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Arterial resection (AR) for pancreatic adenocarcinoma is increasingly considered at specialized centers. We aimed to examine the incidence, risk factors, and outcomes of hepatic artery (HA) occlusion after revascularization.We included patients undergoing HA resection with interposition graft (IG) or primary end-to-end anastomoses (EE). Complete arterial occlusion (CAO) was defined as "early" (EO) or "late" (LO) before/after 90 days respectively. Kaplan-Meier and change-point analysis for CAO was performed.HA resection was performed in 108 patients, IG in 61% (66/108) and EE in 39% (42/108). An equal proportion (50%) underwent HA resection alone or in combination with celiac and/or superior mesenteric artery. CAO was identified in 18% of patients (19/108) with arterial IG least likely to occlude (p=0.019). Hepatic complications occurred in 42% (45/108) and correlated with CAO, symptomatic patients, venous resection, and postoperative portal venous patency. CAO-related operative mortality was 4.6% and significantly higher in EO vs LO (p = 0.046). Median CAO occlusion was 126 days. With change-point analysis, CAO was minimal beyond postoperative day 158.CAO can occur in up to 18% of patients and the first 5-month post-operative period is critical for surveillance. LO is associated with better outcomes compared to EO unless there is inadequate portal venous inflow.

High-quality research underpins the best healthcare practice. This article focuses on analyzing the current literature to promote research integrity across clinical trials.Recent admissions of questionable practices by researchers have undermined practitioner and public confidence. There is limited evidence specifically for ethical and professional standards in clinical trials to guide researchers and institutions to embed integrity into research practice.Unintentional errors and spin in research are not uncommon as training in design and conduct of clinical trials is not part of health education for medical and allied health professions. There is unfamiliarity with procedures, such as prospective registration, a priori documentation of statistical analysis plans, openness in data sharing, and so forth. This, combined with the academic culture of secrecy, has led to an environment where scientific suspicion, instead of trust, is the norm. Existing science integrity documents are devoid of specific recommendations about how to translate any guidance into clinical trial practice. There is a need for constructive, supportive and multidisciplinary approaches based on open dialogue and continuous training, targeting the research environment. Research integrity now needs to take centre stage to re-instill confidence in randomized trial evidence to inform clinical practice.

Huntington’s disease (HD) mouse models suggest that cardiovascular exercise may enhance neuroplasticity and delay disease signs, however, the effects of exercise on neuroplasticity in people with HD are unknown. Using a repeated-measures experimental design, we compared the effects of a single bout of high-intensity exercise, moderate-intensity exercise, or rest, on motor cortex synaptic plasticity in 14 HD CAG-expanded participants (9 premanifest & 5 early manifest) and 20 CAG-healthy control participants, using transcranial magnetic stimulation. Measures of cortico-motor excitability, short-interval intracortical inhibition and intracortical facilitation were obtained before and after a 20-minute bout of either high-intensity interval exercise, moderate-intensity continuous exercise, or rest, and again after intermittent theta burst stimulation (iTBS). HD participants showed less inhibition at baseline compared to controls. Whereas the control group showed increased excitability and facilitation following high-intensity exercise and iTBS, the HD group showed no differences in neuroplasticity responses following either exercise intensity or rest, with follow-up Bayesian analyses providing consistent evidence that these effects were absent in the HD group. These findings indicate that exercise-induced synaptic plasticity mechanisms in response to acute exercise may be attenuated in HD, and demonstrate the need for future research to further investigate exercise and plasticity mechanisms in people with HD.

Background In many cancers, microRNAs (miRs) contribute to metastatic progression by modulating phenotypic reprogramming processes such as epithelial-mesenchymal plasticity. This can be driven by miRs targeting multiple mRNA transcripts, inducing regulated changes across large sets of genes. The miR-target databases TargetScan and DIANA-microT predict putative relationships by examining sequence complementarity between miRs and mRNAs. However, it remains a challenge to identify which miR-mRNA interactions are active at endogenous expression levels, and of biological consequence. Methods We developed a workflow to integrate TargetScan and DIANA-microT predictions into the analysis of data-driven associations calculated from transcript abundance (RNASeq) data, specifically the mutual information and Pearson’s correlation metrics. We use this workflow to identify putative relationships of miR-mediated mRNA repression with strong support from both lines of evidence. Applying this approach systematically to a large, published collection of unique melanoma cell lines – the Ludwig Melbourne melanoma (LM-MEL) cell line panel – we identified putative miR-mRNA interactions that may contribute to invasiveness. This guided the selection of interactions of interest for further in vitro validation studies. Results Several miR-mRNA regulatory relationships supported by TargetScan and DIANA-microT demonstrated differential activity across cell lines of varying matrigel invasiveness. Strong negative statistical associations for these putative regulatory relationships were consistent with target mRNA inhibition by the miR, and suggest that differential activity of such miR-mRNA relationships contribute to differences in melanoma invasiveness. Many of these relationships were reflected across the skin cutaneous melanoma TCGA dataset, indicating that these observations also show graded activity across clinical samples. Several of these miRs are implicated in cancer progression (miR-211, -340, -125b, −221, and -29b). The specific role for miR-29b-3p in melanoma has not been well studied. We experimentally validated the predicted miR-29b-3p regulation of LAMC1 and PPIC and LASP1, and show that dysregulation of miR-29b-3p or these mRNA targets can influence cellular invasiveness in vitro. Conclusions This analytic strategy provides a comprehensive, systems-level approach to identify miR-mRNA regulation in high-throughput cancer data, identifies novel putative interactions with functional phenotypic relevance, and can be used to direct experimental resources for subsequent experimental validation. Computational scripts are available: http://github.com/uomsystemsbiology/LMMEL-miR-miner Electronic supplementary material The online version of this article (doi:10.1186/s12943-016-0554-y) contains supplementary material, which is available to authorized users.

Increases in the global use of plastics have caused concerns regarding potential adverse effects on human health. Plastic products contain hundreds of potentially toxic chemical additives, yet the exact chemicals which drive toxicity currently remain unknown. In this study, we employed nontargeted analysis and

Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate highly complex multi-omic regulation of melanoma cell intrinsic programs that provide key insights into the molecular maintenance of phenotypic states. These findings have implications for cancer biology and the identification of new therapeutic strategies. Further, these deeply characterized cell lines will serve as an invaluable resource for future research in the field.

Most science, technology, engineering, and mathematics (STEM) departments inadequately evaluate teaching, which means they are not equipped to recognize or reward effective teaching. As part of a project at one institution, we observed that departmental chairs needed help recognizing the decisions they would need to make to improve teaching evaluation practices. To meet this need, we developed the Guides to Advance Teaching Evaluation (GATEs), using an iterative development process. The GATEs are designed to be a planning tool that outlines concrete goals to guide reform in teaching evaluation practices in STEM departments at research-intensive institutions. The GATEs are grounded in the available scholarly literature and guided by existing reform efforts and have been vetted with STEM departmental chairs. The GATEs steer departments to draw on three voices to evaluate teaching: trained peers, students, and the instructor. This research-based resource includes three components for each voice: 1) a list of departmental target practices to serve as goals; 2) a characterization of common starting places to prompt reflection; and 3) ideas for getting started. We provide anecdotal examples of potential uses of the GATEs for reform efforts in STEM departments and as a research tool to document departmental practices at different time points.

