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BACKGROUND: Disability in patients with medically refractory ulcerative colitis (UC) after total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA) is not well understood. The aim of this study was to compare disability in patients with IPAA vs medically managed UC, and identify predictors of disability. METHODS: This was a multi-center cross-sectional study performed at five academic institutions in New York City. Patients with medically or surgically treated UC were recruited. Clinical and socioeconomic data were collected and the inflammatory bowel disease disability index (IBD-DI) was administered to eligible patients. Predictors of moderate-severe disability (IBD-DI≥35) were assessed in univariable and multivariable models. RESULTS: A total of 94 patients with IPAA and 128 patients with medically managed UC completed the IBD-DI. Among patients with IPAA and UC, 35 (37.2%) and 30 (23.4%) had moderate-severe disability, respectively. Patients with IPAA had significantly greater IBD-DI scores compared to patients with medically managed UC (29.8 vs 17.9, p

Background Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10-14 and 50-54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings The global TFR decreased from 2.72 (95% uncertainty interval [UI] 2.66-2.79) in 2000 to 2.31 (2.17-2.46) in 2019. Global annual livebirths increased from 134.5 million (131.5-137.8) in 2000 to a peak of 139.6 million (133.0-146.9) in 2016. Global livebirths then declined to 135.3 million (127.2-144.1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2.1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27.1% (95% UI 26.4-27.8) of global livebirths. Global life expectancy at birth increased from 67.2 years (95% UI 66.8-67.6) in 2000 to 73.5 years (72.8-74.3) in 2019. The total number of deaths increased from 50.7 million (49.5-51.9) in 2000 to 56.5 million (53.7-59.2) in 2019. Under-5 deaths declined from 9.6 million (9.1-10.3) in 2000 to 5.0 million (4.3-6.0) in 2019. Global population increased by 25.7%, from 6.2 billion (6.0-6.3) in 2000 to 7.7 billion (7.5-8.0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58.6 years (56.1-60.8) in 2000 to 63.5 years (60.8-66.1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.

Changes in structure of oral solid dosage forms (OSDF) elementally determine the drug release and its therapeutic effects. In this research, synchrotron radiation X-ray micro-computed tomography was utilized to visualize the 3D structure of enteric coated pellets recovered from the gastrointestinal tract of rats. The structures of pellets in solid state and in vitro compendium media were measured. Pellets in vivo underwent morphological and structural changes which differed significantly from those in vitro compendium media. Thus, optimizations of the dissolution media were performed to mimic the appropriate in vivo conditions by introducing pepsin and glass microspheres in media. The sphericity, pellet volume, pore volume and porosity of the in vivo esomeprazole magnesium pellets in stomach for 2 h were recorded 0.47, 1.55 × 108 μm3, 0.44 × 108 μm3 and 27.6%, respectively. After adding pepsin and glass microspheres, the above parameters in vitro reached to 0.44, 1.64 × 108 μm3, 0.38 × 108 μm3 and 23.0%, respectively. Omeprazole magnesium pellets behaved similarly. The structural features of pellets between in vitro media and in vivo condition were bridged successfully in terms of 3D structures to ensure better design, characterization and quality control of advanced OSDF., Graphical abstract The differences in dynamic structure of enteric pellets during dissolution in vitro and in vivo were first observed. By introducing pepsin and glass microspheres into pharmacopoeia medium, the structures of pellets were bridged.Image 1

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome. Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery. Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores ( P = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized ( P = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts ( P = .87) or between BTB autografts and soft tissue allografts ( P = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft ( P = .010; OR, 0.56; 95% CI, 0.36-0.87). Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.

OBJECTIVE: The SARS-CoV-2 pandemic has had an immense impact on healthcare, but little has been published on its impact on sports medicine physicians. This study aimed to assess the perceived impacts of the pandemic on practice changes, financial implications, and mental health of the physician members of the American Medical Society for Sports Medicine (AMSSM). METHODS: Online surveys were sent to physician members of the AMSSM, with questions asking about demographic information and personal associations to COVID-19. The main outcome measures included self-reported clinical practice volumes, visit types (telemedicine, face-to-face), Patient Health Questionnaire (PHQ-4) scores, personal finances, clarity of practice guidelines, and personal protective equipment (PPE) availability. RESULTS: A total of 825 respondents completed the initial survey, with a subset completing follow-ups. In-person clinical and procedural volumes were reported to be reduced to just 17.9% and 13.7% of the pre-pandemic baseline volumes at the first survey (March 2020), but increased to 81.1% and 77.3% (August 2020), respectively. PHQ-4 anxiety subscores significantly decreased over time (p 0.05). Physicians have become increasingly aware of others testing positive for the virus, but not themselves or someone they live with. CONCLUSIONS: Sports medicine physicians have been heavily impacted by the SARS-CoV-2 pandemic, with some recovery since it started. Sports medicine physicians should be aware of pandemic-related practice changes and resulting mental health and financial implications.

Background Complex liver resection is a risk factor for the development of AKI, which is associated with increased morbidity and mortality. Aim of this study was to assess risk factors for acute kidney injury (AKI) and its impact on outcome for patients undergoing complex liver surgery. Methods AKI was defined according to the KDIGO criteria. Primary endpoint was the occurrence of AKI after liver resection. Secondary endpoints were complications and mortality. Results Overall, 146 patients undergoing extended liver resection were included in the study. The incidence of AKI was 21%. The incidence of chronic kidney disease (CKD) and hepatocellular carcinoma were significantly higher in patients with AKI. In the AKI group, the proportion of extended right hepatectomies was the highest (53%), followed by ALPPS (43%). Increased intraoperative blood loss, increased postoperative complications and perioperative mortality was associated with AKI. Besides age and CKD, ALPPS was an independent risk factor for postoperative AKI. A small future liver remnant seemed to increase the risk of AKI in patients undergoing ALPPS. Conclusion Following extended liver resection, AKI is associated with an increased morbidity and mortality. ALPPS is a major independent risk factor for the development of AKI and a sufficient future liver remnant could avoid postoperative AKI.

Introduction Plain radiographs are a globally ubiquitous means of investigation for injuries to the musculoskeletal system. Despite this, initial interpretation remains a challenge and inaccuracies give rise to adverse sequelae for patients and healthcare providers alike. This study sought to address the limited, existing meta-analytic research on the initial reporting of radiographs for skeletal trauma, with specific regard to diagnostic accuracy of the most commonly injured region of the appendicular skeleton, the lower limb. Method A prospectively registered, systematic review and meta-analysis was performed using published research from the major clinical-science databases. Studies identified as appropriate for inclusion underwent methodological quality and risk of bias analysis. Meta-analysis was then performed to establish summary rates for specificity and sensitivity of diagnostic accuracy, including covariates by anatomical site, using HSROC and bivariate models. Results A total of 3887 articles were screened, with 10 identified as suitable for analysis based on the eligibility criteria. Sensitivity and specificity across the studies were 93.5% and 89.7% respectively. Compared with other anatomical subdivisions, interpretation of ankle radiographs yielded the highest sensitivity and specificity, with values of 98.1% and 94.6% respectively, and a diagnostic odds ratio of 929.97. Conclusion Interpretation of lower limb skeletal radiographs operates at a reasonably high degree of sensitivity and specificity. However, one in twenty true positives is missed on initial radiographic interpretation and safety netting systems need to be established to address this. Virtual fracture clinic reviews and teleradiology services in conjunction with novel technology will likely be crucial in these circumstances.

Background The role of the advanced nurse practitioner (ANP) is not regulated in the UK, which has led to wide variation in the skills, competencies and academic qualifications of nurses using this title. Urgent treatment centres (UTCs) require a broad and experienced knowledge base to meet the demand of patients presenting with undifferentiated illnesses and injuries, which can be stressful and challenging. Aim To examine the perceptions and beliefs about ANP regulation, and to explore and discuss any ideas about proposed regulation. Method The author used interpretative phenomenological analysis to uncover valuable insights into the experiences of two ANPs working in an UTC, and their beliefs around regulation of the ANP role. Results Both ANPs had different backgrounds and qualifications yet still had similar perceptions and beliefs regarding the regulation of ANPs. Five main themes were developed from the interview transcripts. Conclusion This study identified the need to consider the importance of ANPs' identity and the complex regulatory process required to standardise the role.

