Substance abuse is a growing public health concern in the USA (US), especially now that the US faces a national drug overdose epidemic. Over the past decade, the number of drug overdose deaths has rapidly grown, largely driven by increases in prescription opioid-related overdoses. In recent years, increased heroin and illicitly manufactured fentanyl overdoses have substantially contributed to the rise of overdose deaths. Given the role of physicians in interacting with patients who are at risk for or currently abusing opioids and heroin, it is essential that physicians are aware of this issue and know how to respond. Unfortunately, medical school curricula do not devote substantial time to addiction education and many physicians lack knowledge regarding assessment and management of opioid addiction. While some schools have modified curricula to include content related to opioid prescription techniques and pain management, an added emphasis about the growing role of heroin and fentanyl is needed to adequately address the epidemic. By adapting curricula to address the rising opioid and heroin epidemic, medical schools have the potential to ensure that our future physicians can effectively recognize the signs, symptoms, and risks of opioid/heroin abuse and improve patient outcomes. This article proposes ways to include heroin and fentanyl education into medical school curricula and highlights the potential of simulation-based medical education to enable students to develop the skillset and emotional intelligence necessary to work with patients struggling with opioid and heroin addiction. This will result in future doctors who are better prepared to both prevent and recognize opioid and heroin addiction in patients, an important step in helping reduce the number of addicted patients and address the drug overdose epidemic. Substance abuse is a major public health issue in America, especially given that the USA (US) is currently facing a national epidemic of overdose deaths, with more people dying from overdoses than ever recorded before . From 19In recent years, however, heroin and synthetic opioids in particular have contributed to the increased overdose rates ,4. In 20The issue of heroin and fentanyl abuse is a national public health crisis that needs to be addressed in order to counteract the devastating effects it has across the country, ranging from high numbers of overdose deaths and increasing incidences of medical conditions associated with intravenous drug use, such as HIV and Hepatitis C ,18. SuccGiven the role of physicians in dealing with patients at risk for abuse or patients who are abusing (opioids/heroin), it is of utmost importance that physicians are aware of this issue and know how to respond appropriately. Many physicians lack knowledge regarding the identification, assessment, and treatment of opioid addiction ,22. IncrAAMCNEWS article highlighted that many of these schools have developed ways to integrate such education into their curriculum [Recognizing the growing importance of medical school curricula in effectively addressing the national drug overdose issue, the Association of American Medical Colleges created a statement that 74 medical schools signed in order to demonstrate their willingness toward better incorporating opioid-related topics in their training of medical students ,27. An Arriculum . Anotherrriculum . Liaisonrriculum .While progress has certainly been made in adapting curricula to include opioid-related components, there is still more to be done. As the nature of the prescription opioid epidemic changes and heroin and fentanyl take a more central role, they should have more focus in related curriculum as well. While many schools have adapted curriculum to focus on opioid prescription and pain management, for schools that have not yet done so, curriculum should be further enhanced by adding more material and competencies related to the shift from prescription opioids to heroin and fentanyl, as well as how to treat such addictions in order to prevent future overdoses. Due to the alarming increase in heroin use and overdose, coupled with the transition from opioid misuse to heroin use and increased fentanyl added to heroin, a heightened focus on heroin education is needed to adequately prepare medical students for dealing with issues of heroin abuse, dependence, and overdose in the future.The national scope of the opioid and heroin epidemic has reached a crisis among the healthcare community. In order to better prepare our future physicians, it is essential that they learn how to (1) identify patients at risk (2), recognize signs and symptoms of opioid and heroin abuse (3), follow proper opioid prescription guidelines, and (4) identify systems-based practice for referral of patients who are addicted. Therefore, when our graduates from medical schools are residents and future attending physicians, they will be prepared to effectively and efficiently respond to all situations, manage care, and prevent overdoses in the near future.With incorporation of the opioid and heroin epidemic during medical education, the following critical aspect of curricula can be addressed: standard 7.2 organ systems/life cycle/primary care/prevention/wellness/symptoms/signs/differential diagnosis, treatment planning, impact of behavioral, and social factors to address the LCME Accreditation . MedicalOver prescription of opioids is one factor often cited as contributing to the rise of the opioid epidemic ,34. In rGiven the gaps in physician expertise to treat substance abusing patients –25, it wOver the past 20 years, simulation-based medical education (SBME) has become a frequently used asset in undergraduate medical education . The benCreating scenarios for training through the use of SBME is expanding and may hold great advantages in training medical students in future interactions during the current national and international epidemic of heroin (and other opioids). This epidemic has become a Public Health Emergency of International Concern (PHEIC) and requires serious training, awareness, and engagement. SBME allows the use of partial task trainers, standardized patients, and virtual patients, all potentially incorporated into high-fidelity simulations . SMBE inStudents must become cognizant of facts pertaining to the individual patient, familial factors, occupational factors, and economic factors that are related to heroin addiction and relapse . Such lePhysicians play an essential role in addressing the public health crisis of increased overdoses across the nation. Doctors have the ability based on their interactions with patients to potentially identify who may be at risk for or who is currently suffering from an opioid or heroin addiction. Unfortunately, many physicians feel ill-prepared and lack the knowledge and expertise to effectively identify, assess, and treat opioid and heroin addiction in their patients. Adapting medical school curricula is one essential way to address this knowledge gap. With the inclusion of topics related to opioid and heroin addiction and overdose in curriculum, medical schools have the potential to educate medical students early in their careers about the pressing opioid and heroin epidemic and adequately prepare students to identify and address issues of opioid and heroin abuse in their future careers. Moreover, using SBME can further enhance the training of medical students, providing them with simulated opportunities to develop and enhance both their skillset and EI, thereby enabling them to manage opioid and heroin addiction or overdose in future patient encounters. This is important for not only limiting the number of patients who are suffering from opioid and heroin addiction and improving patient outcomes but also to save lives by preventing overdose and relapse. Incorporating opioid and heroin addiction topics into medical school curriculum and SBME will enable medical schools to train our future physicians to be capable of preventing and recognizing opioid and heroin addiction, a crucial component in addressing the rising opioid and heroin epidemic across America.


After publication of this article  it was b“Anthropometric measurement values and Z-scores were flagged for verification if any of the following criteria were met: WAZ < −6 or >5, WLZ < −5 or >5, LAZ < −6 or >6, WLZ > 3 and LAZ < −3; 2) extreme changes in LAZ and WLZ (greater than 2.5 or 3) between consecutive visits; 3) BMI-for-age Z-score ≥ 6. All the flagged anthropometric observations were assessed and values treated as missing if no plausible explanation was determined.”