Objective Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action. Methods We studied 29 nondiabetic subjects on two occasions. On 1 occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day, we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used approximate entropy to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies. Results In univariate analysis, basal insulin secretion (R2 = 0.16) and insulin pulse amplitude (R2 = 0.09) correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex, and weight, these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis) or to stimulate glucose disappearance. Conclusions Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in nondiabetic humans.

Background Individuals can test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by molecular assays following the resolution of their clinical disease. Recent studies indicate that SARS-CoV-2 antigen–based tests are likely to be positive early in the disease course, when there is an increased likelihood of high levels of infectious virus. Methods Upper respiratory specimens from 251 participants with coronavirus disease 2019 symptoms (≤7 days from symptom onset) were prospectively collected and tested with a lateral flow antigen test and a real-time polymerase chain reaction (rt-PCR) assay for detection of SARS-CoV-2. Specimens from a subset of the study specimens were utilized to determine the presence of infectious virus in the VeroE6TMPRSS2 cell culture model. Results The antigen test demonstrated a higher positive predictive value (90%) than rt-PCR (70%) when compared to culture-positive results. The positive percentage agreement for detection of infectious virus for the antigen test was similar to rt-PCR when compared to culture results. Conclusions The correlation between SARS-CoV-2 antigen and SARS-CoV-2 culture positivity represents a significant advancement in determining the risk for potential transmissibility beyond that which can be achieved by detection of SARS-CoV-2 genomic RNA. SARS-CoV-2 antigen testing can facilitate low-cost, scalable, and rapid time-to-result, while providing good risk determination of those who are likely harboring infectious virus, compared to rt-PCR., Antigen-based, real-time polymerase chain reaction (rt-PCR)–based, and VeroE6TMPRSS2 cell culture–based testing was conducted using upper respiratory specimens from COVID-19–symptomatic individuals. Using VeroE6TMPRSS2 culture as reference, antigen-based testing had similar positive percentage agreement but better positive predictive value, compared to rt-PCR, for detecting infectious virus.

Postactivation depression of the Hoffmann reflex is reduced in Parkinson's disease (PD), but how the recovery is influenced by the state of the muscle is unknown. The present pilot study examined postactivation depression in PD at rest and during a voluntary contraction while patients were off treatment and while receiving medications and/or deep brain stimulation.The authors recruited nine patients with PD treated with implanted deep brain stimulation and examined postactivation depression under four treatment conditions. Paired pulses were delivered 25 to 300 ms apart, and soleus Hoffmann reflex recovery was tested at rest and during voluntary plantar flexion. Trials were matched for background muscle activity and compared with 10 age-matched controls.Patients with Parkinson disease who were OFF medications (OFF meds) and OFF stimulation (OFF stim) at rest showed less postactivation depression at the 300 ms interpulse interval (86.1% ± 21.0%) relative to control subjects (36.4% ± 6.1%; P0.05). Postactivation depression was restored when dopaminergic medication and/or deep brain stimulation was applied. Comparisons between resting and active motor states revealed that the recovery curves were similar OFF meds/OFF stim owing to faster recovery in PD seen at rest. In contrast, the effect of the motor state was different ON meds/OFF stim and ON meds/ON stim (both P0.05), with a nonsignificant trend OFF meds/ON stim ( P0.08). During a contraction, recovery curves were similar between all treatment conditions in PD and control.Disrupted Hoffmann reflex recovery is restored to control levels in PD patients at rest when receiving medications and/or deep brain stimulation or when engaged in voluntary contraction.

Background Deep Brain Stimulation (DBS) targeting the subthalamic nucleus (STN) and globus pallidus interna (GPi) is an effective treatment for cardinal motor symptoms and motor complications in Parkinson’s Disease (PD). However, malpositioned DBS electrodes can result in suboptimal therapeutic response. Objective We explored whether recovery of the H-reflex—an easily measured electrophysiological analogue of the stretch reflex, known to be altered in PD—could serve as an adjunct biomarker of suboptimal versus optimal electrode position during STN- or GPi-DBS implantation. Methods Changes in soleus H-reflex recovery were investigated intraoperatively throughout awake DBS target refinement across 26 nuclei (14 STN). H-reflex recovery was evaluated during microelectrode recording (MER) and macrostimulation at multiple locations within and outside target nuclei, at varying stimulus intensities. Results Following MER, H-reflex recovery normalized (i.e., became less Parkinsonian) in 21/26 nuclei, and correlated with on-table motor improvement consistent with an insertional effect. During macrostimulation, H-reflex recovery was maximally normalized in 23/26 nuclei when current was applied at the location within the nucleus producing optimal motor benefit. At these optimal sites, H-reflex normalization was greatest at stimulation intensities generating maximum motor benefit free of stimulation-induced side effects, with subthreshold or suprathreshold intensities generating less dramatic normalization. Conclusion H-reflex recovery is modulated by stimulation of the STN or GPi in patients with PD and varies depending on the location and intensity of stimulation within the target nucleus. H-reflex recovery shows potential as an easily-measured, objective, patient-specific, adjunct biomarker of suboptimal versus optimal electrode position during DBS surgery for PD.

Objectives Yttrium-90 transarterial radioembolization (TARE) is a safe, effective modality of locoregional therapy for intermediate and advanced-stage hepatocellular carcinoma (HCC). We aim to identify novel predictors of important outcomes of TARE therapy. Methods A single-center retrospective study of 166 patients treated with TARE for HCC at Mayo Clinic Rochester between 2005-2015 and followed until December 2017. Multivariate logistic and stepwise regression analysis models were used to identify variables associated with overall survival (OS) and progression-free survival (PFS). Results The median OS and the median PFS were12.9 (95% CI: 11.0-17.3), and 8 months (95% CI: 6-11), respectively. Macrovascular invasion (HR: 1.9 [1.3-2.8]), Child-Pugh score (CPS) B or C vs. A (HR: 1.8 [1.2-2.7]), Eastern Cooperative Oncology Group Performance status (ECOG-PS) 2 or 1 vs. 0 (HR: 1.6 [1.1-2.4]) and activity (A) of administered radiation dose (HR: 1.005[1.00-1.010), independently correlated with poorer OS. Infiltrative HCC (HR: 2.4 [1.3-4.5), macrovascular invasion (HR: 1.6 [1.1-2.7]), and high activity of administered radiation dose (HR: 1.005 [1.00-1.010) were associated with worse PFS. Conclusion In HCC patients treated with TARE; macrovascular invasion, the activity of radiation dose, CPS, ECOG-PS, and infiltrative HCC predict OS and PFS.