Background We previously reported the Alopecia Areata Consensus of Experts study, which presented results of an international expert opinion on treatments for alopecia areata. Objective To report the results of the Alopecia Areata Consensus of Experts international expert opinion on diagnosis and laboratory evaluation for alopecia areata. Methods Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Consensus threshold was set at greater than or equal to 66%. Results Of 148 questions, expert consensus was achieved in 82 (55%). Round 1 consensus was achieved in 10 of 148 questions (7%). Round 2 achieved consensus in 47 of 77 questions (61%). The final face-to-face achieved consensus in 25 of 32 questions (78%). Consensus was greatest for laboratory evaluation (12 of 14 questions [86%]), followed by diagnosis (11 of 14 questions [79%]) of alopecia areata. Overall, etiopathogenesis achieved the least category consensus (31 of 68 questions [46%]). Limitations The study had low representation from Africa, South America, and Asia. Conclusion There is expert consensus on aspects of epidemiology, etiopathogenesis, clinical features, diagnosis, laboratory evaluation, and prognostic indicators of alopecia areata. The study also highlights areas where future clinical research could be directed to address unresolved hypotheses in alopecia areata patient care.

Despite the fact that plants make up 80% of biomass on Earth, sociology rarely examines human–plant relationships. Human societies are inherently dependent on plants, most obviously as the basis of food supply, ecosystems, atmospheric and climate regulation, and water cycles, as well as for sources of oxygen, medicine, fuel, and fibre. Society, or terrestrial animal life for that matter, could not exist without plants. Based on this recognition, here we lay the foundations for sociological plant studies, a field that studies the dialectical relationship between human societies and plants. We ground this foundation in a realist-materialist perspective that recognises the ontological independence of plants and does not reduce them to human social constructions. We show how considering plants can help us to understand the emergence of civilisations, state formation, and mechanisation of production at the macro-level, and how human–plant interactions shape everyday life at a more micro-level. We present our formulation of sociological plant studies as a starting point for future research.

In many vertebrate societies dominant individuals breed at substantially higher rates than subordinates, but whether this hastens ageing remains poorly understood. While frequent reproduction may trade off against somatic maintenance, the extraordinary fecundity and longevity of some social insect queens highlight that breeders need not always suffer more rapid somatic deterioration than their nonbreeding subordinates. Here, we used extensive longitudinal assessments of telomere dynamics to investigate the impact of dominance status on within-individual age-related changes in somatic integrity in a wild social bird, the white-browed sparrow-weaver (Plocepasser mahali). Dominant birds, who monopolise reproduction, had neither shorter telomeres nor faster telomere attrition rates over the long-term (1-5 years) than their subordinates. However, over shorter (half-year) time intervals dominants with shorter telomeres showed lower rates of telomere attrition (and evidence suggestive of telomere lengthening), while the same was not true among subordinates. Dominants may therefore invest more heavily in telomere length regulation (and/or somatic maintenance more broadly); a strategy that could mitigate the long-term costs of reproductive effort, leaving their long-term telomere dynamics comparable to those of subordinates. Consistent with the expectation that reproduction entails short-term costs to somatic integrity, telomere attrition rates were most severe for all birds during the breeding seasons of wetter years (rainfall is the key driver of reproductive activity in this arid-zone species). Our findings suggest that, even in vertebrate societies in which dominants monopolise reproduction, dominants may experience long-term somatic integrity trajectories indistinguishable from those of their nonreproductive subordinates.

Complete upfront resection of pediatric gastrointestinal lymphomas is recommended over biopsy whenever feasible, but either approach may have adverse sequelae. We sought to compare gastrointestinal and oncological outcomes of pediatric gastrointestinal lymphomas who underwent attempted upfront resection or biopsy of the presenting bowel mass. We retrospectively reviewed charts of children with gastrointestinal lymphomas treated on LMB89 and LMB96 protocols from 2000 to 2019 who underwent upfront gastrointestinal surgery, and compared resection and biopsy groups. Of 33 children with abdominal lymphomas, 20 had upfront gastrointestinal surgery—10 each had resection or biopsy. Patients with attempted upfront resections had fewer postoperative gastrointestinal complications compared to biopsies (10% vs. 60%, p = 0.057), but longer time to chemotherapy initiation (median 11.5 vs. 4.5 days, p

Alcohol use during pregnancy is a critical public health issue that results in several adverse outcomes for both mother and child. While the prevalence of and consequences of binge drinking among pregnant women is well-documented in the literature, little is known about the intersectional effect of racial/ethnic identity and veteran status. The purpose of this study was to examine the prevalence of binge drinking among pregnant women using the intersectionality of racial/ethnic identity and veteran status. This study utilized combined data from the 2016, 2017 and 2018 Behavioral Risk Factor Surveillance System (BRFSS). The BRFSS is a telephone survey that collects health-related risk behaviors, chronic health conditions and use of preventative services among U.S residents. Generalized linear mixed models were used to examine the prevalence of binge drinking using the interaction between race/ethnicity and veteran status. Overall binge drinking prevalence was 3.60% among the sample of 6101 pregnant women. Binge drinking prevalence was the highest among racial/ethnic minority veterans at 17.42%, compared to 5.34% among white veterans, 4.05% among non-veteran racial/ethnic minorities and 3% among non-veteran whites, supporting the theory of intersectionality. Intersectionality Theory suggests that the stressors from membership in two vulnerable groups may lead to increased disparities. The results of this study highlight the unique experience of being a veteran and identifying as a member of a racial/ethnic minority group. This calls for a need to customize preventative measures that address the combined impact of both racial/ethnic minority group status and veteran status.

Autosomal dominant polycystic kidney disease is the most common monogenic cause of ESKD. Genetic studies from patients and animal models have informed disease pathobiology and strongly support a "threshold model" in which cyst formation is triggered by reduced functional polycystin dosage below a critical threshold within individual tubular epithelial cells due to (1) germline and somatic PKD1 and/or PKD2 mutations, (2) mutations of genes (e.g., SEC63, SEC61B, GANAB, PRKCSH, DNAJB11, ALG8, and ALG9) in the endoplasmic reticulum protein biosynthetic pathway, or (3) somatic mosaicism. Genetic testing has the potential to provide diagnostic and prognostic information in cystic kidney disease. However, mutation screening of PKD1 is challenging due to its large size and complexity, making it both costly and labor intensive. Moreover, conventional Sanger sequencing-based genetic testing is currently limited in elucidating the causes of atypical polycystic kidney disease, such as within-family disease discordance, atypical kidney imaging patterns, and discordant disease severity between total kidney volume and rate of eGFR decline. In addition, environmental factors, genetic modifiers, and somatic mosaicism also contribute to disease variability, further limiting prognostication by mutation class in individual patients. Recent innovations in next-generation sequencing are poised to transform and extend molecular diagnostics at reasonable costs. By comprehensive screening of multiple cystic disease and modifier genes, targeted gene panel, whole-exome, or whole-genome sequencing is expected to improve both diagnostic and prognostic accuracy to advance personalized medicine in autosomal dominant polycystic kidney disease.

International audience; Plant trait variation drives plant function, community composition, and ecosystem processes. However, our current understanding of trait variation disproportionately relies on aboveground observations. Here we integrate root traits into the global framework of plant form and function. We developed and tested an overarching conceptual framework that integrates two recently identified root trait gradients with a well-established aboveground plant trait framework. We confronted our novel framework with published relationships between above- and belowground trait analogues and with multivariate analyses of aboveground and belowground traits of 2510 species. Our traits represent the leaf- and root conservation gradients (specific leaf area, leaf and root nitrogen concentration and root tissue density), the root collaboration gradient (root diameter and specific root length), and the plant size gradient (plant height and rooting depth). We found that an integrated, whole-plant trait space required as much as four axes. The two main axes represented the fast-slow ‘conservation’ gradient on which leaf and fine-root traits were well aligned, and the ‘collaboration’ gradient in roots. The two additional axes were separate, orthogonal plant size axes for height and rooting depth. This perspective on the multi-dimensional nature of plant trait variation better encompasses plant function and influence on the surrounding environment.

