SoSci Survey tool [For the purpose of our study, we developed an online anonymous survey containing 12 items , to all participants of the regional congress of anesthesiology and intensive care medicine , and to physicians-members of the French Society for Pain Evaluation and Management (SFETD). Inclusion criteria were the responses from physician holding hospital position, including residents, and from those who prescribe nefopam. Excluded were incomplete questionnaires.Data were recorded and processed using Microsoft® Excel® 2016 (16.0.2566.1000). Descriptive statistics were used, data was presented as frequencies and percentage. No sample size calculation was performed for this survey, because we were not able to find any relevant information on the expected prescription rate of nefopam among in-hospital physicians. If we consider the prescription rate at 50%, and margin of precision at 5%, we would need to analyse at least 385 responses to obtain a statistical power of 80% with 95% confidence level .2 or Fisher test as appropriate. The Marascuilo procedure was used to compare proportions between groups, where a significant χ2 test statistic was observed. The significance threshold was set at p<0.05.A comparative analysis was performed using χA total of 531 questionnaires were collected within three months. We excluded 4 questionnaires , finally 527 responses were analysed. The response rate was 13.6%, based on the number of e-mail addresses used (3872 unique e-mail addresses were sent).The majority of responders (86.7% n=457) were from public structures - university hospitals (59.5%) and general hospitals (27.3%); ten percent were from private hospitals, and about 3% from the mixed hospital-community practice. Seventy-two percent were senior physicians. Twenty percent (105 responders) reported daily prescription of nefopam, and more than 50% (301) prescribed nefopam regularly. Only 3% (16) of responders prescribed nefopam in an exceptional manner.Hospital practitioners prescribe nefopam mostly for acute pain , chronic pain was reported by 30% of physicians as a reason for prescription.Prescribers declared that their preferred route of administration was the oral route (47%), followed by intravenous (29% drip perfusion and 22% continuous perfusion), isolated intramuscular (0.9%), and subcutaneous (0.7%) routes. In their current practice, 68% (n=355) responders prescribed nefopam using more than one administration route. The oral route was chosen in 85% of cases, followed by the intravenous route (62% for drip perfusion and 43% for continuous administration). Intramuscular (3%) and subcutaneous (5%) administrations were used occasionally.For the oral route, practitioners advised to ingest nefopam on a piece of sugar (75%), diluted in water (18%), or non-diluted (8%). Ten percent of responders had no preferences regarding the modality of oral administration. The most prescribed unit dose was 20 mg, both orally and intravenously. We did not find significant differences between prescribed unit doses according to the practice location , general hospital (p=0.85), private hospital or community (p=0.10) or the preferential indication (acute post-operative pain (p=0.27), acute medical pain (p=0.20) or chronic pain (p=0.22)).2=66.7; p<0.0001), with the 6h interval being less used for chronic pain .Six hours interval followed by 4 hours interval were the most common interval between nefopam administrations. A significant difference was found when comparing responders who used nefopam for chronic pain to other responders  considering 120 mg the maximal dose less often than others . For chronic pain prescriptions, the preferred route was the oral route (94%), with unit doses of 20 mg every 4 (38%) to 6 (41%) hours.Most responders considered oral nefopam as effective as intravenous nefopam (56.2%), 17.5% did not pronounce on this statement, while 26.3% did not think oral nefopam was as effective as IV nefopam. Most responders thought that oral nefopam was better tolerated than IV nefopam (53.2%), 16.4% did not pronounce on this statement and 30.4% did not think so. Almost all practitioners (91%) were aware of the bitter taste of nefopam, and less than 10% considered the taste as being neutral. Finally, 48.2% of responders estimated that marketing authorization for an oral formulation of nefopam would change their practice.We report nefopam prescription habits of more than 500 French hospital-based practitioners. Nefopam was prescribed mostly by senior physicians from hospitals, mostly for acute pain, preferentially by oral route on a piece of sugar, using a 20 mg unit dose every 6 hours with a maximal daily dose of 120 mg. For chronic pain, the reported frequency of administration was greater, however the maximal daily dose remained the same. More than half prescribers considered oral route being as efficient as intravenous, and was better tolerated. 