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Objective: To evaluate implementation of a patient decision aid for symptomatic uterine fibroid management to improve shared decision-making at five clinical settings across the United States., Methods: We used a type 3 hybrid effectiveness-implementation stepped-wedge design and the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) planning and evaluation framework. We conducted clinician training, monthly reach tracking with feedback to site clinical leads, patient and clinician surveys, and visit audio-recordings. Implementation strategies included assessment of organizational readiness for shared decision-making, synchronous clinician training, audit and feedback of decision aid reach, and access to multiple decision aid formats. Outcomes and analyses included patient-level reach, clinician-level adoption, and associations of patient-reported decision aid exposure (as treated) and setting-level implementation (intention-to-treat) with patient-reported (collaboRATE measure) and observed (OPTION-5 measure) shared decision-making. We also designed and assessed setting-level plans for sustainability and other factors impacting sustained decision aid use., Results: The decision aid was adopted by 72 of the 74 eligible gynecologists (97%) and reached 2553 patients across five settings. CollaboRATE scores improved among patients who reported receiving the decision aid (as-treated analysis, 69% vs. 59%; OR 1.6, 95% CI 1.16-2.27). CollaboRATE scores remained consistent before and after setting-level decision aid implementation (intention-to-treat analysis, 64% vs. 63%; OR 0.86, 95% CI 0.61-1.22). Participants would prefer to receive a decision aid at multiple time points (91.9% before the visit, 90.7% during the visit, 86.5% after the visit). Shared decision-making experiences did not improve when comparing pre vs. post-implementation collaboRATE scores across included settings (intention-to-treat, 64% vs. 63%; OR 0.86, 95% CI 0.61-1.22)., Conclusion: When patients with symptomatic uterine fibroids are given decision aids, they report higher shared decision-making scores. However, the differences we observed between the as-treated and intention-to-treat results suggest that unaddressed implementation challenges continue to limit the extent to which patients receive decision aids and likely hinder their overall impact. Future efforts to implement decision aids should explore enhancing their integration into clinical workflows and standard operating procedures, supported by organizational incentives that prioritize shared decision-making., Trial Registration: ClinicalTrials.gov NCT03985449; registered 6 June 2019., (© 2024. The Author(s).)

Introduction: Rectal bleeding commonly occurs in elderly patients using blood thinners, posing management challenges due to limited guidance on reversal agents and medication restart criteria. This study aims to review the demographics and management of elderly patients with rectal bleeding while on blood thinners., Methods: A retrospective analysis of patients aged 60 or older presenting with rectal bleeding at West Suffolk Hospital's emergency department was conducted from January 2018 to December 2020. Data were extracted from electronic records, focusing on patients using blood thinners and adhering to British Society of Gastroenterology guidelines. All patients ceased blood-thinning medications upon admission. The hospital's ethics committee approved the study, which focused on demographics, diagnosis, and management, particularly regarding re-initiation of blood-thinning medicines., Results: During the study period, 170 patients were admitted to the emergency department of West Suffolk Hospital. 93 (54.71%) patients were included in the study. The average age of the participants was 82 years, and 62.3% were male. All patients were followed up for three months. Atrial fibrillation accounted for 52% of patients, while previous strokes accounted for 20%. The most typical pathology was diverticulosis.Regarding restarting of anticoagulants, Among patients on DOAC (Direct oral anticoagulant), 39% were restarted on discharge, 23% were switched to warfarin, and another 23% were not restarted; 15% planned to restart after seven days. For those on Warfarin, 62% were restarted on discharge, 22% stopped the medication, and the rest were switched to Dual Oral Anticoagulant. Among aspirin patients, 60% were restarted at discharge, while the remaining discontinued. All patients receiving clopidogrel and dual antiplatelet therapy were started at discharge. None of the patients were readmitted during the follow-up period of 3 months., Conclusion: Restarting of blood-thinning drugs in patients with rectal bleeding is subject to individual patient variation. Necessitates more extensive trials to achieve greater standardization., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Bavikatte A et al.)

Background: Sports and physical activity are known risk factors for pelvic floor dysfunction (PFD). The aim of this study is to examine the impact of amateur running on PFD, quality of life (QoL), and sexual function., Methods: Amateur runners were contacted through social media. Their PFD, sexual function, and QoL were evaluated by self-reporting validated questionnaires (PFDI-20, PISQ-12, IIQ-7). They were divided by degree of effort into two categories, 'High effort' and 'Moderate effort'. The differences between the two groups were examined by a Mann-Whitney U Test, T-Test, and Chi-square test., Results: 180 women were included. A high incidence of PFD was found among 'High effort' runners in comparison to 'Moderate effort' runners. In addition, women who scored above the median in the PFDI-20 showed significantly greater impairment in QoL and sexual function. Interestingly, the 'High effort' group reported experiencing higher intensity orgasms compared with women in the 'Moderate effort' group. A correlation was also found between the weekly running distance and the intensity of orgasm experienced (P value = 0.004)., Conclusion: 'High effort' runners present a higher incidence of PFD in comparison to 'Moderate effort' runners. Professional pelvic floor muscle training counselling should be considered even for amateur runners. Future interventional physical therapy studies should be carried out in order to investigate preventative strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To assess whether advanced age is a risk factor for complications following pelvic organ prolapse (POP) repair surgeries using the Clavien-Dindo classification system., Methods: In this retrospective cohort study, 260 women who had undergone POP repair surgery at the Soroka University Medical Center (SUMC) between the years 2014-2019 were included. A univariate analysis was conducted to compare the demographical, clinical, obstetrical and operative characteristics of patients by age group (younger or older than 70 years). We performed a similar analysis to assess for the possible association between several variables and post-operative complications. Variables that were found to be associated with post-operative complications (P < 0.2) were included in a multivariate analysis along with advanced age., Results: During the 12 months follow-up period, more than half of the women had experienced at least one post-operative complication. Minor complications (grades 1-2 according to the Clavian-Dindo classification system) were the most common. One woman had died during the follow-up period, and none had experienced organ failure (grade 4). Hysterectomy, as part of POP surgery, was found to be significantly associated with post-operative complications. Additionally, grandmultiparity (> 5 births) showed a tendency towards an increased risk for post-operative complications, however this reached only borderline significance. We found no association between advanced age and post-operative complications., Conclusions: POP repair surgeries are safe for women of all ages. Major complications (grades 3-5) are rare in all age groups. Although advanced age was associated with a higher prevalence of comorbidity and a higher grade of prolapse, no significant difference in the post-operative complications was found between age groups. Concomitant hysterectomy at the time of POP repair surgery is a risk factor for post-operative complications., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Abuse of healthcare workers (HCWs) and lack of public trust threaten the foundation of the physician-patient relationship. This growing global problem creates an even more difficult professional environment and hinders the delivery of high-quality clinical care., Objective: The primary aim was to determine the prevalence of violence against Trinbagonian HCWs in the public sector. Secondary objectives included determining risk factors for violence and mistrust between the public and providers., Method: A cross-sectional analysis of 434 HCWs in the public sector of Trinidad and Tobago was conducted using a modified World Health Organization (WHO) data collection tool, distributed via social media and administrative emails, and snowballed for two months. Fifteen semi-structured interviews were conducted regarding trust in the healthcare system with patients selected from communities., Results: Of the 434 respondents, 45.2% experienced violence and 75.8% witnessed violence against HCWs in the past two years. Verbal abuse (41.5%) was most common. Perpetrators were patients (42.2%) and patients' relatives (35.5%). Chi-square analysis highlighted that HCWs with the highest probability of being abused were aged 25-39 (63.8%), had two to five years of work experience (24.9%), specialized in emergency and internal medicine (48.6%), and cared for psychiatric and physically disabled patients (p-value < 0.001). HCWs believed the threat of violence negatively impacted performance (64.5%), and further action was necessary for mitigation (86.4%). Patients interviewed doubted physicians' altruism and competence (80%) and honesty (53.3%), expressed mistrust in their physician (46.7%), and cited poor infrastructure/management (66.7%) and dissatisfaction with care (60.0%) as factors that contributed to violence., Conclusion: Analysis revealed that violence against Trinbagonian HCWs in the public sector deteriorated patient experience and adversely affected psychological well-being, efficiency, and job satisfaction. Results suggested mistrust of HCWs by the population. Interventions should be instituted to support at-risk HCWs and educate the public to avoid recurrence., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Dookeeram et al.)