The objectives of this randomized, cross-over pilot study were to determine whether isometric plantarflexion exercises resulted in an immediate change in Achilles tendon pain during a loading task, and whether this differed in knee extension or flexion. Eleven participants with mid-portion Achilles tendinopathy were recruited from NHS community physiotherapy services and local running clubs. Participants were then randomized to complete an isometric calf muscle exercise with the knee fully extended or flexed to 80°. Participants switched to the alternate exercise after a minimum seven-day period. Achilles tendon pain during a specific, functional load test was measured on a 11-point numeric pain rating scale (NPRS) pre- and post-intervention. There was a small, immediate, mean reduction in pain following isometric plantar flexion performed in both knee extension (1.6, 95%CI 0.83 to 2.45, p=0.001) and knee flexion (1.3, 95%CI 0.31 to 2.19, p=0.015). There were no significant differences between the two positions. A non-significant, potentially clinically relevant finding was a 20% larger reduction in symptoms in knee extension versus flexion (p=0.110). In conclusion, isometric plantarflexion holds gave an approximately 50% immediate reduction in Achilles tendon pain with a functional load test. There were no significant differences between the two positions and both were well tolerated.The objectives of this randomized, cross-over pilot study were to determine whether isometric plantarflexion exercises resulted in an immediate change in Achilles tendon pain during a loading task, and whether this differed in knee extension or flexion. Eleven participants with mid-portion Achilles tendinopathy were recruited from NHS community physiotherapy services and local running clubs. Participants were then randomized to complete an isometric calf muscle exercise with the knee fully extended or flexed to 80°. Participants switched to the alternate exercise after a minimum seven-day period. Achilles tendon pain during a specific, functional load test was measured on a 11-point numeric pain rating scale (NPRS) pre- and post-intervention. There was a small, immediate, mean reduction in pain following isometric plantar flexion performed in both knee extension (1.6, 95%CI 0.83 to 2.45, p=0.001) and knee flexion (1.3, 95%CI 0.31 to 2.19, p=0.015). There were no significant differences between the two positions. A non-significant, potentially clinically relevant finding was a 20% larger reduction in symptoms in knee extension versus flexion (p=0.110). In conclusion, isometric plantarflexion holds gave an approximately 50% immediate reduction in Achilles tendon pain with a functional load test. There were no significant differences between the two positions and both were well tolerated.

Mild traumatic brain injury (mTBI) is highly prevalent in military populations, with many service members suffering from long-term symptoms. Posttraumatic stress disorder (PTSD) often co-occurs with mTBI and predicts worse clinical outcomes. Functional neuroimaging research suggests there are both overlapping and distinct patterns of resting-state functional connectivity (rsFC) in mTBI versus PTSD. However, few studies have directly compared rsFC of cortical networks in military service members with these two conditions. In the present study, U.S. service members (n = 137; ages 19–59; 120 male) underwent resting-state fMRI scans. Participants were divided into three study groups: mTBI only, PTSD only, and orthopedically injured (OI) controls. Analyses investigated group differences in rsFC for cortical networks: default mode (DMN), frontoparietal (FPN), salience, somatosensory, motor, auditory, and visual. Analyses were family-wise error (FWE) cluster-corrected and Bonferroni-corrected for number of network seeds regions at the whole brain level (pFWE

Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus1,2. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by eight mutations in the spike protein, including three substitutions (K417N, E484K and N501Y) at residues in its receptor-binding domain that may have functional importance3,4,5. This lineage was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape and KwaZulu–Natal provinces within weeks. Although the full import of the mutations is yet to be determined, the genomic data—which show rapid expansion and displacement of other lineages in several regions—suggest that this lineage is associated with a selection advantage that most plausibly results from increased transmissibility or immune escape6,7,8.

Clinical and experimental data from the last nine decades indicate that the preoptic area of the hypothalamus is a critical node in a brain network that controls sleep onset and homeostasis. By contrast, we recently reported that a group of glutamatergic neurons in the lateral and medial preoptic area increases wakefulness, challenging the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic., Clinical and experimental data from the last nine decades indicate that the preoptic area of the hypothalamus is a critical node in a brain network that controls sleep onset and homeostasis. By contrast, we recently reported that a group of glutamatergic neurons in the lateral and medial preoptic area increases wakefulness, challenging the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic. However, the precise role of these subcortical neurons in the control of behavioral state transitions and cortical dynamics remains unknown. Therefore, in this study, we used conditional expression of excitatory hM3Dq receptors in these preoptic glutamatergic (Vglut2+) neurons and show that their activation initiates wakefulness, decreases non-rapid eye movement (NREM) sleep, and causes a persistent suppression of rapid eye movement (REM) sleep. We also demonstrate, for the first time, that activation of these preoptic glutamatergic neurons causes a high degree of NREM sleep fragmentation, promotes state instability with frequent arousals from sleep, decreases body temperature, and shifts cortical dynamics (including oscillations, connectivity, and complexity) to a more wake-like state. We conclude that a subset of preoptic glutamatergic neurons can initiate, but not maintain, arousals from sleep, and their inactivation may be required for NREM stability and REM sleep generation. Further, these data provide novel empirical evidence supporting the hypothesis that the preoptic area causally contributes to the regulation of both sleep and wakefulness. SIGNIFICANCE STATEMENT Historically, the preoptic area of the hypothalamus has been considered a key site for sleep generation. However, emerging modeling and empirical data suggest that this region might play a dual role in sleep-wake control. We demonstrate that chemogenetic stimulation of preoptic glutamatergic neurons produces brief arousals that fragment sleep, persistently suppresses REM sleep, causes hypothermia, and shifts EEG patterns toward a “lighter” NREM sleep state. We propose that preoptic glutamatergic neurons can initiate, but not maintain, arousal from sleep and gate REM sleep generation, possibly to block REM-like intrusions during NREM-to-wake transitions. In contrast to the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic, we provide further evidence that preoptic neurons also generate wakefulness.

Background and objectives Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating PKD1 mutations may also have mild kidney disease, a finding not previously well recognized. Design, setting, participants, & measurements From the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR. Results Among 174 study patients with typical imaging patterns and protein-truncating PKD1 mutations, 32 (18%) were found to have mild disease on the basis of imaging results (i.e., Mayo Clinic Imaging class 1A–1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with PKD2 mutations and Mayo Clinic Imaging class 1A–1B. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability. Conclusions Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease on the basis of clinical and imaging assessment. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_18_CJN11100720_final.mp3

BACKGROUND: Young adult cancer survivors are at risk for subsequent human papillomavirus (HPV)-related malignancies. High-risk sexual behavior increases risk for HPV acquisition; HPV vaccination protects against infection. We aimed to determine the prevalence of sexual behaviors, factors related to high-risk sexual behaviors, and the relationship between sexual behaviors and HPV vaccine non-initiation among survivors. METHODS: Survivors at comprehensive cancer centers, aged 18–26 years and 1–5 years post-treatment, reported sexual behaviors and HPV vaccine initiation (i.e., ≥1 dose). Multivariable logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (95%CI) for factors associated with high-risk sexual behaviors (age at first intercourse

Emerging research has demonstrated that psychosocial trauma exposure may elicit epigenetic changes, with downstream effects on the transcriptional regulation of genes. Epigenome-wide association studies (EWAS) offer an agnostic approach to examine DNA methylation (DNAm) associations and are a valuable tool to aid in the identification of biological pathways involved in posttraumatic stress disorder (PTSD). This study represents the first EWAS of PTSD in an adolescent sample, an important group given the significance of this developmental period regarding both DNAm changes and PTSD risk. The sample (n = 39, M age = 15.41 years, SD = 1.27, 84.6% female) comprised adolescents who experienced interpersonal trauma and were enrolled in a treatment study. Participants were assessed using the UCLA PTSD Reaction Index for DSM-IV–Adolescent Version and provided a blood sample at baseline. Genomic DNA was isolated from whole blood and assayed using the Illumina Infinium MethylationEPIC BeadChip. The primary analysis estimated the associations among individual CpG sites and PTSD symptom scores. Of the 793,575 screened probes tested, two were significant at a false discovery rate (FDR) < 10%. Hypomethylation of both sites was associated with increased PTSD symptom scores. Analysis of differentially methylated regions (DMR) identified a DMR associated with PTSD symptom scores at an FDR < 10%. Results from follow-up models are also discussed. Findings from this preliminary investigation suggest the importance of further research conducted in adolescent samples. The analytic pipeline and results are documented for use in future meta-analytic work as more such samples become available.