48% of responders would change their prescription attitude if an oral route of nefopam was approved.The current French regulation authorised only parental route for nefopam with a recommended regimen of 20 mg every 4-6 hours and maximal cumulated dose of 120 mg over 24 hours. These doses were mainly reported by responders in our study but for the oral use, therefore off-label. Available studies on the efficacy of orally given nefopam are rare, and do not meet contemporary methodology , 17. OneGiven orally, intravenous form of nefopam is first metabolized in the liver, its bioavailability is about 36±13% . The maxMost responders believed that orally given nefopam was as efficient as intravenous, even if the administered dose was the same 20 mg). There are few studies comparing pharmacokinetics of oral vs intravenous equivalent doses of nefopam , 20. The mg. TherThere is a growing use of nefopam in France, with 132% increase reported between 2007 and 2012 . The FreThe tolerance data for oral nefopam are scarce. Acute hypersensibility, psychiatric disorders, cutaneous manifestations were more frequent after intravenous administration, rather than oral , 25. NefThe interest of nefopam for management of chronic pain was already demonstrated , 28. Unfnd, 3rd step (weak and strong opioids) of the World Health Organization (WHO) analgesic ladder [Nefopam has a unique place among non-opioid analgesics because of its mechanism of action, and may be combined with other pain-relievers from the first step  and 2c ladder . The absLimitations: our study has several limitations. First, there was a low response rate. However, some researchers have shown that lower response rate may provide more accurate measurements compared to surveys with higher response rates . Then, sIn-hospital oral prescription of intravenous formulation of nefopam in France is frequent, both for acute surgical (47%), non-surgical (55%) and chronic pain (94%). Despite the evidence of significantly low bioavailability of oral nefopam, responders used the same doses and regimen as for intravenous route. More than a half of prescribers considered intravenous formulation of nefopam efficient when given orally, and reported the need for an official approval of the oral use. Regulatory actions regarding the oral nefopam prescription authorization and duration of such prescription are needed, as well as well-designed randomized studies of the effect of oral nefopam on acute postoperative and chronic pain.Nefopam, a non-opioid analgesic, is widely used in France, however only intravenous formulation is available;In the current in-hospital practice an off-label administration route - oral - is frequent, however there is no national recommendation on this topic.More than 500 in-hospital physicians report their habits to prescribe nefopam, regardless clinical situation, patient speciality or professional category;In almost half of cases intravenous nefopam is prescribed orally - e.g. off label - in the hospital, without taking in account bioavailability;We illustrate an important problem of the misuse of intravenous formulation of nefopam, widely prescribed orally, because of the absence of regulation.


Objective: The North Star Ambulatory Assessment (NSAA) is a validated 17-item functional rating scale and widely used to assess motor function in boys with Duchenne muscular dystrophy (DMD). The SARS-CoV-2 pandemic and subsequent Government ‘lockdown’ resulted in no face-to-face clinic visits hence the motor abilities were not monitored. The aim was to investigate whether the NSAA was feasible and reliable by video assessment. Method: Ten ambulant DMD boys were selected from the electronic hospital records. Two physiotherapists scored the boys’ NSAA independently and the intraclass correlation coefficient was used to assess agreement. The video scores were compared to two previous NSAA in-clinic scores. Results: Mean scores (SD) for clinic visit one were 22.6 (4.19) and clinic visit two 21.8 (5.3). The two physiotherapists video mean scores were 20.6 (5.66) for physiotherapist 1 and 20.6 (6.53) for physiotherapist 2. The intraclass correlation coefficient was 0.98 (95% CI 0.93–1.00) for the total NSAA and 1.00 (95% CI 1.00 to 1.00) for the rise time. The mean decline in score from clinic visit one (−12 months) to video assessment was 2.0 (2.8SD). Conclusion: The results from the study suggest that video NSAA is partially feasible and reliable. Duchenne muscular dystrophy (DMD) is a severe, X-linked disease with a worldwide incidence of 1 in 3600 to 6000 live male births . Those aThe standards of care  recommenThere was a global pandemic of the SARS-CoV-2 virus in 2019 which caused severe respiratory illness resulting in imposed restrictions on physical gathering, travelling, leaving house without a reasonable excuse or ‘lockdown’. This ‘lockdown’, in the United Kingdom, was in place from 23 March 2020, and for those with increased risks of contracting the SARS-CoV-2 the Government implemented a 12-week complete isolation protocol. Additionally, a 12-week complete isolation protocol was in place for those classed as ‘extremely vulnerable’ and at increased risk of contracting