Objective: To inquire whether obesity is a risk factor of peri- and post-operative complications following Mid-urethral sling (MUS) surgeries for SUI repair using the Clavien-Dindo classification system (CDcs)., Methods: This retrospective cohort included 304 women who undergone a MUS in a 1000 beds tertiary University medical center between the years 2012-2018. Univariate analysis was conducted to compare clinical and operative traits by BMI group and to examine associations of obesity and complications rates and severity according to the CDcs. Multivariate analysis was conducted to assess the risk for post-operative complications and adjust to potential confounders., Results: The study group included 106 (34.9%) women with BMI 30 or higher and the comparison group included 198 (65.1%) women with BMI lower than 30. In the study group we found a significantly higher prevalence of hypertension (P = 0.019), previous abdominal surgeries (P = 0.012) including cesarean section (P = 0.025), previous pelvic floor surgeries (P = 0.005) and pelvic organ prolapse (P = 0.02). In the control group we found a significantly higher rates of concomitant hysterectomy which performed during the MUS (P = 0.005). Obesity was not associated with increased rates of peri and post-operative complications (P = 0.973)., Conclusions: In our study, obesity was not associated with peri- and post-operative complications following MUS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Repeated cocaine exposure produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsivity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine exposure. AMPK maintains cellular energy homeostasis at the organismal and cellular levels. Here, our objective was to quantify changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Our additional goal was to determine the behavioral and molecular effects of pretreatment with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensitization. Sex differences largely obscured any protein-level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated cocaine. The rationale for these studies was to inform our understanding of AMPK activation dynamics in subcellular compartments and provide additional support for repurposing metformin for treating cocaine use disorder.

Background: 'Perturbation-based balance training' (PBBT) is a training method that was developed to improve balance reactive responses to unexpected balance loss. This training method is more effective in reducing fall rates than traditional balance training methods. Many PBBTs are performed during standing or treadmill walking which targeted specifically step reactive responses, we however, aimed to develop and build a mechatronic system that can provide unexpected perturbation during elliptical walking the Elliptical Perturbation System (the EPES system), with the aim of improving specifically the trunk and upper limbs balance reactive control., Methods: This paper describes the development, and building of the EPES system, using a stationary Elliptical Exercise device, which allows training of trunk and upper limbs balance reactive responses in older adults., Results: The EPES system provides 3-dimensional small, controlled, and unpredictable sudden perturbations during stationary elliptical walking. We developed software that can identify a trainee's trunk and arms reactive balance responses using a stereo camera. After identifying an effective trunk and arms reactive balance response, the software controls the EPES system motors to return the system to its horizontal baseline position after the perturbation. The system thus provides closed-loop feedback for a person's counterbalancing trunk and arm responses, helping to implement implicit motor learning for the trainee. The pilot results show that the EPES software can successfully identify balance reactive responses among participants who are exposed to a sudden unexpected perturbation during elliptical walking on the EPES system., Conclusions: EPES trigger reactive balance responses involving counter-rotation action of body segments and simultaneously evoke arms, and trunk reactive response, thus reactive training effects should be expected., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Early evidence suggested that the impact of the COVID-19 pandemic was less severe in Africa compared to other parts of the world. However, more recent studies indicate higher SARS-CoV-2 infection and COVID-19 mortality rates on the continent than previously documented. Research is needed to better understand SARS-CoV-2 infection and immunity in Africa., Methods: In early 2021, we studied the immune responses in healthcare workers (HCWs) at Lagos University Teaching Hospital ( n  = 134) and Oxford-AstraZeneca COVID-19 vaccine recipients from the general population ( n  = 116) across five local government areas (LGAs) in Lagos State, Nigeria. Western blots were used to simultaneously detect SARS-CoV-2 spike and nucleocapsid (N) antibodies ( n  = 250), and stimulation of peripheral blood mononuclear cells with N followed by an IFN-γ ELISA was used to examine T cell responses ( n  = 114)., Results: Antibody data demonstrated high SARS-CoV-2 seroprevalence of 72·4% (97/134) in HCWs and 60·3% (70/116) in the general population. Antibodies directed to only SARS-CoV-2 N, suggesting pre-existing coronavirus immunity, were seen in 9·7% (13/134) of HCWs and 15·5% (18/116) of the general population. T cell responses against SARS-CoV-2 N ( n  = 114) were robust in detecting exposure to the virus, demonstrating 87·5% sensitivity and 92·9% specificity in a subset of control samples tested. T cell responses against SARS-CoV-2 N were also observed in 83.3% of individuals with N-only antibodies, further suggesting that prior non-SARS-CoV-2 coronavirus infection may provide cellular immunity to SARS-CoV-2., Conclusions: These results have important implications for understanding the paradoxically high SARS-CoV-2 infection with low mortality rate in Africa and supports the need to better understand the implications of SARS-CoV-2 cellular immunity., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BBH is a co-founder of Mir Biosciences, Inc., a company that develops T cell-based diagnostics/vaccines for infections, cancer, and autoimmunity. No other competing financial interests., (© 2023 The Author(s).)

The major cause for skin cancer is the excessive and unprotected exposure to ultraviolet radiation (UVR), which can be prevented by engaging in sun protection behaviours. As longitudinal studies on both adolescents' and adults' performances of sun protection behaviours are limited, the current study aimed to investigate changes in sun protection in these population segments in Western Australia, a region with high annual UVR. During six summer seasons (2015/16 to 2020/21), cross-sectional surveys were conducted among 1806 adolescents (14 to 17 years old) and 1808 adults (18-45 years old), investigating the frequency of five sun protection behaviours (wearing clothing, applying sunscreen, wearing a hat, wearing sunglasses, and seeking shade) and sun avoidance (staying indoors). Over the six-year period, staying indoors increased in both groups. Among adolescents, a decrease in wearing clothing and sunglasses and an increase in seeking shade was demonstrated, and hat and sunscreen use remained relatively stable. Among adults, an increase in sunscreen use was shown, whereas all other sun-related behaviours remained consistent over the six-year period. The results from this study can provide directions for health communications focusing on improving sun protection behaviours among both adolescent and adult populations.