Global agriculture is challenged with achieving sustainable food security while the climate changes and the threat of drought increases. Much of the research attention has focused on above-ground plant responses with an aim to improve drought resistance. The hidden half, that is, the root system belowground, is receiving increasing attention as the interface of the plant with the soil. Because roots are a sensing organ for nutrients and moisture, we speculate that crop root system traits can be managed using smart nutrient application in order to increase drought resistance. Roots are known to be influenced both by their underlying genetics and also by responses to the environment, termed root plasticity. Though very little is known about the combined effect of water and nutrients on root plasticity, we explore the possibilities of root system manipulation by nutrient application. We compare the effects of different water or nutrient levels on root plasticity and its genetic regulation, with a focus on how this may affect drought resistance. We propose four primary mechanisms through which smart nutrient management can optimize root traits for drought resistance: (1) overall plant vigor, (2) increased root allocation, (3) influence specific root traits, and (4) use smart placement and timing to encourage deep rooting. In the longer term, we envision that beneficial root traits, including plasticity, could be bred into efficient varieties and combined with advanced precision management of water and nutrients to achieve agricultural sustainability.

Cognitive deficits following traumatic brain injury (TBI) remain a major cause of disability and early-onset dementia, and there is increasing evidence that chronic neuroinflammation occurring after TBI plays an important role in this process. However, little is known about the molecular mechanisms responsible for triggering and maintaining chronic inflammation after TBI. Here, we identify complement, and specifically complement-mediated microglial phagocytosis of synapses, as a pathophysiological link between acute insult and a chronic neurodegenerative response that is associated with cognitive decline. Three months after an initial insult, there is ongoing complement activation in the injured brain of male C57BL/6 mice, which drives a robust chronic neuroinflammatory response extending to both hemispheres. This chronic neuroinflammatory response promotes synaptic degeneration and predicts progressive cognitive decline. Synaptic degeneration was driven by microglial phagocytosis of complement-opsonized synapses in both the ipsilateral and contralateral brain, and complement inhibition interrupted the degenerative neuroinflammatory response and reversed cognitive decline, even when therapy was delayed until 2 months after TBI. These findings provide new insight into our understanding of TBI pathology and its management; and whereas previous therapeutic investigations have focused almost exclusively on acute treatments, we show that all phases of TBI, including at chronic time points after TBI, may be amenable to therapeutic interventions, and specifically to complement inhibition.SIGNIFICANCE STATEMENTThere is increasing evidence of a chronic neuroinflammatory response after traumatic brain injury (TBI), but little is known about the molecular mechanisms responsible for triggering and maintaining chronic inflammation. We identify complement, and specifically complement-mediated microglial phagocytosis of synapses, as a pathophysiological link between acute insult and a chronic neurodegenerative response, and further that this response is associated with cognitive decline. Complement inhibition interrupted this response and reversed cognitive decline, even when therapy was delayed until 2 months after injury. The data further support the concept that TBI should be considered a chronic rather than an acute disease condition, and have implications for the management of TBI in the chronic phase of injury, specifically with regard to the therapeutic application of complement inhibition.

Objective To describe aggregated pregnancy outcomes after uterus transplantation from a single, experienced center. Methods This prospective study reports on live births among 20 women who received a uterus transplant from 2016 to 2019 at Baylor University Medical Center at Dallas. These live births occurred between November 2017 and September 2020. The main measures were live birth, maternal complications, and fetal and newborn outcomes. Results There were six graft failures (four surgical complications and two with poor perfusion postoperatively). Of the 14 technically successful transplants, at least one live birth occurred in 11 patients. Thus far, the live birth rate per attempted transplant is 55%, and the live-birth rate per technically successful transplant is 79%. Ten uteri were from nondirected living donors and one uterus was from a deceased donor. In vitro fertilization was performed to achieve pregnancy. Ten recipients delivered one neonate, and one recipient delivered two neonates. One organ rejection episode was detected during pregnancy and was resolved with steroids. The median birth weight was 2,890 g (range 1,770-3,140 g [median 68th percentile]). Maternal weight gain was higher than Institute of Medicine recommendations. Maternal medical complications were observed in five recipients (elevated creatinine level, gestational diabetes, gestational hypertension [n=2], and preeclampsia). In five recipients, maternal medical or obstetric complications led to an unplanned preterm delivery (elevated creatinine level, preeclampsia; preterm labor [n=3]). The median gestational age at delivery was 36 6/7 weeks (range 30 6/7-38 weeks). All neonates were liveborn, with Apgar scores of 8 or higher at 5 minutes. Conclusion Over the first 3 years, our program experienced a live-birth rate per attempted transplant of 55% and a live-birth rate per technically successful transplant of 79%. In our experience, uterus transplantation resulted in a third-trimester live birth in all cases in which pregnancies reached 20 weeks of gestation. Maternal medical and obstetric complications can occur; however, these were manageable by applying principles of generally accepted obstetric practice. Clinical trial registration ClinicalTrials.gov, NCT02656550.

BACKGROUND: Proponents of clinical case formulations argue that the causes and mechanisms contributing to and maintaining a patient's problems should be analysed and integrated into a case conceptualization, on which treatment planning ought to be based. Empirical evidence shows that an individualized treatment based on a case formulation is at least sometimes better than a standardized evidence-based treatment. METHODS: We argue that it is likely to improve decisions when two conditions hold: (a) knowing about the mechanisms underlying the patient's problems makes a difference for treatment, and (b) the case formulation is based on valid knowledge about mechanisms of psychopathology. RESULTS: We propose a protocol for assessment, case formulation and treatment planning (PACT), which incorporates transdiagnostic accounts of psychopathology. PACT describes a 5-step decision making process, which aims to help clinicians to decide when to resort to evidence-based treatments and when to construct a case formulation to individualize the treatment. CONCLUSION: We show how PACT works in practice by discussing treatment planning for a clinical case involving symptoms of social anxiety, depression and post-traumatic stress disorder. ispartof: JOURNAL OF EVALUATION IN CLINICAL PRACTICE vol:27 issue:3 pages:648-656 ispartof: location:England status: published

Background The growing societal and economic impact of Alzheimer’s disease (AD) is further compounded by the present lack of disease-modifying interventions. Non-pharmacological intervention approaches, such as exercise, have the potential to be powerful approaches to improve or mitigate the symptoms of AD without added side effects or financial burden associated with drug therapies. Various forms and regiments of exercise (i.e., strength, aerobic, multicomponent) have been reported in the literature; however, conflicting evidence obscures clear interpretation of the value and impact of exercise as an intervention for older adults with AD. The primary objective of this review will be to evaluate the effects of exercise interventions for older adults with AD. In addition, this review will evaluate the evidence quality and synthesize the exercise training prescriptions for proper clinical practice guidelines and recommendations. Methods This systematic review and meta-analysis will be carried out by an interdisciplinary collective representing clinical and research stakeholders with diverse expertise related to neurodegenerative diseases and rehabilitation medicine. Literature sources will include the following: Embase, PsychINFO, OVID Medline, and Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily. Inclusion criteria are participants with late onset AD and structured exercise interventions with prescribed duration, frequency, and intensity. The primary outcome of this study will center on improved or sustained cognitive functioning. Secondary outcomes will include institutionalization-related outcomes, ability in activities of daily living, mood and emotional well-being, quality of life, morbidity, and mortality. Analysis procedures to include measurement of bias, data synthesis, sensitivity analysis, and assessment of heterogeneity are described in this protocol. Discussion This review is anticipated to yield clinically meaningful insight on the specific value of exercise for older adults with AD. Improved understanding of diverse exercise intervention approaches and their specific impact on various health- and function-related outcomes is expected to guide clinicians to more frequently and accurately prescribe meaningful interventions for those affected by AD. Systematic review registration PROSPERO CRD42020175016.

Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8+ T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2−/− mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2−/− macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8+ T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer., Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) is highly expressed in several cancers. Here the authors investigate the role of CaMKK2 expression in the tumour microenvironment and show that CaMKK2 expression in tumour-associated macrophages promotes tumour growth by suppressing T cell anti-tumour activity.