the virus. Boys with Duchenne muscular dystrophy (DMD) were included in this category and were therefore not able to attend hospital clinic appointments for face-to-face assessments. This lockdown was extended, whereby those patients were discouraged from attending any face-to-face contact unless vital and were advised by the government to shield especially the ones that have been on immunosuppressive treatment like steroids. It was uncertain at the time what future limitations may be in clinical settings with the most vulnerable of the population; however, the necessity will remain to monitor this cohort of patients.There was a clinical need for NSAA to be assessed to track progression or decline in functional abilities, monitor effectiveness of treatment regimens, and alter glucocorticoid (GC) dosage as required. If functional ability is seen to be deteriorating then in addition to changes in GC dosage several other interventions could be considered and implemented, namely home exercise plans, orthotics, stretching programs or hydrotherapy.Although the Government has now relaxed SARS-CoV-2 restrictions, the National Health Service has not been able to provide sufficient appoints to reduce the waiting list, now standing at close to 6 million and may be as many as 13 million over the next 4 years ,11. TeleThis study was done as a service evaluation exercise and approval was sought from the clinical governance department of Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK (2021_017). Written consent was provided remotely by the parent or guardian of all patients. In addition, parents, or guardians of the DMD boys had previously provided written consent for participation in the NSAA United Kingdom natural history study. Ten boys with a genetically confirmed diagnosis of DMD, who were ambulant and had previous NSAA scores in last 6–12 months were selected from the electronic patient record. Ambulant patients who would be unable to comply with test due to behaviour or learning difficulties were excluded .The NSAA has seventeen items and a 3-point scoring structure: 2—’normal’—achieves the assessment goal without any assistance or modification; 1—modified method but achieves goal without the need for physical assistance; 0—unable to achieve the goal independently ,9, meaniThe previous two in-clinic face-to-face NSAA scores were taken as a baseline reference (12 and 6 month) for all patients. This allowed determination of decline or improvement in NSAA scores over a one-year period and served as a standard by which the video scoring could be compared. It has been shown that there is a decline in mean NSAA scores over a 12-month period of −2.2 with a standard deviation of 3.7 [Prior to the test, families were sent information regarding appropriate dress and equipment requirements; including a chair of suitable height (seated with knees and hips at 90 degrees), a step (150 mm in height), and a 10-m walk/run area. The boys were to be barefoot for all items, and in shorts as per NSAA protocol, unless the 10-m run was being performed outside and then shoes/trainers would be worn ,15.Two physiotherapists trained and experienced in carrying out and scoring the NSAA performed the assessment. The families were contacted by letter and phone call, and a time and date was arranged for a secure online video link via Attend Anywhere, the National Health Service England platform for conducting video consultations.During the consultation, the physiotherapists carrying out the video assessment provided guidance of the NSAA protocol for the parents and boys with the assistance of the NSAA protocol information sheet and their tablet computers . Once the boy had completed the NSAA, scores were calculated independently by both physiotherapists. This was in keeping with the assessments ordinarily carried out in a face-to-face clinic environment.The two physiotherapists recorded each item of the NSAA on the score sheet independent of each other and summed the scores to provide a final total out of 34 points. The two physiotherapists were in the same room but did not compare or discuss the scores during or after assessment.To ensure the correct starting position, families were instructed on positioning of the video camera so that the assessors could ensure this was in accordance with the NSAA protocol.The remote-assessed score was compared to the two previous scores from clinic appointments. The physiotherapists carrying out the video NSAA were blinded to the previous NSAA scores.The feasibility of remote scoring was assessed by determining whether items of the NSAA can be performed by parents and their children at home, the technical quality of the videolink and whether using video allowed the physiotherapists to perform the scoring. For this type of study, where the aim is assessing clarity of instructions and ease of administration, a sample size of 10 suffices .Inter-rater reliability of scoring between physiotherapists was assessed by determining the mean absolute difference, a two-way intraclass