We further observed the presence of CsI several tens of micrometres below the surface of the solid UO2 sample, which would be caused by the infiltration of pores network by liquid CsI. Thus, volatile fission products released from molten nuclear fuels with complex internal composition and external structure migrate or evaporate to varying extents, depending on the nature of the solid–liquid interface and the fuel material surface, which becomes the pathway for the released fission products. Introducing the concept of the wettability of liquid chemical species of fission products in contact with solid fuels enabled developing accurate behavioural assessments of volatile fission products released by nuclear fuel.In March 2011, the Fukushima Daiichi Nuclear Power Plant accident caused nuclear fuel to melt and the release of high-volatility fission products into the environment. Caesium and iodine caused environmental contamination and public exposure. Certain fission-product behaviours remain unclear. We found experimentally that liquid CsI disperses extremely favourably toward solid UO Because of this exposure, portions of the core itself melted, and a large quantity of volatile FP, approximately one percent of the volume of materials released during the Chernobyl nuclear disaster, was released. This release caused contamination of the surrounding environment and public exposure to hazardous radioactivity4. Subsequently, to investigate the causes of the incident and stabilise the plant itself, various basic research efforts were launched to assess the fuel behaviour at the time of the incident5, to assess the behaviour of the radioactive materials released6, and to measure the physical properties of the molten fuel7. The highest priority issues among these research efforts include assessing the release behaviour of Cs and I, which are two highly volatile FP chemical species, the extent of Cs-related contamination of the surrounding environment, and public exposure to radioactive I. For example, both European and American research groups have reported on the statuses of atmospheric dispersion and soil surface accumulation of Xe and Cs released into the atmosphere during the 1F incident8.In the severe accident in March 2011 at the Fukushima Daiichi Nuclear Power Plant (1F), the nuclear fuels containing fission products (FP) were exposed to a distinctive environment containing high-temperature water vapour9. In addition, the chemical equilibria of the chemical forms of Cs and I were calculated under various conditions, and the release behaviour of volatile FP has been discussed based on these results10. Furthermore, other studies have evaluated and analysed the migration and dispersal behaviour exhibited by FP contained in fuel11 and the behaviour of FP released from fuel12 through relatively small-scale testing methods, such as heating irradiated fuel samples directly.However, even before the 1F incident, the release behaviour of various types of FP originating from molten fuels has been extensively researched through several out-of-pile large-scale comparative studies using irradiated fuel rods and fuel assemblies following the Three Mile Island No. 2 Reactor (TMI-2) incident in 1979We have learned from the results of these studies that to some extent for Cs and a much greater extent for I, the predominant chemical structure of these materials in nuclear fuel is CsI. These studies also have shown that CsI will switch from a solid to a liquid phase and eventually evaporate into a Cs- and I-bearing vapour phase that separates from the solid-fuel body in certain situations, including conditions when solid-fuel temperatures increase during a severe accident. However, we still have not gained a full understanding of the release behaviour exhibited by Cs and I during a severe accident. For example, as is summarised in greater detail in ref. 13 and reduced melting temperature in various types of metallic nanoparticles14, an unusual combination of phenomena that is typically not observed in the bulk scale can be observed. In this study, we sought, through experimental testing, to evaluate both the wettability of liquid CsI toward uranium dioxide (UO2), a solid typically present in molten nuclear fuel, and the solid–liquid interface energy. This paper will also discuss, based on our results, both the form of liquid CsI present in molten fuel and the behaviour of Cs and I released from molten fuel.Given this background, we believe that multiple factors, such as the wettability and solid–liquid interface properties of CsI relative to solid-fuel surfaces, must influence the degree of migration, evaporation, and even the behaviour of Cs and I released from solid fuels. Because molten fuel typically has a more complex internal structure and external shape than non-molten fuel, the surface ratio between solid fuels and liquid CsI becomes relatively large. In addition, when the surface contribution predominates, increase of lead concentration at the surface of copper–lead alloys15. This study assessed the wettability of liquid CsI relative to solid UO2 using the sessile drop technique. Polycrystalline UO2 pellets, sufficiently polished to exhibit mirror-like smoothness, were selected as solid test materials. Then, CsI was melted onto the surface of these pellets. A series of tests were conducted using an electric furnace filled with high-purity argon gas, to minimise the possibility of oxidation of either UO2 or CsI during testing. The shape and wetting angle of the liquid phase were observed directly through holes in the walls of the electric furnace assembly. Please refer to the Methods section to review additional details of the tests using the sessile drop method.One method for assessing solid and liquid wettability is the sessile drop method. This method assesses wettability and solid–liquid interface energy based on the contact angle formed when a test liquid contacts the surface of a sufficiently smooth solid. This technique has been used for making precise assessments of the solid–liquid interface energy of compounds, such as solid-phase magnesium oxide and molten leadσL and the interface energy between the solid and liquid substances σLS is obtained from the relation.In general, during sessile drop testing, the liquid sample has a constant contact angle relative to its placement on a solid substrate. If there are no chemical reactions between the two substances, Young’s relationship between the liquid surface energy σS is the solid surface energy and θ represents the contact angle of the liquid placed onto the surface of the solid. In this study, the solid–liquid interface energy between solid UO2 and liquid CsI was assessed by direct observation and measurement of these contact angles.In Eq. , σS is σLS between solid UO2 and liquid CsI is calculated from the UO2 granular boundary angle formed by contact between the polycrystalline UO2 and liquid CsI, using the relation16.However, we used the dihedral angle method, a technique based on an entirely different concept from sessile drop testing, to verify the validity of the results assessing the solid–liquid interface energy. In dihedral angular measurement testing, the solid–liquid interface energy 2 grain at the sub-micron scale. Based on this experimental result, we used Eq. (2 is the same below the CsI droplet and in a surface with no CsI. In Eq. (σS represents the UO2 surface energy (0.752 Jm−2 17 at the liquid CsI melting temperature of 973 K) used in Eq. . The same procedure was followed with UO2 pellets not permeated by CsI. Grain boundary angles were determined by measuring the angles created by the boundary formed by contact between two crystals at the points parallel and perpendicular to the observation plane. The resolution of the SEM images used for dihedral angle measurements is enough high, thus it is considered that the error in the measurement due to the limits in the resolution is within ±1°. Approximately 150 dihedral angles were observed for each sample material, and the dihedral angle appearing with the highest frequency was determined by statistically processing the observational data obtained.It was confirmed by the EDX analysis that there was no diffusion of Cs or I into the UO2O3) instead of CsI to obtain reference data for the sessile drop tests. B2O3 was selected as a reference substance because it has a low melting point near the melting point of CsI, high chemical stability that permits easy handling and, as will be described subsequently, surface energy comparable to the surface energy of CsI. Additional characteristics of the UO2, CsI, and B2O3 samples are available in the Supplementary Information.The same tests were performed again using boron oxide 21. Video We recently have observed in various systems the same phenomenon, in which solids have a fluorite structure identical to UO2O3 changed to a hemispherical shape after melting and then gradually wet the surface of the solid UO2. It is considered that bubbles in the B2O3 liquid come from pores that are contained in the starting materials. The contact angle varies with time and finally becomes a constant value. As an example, the variation of the contact angle with time for liquid B2O3 on the YSZ (100) plane is shown in the Supplementary Information. Differing from the behaviour of CsI, liquid B2O3 formed a contact angle of approximately 46° with the solid UO2. We confirmed by using SEM and transmission electron microscopy to observe in detail that the chemical reactivity between the UO2 and CsI, as well as between UO2 and B2O3, was vanishingly low. Low chemical reactivity between the solid-phase UO2 and liquid-phase CsI also was confirmed through thermodynamic equilibrium calculations. The Supplementary Information provides additional details of these determinations.B2 was nearly 0°, and no chemical reactions were observed between them. Therefore, we assumed that Young’s relationship would also hold in this situation, and we performed the calculation using Eq.  as well as solid UO2 surface and liquid B2O3 surface energy values obtained from the literature24. Table The contact angle between the liquid CsI and solid UOsing Eq.  with θ =ase, Eq.  is reduc2 pellets used in the dihedral angle method tests. Using low magnification SEM images for the dihedral angle measurement may lead to significant errors25. Therefore, for accurate dihedral angle measurements, high resolution SEM images were used. As seen in these photographs, the crystal grains developed sufficiently, and grain boundaries can be clearly observed. In addition, Fig. 2 were observed and measured following the same procedure, and the angular measurements were assessed to determine the frequencies of appearance, as shown in Fig. 2, which suggests that the grooves are growing via a diffusion controlled mechanism. In this case, the solubility of UO2 in liquid CsI is negligible. We confirmed that the grain boundary angles exhibited a distribution concentrated close to a specific mean value and calculated the mean value by fitting a Gaussian function to the data obtained. From these results, we determined that the dihedral angle θ1 for UO2 immersed with liquid CsI was 137°, and the dihedral angle θ2 for unwetted UO2 was 139°. When Eq. , which is closer to the surface energy of room temperature liquids 27 than to typical high temperature liquids 19. However, the surface energy of the liquid is not the only factor affecting wettability, as shown by the fact that while CsI and B2O3 have nearly the same surface energy, their contact angle differs significantly. This difference results from the fact that the adhesion energy of CsI on UO2 is higher than the adhesion energy of B2O3.We used this equation for calculating 2. First, as previously stated, traces of the chemical reaction between UO2 and CsI were not confirmed. Subsequently, we confirmed the presence of CsI several tens of micrometres below the surface of the solid UO2 sample used in testing. Because liquid CsI exhibits acceptable wettability toward solid UO2, CsI that has melted onto the surface of solid UO2 is believed to infiltrate inside the UO2 pellets via the pores network. Long range infiltration can occur if the two following conditions are fulfilled, (i) The contact angle θ must be much lower than 90°28 which is indeed the case for the couple CsI/UO2 for which a perfect or nearly perfect wetting was observed; and (ii) The pores fraction ap must be higher than the critical value ap* for pores interconnection. For an isotropic solid with a dihedral angle θ2 ≈ 140°, the ap* is around 0.0229 which is lower than the experimental value ap = 0.05 in the present case. In that case, the infiltration depth increases with time parabolically28. Such liquid-phase wetting phenomenon has been confirmed experimentally through demonstrations filling carbon nanotubes with molten lead by capillary action30, and penetration of polycrystalline alumina by glass at high temperatures31, but such demonstrations are extremely limited.Next, Fig. 12, numerous instances of incomplete release of Cs and I have been reported, even under conditions where the complete release of Cs and I would be normal. In reality, however, such irradiated fuel contains a diversity of phases32 and complex microstructure comprising numerous nanoscopic voids33. Because of this tendency, if liquid CsI appears in irradiated fuel, we can predict that it will be able to permeate the complex microstructure within the solid-fuel mass. In that case, the specific surface area of the liquid CsI becomes large, and thereby, the solid–liquid interface effects between solid UO2 and liquid CsI can be said to act to suppress FP release because of the high adhesion exhibited by liquid CsI with solid UO2. This phenomenon was not expected