Laura Kulik,1 Leonardo G da Fonseca,2 Aiwu Ruth He,3 Jordi Rimola,4 Andrea Wilson Woods,5 York F Zöllner,6 Peter R Galle7 1Northwestern University, Chicago, IL, USA; 2Clinical Oncology, Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil; 3Georgetown University, Washington, DC, USA; 4Radiology Department, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain; 5Blue Faery: The Adrienne Wilson Liver Cancer Association, Birmingham, AL, USA; 6Hamburg University of Applied Sciences, Competence Center Health, Hamburg, Germany; 7University Medical Centre Mainz, Mainz, GermanyCorrespondence: Peter R GalleUniversity Medical Centre Mainz, Mainz, GermanyTel +49 6131 177275Email Peter.Galle@unimedizin-mainz.deAbstract: A virtual expert roundtable was convened on April 16, 2020, to discuss the evolving landscape of care for treating patients with advanced hepatocellular carcinoma (HCC) and discuss questions related to patient care and treatment selection. This commentary presents highlights from this discussion and provides an expert opinion about approaches to treatment for HCC in the Americas and the European Union. We anticipate that atezolizumab plus bevacizumab will become the standard of care for advanced HCC patients. However, this approach will make decisions regarding the sequencing of treatments for second-line therapies and beyond more challenging. Therapy will require individualization based on patient characteristics and preferences, while insurance coverage decisions and requirements may also impact the options that patients can access. Additional research regarding prognostic and predictive biomarkers is needed to help better identify optimal treatment approaches for specific patient populations. Multidisciplinary tumor boards will continue to play a critical role in guiding treatment selection for individual patients. Atezolizumab plus bevacizumab offers a promising new first-line therapeutic option for patients with advanced HCC, but more research is needed to optimize and individualize patient therapy.Keywords: hepatocellular carcinoma, immuno-oncologics, biomarkers, patient-reported outcomes

Hospice care requires person-centered holistic approaches from interprofessional health care teams. Traditional curricular models include teaching hospice care in discipline-specific didactic settings. There are limited opportunities for prelicensure students to engage in real-life and hands-on hospice care. Students are often observers and lack meaningful interactions with patients, families, and interprofessional teams. Using "IPEC Core Competencies for Interprofessional Collaborative Practice" and "AACN CARES" as the framework, nursing and social work faculty collaborated to develop, implement, and evaluate an interprofessional home hospice simulation incorporating standardized patients. The purpose of this interprofessional simulation was to facilitate hands-on application of complex health care concepts in an authentic home hospice setting. Twenty-three Bachelor of Science in Nursing students and 10 Master of Social Work students participated as interprofessional teams to provide home hospice care for patients and families. Faculty evaluated the simulation experience through analysis of presimulation and postsimulation guided reflections, intrasimulation observations, and postsimulation debriefing. Evaluation indicated students gained a greater understanding of how to provide quality person-centered end-of-life care, increased comfort with assessing spiritual needs, increased confidence in initiating sensitive interactions, and greater appreciation for working in an interprofessional health care team. This interprofessional simulation provided a robust learning environment paving the way for future simulations incorporating additional members of the health care team.

Purpose To review the existing available information regarding urolithiasis management and the impact of COVID-19 on this, and propose recommendations for management of emergency urolithiasis presentations in the COVID-19 era. Methods Review of published guidelines produced by Urological Governing Bodies, followed by the literature review regarding urolithiasis management during the COVID-19 pandemic. Results Consistent recommendations across guidelines and literature were that urolithiasis with concurrent sepsis or renal failure remains a urological emergency warranting urgent intervention within the pandemic environment. Ureteric stenting and percutaneous nephrostomy are considered equivalent for decompression in this setting, with both ideally to be performed under local anaesthesia where possible to spare ventilators and reduce aerosol-generating procedures. Greater utilization of medical expulsive therapy and dissolution chemolysis may occur during the pandemic, and longer indwelling stent times may be accepted while definite stone clearance is deferred. Conclusions Urolithiasis will continue to be a source of emergency presentations requiring urgent intervention during the COVID-19 pandemic. However, it is possible to limit these interventions to decompression of the collecting system in the setting of concurrent obstruction or infection, performed under local anaesthesia to limit use of resources and minimise aerosol-generating procedures, with deferral of definitive management. Electronic supplementary material The online version of this article (10.1007/s00345-020-03491-7) contains supplementary material, which is available to authorized users.

Socioeconomic disadvantage and disorder in the residential neighborhood have been linked to multiple health risks, but less is known about the relevance of other spaces of daily life. This article considers whether disadvantage and disorder in the immediate context—within or outside of the residential neighborhood—is associated with physiological symptoms indicative of stress and strain. We use data from a study of 61 older adults in four New York City neighborhoods. Participants carried smartphones to capture GPS locations and ecological momentary assessments during the study week. We find that instantaneous exposure to disorder is associated with momentary spikes in pain and fatigue. This is not explained by cumulative exposure to disorder or concurrent stress or fear. Rather, disordered spaces may be physically and cognitively taxing for older adults in real time. We urge further research on short- and long-term health consequences of activity spaces.

Infection is a rare occurrence after revision anterior cruciate ligament reconstruction (rACLR). Because of the low rates of infection, it has been difficult to identify risk factors for infection in this patient population. The purpose of this study was to report the rate of infection following rACLR and assess whether infection is associated with patient- and surgeon- dependent risk factors. We reviewed two large prospective cohorts to identify patients with postoperative infections following rACLR. Age, sex, body mass index (BMI), smoking status, history of diabetes, and graft choice were recorded for each patient. The association of these factors with postoperative infection following rACLR was assessed. There were 1423 rACLR cases in the combined cohort, with 9 (0.6%) reporting post-operative infections. Allografts had a higher risk of infection than autografts (odds ratio=6.8; 95% CI: 0.9-54.5; p=0.045). Diabetes (odds ratio=28.6; 95% CI: 5.5-149.9; p=0.004) was a risk factor for infection. Patient age, sex, BMI and smoking status were not associated with risk of infection after rACLR. STATEMENT OF CLINICAL SIGNIFICANCE: While there is a low rate of infection following rACLR, use of allograft and comorbidity with diabetes are associated with a higher risk of infection following this surgery.

Study design This was a retrospective review. Objective Provide a validated method of radiographic evaluation of cervical disk replacement (CDR) patients linked to outcomes. Summary of background data Preoperative radiographic criteria for CDRs and the impact of intraoperative positioning remain without formalized guidelines. The association between preexisting degenerative changes, optimal implant positioning, and patient-reported outcome measures (PROMs) are not well understood. Our study establishes a systematic radiographic evaluation of preoperative spondylosis, implant placement, and associated clinical outcomes. Methods Preoperative radiographs for CDR patients were evaluated for disk height, facet arthrosis, and uncovertebral joint degeneration. Postoperative radiographs were scored based on the position of the CDR implant on anterior-posterior (AP) and lateral radiographs. PROMs including Visual Analogue Scale (VAS) arm pain, VAS neck pain, Neck Disability Index (NDI), Short Form 12 physical health (SF12-PCS) and mental health (SF12-M) were collected preoperatively, at early follow, and at late follow-up. Results A total of 115 patients were included. Preoperative disk height had the highest reliability, intraclass correlation coefficient of 0.798). Facet arthrosis had the lowest intraclass correlation coefficient at 0.563. Preoperative disk height scores showed a significant correlation with AP radiographs and implant positioning score. Patients with more advanced uncovertebral degenerative changes showed less improvement 6 months postoperatively, based on SF-12 PCS scores (R=0.446, P=0.025). Postoperative implant position on lateral radiograph showed a significant correlation with SF-12 MCS scores at follow-up beyond 6 months (R=0.385, P=0.011). Overall postoperative implant position scores demonstrated significant correlation with SF-12 PCS (R=0.350, P=0.046) scores. Conclusion This study provides a systematic method of evaluation of preoperative and intraoperative radiographs that can optimize outcomes. On the basis of our study, spine surgeons performing cervical disk replacement surgery should consider: (a) the presence of preexisting uncovertebral joint degeneration can negatively impact outcomes, (b) achieving optimal implant positioning can be increasingly difficult with more severe loss of disk height, and (c) overall implant position as judged on AP and lateral fluoroscopy can impact outcomes.