correlation coefficient (ICC) for agreement and a Bland–Altman plot. The ICC directly measures reliability and can vary from 0 (no reliability) to 1 (perfect reliability). Other measures sometimes used for this purpose, such as the paired t-test or Parson’s correlation coefficient, only assess specific aspects of reliability, whereas the ICC assesses all relevant aspects . The relThe age range of the boys with DMD was 4 years 9 months to 17 years 3 months, with a median of 8 years 2 months. All ten boys were on steroids at the time of in clinic and video NSAA, either prednisolone or deflazacort; nine of the ten boys were on daily dosing and one on intermittent dosing (10 days on 10 days off).All boys completed the NSAA apart from patient 6 who was unable to perform the rise from floor-timed test as he had on his two previous NSAA in clinic visits . The timThe twenty previous one year and six month NSAA were administered by the same physiotherapist in 75% of clinic visits (15/20). The remaining five assessments were administered by the physiotherapist involved in the video trial. The same two physiotherapists scored the NSAA via video.The mean time from the first face-to-face clinic visit to video assessment was 10.8 months (range 7 to 19) and from the second face-to-face clinic to video assessment was 5.4 months (range 4 to 7).All ten video links worked well; the little pixilation on one of the video links did not interfere with scoring the NSAA. No noticeable lag time was present. On three separate occasions, audio was not connected from the attendees’ end but this was easily resolved by either refreshing the link or by exiting the platform and re-entering. The item ‘standing on heels’ proved difficult to assess if the boy was standing on carpet, and therefore any score assessed with the boy on a carpet was lowered by one point. During the assessments, it became clear that the amount of assistance provided by a parent or carer for step climb/descend was difficult to gauge, with the NSAA protocol stating that any assistance is for ‘balance only’. It was therefore decided that any assistance during this part of the NSAA would give the boy a zero score for this item as any score ascribed could not be given with any accuracy.The two physiotherapists scored all 17 items of the NSAA in all ten boys undertaking the video assessment. Each assessment took between 15 and 20 min in all. The NSAA scores of previous and study visits are shown in The mean absolute difference between the two physiotherapists’ scores was 1.0 point  and the ICC was 0.98 (95% CI 0.93–1.00). A Bland–Altman plot underlined the small differences between the two physiotherapists and showed no clear pattern .p = 0.019, p = 0.018). The drop in score was particularly strong in boys over 8 years old (The mean score for face-to-face clinic visit one was 22.6 points (SD 4.2) and for clinic visit two was 21.8 points (SD 5.3). The mean video-assessed score based on either physiotherapist was 20.6 points . The mean decline in scores from face-to-face clinic visit one to the video assessment was 1.9 points (SD 3.1) and from the second face-to-face clinic assessment to the video NSAA was 1.1 points (SD 2.4). The mean drop in NSAA over the three assessments was approximately 2.0 points per year . Moreover, we found evidence that the rate of drop differed significantly between the children . The ICC for the timed rise was 1.00 (95% CI 1.00 to 1.00).The timed 10-m run was completed by 4 boys. The video-timed 10-m run showed a mean absolute difference between the two raters of 0.4 s , and an ICC of 0.97 (95% CI 0.70–1.00).With the present pandemic of the SARS-CoV-2 virus and increasing pressure on NHS for face-to-face appointments, it is imperative to find a means for ensuring patients with long-term conditions can be monitored regularly and in keeping with published standards of care. As all worldwide hospitals started to use ‘virtual clinics’ as a means of ‘seeing’ patients, this presented an opportunity to investigate the possibility of using video to assess boys with DMD and investigate the feasibility and reliability of NSAA scores. The results of this study show that video NSAA is partially feasible and reliable, and decline of the score is consistent with published literature.All families who participated in this study were very co-operative as they provided suitable equipment at home. A variety of set ups were employed; chairs raised up slightly using books, child’s toilet step (exactly 150 mm in height), exercise steps, measuring out a 10-m run, and having the boys dressed appropriately; shorts and barefoot. The study showed that it was possible to score most of the items of NSAA with the video link with good correlation between the two therapists supporting partial feasibility of this assessment. There were however some difficulties, such as a lack of control over types of flooring, some had hard wood floors and some carpets, or difficulties with confirming height of chairs and steps, which may have influenced scoring.The