Using an interactionist perspective and conservation of resources (COR) theory, this study examined the interactive effects of resilience and role overload on family-work enrichment and the outcomes of surface acting, emotional exhaustion, and job satisfaction. The model was tested using a sample of 156 full time employees who completed surveys at two time periods. As expected, resilience was positively related to family-work enrichment and family-work enrichment was negatively related to surface acting and emotional exhaustion and positively related to job satisfaction demonstrating mediating effects for family-work enrichment. Role overload moderated the positive relationship between resilience and family-work enrichment such that the relationship was weaker when role overload was high indicating a boundary condition for the favorable effects of resilience. Finally, support was found for the conditional indirect effects of resilience on surface acting, emotional exhaustion, and job satisfaction through family-work enrichment such that the relationships were weaker when role overload was high.

Transient insulin deprivation with concurrent hyperglucagonemia is a catabolic state that can occur in type 1 diabetes. To evaluate glucagon’s catabolic effect in the setting of its glucogenic effect, we measured the regional exchanges of amino-metabolites across muscle and splanchnic beds in 16 healthy humans during either somatostatin followed by glucagon or a saline infusion alone. Despite a >2-fold increase in the regional exchange of amino-metabolites by glucagon, whole body kinetics and concentrations of amino acids (AAs) remained stable. Glucagon increased the splanchnic uptake of not only gluconeogenic but also essential amino acids (EAAs) while increasing their release from the muscle bed. Regional tracer-based kinetics and 3-methyl-histidine release indicate that EAA release from muscle is likely caused by reduced protein synthesis rather than increased protein degradation. Furthermore, many metabolites known to affect insulin action and metabolism were altered by hyperglucagonemia including increase in branched amino acids and keto acids of leucine and isoleucine in arterial plasma. Further, an increase in arterial concentrations of α-aminoadipic acid arising from increased conversion from lysine in the splanchnic bed was noted. These results demonstrate that hyperglucagonemia during hypoinsulinemia increases net muscle protein catabolism and substantially increases the exchange of amino metabolites across splanchnic and muscle beds.

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ContextSalt and water homeostasis is regulated hormonally, so polyuria can result from endocrine disease directly or via secondary effects. These mechanisms are not consistently considered in primary care management of nocturia.ObjectiveTo conduct a systematic review (SR) of nocturia in endocrine disease and reach expert consensus for primary care management.Evidence acquisitionFour databases were searched from January 2000 to April 2020. A total of 4382 titles and abstracts were screened, 36 studies underwent full-text screening, and 14 studies were included in the analysis. Expert and public consensus was achieved using the nominal group technique (NGT).Evidence synthesisTwelve studies focused on mechanisms of nocturia, while two evaluated treatment options; none of the studies took place in a primary care setting. NGT consensus identified key clinical evaluation themes, including the presence of thirst, a medical background of diabetes mellitus or insipidus, thyroid disease, oestrogen status, medications (fluid loss or xerostomia), and general examination including body mass index. Proposed investigations include a bladder diary, renal and thyroid function, calcium, and glycated haemoglobin. Morning urine osmolarity should be examined in the context of polyuria of >2.5 l/24 h persisting despite fluid advice, with urine concentration >600 mOsm/l after fluid restriction excluding diabetes insipidus. Treatment should involve education, including adjustment of lifestyle and medication where possible. Any underlying endocrine disorder should be managed according to local guidance. Referral to endocrinology is needed if there is hyperthyroidism, hyperparathyroidism, or morning urine osmolarity ConclusionsEndocrine disease can result in nocturia via varied salt and water regulation pathways. The aim of management is to identify and treat causative factors, but secondary effects can restrict improvements in nocturia.Patient summaryPeople with altered hormone function can suffer from severe sleep disturbance because of a need to pass urine caused by problems in controlling water and salt levels. An expert panel recommended the best ways to assess and treat these problems on the basis of the rather small amount of up-to-date published research available.

Abnormal postprandial suppression of glucagon in Type 2 diabetes (T2DM) has been attributed to impaired insulin secretion. Prior work suggests that insulin and glucagon show an inverse coordinated relationship. However, dysregulation of α-cell function in prediabetes occurs early and independently of changes in β-cells, which suggests insulin having a less significant role on glucagon control. We therefore, sought to examine whether hepatic vein hormone concentrations provide evidence to further support the modulation of glucagon secretion by insulin. As part of a series of experiments to measure the effect of diabetes-associated genetic variation in TCF7L2 on islet cell function, hepatic vein insulin and glucagon concentrations were measured at 2-minute intervals during fasting and a hyperglycemic clamp. The experiment was performed on 29 nondiabetic subjects (age = 46 ± 2 years, BMI 28 ± 1 Kg/m

Another benefit of dietary fiber The gut microbiome can modulate the immune system and influence the therapeutic response of cancer patients, yet the mechanisms underlying the effects of microbiota are presently unclear. Spencer et al . add to our understanding of how dietary habits affect microbiota and clinical outcomes to immunotherapy. In an observational study, the researchers found that melanoma patients reporting high fiber (prebiotic) consumption had a better response to checkpoint inhibitor immunotherapy compared with those patients reporting a low-fiber diet. The most marked benefit was observed for those patients reporting a combination of high fiber consumption and no use of over-the-counter probiotic supplements. These findings provide early insights as to how diet-related factors may influence the immune response. —PNK

Background Any health care system that strives to deliver good health and well-being to its population relies on a trained workforce. The aim of this study was to enumerate surgical provider density, describe operative productivity and assess the association between key surgical system characteristics and surgical provider productivity in Liberia. Methods A nationwide survey of operation theatre logbooks, available human resources and facility infrastructure was conducted in 2018. Surgical providers were counted, and their productivity was calculated based on operative numbers and full-time equivalent positions. Results A total of 286 surgical providers were counted, of whom 67 were accredited specialists. This translated into a national density of 1.6 specialist providers per 100,000 population. Non-specialist physicians performed 58.3 percent (3607 of 6188) of all operations. Overall, surgical providers performed a median of 1.0 (IQR 0.5–2.7) operation per week, and there were large disparities in operative productivity within the workforce. Most operations (5483 of 6188) were categorized as essential, and each surgical provider performed a median of 2.0 (IQR 1.0–5.0) different types of essential procedures. Surgical providers who performed 7–14 different types of essential procedures were more than eight times as productive as providers who performed 0–1 essential procedure (operative productivity ratio = 8.66, 95% CI 6.27–11.97, P Conclusion The Liberian health care system struggles with an alarming combination of few surgical providers and low provider productivity. Disaggregated data can provide a high-resolution picture of local challenges that can lead to local solutions.

Prostate-specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with

Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of the durable responses initiated by these drugs remain unknown. Here we show the genetic and phenotypic changes induced by treatment with programmed cell death-1 (PD-1) blockade in a genetically engineered mouse model of melanoma driven by oncogenic BRAF. In this controlled system anti-PD-1 treatment yields responses in ~35% of the tumors, and prolongs survival in ~27% of the animals. We identify increased stroma remodeling and reduced expression of proliferation markers as features associated with prolonged response. These traits are corroborated in two independent early on-treatment anti-PD-1 melanoma patient cohorts. These insights into the biological responses of tumors to ICI provide a strategy for identification of durable response early during the course of treatment and could improve patient stratification for checkpoint inhibitory drugs., Identification of clinical relevant biomarkers to predict response to immune checkpoint blockade (ICB) in melanoma remains challenging. Here, the authors show that stroma remodelling and reduced cell division are associated with durable response to anti-PD1 in a mouse model of melanoma and in ICB-treated patients.

