Prospective cohort study of rotational thromboelastometry in established biliary obstruction: dispelling the myth of auto-anticoagulation.

BACKGROUND: Patients with obstructive jaundice are conventionally described as hypocoagulable due to vitamin K malabsorption. However, associated underlying malignancy and synthetic liver dysfunction are mediators of hypercoagulability. The actual effect of biliary obstruction on the coagulation profile is not well characterised. This study aimed to define the coagulation status of patients with established biliary obstruction using rotational thromboelastometry (ROTEM). METHODS: This prospective cohort study, conducted in an Australian metropolitan hospital, included patients with a total bilirubin level of >150 umol/L and biliary obstruction on imaging. The primary outcome was the coagulation profile assessed using ROTEM. RESULTS: 20 patients were included (median age 74.5 years), 15 were male and 17 had a malignant cause for biliary obstruction. The median bilirubin level was 209 umol/L (IQR: 175.0 umol/L - 255.8 umol/L). On ROTEM, all patients had normal or reduced clot formation times, and normal or increased maximum clot firmness. This confirmed all patients had a normal or hypercoagulable clotting profile, and none were auto-anticoagulated. Vitamin K administration before ROTEM did not vary the coagulation profile. DISCUSSION: Patients with established biliary obstruction and jaundice, predominantly due to malignancy, were normo or hypercoagulable. The belief that obstructive jaundice is associated with a hypocoagulable state should be questioned.

Percutaneous Cholecystostomy for Acute Cholecystitis During Spaceflight.

INTRODUCTION: Acute calculous cholecystitis is a common surgical emergency and cholecystectomy is the gold-standard treatment. However, alternative drainage modalities such as percutaneous cholecystostomy tube (PCT) placement have been proposed for poor surgical candidates or in remote environments, such as space. We reviewed the literature to assess the theoretical utility of PCT to treat acute cholecystitis during long-duration spaceflight or on the Moon or Mars. METHODS: A systematic review of 16 peer-reviewed articles published since 2018 was completed to describe the terrestrial efficacy of PCT placement for acute calculous cholecystitis. RESULTS: The mean initial clinical success rate after PCT was 89.9% (range 82.2-100.0%). Duration of indwelling PCT ranged from median 6 to 58 d. Mean rate of recurrent cholecystitis was 15.8% (range 5.0-36.4%). A mean 35.6% of patients (range 18.0-61.0%) required interval cholecystectomy. Mean 30-d mortality was 9.6% (range 5.8-14.0%). A mean 18.6% of patients (range 7.2-30.0%) required repeat percutaneous intervention due to PCT placement complications. DISCUSSION: While PCT achieves high rates of early resolution of cholecystitis, the long-term outcomes after PCT are relatively poor, with risk of recurrent cholecystitis, need for cholecystectomy, and frequent postprocedural complications requiring repeat procedural interventions. In cislunar space, the return to Earth for cholecystectomy following PCT may be achieved, eliminating some of these concerns. However, with long-duration space travel such as a mission to Mars, PCT is likely inadequate for the long-term treatment of cholecystitis. Prophylactic cholecystectomy, developing surgical capabilities in space, or preflight screening ultrasound for cholelithiasis should be seriously considered for long-duration spaceflight. Lazow SP, Siu M, Brown L, Kamine TH. Percutaneous cholecystostomy for acute cholecystitis during spaceflight. Aerosp Med Hum Perform. 2024; 95(10):771-776.

Nuclear instance segmentation and tracking for preimplantation mouse embryos.