Background\ud The primary aim of this prospective, multicentre feasibility study was to determine whether the biopsied axillary node can be marked using black carbon dye and successfully identified at the time of surgery.\ud \ud Methods\ud We included breast cancer patients undergoing needle biopsy of the axillary node. The biopsied node was tattooed at the time of needle biopsy (fine needle aspiration or core biopsy) or at a separate visit with black carbon dye (Spot® or Black Eye™). Participants underwent primary surgery or neoadjuvant chemotherapy (NACT) and axillary surgery (SNB or ALND) as per routine care.\ud \ud Results\ud 110 patients were included. Median age of the women was 59 (range 31–88) years. 48 (44%) underwent SNB and 62 (56%) ALND. Median volume of dye injected was 2.0 ml (range 0.2–4.2). Tattooed node was identified intra-operatively in 90 (82%) patients. The identification rate was higher (76 of 88, 86%) in the primary surgery group compared with NACT (14 of 22, 64%) (p = 0.03). Of those undergoing NACT, the identification rate was better in the patients undergoing SNB (3 of 4, 75%) compared with ALND (11 of 18, 61%) (p > 0.99). The tattooed node was the sentinel node in 78% (28 of 36) patients in the primary surgery group and 100% (3 of 3) in the NACT group. There was no learning curve for surgeons or radiologists. The identification rate did not vary with timing between dye injection and surgery (p = 0.56), body mass index (p = 0.62) or volume of dye injected (p = 0.25).\ud \ud Conclusion\ud It is feasible to mark the axillary node with carbon dye and identify it intra-operatively.

While academia is moving forward in terms of diversifying recruitment of undergraduate and graduate students, diverse representation is still not found across the academic hierarchy. At the graduate level, new discussions are emerging around efforts to improve the experiences of women and underrepresented minorities through inclusive graduate programming. Inclusive graduate programs are that which actively center and prioritize support for diverse experiences, identities, career goals, and perspectives, from recruitment through graduation. Establishing regular and rigorous evaluation of equity and inclusion efforts and needs is a critical component of this work. This is recognized by funding agencies that increasingly require reporting on inclusion efforts; here, we suggest use of a systems change framework for these evaluations. A systems change approach emphasizes three levels: explicit change (e.g., policies), semi‐explicit change (e.g., power dynamics), and implicit change (e.g., biases). We use the Ecology, Evolution, and Behavior (EEB) PhD Program at the University of Texas at Austin in an exercise to (a) identify areas of concern regarding inclusive programming voiced by graduate students, (b) categorize efforts to address these concerns, and (c) integrating and evaluating which areas of the systems change framework show the greatest progress or potential for progress. We argue this framework is particularly useful for academic systems as they are complex, composed of variable individuals, and must address diverse stakeholder needs., A systems change approach emphasizes three levels of changes: explicit change (e.g., policies), semi‐explicit change (e.g., power dynamics), and implicit change (e.g., biases). Here, we develop and conduct an exercise to evaluate diversity and inclusion concerns and efforts in an Ecology, Evolution, and Behavior (EEB) PhD Program. The exercise (a) identifies areas of concern regarding inclusive programming voiced by graduate students and characterizes them into a systems change framework, (b) categorizes existing efforts to address these concerns, and (c) integrates the two lists to evaluate which areas of the systems change framework show the greatest progress and greatest need.

Background NovoSorbⓇ Biodegradable Temporising Matrix (BTM) is a synthetic dermal template recently approved for treatment of full thickness defects of the skin. It requires a two-stage reconstruction where it is initially placed into a defect to generate a neodermis, which is later covered by a split skin graft. It has previously been described for the treatment of acute full thickness burn injury, necrotising fasciitis and free flap donor site reconstruction. Methods A consecutive case series review of patients treated with BTM at Middlemore Hospital was performed. Patient demographics, defect aetiology, indications for dermal matrix use, surgical details, and complications were recorded using information gathered from the medical records. Results This case series included 25 patients with a range of defects resulting from acute full thickness burn injury, burn scar revision, necrotising soft-tissue infection, tumour excision and traumatic loss. In these patients, 72% of wounds were identified as complex defects with exposed bone or tendon. Complications encountered included infection, non-adherence and incomplete vascularisation. Conclusion BTM provided a good reconstructive option for a wide range of defects, many of which were not amenable to immediate skin grafting. Once vascularised and ready for the second stage, it developed a red-pink colour and demonstrated capillary refill. Similar to other dermal matrices, infection was a commonly encountered problem. However, BTM proved more tolerant to this and was able to be salvaged in most cases, allowing the second stage to proceed as normal.

Immunization is an important component of preventive healthcare services. By recognizing and understanding factors associated with suboptimal vaccination compliance, healthcare providers can better approach at-risk populations and target efforts at reinforcing the vital importance of immunizations. The objective of this study was to understand the factors associated with adherence, beliefs and behaviors of influenza, pneumococcal, and herpes zoster vaccines receipt among commercially insured adults. A cross-sectional survey of patients with medical and pharmacy benefits for a 24-month period between August 1, 2014 and July 31, 2016 who were eligible to receive at least one of three adult vaccines (influenza, pneumococcal, and herpes zoster) was completed. Patients were identified as eligible to receive a vaccine based on current guidelines from the CDC ACIP. Health plan members were identified from administrative claims data in the HealthCore Integrated Research DatabaseSM (HIRD). Among the participants, 11% were eligible and up-to-date on all three vaccines; 52% on some and 37% were not up-to-date on any of the three vaccines. Participants with a healthcare provider were more likely to be up-to-date on eligible vaccines: 79.9% for none, 91.3% for some, and 97.8% for all eligible vaccines. The composite Vaccine Myth Belief score was significantly associated with being up to date on eligible vaccines: 45.0%/12.8% for none, 12/5%/30.8% for some, and 8.9%/33.3% for those up-to-date on all eligible vaccines. Despite numerous interventions designed to increase vaccination rates among adults, compliance remains suboptimal. It is evident that patient and provider education is necessary to fill knowledge gaps and misunderstandings; however knowledge by itself is not sufficient to improve immunization practices. Our results highlight a population that could benefit from a multidisciplinary approach, including interventions at the individual and health system levels.

Zusammenfassung. Hintergrund. Der Zusammenhang zwischen Inhalt und Ausrichtungsfokus von Therapiezielen und erfolgreichem Therapieverlauf ist wenig erforscht, wobei insbesondere eine mögliche Assoziation von Inhalt und Fokus vernachlässigt wurde. Fragestellung. Untersucht wurde die Assoziation von Therapiezielinhalt und -fokus und deren Zusammenhang mit frühem Therapiefortschritt. Methode. 716 Therapieziele von 163 Patientinnen und Patienten in ambulanter KVT wurden nach Inhalt und Fokus (Annäherung vs. Vermeidung) kategorisiert und der Zusammenhang von Zielart und Zielerreichung sowie Symptomreduktion nach 12 Sitzungen analysiert. Ergebnisse. Zielinhalt und –fokus waren assoziiert. Die fremdbeurteilte Zielerreichung war bei problembezogenen Annäherungszielen am höchsten. Die Symptomreduktion war dagegen am höchsten, wenn problembezogene Vermeidungsziele vorlagen. Schlussfolgerung. Therapiefortschritt steht im Zusammenhang mit den gesetzten Therapiezielen. Welche Therapiezielart, insbesondere welcher Fokus Therapiefortschritt und -erfolg begünstigt, bleibt weiterer zu erforschen. Dabei sollten zukünftig Zielinhalt und –fokus gemeinsam untersucht werden.