Supplemental digital content is available in the text., Objective Thirteen human papillomavirus (HPV) genotypes are associated with the highest risk of cervical disease/cancer; however, the risk of disease progression and cancer is genotype dependent. The objective of this systematic review was to examine evidence for high-grade cervical intraepithelial neoplasia (≥CIN 3) risk discrimination using HPV genotyping. Materials and Methods A systematic review of English and non-English articles through MEDLINE, Cochrane, clinicaltrials.gov, and abstracts presented at relevant professional society conferences were searched from 2000 to 2019. Search terms included: cervical cancer screening, HPV genotyping, CIN, HPV persistence, humans, and colposcopy; prospective, controlled trials, observational studies, and retrospective studies of residual specimens; evidence included HPV genotyping (beyond genotypes 16/18/45) results. Data were obtained independently by authors using predefined fields. Risk of bias was evaluated with a modified Newcastle-Ottawa Scale. The Grading of Recommendations, Assessment, Development and Evaluation methodology facilitated overall quality of evidence evaluation for risk estimation. The study protocol was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42018091093). The primary outcome was CIN 3 or worse risk both at baseline and at different follow-up periods. Results Of 236 identified sources, 60 full texts were retrieved and 16 articles/sources were included. Risk of bias was deemed low; the overall quality of evidence for CIN 3 or worse risk with negative for intraepithelial lesions or malignancies or low-grade squamous intraepithelial cytology was assessed as moderate; that with atypical squamous cells-undetermined significance and “all cytology” was assessed as high. Clinical and methodological heterogeneity precluded meta-analysis. Human papillomavirus genotyping discriminated risk of CIN 3 or worse to a clinically significant degree, regardless of cytology result. Conclusions The evidence supports a clinical utility for HPV genotyping in risk discrimination during cervical cancer screening.

Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.

The characteristics of pulsatile insulin secretion are important determinants of type 2 diabetes pathophysiology, but they are understudied due to the difficulties in measuring pulsatile insulin secretion noninvasively. Deconvolution of either peripheral C-peptide or insulin concentrations offers an appealing alternative to hepatic vein catheterization. However, to do so, there are a series of methodological challenges to overcome. C-peptide has a relatively long half-life and accumulates in the circulation. On the other hand, peripheral insulin concentrations reflect relatively fast clearance and hepatic extraction as it leaves the portal circulation to enter the systemic circulation. We propose a method based on nonparametric stochastic deconvolution of C-peptide concentrations, using individually determined C-peptide kinetics, to overcome these limitations. The use of C-peptide (instead of insulin) concentrations allows estimation of portal (and not post-hepatic) insulin pulses, whereas nonparametric stochastic deconvolution allows evaluation of pulsatile signals without any a priori assumptions of pulse shape and occurrence. The only assumption required is the degree of smoothness of the (unknown) secretion rate. We tested this method first on simulated data and then on 29 nondiabetic subjects studied during euglycemia and hyperglycemia and compared our estimates with the profiles obtained from hepatic vein insulin concentrations. This method produced satisfactory results both in the ability to fit the data and in providing reliable estimates of pulsatile secretion, in agreement with hepatic vein measurements. In conclusion, the proposed method enables reliable and noninvasive measurement of pulsatile insulin secretion. Future studies will be needed to validate this method in people with type 2 diabetes.

Objectives Increasing evidence suggests that extended human papillomavirus (HPV) genotyping (beyond 16/18) is effective for risk stratification in women with normal cytology. This report provides extended genotyping results, using the BD Onclarity HPV Assay, for individual genotypes HPV16, 18, 31, 45, 51, and 52 and three pooled genotype results for HPV33/58, 35/39/68, and 56/59/66. Methods 27,037 women with normal cytology, ≥25 years, were enrolled into the Onclarity HPV trial during routine screening. Women positive for any HPV genotype were referred to colposcopy/biopsy. Hierarchical-ranked prevalence and risk values, associated with cervical intraepithelial neoplasia, grade 2 or worse (≥CIN2) or ≥CIN3, were calculated based on extended genotyping results. Results HPV 16 and 31 carried the highest risk for ≥CIN2 (11.6% and 12.1%, respectively) and ≥CIN3 (8.1% and 7.5%, respectively); these genotypes were the most prevalent in both ≥CIN2 (29.6% and 19.3%, respectively) and ≥CIN3 (43.7% and 22.5%, respectively). Of the other 12 genotypes, HPV 18, 33/58, and 52 comprised an intermediate risk band (≥CIN2 risk range: 4.9–6.8%; ≥CIN3 risk range: 3.9–5.0%). Genotypes 45, 51, 35/39/68, and 56/59/66 constituted the lowest risk band for both disease grades (≥CIN2 value risk range: 1.7–3.0%; ≥CIN3 value risk range: 1.2–3.6%). Conclusions Extended genotyping stratifies risk for ≥CIN2/3 in the ≥25 year-old, normal cytology population. While baseline HPV 16/31 values exceeded the risk threshold for colposcopy referral, the management of women with normal cytology who were positive for the intermediate- or lower-risk genotypes may evolve based on refined risk estimates as well as clinical factors.

Determine the relationship between functional status and degree of specific organ involvement, physical performance, and subjective well-being chronic graft-vs-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation.Observational cohort.Outpatient clinic.Adult patients (N=121) with cGVHD with 634 assessments.Not applicable.Karnofsky Performance Status (KPS). Skin, fascia/joints, lungs, upper and lower extremity range of motion, liver, eye, mucosal, and gastrointestinal involvement were measured using the National Institutes of Health GVHD scale. Physical performance was assessed with the 2-minute walk test (2MWT) and hand grip strength. Subjective measures were the Patient Health Questionnaire 9 (PHQ-9) and Lee Symptom Burden (LSB) scale.Myofascial (P.001) and lung (P=.001) involvement, 2MWT (P.001), LSB (P.001), and PHQ-9 (P=.03) had the largest associations with KPS with liver (P=.05) and hand grip strength (P.001) more modest associations with KPS.Patients with cGVHD experience multifactorial impairment in function associated with potentially modifiable symptoms physiatrists have the expertise to address to enhance function. More research is needed to determine rehabilitation interventions to mitigate the impact of cGVHD on function.