Vocalization is a widespread social behavior in vertebrates that can affect fitness in the wild. Although many vocal behaviors are highly conserved, heritable features of specific vocalization types can vary both within and between species, raising the questions of why and how some vocal behaviors evolve. Here, using new computational tools to automatically detect and cluster vocalizations into distinct acoustic categories, we compare pup isolation calls across neonatal development in eight taxa of deer mice (genus Peromyscus) and compare them with laboratory mice (C57BL6/J strain) and free-living, wild house mice (Mus musculus domesticus). Whereas both Peromyscus and Mus pups produce ultrasonic vocalizations (USVs), Peromyscus pups also produce a second call type with acoustic features, temporal rhythms, and developmental trajectories that are distinct from those of USVs. In deer mice, these lower frequency "cries" are predominantly emitted in postnatal days one through nine, whereas USVs are primarily made after day 9. Using playback assays, we show that cries result in a more rapid approach by Peromyscus mothers than USVs, suggesting a role for cries in eliciting parental care early in neonatal development. Using a genetic cross between two sister species of deer mice exhibiting large, innate differences in the acoustic structure of cries and USVs, we find that variation in vocalization rate, duration, and pitch displays different degrees of genetic dominance and that cry and USV features can be uncoupled in second-generation hybrids. Taken together, this work shows that vocal behavior can evolve quickly between closely related rodent species in which vocalization types, likely serving distinct functions in communication, are controlled by distinct genetic loci., Competing Interests: Declaration of interests H.E.H. is a member of the Advisory Board for Current Biology., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical studies and structural analyses of salivary stones strongly suggest a linkage between higher saliva calcium (Ca 2+ ) and salivary stone formation, sialolithiasis; however, the process and the mechanism leading to Ca 2+ overload during sialolithiasis is not well understood. Here, we show that TRPC3 null (-/-) mice presented with a reduction in Ca 2+ entry and current in ductal cells with higher saliva [Ca 2+ ] suggesting diminished transepithelial Ca 2+ flux across the salivary ductal cells, leaving more Ca 2+ in ductal fluid. Significantly, we found that TRPC3 was expressed in mice and human salivary ductal cells, while intraductal stones were detected in both mice (TRPC3 -/- ) and patient (sialolithiasis) salivary glands. To identify the mechanism, we found that TRPC3 was crucial in preventing the expression of calcification genes (BMP2/6, Runx2) in ductal cells which may be due to higher extracellular Ca 2+ in SMG tissues. Similarly, inflammatory (IL6, NLRP3), fibrotic (FN1, TGFβ1) and apoptotic (Bax1/Bcl2) markers were also elevated, suggesting that the loss of TRPC3 induces genetic changes that leads to salivary gland cell death and induction of inflammatory response. Overall, ablation of TRPC3 -/- leads to higher saliva [Ca 2+ ], along with elevated detrimental gene expressions, altogether contributing to salivary gland stone formation., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

A woman in her mid-50s was referred to a plastic surgeon with an 8-year history of undiagnosed, localised severe, reproducible pain of the right thigh. Treatment with oral and topical analgesics, corticosteroids, acupuncture and physiotherapy did not provide symptom relief. She was referred to multiple specialists over the preceding 8 years including chronic pain physicians, physiatry, orthopaedic surgery and plastic surgery. Investigations including sonographic and MRI eventually revealed a non-specific soft tissue abnormality in the area of tenderness, which was excised en bloc. Histopathology revealed an extradigital glomus tumour. The patient's symptoms immediately and permanently resolved postexcision.Physicians seeing patients suffering from undiagnosed focal, reproducible pain should consider extradigital glomus tumours in their differential diagnosis. Workup for extradigital glomus tumour includes focused sonographic or MRI over the area of pain. Additionally, local injection of an anaesthetic agent can be used to assist with diagnosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Older adults face racism, sexism, and ageism. As the U.S. population ages, it is important to understand how the current population views older adults., Methods: Participants recruited through Amazon's Mechanical Turk provided perceptions of older Black and White models' photographs. Using mixed-effect models, we assessed interactions between race and gender of participants and models., Results: Among Participants of Color and White participants ( n  = 712, 70% non-Hispanic White, 70% women, mean 37.81 years), Black models were perceived as more attractive, less threatening, and sadder than White models, but differences were greater for White participants (race-by-race interaction: attractive p  = 0.003, threatening p  = 0.009, sad p  = 0.016). Each gender perceived their respective gender as more attractive (gender-by-gender interaction p  < 0.0001). Male and female participants perceived male models as happier than female models, but differences were greater for male participants ( p  = 0.026). Irrespective of participant age group, women were perceived as more threatening ( p  = 0.012). Other perceptions were not significant., Discussion: Participants had few biases toward older Black and White models, while gender biases favored men., Competing Interests: Authors declare no conflict of interest., (© Forest Melton et al., 2022; Published by Mary Ann Liebert, Inc.)

Background: The mobile integrated health-community paramedicine (MIH-CP) program affiliated with the University of Maryland Medical Center focuses on improving patient transitions from hospital to home by addressing both medical and social determinants of health. Until recently, only self-contained health systems could integrate inpatient and outpatient medication data. Without some means to track patients in transition, there is a significant risk of medication-related problems and errors., Objective: To evaluate the impact of the MIH-CP program on medication adherence among patients with congestive heart failure (CHF) and/or chronic obstructive pulmonary disease (COPD)., Methods: This is a pilot observational study designed to compare adherence to drug regimens prescribed at hospital discharge (measured by the proportion of days covered [PDC]) between patients enrolled in the MIH-CP program and a propensity-matched control group. Propensity scores were calculated using 11 demographic, diagnostic, third-party payer, and patient care-associated variables. Discharge medication details were obtained from electronic medical records. PDC for each of the medications were calculated from pharmacy claims data., Results: Eighty-three patients were included in the study; forty-three patients were placed in the intervention group and 40 were propensity-matched controls. After adjusting for age, sex, and third-party payer, findings indicated that medication adherence was higher among patients enrolled in the MIH-CP program compared with control during the first 30 days post-discharge, specifically among patients diagnosed with CHF (8% difference in PDC, 95% confidence interval [CI], -0.12-0.28%) and COPD (14% difference, 95% CI, -0.15-0.43%), although neither result achieved statistical significance. The differences in medication adherence between patients who were enrolled and those who were not enrolled in the MIH-CP program diminished after 30 days post-discharge., Conclusion: This pilot study demonstrated a trend toward improved medication adherence among patients enrolled in the MIH-CP program. Future research involving a larger patient cohort will be required to confirm these preliminary findings., Competing Interests: None declared., (© 2022 The Authors.)

Identifying the genetic basis of repeatedly evolved traits provides a way to reconstruct their evolutionary history and ultimately investigate the predictability of evolution. Here, we focus on the oldfield mouse ( Peromyscus polionotus ), which occurs in the southeastern United States, where it exhibits considerable color variation. Dorsal coats range from dark brown in mainland mice to near white in mice inhabiting sandy beaches; this light pelage has evolved independently on Florida's Gulf and Atlantic coasts as camouflage from predators. To facilitate genomic analyses, we first generated a chromosome-level genome assembly of Peromyscus polionotus subgriseus . Next, in a uniquely variable mainland population ( Peromyscus polionotus albifrons ), we scored 23 pigment traits and performed targeted resequencing in 168 mice. We find that pigment variation is strongly associated with an ∼2-kb region ∼5 kb upstream of the Agouti signaling protein coding region. Using a reporter-gene assay, we demonstrate that this regulatory region contains an enhancer that drives expression in the dermis of mouse embryos during the establishment of pigment prepatterns. Moreover, extended tracts of homozygosity in this Agouti region indicate that the light allele experienced recent and strong positive selection. Notably, this same light allele appears fixed in both Gulf and Atlantic coast beach mice, despite these populations being separated by >1,000 km. Together, our results suggest that this identified Agouti enhancer allele has been maintained in mainland populations as standing genetic variation and from there, has spread to and been selected in two independent beach mouse lineages, thereby facilitating their rapid and parallel evolution.