Aims Excessive activation of Ca/calmodulin-dependent kinase II (CaMKII) is of critical importance in heart failure (HF) and atrial fibrillation. Unfortunately, lack of selectivity, specificity, and bioavailability have slowed down development of inhibitors for clinical use. We investigated a novel CaMKII delta/CaMKII-selective, ATP-competitive, orally available CaMKII inhibitor (RA608) on right atrial biopsies of 119 patients undergoing heart surgery. Furthermore, we evaluated its oral efficacy to prevent deterioration of HF in mice after transverse aortic constriction (TAC). Methods and results In human atrial cardiomyocytes and trabeculae, respectively, RA608 significantly reduced sarcoplasmic reticulum Ca leak, reduced diastolic tension, and increased sarcoplasmic reticulum Ca content. Patch-clamp recordings confirmed the safety of RA608 in human cardiomyocytes. C57BL6/J mice were subjected to TAC, and left ventricular function was monitored by echocardiography. Two weeks after TAC, RA608 was administered by oral gavage for 7 days. Oral RA608 treatment prevented deterioration of ejection fraction. At 3 weeks after TAC, ejection fraction was 46.1 +/- 3.7% (RA608) vs. 34.9 +/- 2.6% (vehicle), n = 9 vs.n = 12, P < 0.05, ANOVA, which correlated with significantly less CaMKII autophosphorylation at threonine 287. Moreover, a single oral dose significantly reduced inducibility of atrial and ventricular arrhythmias in CaMKII delta transgenic mice 4 h after administration. Atrial fibrillation was induced in 6/6 mice for vehicle vs. 1/7 for RA608,P < 0.05, 'n - 1' chi(2) test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608,P < 0.05, 'n - 1' chi(2) test. Conclusions RA608 is the first orally administrable CaMKII inhibitor with potent efficacy in human myocytes. Moreover, oral administration potently inhibits arrhythmogenesis and attenuates HF development in micein vivo.

Introduction: Coronavirus Disease 2019 (COVID-19) has significantly affected the way healthcare is delivered in Singapore. Healthcare services such as renal transplantation had to rapidly adjust and meet the needs to (1) protect patients and staff, (2) ramp up, conserve or redeploy resources while (3) ensuring that critical services remained operational. This paper aims to describe the experience of the renal transplant programme at the Singapore General Hospital (SGH) in responding to the risks and constraints posed by the pandemic. Methods and Materials: This is a review and summary of the SGH renal transplant programme’s policy and protocols that were either modified or developed in response to the COVID-19 Pandemic. Results: A multi-pronged approach was adopted to respond to the challenges of COVID-19. These included ensuring business continuity by splitting the transplant team into different locations, adopting video and tele-consults to minimise potential patient exposure to COVID-19, streamlining work processes using electronic forms, ensuring safe paths for patients who needed to come to hospital, ring-fencing and testing new inpatients at risk for COVID-19, enhancing precautionary measures for transplant surgery, ensuring a stable supply chain of immunosuppression, and sustaining patient and staff education programmes via video conferencing. Conclusions: Though the COVID-19 pandemic has reduced access to kidney transplantation, opportunities arose to adopt telemedicine into mainstream transplant practice as well as use electronic platforms to streamline work processes. Screening protocols were established to ensure that transplantation could be performed safely, while webinars reached out to empower patients to take precautions against COVID-19. Keywords: COVID-19, Nephrology, Public Health, Renal Transplant, Transplantation, Urology

Immunometabolism refers to the rearrangement of metabolic pathways in response to immune stimulation, and the ability of these metabolic pathways themselves to control immune functions. Many aspects of immunometabolism have been revealed through studies of peripheral immune cells. However, immunometabolic reprogramming of microglia, the resident immune cell of the central nervous system, and the consequential outcome on neuronal activity have remained difficult to unravel. Microglia are highly sensitive to subtle changes in their environment, limiting the techniques available to study their metabolic and inflammatory profiles. Here, using fluorescence lifetime imaging of endogenous NAD(P)H, we measure the metabolic activity of individual microglia within acute hippocampal slices. We observed an LPS-induced increase in aerobic glycolysis, which was blocked by the addition of 5 mM 2-deoxyglucose (2DG). This LPS-induced glycolysis in microglia was necessary for the stabilization of hypoxia inducible factor-1α (HIF-1α) and production of the proinflammatory cytokine, interleukin-1β (IL-1β). Upon release, IL-1β acted via the neuronal interleukin-1 receptor to inhibit the formation of synaptic long-term potentiation (LTP) following high frequency stimulation. Remarkably, the addition of 2DG to blunt the microglial glycolytic increase also inhibited HIF-1α accumulation and IL-1β production, and therefore rescued LTP in LPS-stimulated slices. Overall, these data reveal the importance of metabolic reprogramming in regulating microglial immune functions, with appreciable outcomes on cytokine release and neuronal activity.

Living cells interpret a variety of signals in different contexts to elucidate functional responses. While the understanding of signalling molecules, their respective receptors and response at the gene transcription level have been relatively well-explored, how exactly does a single cell interpret a plethora of time-varying signals? Furthermore, how their subsequent responses at the single cell level manifest in the larger context of a developing tissue is unknown. At the same time, the biophysics and chemistry of how receptors are trafficked through the complex dynamic transport network between the plasma membrane–endosome–lysosome–Golgi–endoplasmic reticulum are much more well-studied. How the intracellular organisation of the cell and inter-organellar contacts aid in orchestrating trafficking, as well as signal interpretation and modulation by the cells are beginning to be uncovered. In this review, we highlight the significant developments that have strived to integrate endosomal trafficking, signal interpretation in the context of developmental biology and relevant open questions with a few chosen examples. Furthermore, we will discuss the imaging technologies that have been developed in the recent past that have the potential to tremendously accelerate knowledge gain in this direction while shedding light on some of the many challenges.

PURPOSE Young cancer survivors are at increased risk for morbidities related to infection with the human papillomavirus (HPV), yet their HPV vaccine initiation rates remain low. Patient-/parent-reported lack of health care provider recommendation for HPV vaccination is strongly associated with vaccine noninitiation. We aimed to identify patient-level factors associated with survivor-/parent-reported lack of provider recommendation for HPV vaccination among young cancer survivors. METHODS Cancer survivors ages 9-26 years and 1-5 years off therapy completed a cross-sectional survey (parent-completed for survivors 9-17 years of age). Lack of health care provider HPV vaccine recommendation was the outcome of interest in a multivariable logistic regression model that included relevant patient-level sociodemographic, clinical, and vaccine-related variables. RESULTS Of 955 survivors, 54% were male, 66% were non-Hispanic White, and 36% had leukemia. At survey participation, survivors were an average age (± standard deviation) of 16.3 ± 4.7 years and 32.8 ± 14.7 months off therapy. Lack of provider HPV vaccine recommendation was reported by 73% (95% CI, 70% to 75%) of survivors. For the entire cohort, patient-level factors associated with lack of reported provider recommendation included perceived lack of insurance coverage for the HPV vaccine (odds ratio [OR], 4.0; 95% CI, 2.7 to 5.9; P < .001), male sex (OR, 2.8; 95% CI, 1.9 to 4.0; P < .001), and decreased parent-survivor communication regarding HPV vaccination (OR, 1.7 per unit decrease in score; 95% CI, 1.3 to 2.2; P < .001). In the sex- and age-stratified models, perceived lack of insurance coverage (all models) and male sex (age-stratified models) were also significantly associated with lack of reported provider recommendation. CONCLUSION We identified factors characterizing survivors at risk for not reporting receipt of a health care provider HPV vaccine recommendation. Future research is needed to develop interventions that facilitate effective provider recommendations for HPV vaccination among all young cancer survivors.

Tedizolid is a new oxazolidinone antibiotic with little real-life data on use outside of skin and soft tissue infections. There is a paucity of safety evidence in courses greater than 6 days. Our centre uses tedizolid predominantly when linezolid-associated adverse events have occurred. This service evaluation describes our experience to date. We performed a retrospective service evaluation by reviewing case notes, prescription charts, and laboratory system results for each patient prescribed tedizolid at our hospital and recording patient demographics, clinical details, and outcomes. Sixty patients received tedizolid between May 2016 and November 2018. Most were treated for bone or joint infections and had stopped linezolid prior to tedizolid prescription. Mean length of tedizolid therapy was 27 days. Haematological adverse effects were infrequent. Most patients (72%) finished the course and their clinical condition improved during treatment (72%). Adverse events were common, but often not thought to be tedizolid related. Tedizolid appears to be safe in prolonged courses within this context. It may be suitable for longer-term antibiotic therapy within a complex oral and parenteral outpatient antibiotic therapy (COPAT) service. Patients who do not tolerate linezolid can be safely switched to tedizolid if appropriate.