beforehand and will be beneficial in explaining the poorly understood behaviour of Cs and I released from fuel materials. In addition, this finding also constitutes a sufficient basis for re-examining the subject of numerous research projects: the behaviour of FP released from nuclear fuels during severe accidents.In the various experiments conducted to clarify the FP release behaviour of molten fuels2 pellet with CsI chunk or B2O3 chunk placed on top) onto a quartz plate fixed at the centre of an infrared heating apparatus. Then, a zoom-equipped complementary metal–oxide–semiconductor camera to the immediate right observed the shape of the liquid droplets on the sample surface. The camera had a maximum zoom of 300×. The sample temperature was measured using a radiation thermometer. Figure We used a special image of the reactor interior for our liquid-phase–wettability observations obtained using sessile drop testing. Using the device entailed placing the sample (UO2 pellet was approximately 9.5 mm, and its height was approximately 7.5 mm. These pellets were cut into disc-like pieces measuring 4 mm × 4 mm × 2 mm for testing. Randomly shaped chunks of either CsI or B2O3, with masses of approximately 1 mg or 0.3 mg, respectively, were placed on top of cut discs of UO2. The rate of temperature increase was set to rise from room temperature at a rate of 20 K/min to just under the melting temperature and then at 1 K/min near the melting temperature. The temperature was fixed after the samples had melted fully. The samples were photographed continuously at a rate of 10 photographs/s, and the most representative images were selected for use in obtaining angular measurements. Testing using both CsI and B2O3 was performed in an argon atmosphere. During angular measurements, photographs focused on the UO2 pellet surfaces. Alternately, composite photographs of the molten CsI or B2O3 were used. The nature of the surfaces of the liquid-phase CsI or B2O3 present on the UO2 pellets could be observed clearly through this approach. We took precise angular measurements. Representative angular measurements are displayed in Figure As Figure Supplementary InformationVideo 1Video 2Video 3Video 4


In this prospective study, we aimed to investigate the diagnostic performance of MET-PET and the long-term results of subsequent patient management.On conventional diagnostic imaging, the features of radiation necrosis (RN) are similar to those of local recurrence (LR) of brain metastases (BM). The eligible subjects had enlarging contrast-enhanced lesions (>1 cm) on MR imaging after any form of radiotherapy for BM, suggesting LR or RN. However, it was difficult to differentiate LR from RN in these cases. From August 2013 to February 2017, MET-PET was performed for 37 lesions in 32 eligible patients. Tracer accumulation in the regions of interest was analysed as the standardised uptake value (SUV) and maximal lesion SUV/maximal normal tissue SUV ratios (LNR) were calculated. The cut-off value for LNR was provisionally set at 1.40. Salvage treatment strategies determined based on MET-PET diagnosis and treatment results were investigated. The diagnostic accuracy of MET-PET was evaluated by receiver operating characteristic (ROC) curve analysis.P = 0.035, log-rank test).The median interval from primary radiotherapy to MET-PET was 19 months and radiotherapy had been performed twice or more for 13 lesions. The MET-PET diagnoses were LR in 19 and RN in 18 lesions. The mean values and standard deviation of LNRs for each diagnostic category were 1.70 ± 0.30 and 1.09 ± 0.25, respectively. At the median follow-up time of 18 months, final diagnoses were confirmed histologically for 17 lesions and clinically for 20 lesions. ROC curve analysis indicated the optimal LNR cut-off value to be 1.40 (area under the curve: 0.84), and the sensitivity and specificity were 0.82 and 0.75, respectively. The median survival times of patient groups with LR and RN based on MET-PET diagnosis were 14.8 months and 35.1 months, respectively (MET-PET showed apparently reliable diagnostic performance for distinguishing between LR and RN. The provisional LNR cut-off value of 1.4 in our institution was found to be appropriate. Limitations of diagnostic accuracy should be recognised in cases with LNR close to this cut-off value. The management of patients with brain metastases (BM) has recently become more important because of the increased incidence of these tumors and the prolonged patient survival times that have accompanied improved control of systemic cancers –3. Gadol11C- methionine (MET) are reportedly useful for positron emission tomography (PET), particularly in the field of neuro-oncology, because of high amino acid uptake by tumor tissue with low uptake by normal brain tissue, resulting in an enhanced tumor-to-background contrast [Amino acid tracers such as contrast , 8. MET-contrast , 10. In contrast . Most prcontrast , 14.The present study aimed to document our early experience with clinical use of MET-PET for distinguishing radiation-induced changes from local tumor recurrence, and to describe in detail the long-term clinical results of modern salvage management based on MET-PET diagnosis. Thus, the diagnostic value and clinical utility of MET-PET imaging for managing patients with BM were critically appraised.The present study was conducted in compliance with the Declaration of Helsinki , and fulfilled all of the requirements for patient anonymity. The Aizawa Hospital Institutional Review Board (IRB) approved this single center prospective clinical study in July 2013 (No. 2013–049). Written permission was obtained prior to MET-PET from all patients and/or their relatives, allowing the use of personal data for clinical research. Patient records and information were anonymised and de-identified prior to analysis.The study candidates were limited to patients with BM. Malignant gliomas were excluded from the present study due to the possibility of there being a difference in optimal cut-off values between BM and malignant gliomas , 15. As MET-PET was performed with a Discovery PET/CT 600 scanner  with a spatial resolution of 5.1 mm full width at half maximum. After intravenous injection of about 370 MBq of 11C–methionine, patients were placed in the scanner to assure that slices parallel to the orbitomeatal line could be obtained. After a transmission CT scan had been obtained, a 10-min static emission scan was begun 20 min after the injection. PET images were reconstructed by CT attenuation correction and a 3D ordered subset expected maximisation algorithm .max) within the suspected lesion and within the normal control were measured. The lesion/normal ratios (LNR) were calculated by dividing the SUVmax of the lesion by the SUVmax of the normal control in order to give priority to detection of a subtle LR mixed with RN. All scans were assessed by an experienced, board-certified, nuclear medicine physician (KO), not involved in any of the treatments for systemic cancer and BM. The cut-off value of the LNR for diagnosis was provisionally set for 1.4, in accordance with previous studies [The region of interest (ROI) for lesions was manually located over the area corresponding to the Gd-enhanced area on the MR images. As a normal control, a circular ROI with a diameter of 10 mm was located within the gray matter of the corresponding contralateral side. The quantitative analysis was performed as follows. The maximum standardised uptake values . Details of subsequent management and results were recorded Fig. .Fig. 1OuFinal clinical diagnoses were determined from surgical specimens, sequential neuroimaging changes and the long-term clinical course secondary to salvage treatment. Shrinkage of the lesion confirmed radiologically after salvage radiotherapy was regarded as LR. A lesion that either remained stable or showed spontaneous shrinkage with no additional treatment on MR imaging follow-up was assumed to be RN. A lesion in which the MET-PET diagnosis could not be confirmed even after adequate follow-up data had been obtained was regarded as a diagnostic failure given the study aim of critical appraisal of MET-PET.Before closing the research database for analysis in April 2017, the authors updated the follow-up data of patients who had not visited our outpatient department for more than three months. Inquiries about the latest clinical and neuroimaging results and the date and mode of death were made by directly corresponding with the referring physicians and/or the families of deceased patients, with written permission obtained at the time of undertaking MET-PET.Patient characteristics were compared using Fisher’s exact test for categorical variables and the Mann–Whitney U test for quantitative variables. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic capability of MET-PET for differentiating between LR and RN and to determine the optimal cut-off value in our institution, with the weights of false negative and positive classifications being equivalent. The overall survival rates were calculated by the Kaplan-Meier product limit method, based on the interval from the date of MET-PET until the event date. The overall survival of each patient group according to MET-PET diagnosis was compared by log-rank test, wherein a patient with both LR and RN was assigned to the LR group. Proportional hazards regression analysis was not performed in the present study because a too-small ratio of events per variable can lead to inaccurate regression estimates .P-value <0.05 was considered to indicate a statistically significant difference.The statistical processing software package “R” version 3.0.1  was used for all statistical analyses. A From August 2013 to February 2017, 33 patients with 38 BM were prospectively registered in the present study. One patient who died of aspiration pneumonia soon after MET-PET was excluded from the analysis. Patient characteristics are presented in detail in Table P = 0.046) , while the time from primary radiotherapy to MET-PET was significantly longer in the RN group (median: 24.9 months) than in the LR group (median: 14.3 months)   showed an obvious increase above that of the first scan (median: 1.70)  . At the time of assessment, 20 patients (63%) were alive and 12 (37%) had died. Nine of the 12 deceased patients had died of CNS disease progression. The median survival time was 45.4 months (95% CI: 26.9 – NR (not reached)) (Fig. After any type of highly focused radiotherapy for BM, one of the toxicities of greatest concern is delayed RN. Because recent advancements in systemic therapy such as targeted therapy have prolonged the survival of even patients with BM –3, the iSeveral previous retrospective studies of MET-PET for BM focused on its diagnostic accuracy and provided an optimal cut-off value for diagnosis but, unfortunately, did not provide subsequent management details. Such specific details are often of critical importance to physicians caring for BM patients. The authors sought to provide information useful for physicians on how to manage such refractory situations, by investigating not only the diagnostic accuracy of MET-PET but also the long-term results of salvage management. We believe this novel viewpoint to be the core value of the present work.This is the first report to demonstrate that MET-PET can predict the patient’s survival as well as providing the immediate diagnosis. This exploratory insight has, in our opinion, clinical significance and can be regarded as relevant because RN follows a self-limited course in most cases while, in contrast, LR can lead to neurological death. In fact, we observed that 9 patients diagnosed with LR on MET-PET ultimately succumbed to central nervous system disease progression despite multimodal treatments. The overall survival time after MET-PET was also found to be prolonged in RN as compared to LR cases. We speculate that this might, at least in part, be attributable to the patients receiving MET-PET having been self-selected to do well by virtue of having had time to develop neuroimaging changes and not dying of their systemic disease. This potential patient population bias should be noted and caution must be exercised in the generalisation of our present findings.There are limitations in the accuracy of imaging diagnosis. LNR values close to 1.4 should be regarded as a “grey zone” with relatively low reliability and the possibility of the initial diagnosis ultimately being found to be incorrect. As demonstrated herein, some of the lesions diagnosed as RN by MET-PET were eventually confirmed to be LR, based on meticulous observation . The secEven with salvage management and long-term follow-up, the validity of MET-PET diagnosis could not be determined in 3 patients Fig. . We specThe results of our present study must be interpreted with caution. The subjects were a heterogeneous group. The number of subjects was small and the lack of adequate statistical power may have resulted in the dataset being underpowered to appropriately assess hypotheses and potential prognostic factors. It should also be noted that it remains difficult to make an accurate diagnosis in some cases with the clinical and radiographic methods employed herein. Thus, we plan to accumulate further experience with this imaging modality, in hopes of establishing more efficient diagnostic and salvage treatment regimens.MET-PET appeared to have a reliable diagnostic capability for distinguishing between LR and RN after radiotherapy for BM. The provisional LNR cut-off value of 1.4 in our institution was found to be appropriate. Diagnostic accuracy limitations should be recognised in cases with LNR close to this cut-off value. An exploratory analysis raised the possibility of MET-PET diagnosis predicting patient survival.


