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Background Patients with advanced biliary tract cancers (BTCs) have poor prognoses and limited therapeutic options. Renin-angiotensin antagonists (ACE-I/ARBs), statins, and aspirin may have potential anti-tumorigenic effects and decrease mortality per retrospective analyses in some solid tumors. Objective To evaluate the efficacy of ACE-Is/ARBs, statins, and/or aspirin concurrent to first-line systemic therapy in patients with advanced or metastatic BTC. Methods Adult patients at University of Michigan with pathologic confirmation of BTC between January 2010 and December 2020 were included in this retrospective analysis. Results Of 1140 patients who met eligibility, a total of 509 patients received one or more concomitant medication(s) of interest in conjunction with systemic therapy for advanced cancer. In the total cohort, the overall survival for locally advanced patients (N = 305) was 16.3 months (95% CI: 12.1-18.6), and metastatic patients (N = 512) 8.6 months (95% CI: 7.6-9.5); P < .0001. Within this concomitant medication cohort, patients with locally advanced stage (n = 132) experienced significantly longer progression-free survival (9.8 vs 4.5; P < 0.0001), and overall survival (17.4 vs 10.6; P < 0.0001) than those with metastatic (n = 297) cancer, respectively. Patients who received ACE-Is/ARBs, statins, and/or aspirin (n = 245) versus not (n = 264) concurrent with systemic anti-cancer therapy did not experience improved progression-free (5.5 vs 5.5 months; hazard ratio (HR) 1.1; P = 0.51), or overall survival (12.3 vs 12.6 months; HR 1.1; P = 0.18), respectively. Conclusion In contrast to prior studies, no progression free or overall survival benefit in patients with advanced BTC from concurrent use of ACE-I/ARBs, statin, and/or aspirin with systemic therapy was observed when assessed by BTC subtype or specific systemic therapy regimen. Patients with advanced biliary tract cancers have poor prognoses and limited therapeutic options. This study evaluated the efficacy of renin-angiotensin antagonists (ACE-Is/ARBs), statins, and/or aspirin when given concurrently with first-line systemic therapy in patients with advanced or metastatic biliary tract cancer.

IntroductionNausea, vomiting, constipation, and diarrhea are common cancer and cancer therapy adverse effects. Pharmacists are uniquely positioned to optimize patient symptom control and minimize excess use of hospital resources, such as emergency department visits.MethodsMichigan Medicine oncology clinical pharmacists have been independently providing patient symptom management through a collaborative drug therapy management (CDTM) program which established guidelines for management of gastrointestinal toxicities (nausea, vomiting, diarrhea, and/or constipation) secondary to a patient’s cancer diagnosis or treatment of the cancer. Patients were referred to the pharmacist by the treating oncologist or hematologist.ResultsFrom June 2019 to May 2020, there were a total of 62 patient referrals. Ten of the 62 referrals did not meet the CDTM inclusion criteria, resulting in 52 patients who were managed by the pharmacists. The total number of individual pharmacist visits was 136, with a median of 2.2 (range, 0–11) visits per patient referred. A total of 169 categorized pharmacist interventions were captured. Most interventions (100/169, 59.2%) were related to nausea/vomiting. Diarrhea-related and constipation-related interventions accounted for 10 (5.9%) and 13 (7.7%) of the total interventions, respectively. Most patients (36/52, 69.2%) had a reduction in the severity of their referral diagnosis symptom(s) based on Common Terminology Criteria for Adverse Events grading.ConclusionThe Michigan Medicine Pharmacist CDTM program allowed pharmacists to independently manage gastrointestinal toxicities of patients with cancer and improved patient symptom severity. The CDTM program has the opportunity to improve quality of care.