Background: Meniscal preservation has been demonstrated to contribute to long-term knee health. This has been a successful intervention in patients with isolated tears and tears associated with anterior cruciate ligament (ACL) reconstruction. However, the results of meniscal repair in the setting of revision ACL reconstruction have not been documented. Purpose: To examine the prevalence and 2-year operative success rate of meniscal repairs in the revision ACL setting. Study Design: Case-control study; Level of evidence, 3. Methods: All cases of revision ACL reconstruction with concomitant meniscal repair from a multicenter group between 2006 and 2011 were selected. Two-year follow-up was obtained by phone and email to determine whether any subsequent surgery had occurred to either knee since the initial revision ACL reconstruction. If so, operative reports were obtained, whenever possible, to verify the pathologic condition and subsequent treatment. Results: In total, 218 patients (18%) from 1205 revision ACL reconstructions underwent concurrent meniscal repairs. There were 235 repairs performed: 153 medial, 48 lateral, and 17 medial and lateral. The majority of these repairs (n = 178; 76%) were performed with all-inside techniques. Two-year surgical follow-up was obtained on 90% (197/218) of the cohort. Overall, the meniscal repair failure rate was 8.6% (17/197) at 2 years. Of the 17 failures, 15 were medial (13 all-inside, 2 inside-out) and 2 were lateral (both all-inside). Four medial failures were treated in conjunction with a subsequent repeat revision ACL reconstruction. Conclusion: Meniscal repair in the revision ACL reconstruction setting does not have a high failure rate at 2-year follow-up. Failure rates for medial and lateral repairs were both

To investigate anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) in relation to ultrasound-detected joint inflammation and bone erosion in patients with rheumatoid arthritis (RA) as previous studies have mainly utilized radiographic damage as imaging outcomes.In this cross-sectional study, patients were grouped based on their Disease Activity Score at 28 joints (DAS28 3.2, DAS28 ≥ 3.2). Ultrasound variables (power Doppler and gray scale joint inflammation graded 0-3 semi-quantitatively; bone erosion graded Yes = 1/No = 0 dichotomously) were correlated with antibodies levels using Pearson correlation. Simple linear regression was used to characterize relationships between variables. Receiver operating characteristic (ROC) analysis was performed to determine statistically optimal cut-off values for identifying patient subgroups with ultrasound erosion scores25th,50th and75th percentiles.One thousand and eighty joints and 1800 joint recesses from 36 peripheral joint sites were scanned in 30 adult RA patients (mean disease duration, 70.3 months; 93.3% female; 93.3% anti-CCP positive; 93.3% RF positive). In the DAS28 3.2 group, no significant correlations were found between antibody levels and ultrasound variables. In the DAS28 ≥ 3.2 group, anti-CCP levels correlated significantly (r = 0.46, P = .048) and were predictive (P = .048) of ultrasound erosion scores. Area under the ROC curve based on cut-off anti-CCP level of ≥95.2 to identify patients with ultrasound erosion scores7 (75th percentile) was 0.72 (sensitivity = 83.3%, specificity = 53.8%).The association of anti-CCP and RF with joint damage appears to differ in RA. Among patients with at least moderate disease activity (DAS28 ≥ 3.2), anti-CCP-but not RF-is associated with joint damage, being moderately correlated with ultrasound-detected bone erosion.

Matrix polysaccharides are a diverse group of structurally complex carbohydrates and account for a large portion of the biomass consumed as food or used to produce fuels and materials. Glucuronoxylan and arabinogalactan protein are matrix glycans that have sidechains decorated with 4-O-methyl glucuronosyl residues. Methylation is a key determinant of the physical properties of these wall glycopolymers and consequently affects both their biological function and ability to interact with other wall polymers. Indeed, there is increasing interest in determining the distribution and abundance of methyl-etherified polysaccharides in different plant species, tissues, and developmental stages. There is also a need to understand the mechanisms involved in their biosynthesis. Members of the Domain of Unknown Function (DUF) 579 family have been demonstrated to have a role in the biosynthesis of methyl-etherified glycans. Here we describe methods for the analysis of the 4-O-methyl glucuronic acid moieties that are present in sidechains of arabinogalactan proteins. These methods are then applied toward the analysis of loss-of-function mutants of two DUF579 family members that lack this modification in muro. We also present a procedure to assay DUF579 family members for enzymatic activity in vitro using acceptor oligosaccharides prepared from xylan of loss-of-function mutants. Our approach facilitates the characterization of enzymes that modify glycosyl residues during cell wall synthesis and the structures that they generate.

Nesfatin-1, a pleotropic peptide, was recently implicated in the regulation of anxiety and depression-like behavior in rats. However, the underlying mechanisms remain unclear so far. Thus, this study aimed to investigate the role of endogenous nesfatin-1 in the mediation of anxiety and depression-like behavior induced by corticotropin-releasing factor (CRF). Therefore, normal weight male intracerebroventricularly (icv) cannulated Sprague Dawley rats received two consecutive icv injections of anti-nesfatin-1 antibody or IgG control antibody followed by CRF or saline, before being exposed to a behavioral test. In the elevated zero maze test, assessing anxiety and explorative behavior, blockade of nesfatin-1 using an anti-nesfatin-1 antibody under basal conditions increased the number of entries into the open arms compared to control antibody/vehicle (1.6-fold, p 0.05) and the time in open arms compared to the other groups (p 0.05). Control antibody/CRF-treated animals tended to spend less time in the open arms compared to control antibody/vehicle (0.7-fold, p = 0.17), an effect not altered by the nesfatin-1 antibody (control antibody/CRF-treated animals vs. nesfatin-1 antibody/CRF group, p = 1.00). In the novelty-induced hypophagia test, assessing anhedonia as part of depression-like behavior, no significant differences were observed between the four groups for the latency to the first bout, number of bouts and the amount of palatable snack eaten (p 0.05). In summary, CRF tended to increase anxiety and explorative behavior an effect not altered by blockade of nesfatin-1, whereas no significant effect of CRF on anhedonia was observed. Blockade of endogenous nesfatin-1 significantly decreased anxiety-like behavior giving rise to a physiological role of brain nesfatin-1 in the mediation of anxiety.

Rationale & Objective:\ud Trials in autosomal dominant polycystic kidney disease (ADPKD) have increased, but their impact on decision making has been limited. Because heterogeneity in reported outcomes may be responsible, we assessed their range and variability in ADPKD trials.\ud \ud Study Design:\ud Systematic review.\ud \ud Setting & Study Population:\ud Adult participants in clinical trials in ADPKD.\ud \ud Selection Criteria for Studies:\ud We included trials that studied adults and were published in English. For trials that enrolled patients without ADPKD, only those enrolling ≥50% of participants with ADPKD were included.\ud \ud Data Extraction:\ud We extracted information on all discrete outcome measures, grouped them into 97 domains, and classified them into clinical, surrogate, and patient-reported categories. For each category, we choose the 3 most frequently reported domains and performed a detailed analysis of outcome measures.\ud \ud Analytical Approach:\ud Frequencies and characteristics of outcome measures were described.\ud \ud Results:\ud Among 68 trials, 1,413 different outcome measures were reported. 97 domains were identified; 41 (42%) were surrogate, 30 (31%) were clinical, and 26 (27%) were patient reported. The 3 most frequently reported domains were in the surrogate category: kidney function (54; 79% of trials; using 46 measures), kidney and cyst volumes (43; 63% of trials; 52 measures), and blood pressure (27; 40% of trials, 30 measures); in the clinical category: infection (10; 15%; 21 measures), cardiovascular events (9; 13%; 6 measures), and kidney failure requiring kidney replacement therapy (8; 12%; 5 measures); and in the patient-reported category: pain related to ADPKD (16; 24%; 26 measures), pain for other reasons (11; 16%; 11 measures), and diarrhea/constipation/gas (10; 15%; 9 measures).\ud \ud Limitations:\ud Outcome measures were assessed for only the top 3 domains in each category.\ud \ud Conclusions:\ud The outcomes in ADPKD trials are broad in scope and highly variable. Surrogate outcomes were most frequently reported. Patient-reported outcomes were uncommon. A consensus-based set of core outcomes meaningful to patients and clinicians is needed for future ADPKD trials.