There are sex-related differences in the epidemiology, presentation, diagnostic testing, and management of ischemic heart disease in women compared with men. The adjusted morbidity and mortality are persistently higher, particularly in younger women and Blacks. Women have more angina but less obstructive coronary artery disease, which affects delays in presentation and diagnosis and testing accuracy. The nonbiological factors play a significant role in access to care, ischemic heart disease management, and guideline adherence. Future research focus includes sex-specific outcomes, characterization of the biological differences, and implementation science around quality of clinical care., Competing Interests: Funding Support and Author Disclosures Dr Daugherty has received support from National Institute of Health grants HL133343 and DC0169065, and a grant from the Patient-Centered Outcomes Research Institute. Dr Mehran has received institutional research grants from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Biotronik, Boston Scientific, CardiaWave, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Duke University, Humacyte, Insel Gruppe AG, Janssen, Medtronic, OrbusNeich, Philips, Vivasure, and Zoll; has received personal fees from the American College of Cardiology, Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen, WebMD, and Society for Cardiovascular Angiography and Interventions; has received consulting fees paid to the institution from Medtronic, Idorsia Pharmaceuticals, Novartis, and Philips; has equity <1% in Applied Therapeutics, Elixir Medical, STEL, CONTROLRAD (spouse); has served on the Scientific Advisory Board for AMA and Biosensors (spouse); and has served as Faculty CRF (no fee). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Context.—: Competency-based medical education relies on frequent formative in-service assessments to ascertain trainee progression. Currently at our institution, trainees receive a summative end-of-rotation In-Training Evaluation Report based on feedback collected from staff pathologists. There is no method of simulating report sign-out., Objective.—: To develop a formative in-service assessment tool that is able to simulate report sign-out and provide case-by-case feedback to trainees. Further, to compare time- versus competency-based assessment models., Design.—: Twenty-one pathology trainees were assessed for 20 months. Hot Seat Diagnosis by trainees and trainee assessment by pathologists were recorded in the laboratory information system. In the first iteration, trainees were assessed by using a time-based assessment scale on their ability to diagnose, report, use ancillary tests, comment on clinical implications, and provide intraoperative consultation and/or gross cases. The second iteration used a competency-based assessment scale. Trainees and pathologists completed surveys on the effectiveness of the In-Training Evaluation Report versus the Hot Seat Diagnosis tool., Results.—: Scores from both iterations correlated significantly with other assessment tools including the Resident In-Service Examination (r = 0.93, P = .04 and r = 0.87, P = .03). The competency-based model was better able to demonstrate improvement over time and stratify junior versus senior trainees than the time-based model. Trainees and pathologists rated Hot Seat Diagnosis as significantly more objective, detailed, and timely than the In-Training Evaluation Report, and effective at simulating report sign-out., Conclusions.—: Hot Seat Diagnosis is an effective tool for the formative in-service assessment of pathology trainees and simulation of report sign-out, with the competency-based model outperforming the time-based model.

Early-career female faculty, both physician scientists and basic researchers, have disproportionately experienced negative professional, financial, and personal consequences associated with the novel coronavirus disease 2019 (COVID-19) pandemic. This career phase represents a critical time for establishing a network of mentors and collaborators, demonstrating professional independence, and balancing new teaching, research, and service duties while simultaneously navigating personal and familial responsibilities. Persistent gender inequality perpetuated by adherence to traditional gender roles place early-career women faculty at a further disadvantage. Women in academic medicine and research do not attain promotion, leadership positions, and other established markers of success at the same rate as their male counterparts. This disparity was the impetus for the creation of a Recruitment and Retention action group within the Center for Women in Medicine and Science (CWIMS) at the University of Minnesota Medical School (UMN). This perspective piece is written from the viewpoint of a group of female-identifying early-career faculty participating in a career development program for early-stage and newly appointed faculty at UMN, sponsored by the Recruitment and Retention CWIMS action group and our Office of Faculty Affairs. We describe areas of stress exacerbated by the COVID-19 pandemic: work, financial, and work-life well-being, and propose an adapted diversity, equity and inclusion (DEI) model to guide the response to future challenges within a faculty competency framework. We offer recommendations based on the DEI-competency framework, including opportunities for lasting positive change that can emerge from this challenging moment of our collective history., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier Inc.)

Background: In addition to farming exposures in childhood, maternal farming exposures provide strong protection against allergic disease in their children; however, the effect of farming lifestyle on human milk (HM) composition is unknown., Objective: This study aims to characterize the maternal immune effects of Old Order Mennonite (OOM) traditional farming lifestyle when compared with Rochester (ROC) families at higher risk for asthma and allergic diseases using HM as a proxy., Methods: HM samples collected at median 2 months of lactation from 52 OOM and 29 ROC mothers were assayed for IgA 1 and IgA 2 antibodies, cytokines, endotoxin, HM oligosaccharides (HMOs), and targeted fatty acid (FA) metabolites. Development of early childhood atopic diseases in children by 3 years of age was assessed. In addition to group comparisons, systems level network analysis was performed to identify communities of multiple HM factors in ROC and OOM lifestyle., Results: HM contains IgA 1 and IgA 2 antibodies broadly recognizing food, inhalant, and bacterial antigens. OOM HM has significantly higher levels of IgA to peanut, ovalbumin, dust mites, and Streptococcus equii as well TGF-β2, and IFN-λ3. A strong correlation occurred between maternal antibiotic use and levels of several HMOs. Path-based analysis of HMOs shows lower activity in the path involving lactoneohexaose (LNH) in the OOM as well as higher levels of lacto- N -neotetraose (LNnT) and two long-chain FAs C-18OH (stearic acid) and C-23OH (tricosanoic acid) compared with Rochester HM. OOM and Rochester milk formed five different clusters, e.g., butyrate production was associated with Prevotellaceae , Veillonellaceae , and Micrococcaceae cluster. Development of atopic disease in early childhood was more common in Rochester and associated with lower levels of total IgA, IgA 2 to dust mite, as well as of TSLP., Conclusion: Traditional, agrarian lifestyle, and antibiotic use are strong regulators of maternally derived immune and metabolic factors, which may have downstream implications for postnatal developmental programming of infant's gut microbiome and immune system., Competing Interests: 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., (Copyright © 2021 Seppo, Choudhury, Pizzarello, Palli, Fridy, Rajani, Stern, Martina, Yonemitsu, Bode, Bu, Tamburini, Piras, Wallach, Allen, Looney, Clemente, Thakar and Järvinen.)

Increased interest in anti-racist education has motivated the rapidly growing but politically contentious adoption of ethnic studies (ES) courses in US public schools. A long-standing rationale for ES courses is that their emphasis on culturally relevant and critically engaged content (e.g., social justice, anti-racism, stereotypes, contemporary social movements) has potent effects on student engagement and outcomes. However, the quantitative evidence supporting this claim is limited. In this preregistered regression-discontinuity study, we examine the longer-run impact of a grade 9 ES course offered in the San Francisco Unified School District. Our key confirmatory finding is that assignment to this course significantly increased the probability of high school graduation among students near the grade 8 2.0 grade point average (GPA) threshold used for assigning students to the course. Our exploratory analyses also indicate that assignment increased measures of engagement throughout high school (e.g., attendance) as well as the probability of postsecondary matriculation., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Context: The pandemic has substantially increased the workload of hospital palliative care providers, requiring them to be responsive and innovative despite limited information on the specific end of life care needs of patients with COVID-19. Multi-site data detailing clinical characteristics of patient deaths from large populations, managed by specialist and generalist palliative care providers are lacking., Objectives: To conduct a large multicenter study examining characteristics of COVID-19 hospital deaths and implications for care., Methods: A multi-center retrospective evaluation examined 434 COVID-19 deaths in 5 hospital trusts over the period March 23, 2020 to May 10, 2020., Results: Eighty three percent of patients were over 70%-32% were admitted from care homes. Diagnostic timing indicated over 90% of those who died contracted the virus in the community. Dying was recognized in over 90% of patients, with the possibility of dying being identified less than 48 hours from admission for a third. In over a quarter, death occurred less than 24 hours later. Patients who were recognized to be dying more than 72 hours prior to death are most likely to have access to medication for symptom control., Conclusion: This large multicenter study comprehensively describes COVID-19 deaths throughout the hospital setting. Clinicians are alert to and diagnose dying appropriately in most patients. Outcomes could be improved by advance care planning to establish preferences, including whether hospital admission is desirable, and alongside this, support the prompt use of anticipatory subcutaneous medications and syringe drivers if needed. Finally, rapid discharges and direct hospice admissions could better utilize hospice beds and improve care., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for the coronavirus disease 2019 (COVID-19) pandemic, highlighted and compounded problems while posing new challenges for the pregnant population. Although individual organizations have provided disparate information, guidance, and updates on managing the pregnant population during the current COVID-19 pandemic, it is important to develop a collective model that highlights all the best practices needed to protect the pregnant population during the pandemic. To establish a standard for ensuring safety during the pandemic, we present a framework that describes best practices for the management of the pregnant population during the ongoing COVID-19 pandemic., Competing Interests: Conflicts of Interest: None from all authors and co-authors., (Copyright © 2021 Dongarwar, et al.)