Conclusions. IgG4-RD is a broad disease, and all physicians involved have to be aware of the possibility of pituitary dysfunction. Younger patients should be expected. The histopathological feature of pituitary gland biopsy could be atypical. For patients with a longer history, the combination of GC and immunosuppressive agents is favorable. Early and adequate courses of treatment are crucial for the management of IgG4-RH. With GC and/or immunosuppressant treatment, however, pituitary function or diabetes insipidus did not improve considerably.This study aims to outline the clinical features and outcomes of IgG4-related hypophysitis (IgG4-RH) patients in a tertiary medical center. We reviewed clinical manifestations and imaging and pituitary function tests at baseline, as well as during follow-up. Ten patients were included. The mean age at diagnosis of IgG4-RH was 48.4 (16.0–64.0) years. An average of 3 (0–9) extrapituitary organs were involved. Five patients had panhypopituitarism, three had only posterior hypopituitarism, one had only anterior hypopituitarism, and one had a normal pituitary function. One patient in our study had pituitary mass biopsy, lacking IgG4-positive cells despite lymphocyte infiltration forming an inflammatory pseudotumor. Five patients with a clinical course of IgG4-RH less than nine months and a whole course of IgG4-RD less than two years were managed with glucocorticoids, while three patients with a longer history were administered glucocorticoids plus immunosuppressive agents. One patient went through surgical excision, and one patient was lost to follow-up. All patients showed a prompt response clinically, but only three patients had normalized serum IgG4 levels. Two patients who took medications for less than six months relapsed.  Immunoglobulin G4-related disease (IgG4-RD)  is a chrSince 2011, when Leporati proposed new diagnostic criteria for the disease without the need for pituitary biopsy , IgG4-RHThere have been several case reports and reviews regarding IgG4-RH in the literature. However, because of its low prevalence, a very limited number of clinical studies from a single medical center were published. In this study, we outlined the clinical, radiological, and pathological features of ten patients diagnosed with IgG4-RH in a tertiary medical center and pointed features different from previous reports. We also focused on the treatment and outcome of our patients and proposed a recommended treatment protocol.All of the studies were performed according to the rules of the hospital's medical ethics committee. Informed consent was obtained in accordance with the institutional guidelines.Data from all of the patients diagnosed with IgG4-RD in our center were reviewed, and those with pituitary involvement were noted. Clinical data from 10 patients diagnosed with IgG4-related hypophysitis at the Peking Union Medical College Hospital from December 2012 to January 2017 were retrospectively analyzed. Parameters collected include clinical manifestations and imaging and pituitary function tests at baseline and during follow-up.The diagnosis of IgG4-RH was made according to Leporati's diagnostic criteria : (1) theμg/dl) and ACTH levels (<15 pg/ml). Secondary hypogonadism was defined as FSH/LH concentration that was not elevated for women with amenorrhoea/oligomenorrhea or for adult men with low serum testosterone levels; secondary hypothyroidism was diagnosed when serum fT4 levels were below the normal range and serum TSH level was inappropriately low or normal. The diagnosis of CDI was based on the clinical findings of polyuria and polydipsia, low urine osmolality (<300 mOsm/kg H2O) in a water deprivation test, and an increase in urinary osmolality or a decrease in urine volumes in response to a desmopressin trial.All patients went through endocrine examination regarding pituitary function, including measurements of adrenocorticotropic hormone (ACTH), cortisol, thyroid-stimulating hormone (TSH), free tetraiodothyronine (fT4), growth hormone (GH), insulin-like growth factor 1 (IGF1), FSH/LH, testosterone (T), estradiol (E2), urinary volume, urine, and plasma osmolality. Anterior pituitary hypofunction was defined as follows: GH deficiency was confirmed when low age-adjusted IGF1 levels were present with additional three pituitary deficiencies. Secondary adrenal deficiency was diagnosed if a symptomatic patient demonstrated low morning serum cortisol . Descriptive data are shown as mean ± SD.Until January 2017, 262 patients had been diagnosed with IgG4-RD at the Peking Union Medical College Hospital, 10 (3.8%) of whom had pituitary involvement and were diagnosed with IgG4-RH. The mean age at diagnosis of IgG4-RH was 48.4 (16.0–64.0) years, with a male to female ratio of 4 : 1. The patients made their first visits in the departments of endocrinology (3 cases), rheumatology (2 cases), neurosurgery (2 cases), nephrology (1 case), general internal medicine (1 case), and stomatology (1 case).The principal clinical characteristics, endocrine abnormalities, and MRI features of IgG4-RH patients are listed in Tables A pituitary biopsy was performed in patient 10. The pathological analysis revealed an inflammatory pseudotumor with lymphocyte infiltration (IgG positive and IgG4 negative). In the literature, 28 IgG4-RH cases with pituitary biopsies (including this study) were reported. Among them, 4 (14.3%) . He. He13]. The histopathological analysis of the pituitary mass can be atypical. The pituitary biopsy of patient 10 revealed hypophysitis showing features of an inflammatory pseudotumor (IPT) with positive focal IgG but negative IgG4. IPT is a typical histopathological feature of IgG4-RD and is commonly shared by multiple organs involved . IntracrGC is considered the first-line treatment of IgG4-RD, and immunosuppressive agents are also widely used . HoweverNotably, this study was limited by the inherent drawbacks of retrospective analyses. There may be missed diagnosis of GH deficiency due to the lack of dynamic hormone tests. Small sample sizes due to the low incidence rate of IgG4-RH are partially resolved by the supportive literature review.IgG4-RD is a broad disease, and all physicians involved have to be aware of the possibility of pituitary dysfunction. Younger patients should be expected. The histopathological feature of pituitary gland biopsy could be atypical. For patients with a longer history, the combination of GC and immunosuppressive agents is favorable. Early and adequate courses of treatment are crucial for the management of IgG4-RH. With GC and/or immunosuppressant treatment, however, pituitary function or diabetes insipidus did not improve considerably.