type of flooring made one aspect of scoring problematic, namely ‘stand on heels’. For families who only had carpeted floors, the ability to ‘stand on heels’ was difficult to assess accurately, so any scores given were scored down regardless of the previous in-clinic scores or likelihood of the boy being able to successfully stand on heels. This obviously may have affected the overall NSAA scores; however, when video scores were compared to previous in-clinic scores any difference was in keeping with the studies conducted by Mazzone et al. ,22. In aThe timed tests are an important aspect of the NSAA and perhaps the most contentious aspect of using video due to the potential time lag of Internet connections. However, by starting the stopwatch at the first sign of movement from the boy undertaking a timed functional test and stopping when he achieved the correct finishing position, we tried to remove the effects of any video lag time. This is contrary to the instructions of the NSAA protocol which states the stopwatch should be started on the instruction ‘go’ and any delay in the boy initiating run or rise from floor could be viewed as a decline in their condition. The timed tests appear to be consistent with expected decline, but it would be recommended that any timed tests are treated with caution and only be used as a guide to possible ability and function. It is obvious that far more work needs to be undertaken to confirm the feasibility of performing timed tests via video.The rise from floor would only be timed if the boy was able to perform the task unaided. He would then be scored for functional ability to perform rise from floor; either 2, or 1 and a time given. A score of 0 would be given as the boy was unable to complete the task due to him requiring external help. Nine out of the ten boys were able to perform the timed rise from floor. One boy could not perform a timed rise from floor but also had been unable to do so in his previous two face-to-face clinic visits . The mean decline for the nine boys in our study able to perform the rise from floor item was 3.8 s per year (SD 7.4). This is similar to the research by Mazzone et al. , who repAn obvious problem was the possible variability in the 10 m ‘run’; the distance of which could not be confirmed and used different surfaces . Although the 10-m distance could not be confirmed, the 4 boys who completed the ‘run’ all had times consistent with face-to-face appointments and expected declines in time to complete the run ,22. The In spite of these limitations the scores from video seemed consistent with the previous in clinic assessments. Although there was some variability in the scores seen in the video when compared to their face-to-face in clinic visit, this was most likely related to disease progression. A mean decline in NSAA scores of 2.0 points per year in our study is similar to the 2.2 points found in earlier studies . ConsistIn this study we demonstrated that remotely assessing the NSAA is partially feasible, and that the NSAA scores obtained had a high inter-rater reliability of 0.98. The mean annual change of 1.9 points over a mean 12-month period is in accordance with the expected change in scores reported by Mazzone et al. ,22. HoweThe main limitations of this study are the small sample size, the lack of control over flooring, the inability to confirm the height of steps or the length of 10 m runs and the quality of Internet video links. However, our small sample size was sufficient for the main aims of the study, assessing feasibility and reliability of remotely assessing the NSAA. A more proper validation of our method of home assessment requires a different type of study, where boys are clinically assessed shortly before or after their remote assessment. However, even if the two types of assessment had a slightly lower ICC of 0.9, such a study would still only require a sample size of 15 to assess the ICC with a 95% CI width of 0.2. We therefore suggest that the high intra-rater reliability, combined with the consistency of the NSAA and timed rise from the floor with previous NSAA scores and when compared to larger cohort studies ,22, woulOne aspect of the study not considered, but important, is the parents’ appreciation of their sons’ assessments. The video assessment reassured them that their sons were still being reviewed and gave them opportunity to discuss any concerns. The familiarity of both the boys and their parents with the physiotherapists helped with the NSAA assessments and allowed for an open discussion and a relaxed atmosphere, even when one or two of the boys were being a little ‘difficult’ and coaxing was required to get best performance. Work by Greenhalgh  and collThe next step will be a comparison of face-to-face in-clinic NSAA to the video assessments to assess its accuracy, which will add further evidence to the usefulness of the video assessments as a means of keeping track of disease progression, allow more frequent assessments if required and save some families long difficult journeys.