To evaluate prognostic factors associated with peri-procedural (30 days) and short-term (90 days) mortality in the United States cohort of patients following emergent transarterial embolization for ruptured hepatocellular carcinoma.Patients with ruptured hepatocellular carcinoma treated with emergent TAE between January 2001 and December 2019 were retrospectively identified (n = 24). Average age was 62 years (range, 23-78 year); 15 (62.5%) were men. Univariate and Cox proportional hazard modeling were used to determine independent predictors of overall survival (OS) following TAE. OS stratified by Model for End-Stage Liver Disease-Sodium score was assessed using Kaplan-Meier analysis.Twenty-one patients (88%) died during a mean clinical follow-up period of 328 ± 139 days. MELD-Na score (HR 1.22 per 1-unit increase; 95% CI 1.06-1.46; p = 0.005) and pre-rupture ECOG PS score (HR 8.1; 95% CI 1.28-51.2; p = 0.026) were independent predictors of decreased overall survival. There was no significant association between overall survival and presence of cardiovascular co-morbidities (p = 0.60), hemorrhagic shock on presentation (p = 0.16), portal vein thrombus (p = 0.08), vasopressor support required (p = 0.79), intubation required (p = 0.40), acute kidney injury (p = 0.58), and number of packed red blood cell transfusions (p = 0.22). The median OS was 64 days. Median OS was significantly greater in patients with a MELD-Na score ≤ 16 as compared to those with a MELD-Na score 16 (166.5 days vs 9 days, p = 0.011). Cumulative OS rates in those with a MELD-Na score ≤ 16 at 30, 60, 90, and 360 days were 79%, 64%, 64%, and 25%, respectively, vs 33%, 33%, 11%, and 0%, respectively, in those with a MELD-Na score 16.MELD-Na 16 is associated with very high peri-procedural (67% at 30 days) and short-term (89% at 90 days) mortality in patients with ruptured HCC treated with emergent transarterial embolization. A better understanding of these prognostic factors may help guide treatment decisions and provide realistic expectations when counseling patients and their families.

International audience; Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Malnutrition continues to threaten the lives of millions across the world, with children being hardest hit. Although inadequate access to food and infectious disease are the primary causes of childhood malnutrition, the gut microbiota may also contribute. This review considers the evidence on the role of diet in modifying the gut microbiota, and how the microbiota impacts childhood malnutrition. It is widely understood that the gut microbiota of children is influenced by diet, which, in turn, can impact child nutritional status. Additionally, diarrhoea, a major contributor to malnutrition, is induced by pathogenic elements of the gut microbiota. Diarrhoea leads to malabsorption of essential nutrients and reduced energy availability resulting in weight loss, which can lead to malnutrition. Alterations in gut microbiota of severe acute malnourished (SAM) children include increased Proteobacteria and decreased Bacteroides levels. Additionally, the gut microbiota of SAM children exhibits lower relative diversity compared with healthy children. Thus, the data indicate a link between gut microbiota and malnutrition in children, suggesting that treatment of childhood malnutrition should include measures that support a healthy gut microbiota. This could be of particular relevance in sub-Saharan Africa and Asia where prevalence of malnutrition remains a major threat to the lives of millions.

Pakistan has hosted millions of Afghan refugees over the last several decades. Due to poor socioeconomic status, food insecurity and inadequate access to health care, these refugees are considered to be at high risk of malnutrition. Previous studies on nutritional assessment of high-risk populations (refugees) have focused mainly on women and children (0–59 months). The current study aims to assess nutritional status of adolescent Afghan refugees, the population who are equally vulnerable to malnutrition and its consequences. In this cross sectional study, the nutritional status of 206 adolescent (10–19 years old) Afghans boys and girls living in a refugee camp in Peshawar, Pakistan was assessed using standard methods. The results indicate a prevalence of stunting, thinness, and overweight and obesity at 35.3%, 4.4% and 14.8%, respectively. Furthermore, there was a significantly high prevalence of micronutrient deficiencies (vitamin D, 80.5%, vitamin B12, 41.9%, and folate, 28.2%), and anemia (10.1%). Together, these findings indicate that this vulnerable population group suffers from the double burden of malnutrition and are thus at serious risk of impaired psychosocial cognitive development, general ill-health and diminished wellbeing. This study therefore highlights the urgent need to include adolescents in regular screening and intervention programs of such at-risk populations.

Objective: This study aimed to investigate how sleep and physical activity habits related to cognitive functioning, in naturalistic settings, in early Huntington's disease (HD). Method: Forty-two participants with the expanded HD repeat (20 manifest, 22 premanifest) and 29 healthy controls wore Fitbit One sleep and activity monitors for 7 days and 7 nights. They used a smartphone application to complete daily sleep and activity diaries, sleep and mood inventories, and a brief battery of cognitive tests, which were completed on Day 8 of the study. All data were collected in naturalistic home and community settings. Results: Amongst participants with the expanded HD repeat, greater time spent in bed, measured by Fitbit, was associated with poorer accuracy and response speed on a test of visual memory, whereas lower levels of physical activity, measured by Fitbit, were associated with poorer accuracy on a test involving a working memory component. Neither time in bed nor physical activity is associated with a test of psychomotor speed. Groups were mostly similar across a range of Fitbit and self-report measures of sleep and physical activity, although the Manifest-HD group spent more time in bed than the Premanifest-HD and Healthy Control groups and had better self-reported sleep quality and more self-reported time spent sitting than the Healthy Control group and the Premanifest-HD group, respectively. Conclusions: Sleep timing and physical activity relate to cognitive functioning in HD and may be important targets for management in behavioral intervention studies aimed at improving cognition in HD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Habits play an important role in physical activity (PA) engagement; however, these associations in older people are not well understood. The present study aimed to investigate the relationship between engagement in types of PA and their automaticity in older people, using an observational, cross-sectional design. Current hours engaged in planned exercise (excluding walking), planned walking, and incidental activities and the automaticity of those PA behaviors were measured in 127 community-dwelling Australians aged 65 years and older via an online questionnaire. After controlling for demographic and health factors (age, gender, education level, body mass index, history of falls, and anxiety and depression symptoms), higher automaticity scores were associated with more hours undertaking planned walking and incidental activity but not planned exercise. Although preliminary, these findings indicate that the role of habit in maintaining PA in older people may, therefore, differ depending on the type of activity.

BackgroundCognitive impairment is a core feature of Huntington's disease (HD), however, the onset and rate of cognitive decline is highly variable. Apathy is the most common neuropsychiatric symptom of HD, and is associated with cognitive impairment. The aim of this study was to investigate apathy as a predictor of subsequent cognitive decline over 2 years in premanifest and early HD, using a prospective, longitudinal design.MethodsA total of 118 premanifest HD gene carriers, 111 early HD and 118 healthy control participants from the multi-centre TRACK-HD study were included. Apathy symptoms were assessed at baseline using the apathy severity rating from the Short Problem Behaviours Assessment. A composite of 12 outcome measures from nine cognitive tasks was used to assess cognitive function at baseline and after 24 months.ResultsIn the premanifest group, after controlling for age, depression and motor signs, more apathy symptoms predicted faster cognitive decline over 2 years. In contrast, in the early HD group, more motor signs, but not apathy, predicted faster subsequent cognitive decline. In the control group, only older age predicted cognitive decline.ConclusionsOur findings indicate that in premanifest HD, apathy is a harbinger for cognitive decline. In contrast, after motor onset, in early diagnosed HD, motor symptom severity more strongly predicts the rate of cognitive decline.

Glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) form the delta family of ionotropic glutamate receptors; these proteins plays widespread roles in synaptic architecture, motor behavior, and cognitive function. Though the role of GluD2 at cerebellar parallel fiber-Purkinje cell synapses is well established, attention now turns to the function of GluD receptors in the forebrain. GluD1 regulates synaptic assembly and modulation in multiple higher brain regions, acting as a postsynaptic cell adhesion molecule with effects on both excitatory and inhibitory transmission. Furthermore, variations and mutations in the GRID1 gene, which codes for GluD1, and in genes which code for proteins functionally linked to GluD1, are associated with mental disorders including autism, schizophrenia, bipolar disorder, and major depression. Cerebellin (Cbln) family proteins, the primary binding partners of delta receptors, are secreted C1q-like proteins which also bind presynaptic neurexins (NRXNs), forming a tripartite synaptic bridge. Published research explores this bridge’s function in regions including the striatum, hippocampus, cortex, and cer-ebellum. In this review, we summarize region- and circuit-specific functions and expression patterns for GluD1 and its related proteins, and their implications for behavior and disease.

Background Medically-refractory trigeminal neuralgia (TN) can be treated successfully with operative intervention, but a significant proportion of patients are non-responders despite undergoing technically successful surgery. The thalamus is a key component of the trigeminal sensory pathway involved in transmitting facial pain, but the role of the thalamus in TN, and its influence on durability of pain relief after TN surgery, are relatively understudied. We aimed to test the hypothesis that variations in thalamic structure and metabolism are related to surgical non-response in TN. Methods We performed a longitudinal, peri-operative neuroimaging study of the thalamus in medically-refractory TN patients undergoing microvascular decompression or percutaneous balloon compression rhizotomy. Patients underwent structural MRI and MR spectroscopy scans pre-operatively and at 1-week following surgery, and were classified as responders or non-responders based on 1-year post-operative pain outcome. Thalamus volume, shape, and metabolite concentration (choline/creatine [Cho/Cr] and N-acetylaspartate/creatine [NAA/Cr]) were evaluated at baseline and 1-week, and compared between responders, non-responders, and healthy controls. Results Twenty healthy controls and 23 patients with medically-refractory TN treated surgically (17 responders, 6 non-responders) were included. Pre-operatively, TN patients as a group showed significantly larger thalamus volume contralateral to the side of facial pain. However, vertex-wise shape analysis showed significant contralateral thalamus volume reduction in non-responders compared to responders in an axially-oriented band spanning the outer thalamic circumference (peak p = 0.019). Further, while pre-operative thalamic metabolite concentrations did not differ between responders and non-responders, as early as 1-week after surgery, long-term non-responders showed a distinct decrease in contralateral thalamic Cho/Cr and NAA/Cr, irrespective of surgery type, which was not observed in responders. Conclusions Atrophy of the contralateral thalamus is a consistent feature across patients with medically-refractory TN. Regional alterations in preoperative thalamic structure, and very early post-operative metabolic changes in the thalamus, both appear to influence the durability of pain relief after TN surgery.

Objectives\ud ST11 is a high-risk sequence type associated with carbapenem-resistant Klebsiella pneumoniae strains. Carbapenemase-producing hypervirulent K. pneumoniae (hvKp) are a major concern as they harbour a diverse range of pathogenicity traits. Here we describe the characteristics of K. pneumoniae strain KP75w isolated from a tertiary-care hospital in Pakistan.\ud \ud Methods\ud Antimicrobial susceptibility testing was performed by the Kirby–Bauer disk diffusion test and broth microdilution assay. The virulence phenotype was determined by string test as well as biofilm and cell adhesion assays. Genome sequencing was performed using MiSeq and HiSeq 2500 platforms with 30 × coverage.\ud \ud Results\ud Antimicrobial resistance profiling characterised strain KP75w as a multidrug-resistant carbapenemase-producing strain with a meropenem minimum inhibitory concentration (MIC) of 4 μg/mL, which is above the CLSI susceptible breakpoint (≤1 μg/mL). The annotated contigs indicated a genome size of 5 644 609 bp with 5679 coding regions. KP75w (ST11) was designated as a carbapenemase-producing hvKp strain on the basis of the presence of a carbapenemase gene (blaNDM-1) and hypervirulence genes (rmpA2, iucABCD–iutA, fyuA, irp, mrk, ybt, fep and virB2). KP75w was found to contain a 163-kb virulence region showing 58.8% identity to the large virulence plasmid pLVPK, supporting the hypervirulence of KP75w.\ud \ud Conclusion\ud KP75w is a novel non-hypermucoviscous carbapenemase-producing hvKp ST11 strain that appears to represent the convergence of multidrug resistance with hypervirulence traits in clinical K. pneumoniae strains from the Southeast Asian region.

IntroductionTuberculosis (TB) caused by Mycobacterium tuberculosis is a common infectious disease associated with significant morbidity and mortality, especially in low-income and middle-income countries. Successful treatment of the disease requires prolonged intake (6–8 months) of multiple antibiotics with potentially detrimental consequences on the composition and functional potential of the human microbiome. The protocol described in the current study aims to identify microbiome (oral and gut) signatures associated with TB pathogenesis, treatment response and outcome in humans.Methods and analysisFour hundred and fifty, newly diagnosed patients with TB from three district levels (Peshawar, Mardan and Swat) TB diagnosis and treatment centres, will be recruited in this non-interventional, prospective cohort study and will be followed and monitored until treatment completion. Demographic and dietary intake data, anthropometric measurement and blood, stool and salivary rinse samples will be collected at baseline, day 15, month-2 and end of the treatment. Additionally, we will recruit age (±3 years) and sex-matched healthy controls (n=30). Blood sampling will allow monitoring of the immune response during the treatment, while salivary rinse and faecal samples will allow monitoring of dynamic changes in oral and gut microbiome diversity. Within this prospective cohort study, a nested case–control study design will be conducted to assess perturbations in oral and gut microbiome diversity (microbial dysbiosis) and immune response and compare between the patients groups (treatment success vs failure).Ethics and disseminationThe study has received ethics approval from the Ethic Board of Khyber Medical University Peshawar, and administrative approval from Provincial TB Control Programme of Khyber Pakhtunkhwa, Pakistan. The study results will be presented in national and international conferences and published in peer-reviewed journals.Trial registration numberNCT04985994.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jlgtd.com)., Objective The aim of the study was to examine whether high-grade cervical intraepithelial neoplasia (CIN) was more closely associated with human papillomavirus (HPV) same-genotype persistence (SGTP) versus clearance of prior infection with a subsequent infection by a new genotype (genotype switch [GS]), clearance of HPV infection, or acquisition of a new HPV infection after a negative infection status, during a follow-up testing subsequent to abnormal screening results. Materials and Methods MEDLINE, Cochrane Library, Health Technology Assessment, and clinicaltrials.gov were searched from January 2000 to July 2019 for prospective controlled trials and observational studies of women and retrospective studies using HPV assays with extended- or full-genotype reporting. The primary outcome was high-grade CIN after at least 2 rounds of testing. Overall quality of evidence for the risk estimate outcomes was assessed. Of the 830 identified abstracts, 66 full-text articles were reviewed, and 7 studies were included in the synthesis. The study protocol was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42018091093). Results Continued HPV-positive women falls in 2 equally large groups: SGTP and GS. Sensitivity, positive predictive value, and positive likelihood ratio of SGTP were significantly higher than for GS. Human papillomavirus genotypes may be ranked into 3 tiers (immediate colposcopy, follow-up testing, return to routine screening), according to associated risk of persistence for high-grade CIN and to prevailing clinical action thresholds. Conclusions There is moderately high-quality evidence to support the clinical utility of SGTP to improve risk discrimination for high-grade CIN compared with qualitative HPV testing without genotype-specific information.