For the world can get rid of the HIV/AIDS pandemic by 2030, there is need for more to be done especially in the case of countries in Africa. In Nigeria, such efforts have included Faith-Based Organizations (FBOs) recognized as partners in the National Response Framework. However, the extent to which these FBOs contribute to efforts to control the pandemic will depend on their capacity. Therefore, this study aimed to ascertain the technical and managerial capacity of these FBOs to respond to the pandemic in Nigeria.We utilized social survey in examining the capacity of three purposively selected FBOs in the Southeast of Nigeria to respond to the pandemic. Thus, the focus group discussion and the key informant interviews were used. The data for the study was collected between Feb and Apr 2014.The study discovered a general low capacity but high willingness of the FBOs to get involved. One of the FBOs studied was better placed than others and had even established committee on the pandemic. However, in another FBO, the pandemic was still seen largely with moral lens that blame those infected rather than provide support. All the FBOs were ambivalent on the use of condoms as a prevention method.There is need for sustained capacity building for the FBOs in order to provide them with knowledge on the pandemic and help them act out the role envisaged for them in the National Response Framework in Nigeria. In spite of the optimism of the UNAIDS, that the world can get rid of the HIV/AIDS pandemic in 2030 , a lot sSince it was discovered, HIV/AIDS has become one of the most important development concerns globally. This concern is without doubt primary in the developing world especially in Africa where the disease can be considered the most potent challenge to the development of the continent. UNAIDS had earlier on reported that the epidemic has overtaken malaria as the traditional killer disease in Africa, home also to about 95% of all AIDS orphans in the world (The impact of the epidemic as obvious from the above facts has necessitated a broad-based approach that involves different institutions. The Faith-Based Organisations (FBOs) have been identified in the National Framework on HIV/AIDS as one of the state level institutions in the fight against HIV/AIDS. Without doubt, the FBOs have played significant roles in the African response to the HIV/AIDS pandemic. These roles which have often gone against the grain of ideal medical strategies against the pandemic have all the same remained among the health seeking alternatives for those affected and inflicted by the pandemic. The niche occupied by the FBOs is perhaps highlighted by the fact that they can rightly be seen as providing a significant percentage of health services in Sub-Saharan Africa. Thus, the FBOs have been very critical in the mitigation, care and treatment of HIV/AIDS in Africa –11. ThisSocio-cultural practices which have refused change have been also related to HIV/AIDS risk in Nigeria . One of There is a certain ambivalence regarding both the ideal role and even the involvement of the FBOs in the HIV/AIDS response continuum , 16, 8. The area of the study was Enugu state in Southeastern zone of Nigeria seen as typifying any other state in geo-political Nigeria and generally considered the capital and epicenter of the Southeast zone. Apart from a vibrant public service and commercial sectors, the state has a robust tertiary education sector with over five tertiary institutions. This large number of tertiary institutions in the state explains the high number of young people there. Enugu state in the sentinel survey in 2012 has an HIV prevalence rate of 4.1% to 6.0% in the general population  can be seen as having gone beyond the average response level or systematically achieving especially in terms of having well-established structures and officers in charge of HIV/AIDS; another like the Assemblies of God is at the primary level of response and so have not established HIV/AIDS response structures. However, the Methodist Church was somewhere between the above two groups i.e. it has been able to identify the need for the response and has taken action though a systematic structure has not yet emerged. All the same, all of them had huge capacity gaps particularly in terms of partnership, networking, and linkages. As would be expected, the parochial nature of these organizations which often even when not voiced portrays the afflicted persons as wayward has negatively affected and limited their response.GovernanceThe Assemblies of God Church: The church members and the board are interested in the involvement of the church in the HIV/AIDS response. However, there is no obvious attempt to achieve gender equity in the membership of the board and there is no clear-cut policy that should inform the HIV/AIDS response of the church. In spite of this, there is the likelihood of high-level participation of the church members if well-coordinated.DACA: The church has a relatively better structure since there is in existence a working committee on HIV/AIDS with experience and which enjoys the support of the top echelon of the church. However, the committee needs to be strengthened and this would improve its effectiveness. There is also need to take opportunity offered by the support of the church hierarchy to formulate a policy on HIV/AIDS response. In fact, the participants in the FGD felt that this could be easily achieved even though they were of the view that the church would need technical support from the government AIDS control agency in order to succeed with this.The Methodist Church: The church has a constitution that even though good enough for regular church matters does not address HIV/AIDS; hence the governance of such activities is mainly on ad-hoc basis as directed by the leadership. However, the FGD participants and KII respondents felt that it was time for a more structured and focused approach. They were also particular about the need to strengthen and expand the social ministry of the church to take on board HIV/AIDS matters. They also agitated for increase in sermons that deal with the realities of the pandemic especially among young people.PartnershipThe Assemblies of God Church: The participants claimed that the FBO has collaborated with other religious groups and even the state AIDS agency in efforts in the past three years. However, in spite of this claim, there was evidently no established partnership on HIV/AIDS. Therefore, the participants agreed that the FBO seriously needs technical support and collaboration with other NGOs as well as linkages with external donors.DACA: The consensus here was that the committee or DACA enjoys the commitment of members and had even included PLWHA as DACA members. It also needs to seek for more partners especially in terms of technical and financial support. In the words of one of the KII respondents, “there is so much that needs to be done and the church does not have inexhaustible resources. Apart from this, there is need for more training and even workshops”.The Methodist Church: The results of the FGD showed that this FBO is still at the starting stage in terms of forging critical partnerships needed for effective response. However, the participants saw the commitment of members of the social committee as very high and that this could be harnessed to improve the overall capacity of the church to respond to the pandemic. The participants advocated for technical support and collaboration with other NGOs. They saw whatever exists in this regard now as haphazard and not formalized in any way.Experience and Skills of the FBOsAssemblies of God Church: The participants agreed that in terms of the required skills and experience to respond to the pandemic the church has nothing significant. In this sense, apart from the natural ability of the church to provide care and compassion to all those members who are sick (not limited to HIV/AIDS), there is no HIV/AIDS specific skill set or experience. In fact, the members were mainly in denial arguing that this situation may be a product of the fact that none of them can recall any member afflicted by the pandemic recently. In the words of one of them, “if such people exist then it must be that we are not aware of their real sickness. Of course, we have some sick members now and then and even some have been sick for long. What we have done is prepare and try to do the things that government says we need to do in terms of this pandemic”. However, in the course of the KII, a very senior member of the church conceded that such people might exist in the church and that “the only problem is that people are hardly bold to claim such status. Even when people want to access ARV, they often cover themselves or try to use proxies”.DACA: Unlike the above, the participants here were of the opinion that the FBO has experienced, committed and skilled volunteer members of DACA. They also expressed the fact that the DACA was involved in organizing step down training on HIV/AIDS for different parishes under the diocese. They, however, agreed that there was need to build capacity of members of DACA on basic knowledge about HIV/AIDS and skills acquisition especially in the areas of treatment and referral.Methodist Church: The participants in the FGD here were of the consensus that some members are experienced and knowledgeable about the pandemic and that even some of them serve as resource persons for other religious organizations and NGOs. They saw the need now for the inclusion of HIV/AIDS response as a broad portfolio in the activities of the social ministry of the church. In addition, they were of the opinion that the FBO needs to engage experts to build the capacity of members of the social ministry as well as help the church to organize step down training on HIV AIDSService DeliveryAssemblies of God Church: Unsurprisingly, the participants in the FGD here could not point to any evidentiary show of service delivery in terms of HIV/AIDS. Apart from reference to general cases of coming to the support and help of members who were sick, they could not delineate where such support was for HIV/AIDS specifically. However, it is likely that some of those who have been sick for long amongst their members may have become afflicted with the pandemic and are either unaware of the nature of their ailment or are not bold enough to come out openly with their ailment.DACA: The participants here started off by enumerating the factors which position DACA as a reliable provider of services including the support of the Bishop and top echelon of the church; the multidisciplinary composition of DACA; and commitment of DACA members. The group went on to say that, the DACA is currently engaged in activities that can bring succor to PLWHA members and building capacity on health service delivery especially the opportunistic infections associated with HIV/AIDS.Methodist Church: The FBO is seen as having established care and support program in reference to the pandemic and has engaged in activities that can bring succor to PLWHA. It has equally increased its preaching and exhortations against lifestyles that expose people to the affliction. Interestingly, the FGD participants knew about members suspected of being afflicted by the pandemic. However, the church should be supported by government and its agencies to do more. In collaborating this, a respondent in the KII averred that while it is “good to get the churches involved in the fight against AIDS in Nigeria which is like a recognition of the importance of religion, the government needs to now enable the church through providing resources and training to do this well”.The study examined the these FBOs in terms of issues of governance, experience and skill, partnership and service delivery seen in the National Response Framework as critical to the ability of any FBO to contribute meaningfully to the response. The key findings are presented below:What emerges from the above is that the DACA comes out first in terms of responding to the pandemic; it is followed closely by the Methodist Church. However, the Assemblies of God Church has nothing concrete in relation to experience/skills and even cannot show evidence-based service delivery on HIV/AIDS. The FBO is mainly still engaged in the denial and self-righteous mode of the late 1980s and 1990s that blame people for getting infected rather than providing support. However, the church in spite of this conservatism recognizes both the overwhelming reality of the pandemic and the need for its response. The above difference in response and response readiness calls attention to the need for nuanced program on capacity building for FBOs, which factors in the different levels of capacity acquired by each of them.There is also need as evident from the above findings for the FBOs to rise beyond seeing the response as part of traditional church charity. The churches generally perceive and respond to the pandemic mainly as one more issue of charity. This perception was very clear in the FGD sessions in all the three FBOs. However, very representative of this view is the opinion of a middle-aged female participant in the Methodist Church thus, “the church is a place where people come and receive charity. The church cannot stop its charity works even when it is in the case of this deadly affliction. This church always reached out to people in need and that is why we are very close here”. This is unhelpful since the HIV/AIDS pandemic demands the emergence of well-informed and skilled people in order to ensure that even FBOs add value to the national response.In addition, there was glaring lack of knowledge even amongst some key members of the HIV/AIDS committees. In other words, there is need for training and the enhancement of the capacity of the FBOs if they are to fulfill the aim of including them as partners in the national response framework in Nigeria. In spite of acknowledged reality of the pandemic, some of the FGD participants found it difficult to talk at length about it. Even in some cases, energy was dissipated trying to establish either that the pandemic is rare among adherents or that those afflicted are new members who drifted in from other congregations. As one of the respondents in the KII contended, “we cannot close our doors to people even when they come with such sickness, we are a church. Most times, they would not even reveal the real nature of their aliment until much later”.In spite of the FBOs being short on treatment and referral; they were critical both directly and indirectly (through membership exhortation on the need to take care of the afflicted) in the provision of home-based care (HBC) for those afflicted and in materially supporting those affected by the pandemic who are members of their congregation. The above findings reverberate with similar findings in the case of South Africa . In the In spite of the relatively impressive strides of one of the FBOs studied (DACA) in terms of capacity to respond, there is no doubt that the involvement of these FBOs in the response is fraught with challenges bordering on their parochial liturgical stance and rejection of some of the fundamental options in the national response i.e. the advocacy and promotion of condom use seen in another study as affecting their effectiveness . TherefoEthical issues  have been completely observed by the authors.