Men who have sex with men (MSM) are disproportionately affected by HIV in Nigeria. A key strategy in reducing transmission is to increase HIV testing uptake and linkage to treatment for those who test positive. HIV self-testing (HIVST) is an innovative strategy with the potential to increase uptake of HIV testing among key populations at higher risk for HIV. We conducted 23 in-depth-interviews with MSM and two focus group discussions with key opinion leaders to explore perceptions about the feasibility and acceptability of oral HIVST among MSM in Lagos, Nigeria. HIVST was highly acceptable because it was considered convenient to use, painless, private and addressed concerns about stigma. Concerns cited by participants included comprehensibility of instructions to perform and interpret results correctly, as well as lack of support mechanisms to facilitate post-test follow-up and linkage to care. Provision of adequate pre-test information was considered vital as part of the kit distribution process to ensure seamless use of HIVST kits. One-on-one peer-to-peer distribution strategies and retail outlets that facilitate anonymous pick-up are potential distribution channels identified in this study. Overall, our findings suggest that an HIVST program that incorporates these considerations would improve access to HIV testing among MSM in Nigeria., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate the perinatal outcome of women with tuberculosis and to assess a possible association between maternal tuberculosis and long-term infectious morbidity of the offspring., Study Design: Perinatal outcome and long-term infectious morbidity of offspring of mothers with and without tuberculosis were assessed. The study groups were followed until 18 years of age tracking infectious-related morbidity and infectious-related hospitalizations and then compared. For perinatal outcome, generalized estimation equation models were used. A Kaplan-Meier survival curve was used to compare cumulative incidence of long-term infectious morbidity. A Cox proportional hazards model was conducted to control for confounders., Results: During the study period, 243,682 deliveries were included, of which 46 (0.018%) occurred in women with tuberculosis. Maternal tuberculosis was found to be independently associated with placental abruption, cesarean deliveries, and very low birth weight. However, offspring born to mothers with tuberculosis did not demonstrate higher rates of infectious-related morbidity. Maternal tuberculosis was not noted as an independent risk factor for long-term infectious morbidity of the offspring., Conclusion: In our study, maternal tuberculosis was found to be independently associated with adverse perinatal outcomes. However, higher risk for long-term infectious morbidity of the offspring was not demonstrated. Careful surveillance of these women is required.

Objective: Higher rates of mental disorders, specifically depression, were found among affected people in previous epidemiological studies taken after disasters. The aim of the current study was to assess risk for depression among pregnant women hospitalized during the "coronavirus disease 2019" (COVID-19) pandemic, as compared to women hospitalized before the COVID-19 pandemic., Study Design: A cross-sectional study was performed among women hospitalized in the high-risk pregnancy units of the Soroka University Medical Center (SUMC). All participating women completed the Edinburgh Postnatal Depression Scale (EPDS), and the results were compared between women hospitalized during the COVID-19 strict isolation period (19 March 2020 and 26 May 2020) and women hospitalized before the COVID-19 pandemic. Multivariable logistic regression models were constructed to control for potential confounders., Results: Women hospitalized during the COVID-19 strict isolation period ( n = 84) had a comparable risk of having a high (>10) EPDS score as compared to women hospitalized before the COVID-19 pandemic ( n = 279; 25.0% vs. 29.0%, p = 0.498). These results remained similar in the multivariable logistic regression model, while controlling for maternal age, ethnicity and known mood disorder (adjusted odds ratio (OR) 1.0, 95% CI 0.52-1.93, p = 0.985)., Conclusion: Women hospitalized at the high-risk pregnancy unit during the COVID-19 strict isolation period were not at increased risk for depression, as compared to women hospitalized before the COVID-19 pandemic.

Importance: Racial bias is associated with the allocation of advanced heart failure therapies, heart transplants, and ventricular assist devices. It is unknown whether gender and racial biases are associated with the allocation of advanced therapies among women., Objective: To determine whether the intersection of patient gender and race is associated with the decision-making of clinicians during the allocation of advanced heart failure therapies., Design, Setting, and Participants: In this qualitative study, 46 US clinicians attending a conference for an international heart transplant organization in April 2019 were interviewed on the allocation of advanced heart failure therapies. Participants were randomized to examine clinical vignettes that varied 1:1 by patient race (African American to white) and 20:3 by gender (women to men) to purposefully target vignettes of women patients to compare with a prior study of vignettes of men patients. Participants were interviewed about their decision-making process using the think-aloud technique and provided supplemental surveys. Interviews were analyzed using grounded theory methodology, and surveys were analyzed with Wilcoxon tests., Exposure: Randomization to clinical vignettes., Main Outcomes and Measures: Thematic differences in allocation of advanced therapies by patient race and gender., Results: Among 46 participants (24 [52%] women, 20 [43%] racial minority), participants were randomized to the vignette of a white woman (20 participants [43%]), an African American woman (20 participants [43%]), a white man (3 participants [7%]), and an African American man (3 participants [7%]). Allocation differences centered on 5 themes. First, clinicians critiqued the appearance of the women more harshly than the men as part of their overall impressions. Second, the African American man was perceived as experiencing more severe illness than individuals from other racial and gender groups. Third, there was more concern regarding appropriateness of prior care of the African American woman compared with the white woman. Fourth, there were greater concerns about adequacy of social support for the women than for the men. Children were perceived as liabilities for women, particularly the African American woman. Family dynamics and finances were perceived to be greater concerns for the African American woman than for individuals in the other vignettes; spouses were deemed inadequate support for women. Last, participants recommended ventricular assist devices over transplantation for all racial and gender groups. Surveys revealed no statistically significant differences in allocation recommendations for African American and white women patients., Conclusions and Relevance: This national study of health care professionals randomized to clinical vignettes that varied only by gender and race found evidence of gender and race bias in the decision-making process for offering advanced therapies for heart failure, particularly for African American women patients, who were judged more harshly by appearance and adequacy of social support. There was no associated between patient gender and race and final recommendations for allocation of advanced therapies. However, it is possible that bias may contribute to delayed allocation and ultimately inequity in the allocation of advanced therapies in a clinical setting.