Mage = 19.19 years, SD = 0.98) who were from four universities and had at least one time of heavy episodic drinking during the last year completed self-report questionnaires. After controlling for sex, age, and university variable, stronger descriptive norms regarding peer drinking were positively associated with a greater frequency of binge drinking. Enhancement drinking motives partially mediated the effects of descriptive peer drinking norms on binge drinking. Furthermore, alcohol resistance self-efficacy moderated the direct effects of descriptive peer drinking norms on binge drinking. Compared with college students who reported high alcohol resistance self-efficacy, the direct effects of descriptive peer drinking norms on binge drinking were stronger among students with low alcohol resistance self-efficacy. These findings point to the potential value of alcohol intervention approaches including efforts to help first-and second-year college students change enhancement drinking motives and increase their ability of resisting drinks in the context of pervasive peer drinking.The association between descriptive norms regarding peer drinking and college students’ binge drinking has been established; however, the mediating and moderating mechanisms underlying this relationship among first-and second-year college students remain minimally explored. Drawing on social norms theory, motivational model of alcohol use, and the theory of normative social behavior, the current study investigated whether enhancement drinking motives mediated the relationship between descriptive norms regarding peer drinking and college students’ binge drinking, and whether this relationship was moderated by alcohol resistance self-efficacy. Five hundred and nineteen first-and second-year college students ( Binge drinking among college students is a major public health concern, which can produce a variety of problems, including decreased academic achievement , increasdescriptive norms on drinking behaviors vary by proximity of reference groups. The descriptive norms of proximal referents  exert a greater influence on college students’ alcohol use as compared to more distal referents  may play a significant role in contributing to their alcohol use. The perceived drinking norms are often conceptually distinguished between descriptive norms and injunctive norms . Descripnts used , whereasnts used . In lighMost prior research on the relation between descriptive norms regarding peer drinking and alcohol consumption has been conducted in Western countries, and it is uncertain whether the findings of such studies could be generalized to other cultures. In China, frequent toasting during meals with friends is very common, and the cultural norms emphasize the value of mutual intoxication through heavy alcohol use among adults, including college students . Thus, hResearchers have focused on the role of motivational mechanisms in the association between descriptive norms regarding peer drinking and alcohol consumption, namely, drinking motives . The motvia enhancement motives, we hypothesized that descriptive norms regarding peer drinking would have a positive effect on enhancement motives, which would, in turn, increase binge drinking (H2).The motivational model of alcohol use  depicts Alcohol resistance self-efficacy, the belief about one’s ability to resist pro-alcohol influences , may plaThe theory of normative social behavior TNSB;  extends The purpose of this study was to replicate and extend the results of previous studies  concerniH1: Stronger descriptive norms regarding peer drinking would be associated with higher levels of binge drinking  from four universities in Zhejiang province, China, participated in the current study. The participants were recruited via posters, flyers, and personal communications. The participation was voluntary, and no incentives were provided. Before data collection, participants were asked if they had engaged in heavy episodic drinking during the past 12 months. The heavy episodic drinking was defined as “consuming 4 or more alcoholic drinks for females, and 5 or more for males within a two-hour period”  to 5 . The items were averaged to form a composite score of descriptive norms regarding peer drinking. Cronbach’s alpha of the measure was 0.63 in the current sample.Items from the Drinking Norms Rating Form  were empAlmost Never/Never) to 5 (Almost Always/Always). Items were averaged to create a single-item index of enhancement motives. Cronbach’s alpha of the subscale was 0.93 in this sample.The enhancement subscale of the Chinese version of Drinking Motives Questionnaire-Revised DMQ-R;  was usedI would definitely drink) to 4 (I would definitely not drink). Items were averaged with higher scores indicating that students were more confident in their ability to resist alcohol offers. Cronbach’s alpha of the measure was 0.74 in the present sample.The alcohol resistance self-efficacy was assessed using a measure from the Project ALERT study . Particinone) to 9 (everyday). The higher scores represented more frequent binge drinking during the past 12 months.Consistent with the definition of binge drinking provided by via SPSS 22.0. We firstly checked normality of the study variables. The distribution of binge drinking scores was positively skewed. A Log 10 transformation was used, and the values of skewness and kurtosis were in acceptable ranges  of standardized effects were calculated using 1,000 bootstrapped samples. A 95% CI that did not contain zero provided evidence of a significant effect  = 4.28, p < 0.01], the university variable was dummy coded and was added as covariates.The zero-order correlations were computed to investigate the relationships among descriptive norms regarding peer drinking, enhancement motives, alcohol resistance self-efficacy, and binge drinking. Hayes’ PROCESS macro (version 3.5) for SPSS  was usedt effect . Age andThe means, standard deviations, and bivariate correlations for the variables are presented in β = 0.20, p < 0.001, see Model 1 of β = 0.19, p < 0.001, see Model 2 of β = 0.23, p < 0.001, see Model 2 of via enhancement motives were significant , accounting for 14.81% of the total effect (0.27). In sum, enhancement motives partially mediated the effects of descriptive norms regarding peer drinking on frequency of binge drinking.To examine the hypothesized model see , Hayes’ β = −0.09, p = 0.02, see the Model 2 of SD below and above the mean, respectively; see βsimple = 0.14, t = 2.37, p = 0.02). However, the strength of such positive association was stronger for those reporting low alcohol resistance self-efficacy .In addition, alcohol resistance self-efficacy was shown to significantly moderate the association between descriptive norms regarding peer drinking and binge drinking frequency  were measured at individual-level among college students from four universities. The lack of information regarding university-level variables  prevented an examination of the effects of university-level characteristics through cluster-based approaches .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.