To determine if trimethoprim use for urinary tract infection (UTI) is associated with an increased risk of acute kidney injury, hyperkalaemia, or sudden death in the general population.Cohort study.UK electronic primary care records from practices contributing to the Clinical Practice Research Datalink linked to the Hospital Episode Statistics database.Adults aged 65 and over with a prescription for trimethoprim, amoxicillin, cefalexin, ciprofloxacin, or nitrofurantoin prescribed up to three days after a primary care diagnosis of UTI between April 1997 and September 2015.The outcomes were acute kidney injury, hyperkalaemia, and death within 14 days of a UTI treated with antibiotics.Among a cohort of 1 191 905 patients aged 65 and over, 178 238 individuals were identified with at least one UTI treated with antibiotics, comprising a total of 422 514 episodes of UTIs treated with antibiotics. The odds of acute kidney injury in the 14 days following antibiotic initiation were higher following trimethoprim  and ciprofloxacin  compared with amoxicillin. The odds of hyperkalaemia in the 14 days following antibiotic initiation were only higher following trimethoprim  compared with amoxicillin. However, the odds of death within the 14 days following antibiotic initiation were not higher with trimethoprim than with amoxicillin: in the whole population the adjusted odds ratio was 0.90  while among users of renin-angiotensin system blockers the odds of death within 14 days of antibiotic initiation was 1.12 (0.80 to 1.57). The results suggest that, for 1000 UTIs treated with antibiotics among people 65 and over, treatment with trimethoprim instead of amoxicillin would result in one to two additional cases of hyperkalaemia and two admissions with acute kidney injury, regardless of renin-angiotensin system blockade. However, for people taking renin-angiotensin system blockers and spironolactone treatment with trimethoprim instead of amoxicillin there were 18 additional cases of hyperkalaemia and 11 admissions with acute kidney injury.Trimethoprim is associated with a greater risk of acute kidney injury and hyperkalaemia compared with other antibiotics used to treat UTIs, but not a greater risk of death. The relative risk increase is similar across population groups, but the higher baseline risk among those taking renin-angiotensin system blockers and potassium-sparing diuretics translates into higher absolute risks of acute kidney injury and hyperkalaemia in these groups. Co-trimoxazole is a combination antibiotic drug containing trimethoprim and sulfamethoxazole, prescribed for multiple indications and is the fourth most commonly prescribed antibiotic in the USA.Existing evidence has important limitations. It is not clear if the association between co-trimoxazole and adverse outcomes is owing to the sulfamethoxazole or the trimethoprim component. The observed association may be owing to confounding if the combination antibiotic was used for patients with more severe infections than the antibiotics it was compared with. Finally, existing evidence is primarily associated with specific groups of patients such as those taking renin-angiotensin system blockers. In the UK, co-trimoxazole is licensed for specific, uncommon indications and trimethoprim is more commonly used. However, there are efforts to reduce trimethoprim prescribing due to increasing antimicrobial resistance.Our study therefore aimed to investigate the association between trimethoprim and acute kidney injury, hyperkalaemia, or sudden death in a cohort of patients aged 65 and over. To limit confounding by antibiotic indication we restricted our analysis to patients with an antibiotic prescription for the same indication (UTI) and examined the risk of adverse outcomes in patients prescribed trimethoprim and four comparison antibiotics . However, even when treatment is restricted to the same indication, different classes of antibiotic drugs are prescribed in slightly different clinical scenarios. For simple UTIs in adults, current UK guidelines recommend nitrofurantoin as the first line treatment  and trimethoprim as a first line alternative where there is low risk of microbial resistance.We undertook a cohort study using electronic clinical records from adults attending primary care practices contributing to the UK Clinical Practice Research Datalink (CPRD GOLD) and linked hospital record data from the Hospital Episode Statistics (HES) database. CPRD is a database of primary care electronic health record data from participating general practices, covering 7% of the UK population.We identified all adults aged 65 years and over during the study period (April 1997 to September 2015). We chose an older population as this is a clinically important group at high risk of adverse health outcomes. In addition, they are more likely to be well monitored, enabling reliable recording of comorbidities and quantification of baseline renal function.Individuals were eligible for the study by receiving a prescription for an antibiotic for a urinary tract infection (UTI) after the latest of the following: 65th birthday; date practice reached CPRD quality control standards ; or one year after practice registration date (to ensure that we had reliable measures of incident morbidity). Patients were no longer eligible to be included from the earliest of the following: date of death; left practice; or last data collection from practice. We excluded patients who developed end stage renal disease before they were eligible for inclusion.The date of inclusion was the day of initiation for any of five antibiotic drugs  recorded up to three days after a primary care morbidity code for uncomplicated UTI . We allowed a gap of three days between UTI diagnosis and treatment with an antibiotic to allow for delays between microbiological diagnosis and treatment. To ensure reliable measures of antibiotic exposure, we excluded any UTI episodes treated with antibiotics where two or more of the study antibiotics were prescribed on the same day. We excluded prescriptions for co-trimoxazole and did not include patients treated with co-amoxiclav in the amoxicillin comparison group as in the UK these drugs are prescribed for more severe or atypical UTIs. We also excluded any UTI episodes where a patient received one or more of the five study antibiotics in the 14 days before the UTI record to ensure that we were identifying the first consultation for an episode of UTI. Finally, we excluded any UTI episodes where a code for a non-UTI infection was recorded in the three days before antibiotic prescription.We investigated the outcomes acute kidney injury, hyperkalaemia, and death recorded within 14 days of antibiotic initiation for UTI. Acute kidney injury was defined as hospital admission with acute kidney injury using ICD-10  codes recorded in any diagnostic position of any inpatient episode starting within 14 days of antibiotic initiation.All morbidity code lists are available to download,Based on a priori knowledge, we considered the following variables as potential confounders of the relation between trimethoprim and acute kidney injury, hyperkalaemia, or sudden death: sex, age, calendar period, chronic comorbidities, history of renal or urological disease, baseline renal function, prescription for renin-angiotensin system blockers (including angiotensin converting enzyme inhibitors and angiotensin receptor blockers) or potassium-sparing diuretics, lifestyle factors , ethnicity, and socioeconomic status. All covariates other than sex and ethnicity were updated over time.Age group was defined in the following bands at time of antibiotic initiation: 65–69; 70–74; 75–79; 80–84; and 85 and over.We included calendar period  as a covariate to adjust for the many changes in clinical, diagnostic, and administrative practices over the study period that may influence the choice of antibiotic treatment for UTI, the measurement of renal function, and registration of outcomes.Chronic comorbidities included as confounders were diabetes mellitus, ischaemic heart disease, cardiac failure, arrhythmia, and hypertension, identified from both primary care and hospital data. Individuals were considered to have a specific comorbidity if they had a code recorded in their electronic health records before a UTI episode treated with antibiotics.2 and over; 45–59 mL/min/1.73m2; 30–44 mL/min/1.73m2; and less than 30 mL/min/1.73m2. This created possible selection bias since those at greater risk of renal disease are more likely to have renal function measured. Therefore, we included an absent renal function category for those with no recorded serum creatinine test result before UTI treated with antibiotics.Baseline renal function was defined using the most recent biochemical test results recorded in primary care at any time before each UTI treated with antibiotics. We used serum creatinine test results to calculate estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.History of renal and urological disease were identified using primary care records and classified in the following categories: prostatic hypertrophy, renal calculi, urological malignancies, and renal structural anomalies. To identify historic diagnoses that may influence prescribing rather than a more immediate condition that may have caused the infection  we identified renal disease based on codes recorded more than a year before each UTI episode treated with antibiotics.Exposure to renin-angiotensin system blockers or potassium-sparing diuretics was defined using prescription data as a current prescription at the time of a UTI treated with antibiotics and categorised as neither a renin-angiotensin system blocker nor a potassium-sparing diuretic, either a renin-angiotensin system blocker or a potassium-sparing diuretic, or renin-angiotensin system blockers