Background Race influences medical decision making, but its impact on advanced heart failure therapy allocation is unknown. We sought to determine whether patient race influences allocation of advanced heart failure therapies. Methods and Results Members of a national heart failure organization were randomized to clinical vignettes that varied by patient race (black or white man) and were blinded to study objectives. Participants (N=422) completed Likert scale surveys rating factors for advanced therapy allocation and think-aloud interviews (n=44). Survey results were analyzed by least absolute shrinkage and selection operator and multivariable regression to identify factors influencing advanced therapy allocation, including interactions with vignette race and participant demographics. Interviews were analyzed using grounded theory. Surveys revealed no differences in overall racial ratings for advanced therapies. Least absolute shrinkage and selection operator regression selected no interactions between vignette race and clinical factors as important in allocation. However, interactions between participants aged ≥40 years and black vignette negatively influenced heart transplant allocation modestly (-0.58; 95% CI, -1.15 to -0.0002), with adherence and social history the most influential factors. Interviews revealed sequential decision making: forming overall impression, identifying urgency, evaluating prior care appropriateness, anticipating challenges, and evaluating trust while making recommendations. Race influenced each step: avoiding discussing race, believing photographs may contribute to racial bias, believing the black man was sicker compared with the white man, developing greater concern for trust and adherence with the black man, and ultimately offering the white man transplantation and the black man ventricular assist device implantation. Conclusions Black race modestly influenced decision making for heart transplant, particularly during conversations. Because advanced therapy selection meetings are conversations rather than surveys, allocation may be vulnerable to racial bias.

Atopic dermatitis (AD) is the most common chronic and relapsing inflammatory skin disease. AD is typically characterized by skewed T helper (Th) 2 inflammation, yet other inflammatory profiles (Th1, Th17, Th22) have been observed in human patients. How cytokines from these different Th subsets impact barrier function in this disease is not well understood. As such, we investigated the impact of the canonical Th17 cytokine, IL-17A, on barrier function and protein composition in primary human keratinocytes and human skin explants. These studies demonstrated that IL-17A enhanced tight junction formation and function in both systems, with a dependence on STAT3 signaling. Importantly, the Th2 cytokine, IL-4 inhibited the barrier-enhancing effect of IL-17A treatment. These observations propose that IL-17A helps to restore skin barrier function, but this action is antagonized by Th2 cytokines. This suggests that restoration of IL-17/IL-4 ratio in the skin of AD patients may improve barrier function and in so doing improve disease severity.

Objectives: To test the hypothesis that there are differences in neuroradiological measures between single and repeated mild traumatic brain injury using multimodal MRI., Methods: A closed-head momentum exchange model was used to produce one or three mild head injuries in young adult male rats compared to non-injured, age and weight-matched controls. Six-seven weeks post-injury, rats were studied for deficits in cognitive and motor function. Seven-eight weeks post-injury changes in brain anatomy and function were evaluated through analysis of high resolution T2 weighted images, resting-state BOLD functional connectivity, and diffusion weighted imaging with quantitative anisotropy., Results: Head injuries occurred without skull fracture or signs of intracranial bleeding or contusion. There were no significant differences in cognitive or motors behaviors between experimental groups. With a single mild hit, the affected areas were limited to the caudate/putamen and central amygdala. Rats hit three times showed altered diffusivity in white matter tracts, basal ganglia, central amygdala, brainstem, and cerebellum. Comparing three hits to one hit showed a similar pattern of change underscoring a dose effect of repeated head injury on the brainstem and cerebellum. Disruption of functional connectivity was pronounced with three mild hits. The midbrain dopamine system, hippocampus, and brainstem/cerebellum showed hypoconnectivity. Interestingly, rats exposed to one hit showed enhanced functional connectivity (or hyperconnectivity) across brain sites, particularly between the olfactory system and the cerebellum., Interpretation: Neuroradiological evidence of altered brain structure and function, particularly in striatal and midbrain dopaminergic areas, persists long after mild repetitive head injury. These changes may serve as biomarkers of neurodegeneration and risk for dementia later in life.

Purpose: To assess adverse pregnancy outcomes in patients complicated with mild or severe Hyperemesis Gravidarum (HG)., Methods: A retrospective cohort study of women aged 18-45 with a singleton pregnancy that were admitted to the gynecological ward at the Soroka University Medical Center due to HG between the years 2013-2016 and gave birth at the same hospital was conducted. During the study period 89 patients met the inclusion criteria and comprised the study group. Women without HG who gave birth at the same time period comprised the comparison group (n = 91). Univariate analysis was carried out using Chi square or Fisher's exact test for nominal variables, and T test for numeric variables. Significance was defined as a P value < 0.05., Results: Women with HG were more likely to have experienced HG in a previous pregnancy. Rate of amniotic fluid abnormalities was significantly lower in the study group. However, rates of all other pregnancy complications were comparable between the groups. A sub-analysis of the HG group comparing mild and severe cases demonstrated no significant differences in rates of adverse pregnancy outcomes between the groups., Conclusions: In this retrospective cohort study no association was demonstrated between HG and adverse pregnancy outcomes regardless of HG severity. Women with severe nausea and vomiting during pregnancy can be reassured that HG is not associated with unfavorable maternal and neonatal outcomes.

Background: Continuous-flow left ventricular assist devices have revolutionized the management of advanced heart failure. Device complications continue to limit survival, but enhanced management strategies have shown promise. This study compared outcomes for HeartMate II recipients before and after implementation of a multidisciplinary continuous support heart team (HTMCS) strategy., Methods: Between January 2012 and December 2016, 124 consecutive patients underwent primary HeartMate II implantation at our institution. In January 2015, we instituted a HTMCS approach consisting of (1) daily simultaneous cardiology/cardiac surgery/critical care/pharmacy/coordinator rounds, (2) pharmacist-directed anticoagulation, (3) speed optimization echocardiogram before discharge, (4) comprehensive device thrombosis screening and early intervention, (5) blood pressure clinic with pulsatility-adjusted goals, (6) early follow-up after discharge and individual long-term coordinator/cardiologist assignment, and (7) systematic basic/advanced/expert training and credentialing of ancillary in-hospital providers. All patients completed 1-year of follow-up., Results: Demographic characteristics for pre-HTMCS (n = 71) and HTMCS (n = 53) groups, including age (55.8 ± 12.1 versus 52.5 ± 14.1 years, p = not significant), percentage of men (77.5% versus 71.7%, p = not significant), and Interagency Registry for Mechanically Assisted Circulatory Support class 3 (84.5% versus 83.0%, p = not significant), were comparable. One-year survival was 74.6% versus 100% for the pre-HTMCS and HTMCS groups, respectively (p = 0.0002). One-year survival free of serious adverse events (reoperation to replace device or disabling stroke) was 70.4% versus 84.9% for the pre-HTMCS and HTMCS groups, respectively (p = 0.059). Event per patient-year rates for disabling stroke (0.15 versus 0, p = 0.019), gastrointestinal bleeding (0.87 versus 0.51, p = 0.11), and driveline infection (0.24 versus 0.10, p = 0.18) were lower for the HTMCS group, whereas pump thrombosis requiring device exchange was higher (0.09 versus 0.18, p = 0.14)., Conclusions: Implementing a comprehensive multidisciplinary approach substantially improved outcomes for recipients of continuous-flow left ventricular assist devices., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Chronic pain during childhood is prevalent and costly, but the access to interdisciplinary pain care is limited. Studies investigating adults waiting for pain clinic evaluation found that symptoms and quality of life deteriorate over the waiting period, but little is known about the experience of adolescents. Therefore, we aimed to determine wait list times and the longitudinal trends of pain and physical, mental, and social health over a 12-week period. In total, 97 adolescents, aged 10 to 18 years (M = 14.7 years, 82% female), waiting for evaluation at an interdisciplinary pediatric pain clinic completed assessments at enrollment and at 4-, 8-, and 12-week follow-up. We performed a review of the medical record of attendance patterns 12 months later. Twelve adolescents and their parents also completed qualitative interviews, describing their experience of waiting for evaluation. Wait times averaged 197.5 days (range = 69-758 days) from the time of referral to the first-attended appointment, and 86.6% of youths completed appointments. Longitudinal repeated measures analyses demonstrated little improvement in pain or other domains of functioning over the 12-week period. In qualitative interviews, families described anxious anticipation for the upcoming appointment, combined with frustration in waiting. Findings highlight the need to consider approaches to reduce wait times and provide early intervention for youths awaiting pain clinic evaluation. Perspective: This study extends the literature on the characteristics and symptom trajectories of adolescents during the wait period for interdisciplinary pain clinic evaluation, described previously only in adults with chronic pain. Findings demonstrated an average wait time of 6.5 months, during which youths' pain and physical and social health remained impaired., (Copyright © 2018 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Melamine, which induces proximal tubular (PT) cell damage has a greater nephrotoxic effect when combined with cyanuric and uric acids; however, it is unknown whether such effect can stimulate calcium phosphate (CaP)/calcium oxalate (CaOx) stone formation. Here, we show that melamine acts as an inducer of CaP, CaOx and CaP + CaOx (mixed) crystal formations in a time and concentration-dependent manner by stabilizing those crystals and further co-aggregating with melamine. To explore the physiological relevance of such melamine-augmented calcium crystal formation, we used 2-dimensional (2D) and 3D microfluidic (MF) device, embedded with PT cells, which also resembled the effect of melamine-stimulated CaP, CaOx and mixed crystal formation. Significantly, addition of preformed CaP and/or CaOx crystal in the presence of melamine, further potentiated those crystal formations in 3D MFs, which helped the growth and aggregation of mixed crystals. Our data show that the mechanism of such predisposition of stone formation could be largely due to co-crystallization between melamine and CaP/CaOx and pronounced effect on induction of stone-forming pathway activation in 3D MF. Taken together, melamine-induced CaP and/or CaOx crystal formation ex-vivo will help us in understanding the larger role of melamine as an environmental toxicant in producing the pathology in similar cellular microenvironments.