In a time of unprecedented ecological change, understanding natural biophysical relationships between reef resilience and physical drivers is of increasing importance. This study evaluates how wave forcing structures coral reef benthic community composition and recovery trajectories after the major 2015/2016 bleaching event in the remote Chagos Archipelago, Indian Ocean. Benthic cover and substrate rugosity were quantified from digital imagery at 23 fore reef sites around a small coral atoll (Salomon) in 2020 and compared to data from a similar survey in 2006 and opportunistic surveys in intermediate years. Cluster analysis and principal component analysis show strong separation of community composition between exposed (modelled wave exposure > 1000 J m−3) and sheltered sites (< 1000 J m−3) in 2020. This difference is driven by relatively high cover of Porites sp., other massive corals, encrusting corals, soft corals, rubble and dead table corals at sheltered sites versus high cover of pavement and sponges at exposed sites. Total coral cover and rugosity were also higher at sheltered sites. Adding data from previous years shows benthic community shifts from distinct exposure-driven assemblages and high live coral cover in 2006 towards bare pavement, dead Acropora tables and rubble after the 2015/2016 bleaching event. The subsequent recovery trajectories at sheltered and exposed sites are surprisingly parallel and lead communities towards their respective pre-bleaching communities. These results demonstrate that in the absence of human stressors, community patterns on fore reefs are strongly controlled by wave exposure, even during and after widespread coral loss from bleaching events.

BackgroundThe 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as ‘strong’ evidence (PS4) towards pathogenicity.MethodsWe developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non-association (eg, OR≤1).ResultsPS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation.ConclusionPS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework.

Background Recent literature has indicated altitude may be a protective factor for concussion but it is unknown whether altitude or heat index affects recovery. Objective To examine whether on-field heat index and altitude at the time of injury alter acute (< 48 h) concussion assessments, days-to-asymptomatic, and days-to-return-to-play in collegiate athletes following concussion. Methods Collegiate athletes ( n  = 187; age = 19.7 ± 1.4 years; male = 70.6%) underwent baseline assessments across 30 universities and experienced a concussion in this retrospective cohort study. Altitude (m) and heat index (°C) at the time and location of injury were determined using valid online database tools. Acute concussion assessments included the Sport Concussion Assessment Tool (SCAT) symptom inventory, Balance Error Scoring System (BESS), and the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). We used multiple linear regression models to determine whether heat index and altitude predicted each acute assessment outcome, days-to-asymptomatic, and days-to-return-to-play. Results Collegiate athletes were concussed at a 181.1 m (range − 0.6 to 2201.9 m) median altitude and 17.8 °C (range − 6.1 to 35.6 °C) median heat index. Altitude did not predict ( p  ≥ 0.265) any outcomes. Every one-degree increase in heat index reduced days-to-asymptomatic ( p  = 0.047; R 2  = 0.06) and days-to-return-to-play ( p  = 0.006; R 2  = 0.09) by 0.05 and 0.14 days, respectively. Heat index and altitude did not explain significant variance in SCAT, BESS, and ImPACT composite scores ( p ’s = 0.20–0.922). Conclusion Our findings suggest that on-field altitude and heat index at the time of injury do not contribute to clinically meaningful changes on acute assessments or concussion recovery. On-field altitude and heat index do not appear to significantly alter assessment outcomes or clinical recovery, suggesting that environmental factors at altitudes below < 2500 m are negligible outcomes for researchers and clinicians to consider post-concussion.

Early in ontogeny, the secondary lymphoid organs become populated with numerous cells of mesodermal origin which forms both the lymphoid and stromal elements. The critical receptor/ligand interactions necessary for lymphoid organogenesis to occur are for the most part unknown. Although lymphotoxin-α (LTα ) has been shown to be required for normal lymph node, Peyer's patch, and splenic development, it is unclear if soluble LTα 3, and/or cell-bound lymphotoxin-α β (LTα β ) mediate these developmental events. Here we report that blocking LTα β /lymphotoxin-β receptor (LTβ R) interaction in vivo by generating mice which express a soluble LTβ R-Fc fusion protein driven by the human cytomegalovirus promoter results in an array of anatomic abnormalities affecting both the spleen and Peyer's patches, but not the lymph nodes. These results demonstrate that surface LTα β ligand plays a critical role in normal lymphoid organ development.

The results of a study demonstrate that surface lymphotoxinalphabeta ligand plays a critical role in normal lymphoid organ development. In the study, the human IgG1 Fc component was specifically mutated to inhibit FcR binding and complement fixation.