in combination with potassium-sparing diuretics. We calculated prescription duration using the quantity of medication prescribed and daily dose recorded; when these data were not available, we assumed the population median prescription duration of 28 days. We assumed exposure to medications started on the date of the prescription. We constructed continuous courses of therapy by allowing for a gap of 60 days between consecutive prescriptions. We therefore defined a current prescription when a UTI episode treated with antibiotics occurred during a continuous course of drug therapy.We used existing morbidity code lists and algorithms for ethnicity,We calculated odds ratios for each outcome  within 14 days of antibiotic initiation for a UTI comparing each antibiotic drug  to amoxicillin (as the reference category) adjusting for potential confounders using logistic regression. We used robust standard errors to account for clustering by general practice. Separately, we repeated the analyses using robust standard errors to account for clustering by patient to account for some patients contributing multiple UTI episodes to the analysis. We initially adjusted for sex and age only, and then fitted an adjusted model using sex, age, calendar period, chronic comorbidities, baseline renal function, history of renal or urological disease, and use of renin-angiotensin system blockers and potassium-sparing diuretics.We tested the impact of our antibiotic exposure definition by repeating the main analysis after: defining exposure as antibiotic prescription on the same day as a record of a UTI morbidity code; excluding prescriptions for antibiotics where the patient received an antibiotic in the 28 days before index infection; and limiting the analysis to the first recorded UTI treated with antibiotics for each individual during eligible follow-up. We then tested the impact of defining more immediate outcomes by repeating the main analysis with all three outcomes defined within seven days (rather than 14 days) of index antibiotic initiation. We also repeated the main analysis additionally adjusting for lifestyle factors  and socioeconomic status. We repeated the main analysis limiting to individuals who had ethnicity recorded in Clinical Practice Research Datalink (CPRD) or Hospital Episode Statistics (HES), and became eligible for study entry from 2006 when recording of ethnicity was rewarded in primary care leading to improvements in CPRD data completeness.All data management and analyses were performed using Stata version 14 .No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. We are not able to disseminate the results of the research directly to study participants because the data used were anonymised. 2, compared with 37% to 43% for other antibiotics). Ciprofloxacin was more likely to be prescribed for UTIs in patients with a history of prostatic hypertrophy or renal calculi .We saw minimal differences in the odds ratios for acute kidney injury, hyperkalaemia, or sudden death comparing trimethoprim, cefalexin, ciprofloxacin, or nitrofurantoin with amoxicillin after the majority of sensitivity analyses, or after additionally adjusting for lifestyle factors, ethnicity, and socioeconomic status (web appendix 1). Repeating the main analysis excluding patients without known baseline renal function made minimal differences to the results (web appendix 1). Redefining exposure as antibiotic prescription for any indication (rather than only for a UTI) increased the observed effect size of the association between trimethoprim and acute kidney injury: the odds ratio comparing trimethoprim with amoxicillin increased from 1.72 to 2.36 . There were minimal changes in the sizes of the association with hyperkalaemia and death. When the analysis was restricted to users of renin-angiotensin system blockers at the time of a UTI (as opposed to adjusting for these drugs as covariates), the risk of acute kidney injury and hyperkalaemia after trimethoprim use were similar to the main analysis; adjusted odds ratio of 1.92 (1.29 to 2.87) for acute kidney injury and 2.22 (1.34 to 3.68) for hyperkalaemia. While the point estimate for death comparing trimethoprim with amoxicillin among users of renin-angiotensin system blockers was higher than among the whole population, confidence intervals were wide; within 14 days adjusted odds ratio for death was 1.12 (0.80 to 1.57). To enable comparison with other studies we counted the number of people prescribed renin-angiotensin system blockers who died with codes specifically suggestive of sudden death  in the 14 days after antibiotic initiation. However, this included only six people so we were unable to analyse this outcome.Finally, analyses using multivariable regression and inverse probability treatment weighting approaches comparing trimethoprim with amoxicillin users (prescribed for a UTI) were consistent with those from the main analysis (web appendix 1).Our results show that in older patients in the general population, regardless of use of renin-angiotensin system blockers or potassium-sparing diuretics, treatment with trimethoprim for a urinary tract infection (UTI) is associated with a 72% increase in the odds of acute kidney injury and a greater than doubling of the odds of hyperkalaemia compared with amoxicillin. We also show that ciprofloxacin is associated with a 48% increase in the odds of acute kidney injury compared with amoxicillin. In contrast, no antibiotic was associated with increased risk of death within 14 days compared with amoxicillin. The relative risks of acute kidney injury, hyperkalaemia, and death were similar in the general population and among those prescribed renin-angiotensin system blockers after trimethoprim use for a UTI.This is the first study to quantify the association of trimethoprim with these outcomes, for an unselected general population cohort after a UTI. Our study used a large number of routine, prospectively collected clinical records from a UK general practice database that is broadly representative of the UK population.However, there are some important limitations. While we attempted to capture only simple UTIs  in our main analysis, we may have included patients with underlying urinary tract disorders, or other infections. Since different classes of antibiotic drugs are prescribed for different clinical scenarios, some degree of confounding by indication is unavoidable. However, we were able to reduce confounding by robustly defining and adjusting for variables that may have influenced the choice of antibiotic drug prescribed such as baseline renal function. As trimethoprim was less frequently prescribed for patients with urological pathology, this would likely have led to underestimating the odds of adverse outcomes, particularly acute kidney injury, for trimethoprim compared with the true result. Similarly, clinicians may have been cautious in prescribing trimethoprim to those at highest risk of acute kidney injury and hyperkalaemia, again leading to an underestimation of the true risk of adverse outcomes, particularly for those taking renin-angiotensin system blockers. However, the strongest evidence of adverse outcomes in association with trimethoprim use for those taking renin-angiotensin system blockers was only published towards the end of the period of this study.Our assessment of antibiotic exposure was based on prescriptions alone and patients may not have collected or taken their medicine. This may have led to differential misclassification owing to the severity of the infection, with resulting over or under estimation of the true effect size. However, we have attempted to mitigate for this by limiting the study to simple UTIs and adjusting, in particular, for history of renal or urological disease.We may also have misclassified the outcomes. Trimethoprim reduces tubular secretion of creatinine causing apparent renal impairment, although glomerular filtration rate does not fall.Multiple historic case reports and case series have implicated co-trimoxazole as a cause of reduced renal function,An association between both co-trimoxazole, or trimethoprim alone, with hyperkalaemia is well reported, particularly in association with renin-angiotensin system blockers.This cohort covers the years 1997-2015, and we have shown a progressive increase in the odds of developing hyperkalaemia and acute kidney injury after a UTI in more recent years. The increase in hyperkalaemia may be due to an increased rate of blood testing in primary care  or improved automatic recording of test results in general practice records. The marked increase in acute kidney injury over time as defined by Hospital Episode Statistics (HES) coding is well established and likely to be predominantly related to increased clinical focus and the adoption of consensus definitions defined by changes in creatinine levels.In contrast to previous studies, we did not identify an increased risk of death from any cause in users of trimethoprim. The two previous papers that identified an increased risk of sudden death among users of renin-angiotensin system blockade taking co-trimoxazole, used a case-control design with cases defined by sudden death, among residents of Ontario over 18 years of follow-up.Recent national prescribing guidance recommends nitrofurantoin as the first line choice for treating UTIs in adults, with trimethoprim an equivalent choice for those with low risk of antimicrobial resistance, meaning that trimethoprim will continue to be commonly prescribed.A small increased absolute risk of a rare outcome  from trimethoprim may be acceptable when set against a need for multiple treatment options for patients with allergy to other antibiotics or bacterial resistance patterns. While acute kidney injury and hyperkalaemia may result in avoidable morbidity and hospital