N-acetylcysteine (NAC), a promising glutamatergic therapeutic agent, has shown some clinical efficacy in reducing nicotine use in humans and has been shown to reverse drug-induced changes in glutamatergic neurophysiology. In rats, nicotine-seeking behavior is associated with alterations in glutamatergic plasticity within the nucleus accumbens core (NAcore). Specifically, cue-induced nicotine-seeking is associated with rapid, transient synaptic plasticity (t-SP) in glutamatergic synapses on NAcore medium spiny neurons. The goal of the present study was to determine if NAC reduces nicotine-seeking behavior and reverses reinstatement-associated NAcore glutamatergic alterations. Rats were extinguished from nicotine self-administration, followed by subchronic NAC administration (0 or 100 mg/kg/d) for 4 days prior to cue-induced reinstatement. NAcore synaptic potentiation was measured via dendritic spine morphology and mRNA and protein of relevant glutamatergic genes were quantified. Nicotine-seeking behavior was not reduced by subchronic NAC treatment. Also, NAcore transcript and protein expression of multiple glutamatergic genes, as well as spine morphological measures, were unaffected by subchronic NAC. Finally, chronic NAC treatment (15 days total) during extinction and prior to reinstatement significantly decreased extinction responding and reduced reinstatement of nicotine-seeking compared to vehicle. Together, these results suggest that chronic NAC treatment is necessary for its therapeutic efficacy as a treatment strategy for nicotine addiction and relapse., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Introduction: HIV self-testing (HIVST) offers an alternative to facility-based HIV testing services, particularly for populations such as men who have sex with men (MSM) who may fear accessing testing due to stigma, discrimination and criminalization. Innovative HIV testing approaches are needed to meet the goal of 90% of people living with HIV being diagnosed. This study piloted an intervention to distribute oral HIVST kits to MSM through key opinion leaders (KOLs) in Lagos, Nigeria and assessed the feasibility, acceptability, uptake of HIVST and linkage to HIV treatment., Methods: A cohort study was conducted (May through September 2017) with 319 participants who were recruited by 12 KOLs through their networks. A baseline survey was conducted at the time of the oral HIVST kit (OraQuick ® HIV antibody test) distribution to eligible MSM followed by a 3-month follow-up survey to assess usage of and experience with the HIVST kits. Each participant was given two kits., Results: The median age of the participants was 25 years, 88.7% were literate and 17.9% were first-time testers. Of the 257 participants (80.7% retention) who completed the three-month follow-up interview, 97.7% reported using the HIVST kit and 14 (5.6%) self-reported an HIV positive result. A quarter (22.7%) tested themselves the same day they received the kit, and 49.4% tested within one week. Almost all participants reported that the HIVST kit instructions were easy or somewhat easy to understand (99.6%) and perform the test (98.0%). The most common reasons they liked the test were ease of use (87.3%), confidentiality/privacy (82.1%), convenience (74.1%) and absence of needle pricks (64.9%). All 14 participants who tested positive had sought confirmatory testing and initiated HIV treatment by the time of the three-month survey., Conclusions: HIVST distribution through KOLs was feasible and oral self-testing was highly acceptable among this urban MSM population. Despite concerns about linkage to treatment when implementing self-testing, this study showed that linkage to treatment can be achieved with active follow-up and access to a trusted MSM-friendly community clinic that offers HIV treatment. HIVST should be considered as an additional option to standard HIV testing models for MSM., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

RNASET2 deficiency in humans is associated with infant cystic leukoencephalopathy, which causes psychomotor impairment, spasticity and epilepsy. A zebrafish mutant model suggests that loss of RNASET2 function leads to neurodegeneration due to the accumulation of non-degraded RNA in the lysosomes. The goal of this study was to characterize the first rodent model of RNASET2 deficiency. The brains of 3- and 12-month-old RNaseT2 knockout rats were studied using multiple magnetic resonance imaging modalities and behavioral tests. While T1- and T2-weighted images of RNaseT2 knockout rats exhibited no evidence of cystic lesions, the prefrontal cortex and hippocampal complex were enlarged in knockout animals. Diffusion-weighted imaging showed altered anisotropy and putative gray matter changes in the hippocampal complex of the RNaseT2 knockout rats. Immunohistochemistry for glial fibrillary acidic protein (GFAP) showed the presence of hippocampal neuroinflammation. Decreased levels of lysosome-associated membrane protein 2 (LAMP2) and elevated acid phosphatase and β-N-acetylglucosaminidase (NAG) activities indicated that the RNASET2 knockout rats likely had altered lysosomal function and potential defects in autophagy. Object recognition tests confirmed that RNaseT2 knockout rats exhibited memory deficits. However, the Barnes maze, and balance beam and rotarod tests indicated there were no differences in spatial memory or motor impairments, respectively. Overall, patients with RNASET2 deficiency exhibited a more severe neurodegeneration phenotype than was observed in the RNaseT2 knockout rats. However, the vulnerability of the knockout rat hippocampus as evidenced by neuroinflammation, altered lysosomal function and cognitive defects indicates that this is still a useful in vivo model to study RNASET2 function., Competing Interests: Competing interestsAlexion Pharmaceuticals provided the funding for this study. K.W.S. and K.L.A. are former Alexion Pharmaceuticals employees with equity ownership in Alexion Pharmaceuticals. C.F.F. has a financial interest in Animal Imaging Research, the company that produces the radiofrequency electronics and holders for animal imaging., (© 2018. Published by The Company of Biologists Ltd.)