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (��-CTLA-4 or ��-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten���/���). Short-term treatment with ��-PD-1 and ��-CTLA-4 monotherapies were relatively ineffective, while treatment with ��-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined ��-OX40/��-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/��-CTLA-4/��-PD-1 or DT/��-OX40/��-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies.

Introduction The coronavirus disease 2019 (COVID-19) pandemic has accelerated the growth of telemedicine services across the United States. In this study, we examined cancer rehabilitation patient and physician satisfaction with telemedicine visits. We also sought to evaluate the types of provider services that are given during telemedicine visits. Objective To assess overall patient and provider satisfaction with telemedicine visits and explore whether satisfaction varied by contact method (phone or video) and encounter type (new problem, worsening problem, stable/improving problem). Design Prospective survey study. Setting Cancer rehabilitation program at an academic medical center. Participants Three cancer rehabilitation providers and 155 unique patients participated in the study. Interventions Not applicable. Main outcome measures Provider and patient satisfaction measured by customized surveys. Results One hundred eighty-four encounters with 169 unique patients were scheduled. Of these, 14 were new visits and 170 were follow-up visits. Eighteen encounters (9.8%) were either no shows or rescheduled, making for 166 encounters with 155 unique patients. Patient and provider responses comprised the following: 94.8% of patient responses reported "quite a bit" or "very much" for the telemedicine visit being a good experience; 63.1% of patient responses reported "quite a bit" or "very much" for interest in using telemedicine visits in the future; and 83.9% of provider responses reported "quite a bit" or "very much" for the patient's main problem being addressed by the visit. Providers were more likely to prefer an in-person visit for a new or worsening problem versus a stable/improving problem. The most common services provided were medication prescription/titration and education/counseling. The least common services provided were making of new diagnoses, ordering interventional procedures, and making referrals. Conclusion Telemedicine visits were well received by both patients and providers in a cancer rehabilitation medicine clinic setting. However, in the case of a new or worsening problem, satisfaction declined. These data support that telemedicine visits should be considered essential as part of comprehensive cancer rehabilitation care, especially during a public health crisis.

The clinical performance of the BD Veritor System for Rapid Detection of SARS-CoV-2 nucleocapsid antigen (Veritor), a chromatographic immunoassay used for SARS-CoV-2 point-of-care testing, was evaluated using nasal specimens from individuals with COVID-19 symptoms. Two studies were completed to determine clinical performance. In the first study, nasal specimens and either nasopharyngeal or oropharyngeal specimens from 251 participants with COVID-19 symptoms (≤7 days from symptom onset [DSO], ≥18 years of age) were utilized to compare Veritor with the Lyra SARS-CoV-2 PCR assay (Lyra). In the second study, nasal specimens from 361 participants with COVID-19 symptoms (≤5 DSO, ≥18 years of age) were utilized to compare performance of Veritor to that of the Sofia 2 SARS Antigen FIA test (Sofia 2). The positive, negative, and overall percent agreement (PPA, NPA, and OPA, respectively) were the primary outcomes. In study 1, the PPA for Veritor, compared to Lyra, ranged from 81.8 to 87.5% across the 0 to 1 and 0 to 6 DSO ranges. In study 2, Veritor had PPA, NPA, and OPA values of 97.4, 98.1, and 98.1%, respectively, with Sofia 2. Discordant analysis showed one Lyra positive missed by Veritor and five Lyra positives missed by Sofia 2; one Veritor positive result was negative by Lyra. Veritor met FDA emergency use authorization (EUA) acceptance criteria for SARS-CoV-2 antigen testing for the 0 to 5 and 0 to 6 DSO ranges (PPA values of 83.9% and 82.4%, respectively). Veritor and Sofia 2 showed a high degree of agreement for SARS-CoV-2 detection. The Veritor test allows for more rapid COVID-19 testing utilizing easy-to-collect nasal swabs but demonstrated

Background and Aims Select patients with acute cholecystitis (AC) are poor candidates for cholecystectomy. ERCP-guided transpapillary gallbladder (GB) drainage (ERGD) is one modality for nonoperative management of AC in these patients. Our primary aim was to evaluate long-term success of destination ERGD. Secondary aims were the rate of technical and clinical success, number of repeat procedures, rate of adverse events, and risk factors for recurrent AC. Methods Consecutive patients with AC who were not candidates for cholecystectomy underwent ERGD with attempted transpapillary GB plastic double-pigtail stent placement at a tertiary hospital from January 2008 to December 2019. Long-term success was defined as no AC after ERGD until 6 months, death, or reintervention. Technical success was defined as placement of at least 1 transpapillary stent into the GB and clinical success as resolution of AC symptoms with discharge from the hospital. Results Long-term success was achieved in 95.9% of patients (47/49), technical success in 96% (49/51), and clinical success 100% in those with technical success. Mild adverse events occurred in 5.9% (n = 3). Mean follow-up was 453 days after ERGD (range, 18-1879). A trend toward longer time to recurrence of AC was seen in patients with 2 rather than 1 GB stent placed (P = .13), and more repeat procedures were performed when a single stent was placed (P = .045). Conclusions ERGD with transpapillary GB double-pigtail stent placement is a safe and effective long-term therapy for poor surgical candidates with AC. Risk factors for recurrence include stent removal and single-stent therapy. Double-stent therapy is not always technically feasible but may salvage failed single-stent therapy or recurrence after elective stent removal and may therefore be the preferred treatment modality.

In seeking to develop single entity combination anti-Leishmanial complexes six heteropletic organometallic Sb(V) hydroxido quinolinolate complexes of general formula [SbPh3(C9H4NORR’)(OH)] have been synthesised and characterised, derived from a series of halide substituted quinolinols (8-hydroxyquinolines). Single crystal X-ray diffraction on all the complexes show a common distorted six-coordinate octahedral environment at the Sb(V) centre, with the aryl groups and nitrogen atom of quinolinolate ligand bonding in the equatorial planes, with the two oxygen atoms (hydroxyl and quinolinolate) occupying the axial plane in an almost linear configuration. Each complex was tested for their anti-promastigote activity and mammalian cytotoxicity and a selectivity indices established. The complexes displayed excellent anti-promastigote activity (IC50: 2.03–3.39 μM) and varied mammalian cytotoxicity (IC50: 12.7–46.9 μM), leading to a selectivity index range of 4.52–16.7. All complexes displayed excellent anti-amastigote activity with a percentage infection range of 2.25%–9.00%. All complexes performed substantially better than the parent quinolinols and comparable carboxylate complexes [SbPh3(O2CRR’)2] indicating the synergistic role of the Sb(V) and quinolinol moieties in increasing parasite mortality. Two of the complexes [SbPh3(C9H4NOBr2)(OH)] 4, [SbPh3(C9H4NOI2)(OH)] 5, provide an ideal combination of high selective and good activity towards the leishmanial amastigotes and offer the potential as good lead compounds.