admission, it is reassuring that we have not identified an increased risk of death, suggesting that there is appropriate response to these outcomes. Our results show that trimethoprim continues to be prescribed to people at high risk of adverse outcomes including patients with advanced renal impairment and those taking renin-angiotensin system blockers with potassium-sparing diuretics. For groups at high risk of acute kidney injury and hyperkalaemia, other antibiotics should be considered, but, if this is not possible, monitoring of renal function and potassium levels should be performed, in line with the existing summary of product characteristics for trimethoprim. Our results show that trimethoprim is associated with greater risk of acute kidney injury and hyperkalaemia compared with other antibiotic drugs for a UTI, among the general population aged 65 and over, and not just those treated with renin-angiotensin system blockers. However, this is not associated with an increased risk of death.Co-trimoxazole (a combination antibiotic drug containing trimethoprim and sulfamethoxazole) has been associated with an increased risk of sudden death, which may be mediated by increased serum potassiumPrevious research is limited to specific patient groups  and is limited by possible confounding by type and severity of infectionIt is not known if the risks for trimethoprim are similar to those for co-trimoxazoleCompared with amoxicillin, the risk of acute kidney injury and hyperkalaemia increased in the two weeks after taking trimethoprim for a UTI The risk of sudden death was not higher among patients prescribed trimethoprim compared with amoxicillinTrimethoprim is associated with a greater risk of acute kidney injury and hyperkalaemia compared with other antibiotic drugs for a UTI among the general population as well as those taking renin-angiotensin system blockers


At a low pulse voltage (1.6–2.3 V), a conductance switching delay of a few seconds was observed in some SL areas, where the switch to the high conductance state (HCS) is accompanied with an SL expansion under the strong electric field of the SPM probe. At a high pulse voltage (2.5–3.0 V), the HCS current was unstable and decayed in a few seconds; this is ascribed to the degradation of the HCS crystal phase under excessive heating. The reversible conductance change under a pulse voltage of opposite polarity emphasised the role of the electric field in the phase-transition mechanism.Chalcogenide superlattice (SL) phase-change memory materials are leading candidates for non-volatile, energy-efficient electric memory where the electric conductance switching is caused by the atom repositioning in the constituent layers. Here, we study the time evolution of the electric conductance in [(GeTe) It was found that superlattice films consisting of periodic nanometre-thick layers of GeTe and Sb2Te4 in ref. 2Te3 in ref. 2Te3)(3 nm)]15 SLs using high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) has shown SL grains with mixed Ge/Sb atomic layers prepared by molecular beam epitaxial growth on the Sb-terminated surfaces of Si(111)18There have been significant efforts in the fabrication of novel non-volatile memory cells91013142/(Sb2Te3)1]4 SLs by employing scanning probe microscopy (SPM) and scanning probe lithography (SPL). SPM is a powerful technique for investigating the conductance states of solid films because of its high spatial resolution. SPL has emerged as a type of lithography for academic research, and it combines the ability to create nanoscale features and to handle soft matter such as proteins and polymers2/(Sb2Te3)1]4 SL, as it has the simplest SL unit cell structure consisting of (GeTe)2/Sb2Te3 units. By holding a sharp metal probe at a predefined distance from the SL surface  SLs in ref. IN = 2.1 V, and 200 pJ at VIN = 2.8 V, as shown in 2/(Sb2Te3)5]8 SLs grown on a tungsten film2Te3 layers, different degrees of Ge/Sb mixing and changes to the layer thicknessUnder pulse excitation, the SL conductance switching occurred above a threshold voltage of VThe reversible switching was confirmed in separate measurements where an ERASE voltage pulse of negative polarity and a second READ period were added at each stop point, resulting in a WRITE-ERASE pattern. A WRITE voltage of +2.3 V and a time duration of 500 ms were selected as optimal parameters for the SL conductance switching with an injection energy of 15–100 pJ. An ERASE voltage of −2.6 V and a duration of 500 ms were used to create sufficiently strong electric field reversal. The typical behaviour of the current response is shown in Different switching behaviour was observed at WRITE (ERASE) pulse amplitudes of +2.6 V (−2.8 V). The HCS current appeared and decayed within ~2 s after both WRITE and ERASE voltage pulses in The fact that the HCS current appeared at both positive and negative voltage polarity indicates that two similar HCSs were created under the strong electric field from the SPM tip normal to the SL film surface.2/(Sb2Te3)1]4 SLs. Geometrical reordering of atoms in the SL layers results in a change in the SL volume. The fact that the SL suddenly expands by ~3.4% upon conductance state switching, as shown in 1310The results obtained suggest that different factors contribute to the variability observed in the conductance state switching of the [(GeTe)2/Sb2Te1]4 SLs. VIN ~2.8 V. A large fraction of the SL responses (group C2) showed a delay in the conductance switching, a behaviour that is observed in ferroelectric materials where a persistent polarisation produced by an external electric field controls the charge transport properties. The delay time varied between ~3 s at VIN = 2.1 V and 5 × 10−3 s at 2.8 V. The presence of the delay in the current switching provides evidence that the WRITE current is unlikely to be the primary trigger for the conductance change in group C2. Alternatively, a strong electric field from the probe tip may induce electric polarisation of the SL. The electric field applied was estimated using a capacitor model including the vacuum gap and the SL film. A minimum vacuum gap of 0.44 nm was estimated from a sum of the inter-atomic distance in the top Sb2Te3 layer , referred to as group C1, showed a LCS-to-HCS transition with a delay shorter than 6 ms (the time resolution in our setup). A long (0.1–3 s) delay in the conductance state transition was observed in 40% of the responses, referred to as group C2. The remaining part (~8%), referred to as group C3, showed no conductance switching below steady HCS current after excitation at 2.1 and 2.3 V is shown in IN > 3.0 V, a regrowth of SL grains has been reported in ref. unsteady HCS current was caused by excessive heating because of the hot electrons injected from the SPM tip at VIN ~2.8 V and the injected electric energy above 200 pJ. Alternatively, at VIN ~2.3 V, the steady HCS current in 4The excitation voltage and the excitation current are two competing factors in conductance state switching. A IN >3.0 V in ref. The obtained data suggest the following mechanism for conductance switching. When the pulse voltage is above the switching threshold, high-energy electrons were injected into the SL from the SPM probe through the vacuum gap. The injected energetic electrons cause (i) excitation of atomic bonds and (ii) generation of phonons, which in turn activate atom re-bonding and displacement under the strong electric field beneath the SPM probe. An optimal crystal structure was achieved either in the short period of time (for group C1) when a strong electric field of ~0.1 MV/cm and a high electron current were applied or after the time delay required to complete the structural transition at a low electric field (for group C2). An increase in the transverse electric conduction by ~300-fold and an expansion of the SL film are the manifestations of significant structural changes during the LCS-to-HCS transition. We assume that the transition occurs on a short time scale (<1 ms) for group C1, although we are unable to resolve it with our time resolution. At a high voltage and high current injection, the phonon generation process prevails, leading to excessive heating of the SL grain and causing the unsteady HCS current shown in 2/(Sb2Te3)1]4 SLs grains by employing SPM and SPL techniques. Three groups of SL responses were recognised by their behaviour under voltage pulse excitation. The HCS current delay observed in some areas of the SL film provides evidence that the strong electric field applied causes long-lasting changes in the SL structure. The data emphasise the role of the electric field in local conductance switching of the SL films.In conclusion, HCS current values and a different switching dynamic were observed for individual [(GeTe)2/(Sb2Te3)1]4 films were grown on Si(100) substrates by a two-step process that involved using an Ar-ion sputtering system with a base pressure of 1.8 × 10−4 Pa. Reverse sputtering of a 3′ Si substrate was performed at a power of 100 W with an Ar flow rate of 10 sccm. The growth process included the following: (1) the deposition of a 3-nm-thick Sb2Te3 seed layer at room temperature and subsequent annealing at 230 °C, and (2) the deposition of 4 periods of GeTe(0.8 nm)/Sb2Te3(1 nm) by repeated sputtering of GeTe and Sb2Te3 alloy targets at a pressure of 0.5 Pa, with an Ar flow rate of 10 sccm, a power of 20 W and a substrate temperature of 230 °CSL [(GeTe)−7 Pa) at room temperature was used222522252930IN) of 1.0–2.9 V and a duration (Δt) of 0.05–3.2 s were used; the voltage was applied to the sample. Time-dependent changes in the SPM probe height, sample voltage and SPM current were recorded with a time interval of 6 ms.For SPM measurements, an Omicron SPM operating in an ultra-high vacuum chamber 2/Sb2Te3 Superlattices. Sci. Rep.6, 33223; doi: 10.1038/srep33223 (2016).