Drug addiction has often been described as a "hijacking" of the brain circuits involved in learning and memory. Glutamate is the principal excitatory neurotransmitter in the brain, and its contribution to synaptic plasticity and learning processes is well established in animal models. Likewise, over the past 20 years the addiction field has ascribed a critical role for glutamatergic transmission in the development of addiction. Chronic drug use produces enduring neuroadaptations in corticostriatal projections that are believed to contribute to a maladaptive deficit in inhibitory control over behavior. Much of this research focuses on the role played by ionotropic glutamate receptors directly involved in long-term potentiation and depression or metabotropic receptors indirectly modulating synaptic plasticity. Importantly, the balance between glutamate release and clearance tightly regulates the patterned activation of these glutamate receptors, emphasizing an important role for glutamate transporters in maintaining extracellular glutamate levels. Five excitatory amino acid transporters participate in active glutamate reuptake. Recent evidence suggests that these glutamate transporters can be modulated by chronic drug use at a variety of levels. In this review, we synopsize the evidence and mechanisms associated with drug-induced dysregulation of glutamate transport. We then summarize the preclinical and clinical data suggesting that glutamate transporters offer an effective target for the treatment of drug addiction. In particular, we focus on the role that altered glutamate transporters have in causing drug cues and contexts to develop an intrusive quality that guides maladaptive drug seeking behaviors., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Aim: This study aimed to document the traditional knowledge of medicinal plants and antimicrobial validation of Thespesia populnea used by Yanadi tribe of Chittoor district, Andhra Pradesh, India., Materials and Methods: The study was mainly focused on documentation of medicinal plants used by Yanadi tribe to treat different diseases with a standard questionnaire. These plants were cross-checked in Dr. Dukes Database and available literature to know the significance of this tribe on medicinal knowledge. Among the documented plants, T. populnea was selected for antimicrobial activity with disc diffusion assay., Results: Among the documented medicinal plants, herbs were the most utilized plants, followed by leaf part of the plants; paste form of medicinal preparation was the dominant one among the mode of preparations and oral administration was generally followed by this tribe. When checked these plants in Dr. Duke's Phytochemical and Ethnobotanical Database most of the medicinal plants were matched at least one medicinal use and most of them were correlated with existing literature. In antimicrobial activity, the microbial pathogens Klebsiella pneumonia among bacteria and Rhizopus arrhizus among fungi were most susceptible to methanol extract of T. populnea ., Conclusion: From this study, we conclude that the preparation and dosage of the medicines by Yanadi tribe of this area is unique and the correlation of medicinal data with Duke's Database and existing literature reveals high medicinal significance of claimed data of this tribe and potential inhibitory activity of T. populnea could be studied further to isolate effective antimicrobial agents., Competing Interests: Conflict of Interest: None declared.

Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine seeking result from glutamate spillover, initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production. Pharmacological stimulation of mGluR5 in NAcore recapitulated cue-induced reinstatement in the absence of drug-associated cues. Using NO-sensitive electrodes, mGluR5 activation by glutamate was shown to stimulate NO production that depended on activation of neuronal nitric oxide synthase (nNOS). nNOS is expressed in ∼1% of NAcore neurons. Using a transgene strategy to express and stimulate designer receptors that mimicked mGluR5 signaling through Gq in nNOS interneurons, we recapitulated cue-induced reinstatement in the absence of cues. Conversely, using a transgenic caspase strategy, the intensity of cue-induced reinstatement was correlated with the extent of selective elimination of nNOS interneurons. The induction of t-SP during cued reinstatement depends on activating matrix metalloproteinases (MMPs) and selective chemogenetic stimulation of nNOS interneurons recapitulated MMP activation and t-SP induction (increase in AMPA currents in MSNs). These data demonstrate critical involvement of a sparse population of nNOS-expressing interneurons in cue-induced cocaine seeking, revealing a bottleneck in brain processing of drug-associated cues where therapeutic interventions could be effective in treating drug addiction., Significance Statement: Relapse to cocaine use in a rat model is associated with transient increases in synaptic strength at prefrontal cortex synapses in the nucleus accumbens. We demonstrate the sequence of events that mediates synaptic potentiation and reinstated cocaine seeking induced by cocaine-conditioned cues. Activation of prefrontal inputs to the accumbens by cues initiates spillover of synaptic glutamate, which stimulates metabotropic glutamate receptor 5 (mGluR5) on a small population of interneurons (∼1%) expressing neuronal nitric oxide synthase. Stimulating these glutamate receptors increases nitric oxide (NO) production, which stimulates matrix metalloprotease-2 (MMP-2) and MMP-9 activity in the extracellular space. Manipulating the interaction between mGluR5, NO production, or MMP-2 and MMP-9 pharmacologically or genetically is sufficient to recapitulate transient synaptic potentiation and reinstate cocaine seeking., (Copyright © 2017 the authors 0270-6474/17/370742-15$15.00/0.)

Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (μ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high μ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala, and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex, and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala, and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the μ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the μ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other μ opioid agonists.

Aim: Ethnomedicinal studies on medicinal plants used by Yanadi tribe of Chandragiri reserve forest area are documented during the period of 2014-2015. The study is mainly focused on medicinal importance of plants used by Yanadi tribe to treat various ailments., Materials and Methods: The information collected on treated ailments, part used, preparation, combination, and addition of ingredients to prepare herbal medicines with the help of standard questionnaire., Results: During the study, 53 types of ailments were treated using 48 medicinal plants belongs to 26 families were documented. Among the medicinal plants, shrubs (15) were most using life form of plants for the preparation of herbal medicines. Leaf part (40%), paste form (33%), and oral administration (63%) of herbal medicines were most preferable. The documented ethnomedicinal importance of this tribe was cross-checked with Dr. Duke's Phytochemical and Ethnobotanical database shows most of the plants were correlated with this database., Conclusion: There is no record of traditional medicinal knowledge of these villages so far, hence the present study is aimed to document the information on medicinal plants used by Yanadi tribe in Chandragiri reserve forest area. The correlation of ethnomedicinal uses with Dr. Duke's Phytochemical and Ethnobotanical database clearly indicates the high medicinal significance of claimed data of this Yanadi tribe.

Fetal exposure to endocrine disruptors (EDs) is believed to predispose males to reproductive abnormalities. Although males are exposed to combinations of chemicals, few studies have evaluated the effects of ED mixtures at environmentally relevant doses. Our previous work showed that fetal exposure to a mixture of the phytoestrogen genistein (GEN) and the plasticizer di-(2-ethylhexyl) phthalate (DEHP) induced unique alterations in adult testis. In this follow-up study, we examined Postnatal Day 3 (PND3) and PND6 male offspring exposed from Gestational Day 14 to parturition to corn oil, 10mg/kg GEN, DEHP, or their combination, to gain insight into the early molecular events driving long-term alterations. DEHP stimulated the mRNA and protein expression of the steroidogenic enzyme HSD3B, uniquely at PND3. DEHP also increased the mRNA expression of Nestin, a Leydig progenitor/Sertoli cell marker, and markers of Sertoli cell (Wt1), gonocyte (Plzf, Foxo1), and proliferation (Pcna) at PND3, while these genes were unchanged by the mixture. Redox (Nqo1, Sod2, Sod3, Trx, Gst, Cat) and xenobiotic transporter (Abcb1b, Abcg2) gene expression was also increased by DEHP at PND3, while attenuated when combined with GEN, suggesting the involvement of cellular stress in short-term DEHP effects and a protective effect of GEN. The direct effects of GEN and mono-(2-ethylhexyl) phthalate, the principal bioactive metabolite of DEHP, on testis were investigated in PND3 organ cultures, showing a stimulatory effect of 10 μM mono-(2-ethylhexyl) phthalate on basal testosterone production that was normalized by GEN. These effects contrasted with previous reports of androgen suppression and decreased gene expression in perinatal rat testis by high DEHP doses, implying that neonatal effects are not predictive of adult effects. We propose that GEN, through an antioxidant action, normalizes reactive oxygen species-induced neonatal effects of DEHP. The notion that these EDs do not follow classical dose-response effects and involve different mechanisms of toxicity from perinatal ages to adulthood highlights the importance of assessing impacts across a range of doses and ages., (© 2015 by the Society for the Study of Reproduction, Inc.)