The clinical performance of the BD Veritor System for Rapid Detection of SARS-CoV-2 nucleocapsid antigen (Veritor), a chromatographic immunoassay used for SARS-CoV-2 point-of-care testing, was evaluated using nasal specimens from individuals with COVID-19 symptoms. Two studies were completed to determine clinical performance. In the first study, nasal specimens and either nasopharyngeal or oropharyngeal specimens from 251 participants with COVID-19 symptoms (≤7 days from symptom onset [DSO], ≥18 years of age) were utilized to compare Veritor with the Lyra SARS-CoV-2 PCR assay (Lyra). In the second study, nasal specimens from 361 participants with COVID-19 symptoms (≤5 DSO, ≥18 years of age) were utilized to compare performance of Veritor to that of the Sofia 2 SARS Antigen FIA test (Sofia 2). The positive, negative, and overall percent agreement (PPA, NPA, and OPA, respectively) were the primary outcomes. In study 1, the PPA for Veritor, compared to Lyra, ranged from 81.8 to 87.5% across the 0 to 1 and 0 to 6 DSO ranges. In study 2, Veritor had PPA, NPA, and OPA values of 97.4, 98.1, and 98.1%, respectively, with Sofia 2. Discordant analysis showed one Lyra positive missed by Veritor and five Lyra positives missed by Sofia 2; one Veritor positive result was negative by Lyra. Veritor met FDA emergency use authorization (EUA) acceptance criteria for SARS-CoV-2 antigen testing for the 0 to 5 and 0 to 6 DSO ranges (PPA values of 83.9% and 82.4%, respectively). Veritor and Sofia 2 showed a high degree of agreement for SARS-CoV-2 detection. The Veritor test allows for more rapid COVID-19 testing utilizing easy-to-collect nasal swabs but demonstrated100% PPA compared to PCR.

Background DriveSafe DriveAware (DSDA) has been validated as an off-road screening tool for predicting on-road driving performance in clinical populations, but its utility in people with Huntington's disease (HD) is unknown. Objective Our aim was to evaluate the utility of DSDA in people with HD by demonstrating sensitivity of DSDA scores to HD progression and exploring associations between DSDA performance and cognitive functions that are essential to driving and impaired in people with HD. Methods We administered the iPad application version of DSDA to 26 pre-symptomatic and symptomatic participants with HD. Disease progression was assessed via measures of motor impairment, disease burden and functional capacity. Standardised neuropsychological tests were used to assess cognitive function across several domains including attention, processing speed, planning, and visuoperception. Results Results underscore the sensitivity of DSDA to HD progression and cognitive impairment; that is, poorer DSDA performance was associated with greater HD severity and poorer cognitive ability across the domains of attention, processing speed, and planning. Nevertheless, we identified a proportion of participants with HD who were predicted to pass on-road testing based on DSDA, but scored in the impaired range on multiple cognitive tests. These participants tended to score closer to the cut-off score used by DSDA to categorise pass/fail outcomes. Conclusions Our findings demonstrate potential for use of DSDA in the HD population, however, significant variability in cognitive performance among those predicted to 'pass' on-road driving assessment suggests the screening tool requires further development for use with HD drivers.

Smartphone-based cognitive assessment measures allow efficient, rapid, and convenient collection of cognitive datasets. Establishment of feasibility and validity is essential for the widespread use of this approach. We describe a novel smartphone application (HD-Mobile) that includes three performance-based cognitive tasks with four key outcome measures, for use with Huntington's disease (HD) samples. We describe known groups and concurrent validity, test-retest reliability, sensitivity, and feasibility properties of the tasks.Forty-two HD CAG-expanded participants (20 manifest, 22 premanifest) and 28 healthy controls completed HD-Mobile cognitive tasks three times across an 8-day period, on days 1, 4, and 8. A subsample of participants had pen-and-paper cognitive task data available from their most recent assessment from their participation in a separate observational longitudinal study, Enroll-HD.Manifest-HD participants performed worse than healthy controls for three of four HD-Mobile cognitive measures, and worse than premanifest-HD participants for two of four measures. We found robust test-retest reliability for manifest-HD participants (ICC = 0.71-0.96) and with some exceptions, in premanifest-HD (ICC = 0.52-0.96) and healthy controls (0.54-0.96). Correlations between HD-Mobile and selected Enroll-HD cognitive tasks were mostly medium to strong (r = 0.36-0.68) as were correlations between HD-Mobile cognitive tasks and measures of expected disease progression and motor symptoms for the HD CAG-expanded participants (r = - 0.34 to - 0.54).Results indicated robust known-groups, test-retest, concurrent validity, and sensitivity of HD-Mobile cognitive tasks. The study demonstrates the feasibility and utility of HD-Mobile for conducting convenient, frequent, and potentially ongoing assessment of HD samples without the need for in-person assessment.

BackgroundAlzheimer’s disease (AD) is an irreversible neurodegenerative disease without a cure or prevention to date. The defining features of AD include neurofibrillary tangles (NFTs) of hyperphosphorylated tau fibrils, and the senile plaques of β amyloid (Aβ) aggregates. In addition to AD, aggregation of hyperphosphorylated tau underlies approximately 20 neurodegenerative disorders collectively known as tauopathies, suggesting a pathogenic role of tau fibrils. The majority of AD disease-modifying drug trials targeted Aβ control, which have yet to produce satisfactory outcomes. The interest of developing anti-NFT drugs has been increasing. However, an effective method that produces hyperphosphorylated tau with disease relevant characters to support drug discovery is lacking.MethodsWe previously reported the PIMAX system for the production of recombinant proteins bearing a desired post-translational modification. Here we use PIMAX to express hyperphosphorylated tau (p-tau) in E. coli, and subjected this p-tau to mass spectrometry mapping of phosphorylation, to biochemical and biophysical assays of fibrillogenesis, and to cell culture treatment for the effects of hyperphosphorylation on tau molecular characters.ResultsMass spectrometry mapped p-tau phosphorylation to phosphoepitopes linked to AD pathological progression. In stark contrast to the unmodified tau that required an inducer for efficient aggregation, and which had only mild effects on cell functions, p-tau formed fibrils in an inducer-free and redox-independent manner. Immediately after the purification, a disease-specific conformation recognized by the MC-1 monoclonal antibody was readily detectable, which continued to increase during the fibrillization reaction. When applied to cultured cells, p-tau triggered a spike of mitochondrial superoxide, induced apoptosis, and caused cell death at sub-micromolar concentrations. In both aggregation and cytotoxicity assays, p-tau exhibited seeding activities that converted the unmodified tau into a cytotoxic species with increased propensity for fibrillization, consistent with the emerging view that hyperphosphorylated tau spreads in a prion-like fashion.ConclusionsHyperphosphorylation potentiates tau fibrillization and cytotoxicity. These characters are consistent with the model that abnormally phosphorylated tau plays a direct role in neurodegeneration in tauopathies. We suggest that p-tau produced by PIMAX affords a feasible tool for drug discovery and disease mechanistic studies for Alzheimer's disease and other tauopathies.