For investigations into fate specification and morphogenesis in time-lapse images of preimplantation embryos, automated 3D instance segmentation and tracking of nuclei are invaluable. Low signal-to-noise ratio, high voxel anisotropy, high nuclear density, and variable nuclear shapes can limit the performance of segmentation methods, while tracking is complicated by cell divisions, low frame rates, and sample movements. Supervised machine learning approaches can radically improve segmentation accuracy and enable easier tracking, but they often require large amounts of annotated 3D data. Here we first report a novel mouse line expressing near-infrared nuclear reporter H2B-miRFP720. We then generate a dataset (termed BlastoSPIM) of 3D images of H2B-miRFP720-expressing embryos with ground truth for nuclear instances. Using BlastoSPIM, we benchmark seven convolutional neural networks and identify Stardist-3D as the most accurate instance segmentation method. With our BlastoSPIM-trained Stardist-3D models, we construct a complete pipeline for nuclear instance segmentation and lineage tracking from the 8-cell stage to the end of preimplantation development (>100 nuclei). Finally, we demonstrate BlastoSPIM's usefulness as pre-train data for related problems, both for a different imaging modality and for different model systems.

Blending space and time to talk about cancer in extended reality.

We introduce a proof-of-concept extended reality (XR) environment for discussing cancer, presenting genomic information from multiple tumour sites in the context of 3D tumour models generated from CT scans. This tool enhances multidisciplinary discussions. Clinicians and cancer researchers explored its use in oncology, sharing perspectives on XR's potential for use in molecular tumour boards, clinician-patient communication, and education. XR serves as a universal language, fostering collaborative decision-making in oncology.

Predictors of Discharge with Supplemental Oxygen after Lobectomy for Lung Cancer.

BACKGROUND: Before lung cancer resection, patients inquire about dyspnea and the potential need for supplemental oxygen. Our objective was to identify predictors of discharge with supplemental oxygen for patients undergoing lobectomy for lung cancer. METHODS: Using the Society of Thoracic Surgeons General Thoracic Surgery Database, we conducted a retrospective cohort study of patients undergoing lobectomy for lung cancer from July 2018 - December 2021. Multivariable logistic regression was used to determine the adjusted association of pulmonary function with discharge on supplemental oxygen and identify independent predictors of discharge with supplemental oxygen. Pulmonary function was modeled as the minimum of either ppoFEV1 or ppoDLCO. RESULTS: Overall, 2,100 (8.4%) patients undergoing lobectomy were discharged with supplemental oxygen. Those with a minimum of either ppoFEV1 or ppoDLCO ≤60% had a progressively increased risk of discharge with supplemental oxygen than those with minimum function >60%. The two strongest predictors of discharge with supplemental oxygen were increasing BMI (25-29 aOR 1.38, 95%CI 1.21-1.57, 30-39 aOR 2.14, 95%CI 1.88-2.45, ≥40 aOR 3.51, 95%CI 2.79-4.39, reference 18.5-24) and former (aOR 2.04, 95%CI 1.67-2.52) and current (aOR 2.61, 95%CI 2.10-3.26) smoking status (reference never smoker). CONCLUSIONS: Of those undergoing lobectomy for lung cancer, 8.4% were discharged with supplemental oxygen. We identified preoperative independent predictors of discharge with supplemental oxygen that may be useful during shared decision-making discussions of treatment options for lung cancer and setting expectations with patients.

Comparative effectiveness of perioperative physical activity in older adults with lung cancer and their family caregivers: design of a multicenter pragmatic randomized trial.

BACKGROUND: With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. METHODS: In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. DISCUSSION: The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06196008.

Association between echocardiographic velocity time integral ratio of mitral valve and left ventricular outflow tract and clinical outcomes post transcatheter edge-to-edge mitral valve repair.

Background: Residual mitral regurgitation (MR) is frequent after transcatheter edge-to-edge repair (TEER). There is controversy regarding the clinical impact of residual MR and its quantitative assessment by transthoracic echocardiography (TTE), which is often challenging with multiple eccentric jets and artifact from the clip. The utility of the velocity time integral (VTI) ratio between the mitral valve (MV) and left ventricular outflow tract (LVOT), (VTIMV/LVOT), a simple Doppler measurement that increases with MR, has not been assessed post TEER. Methods: Baseline characteristics, clinical outcomes, and TTE data from patients who underwent TEER between 2014 and 2021 across three academic centers were retrospectively analyzed. Post-procedure TTEs were evaluated for VTIMV/LVOT in the first three months after TEER. One-year outcomes including all-cause and cardiac mortality, major adverse cardiac events, and MV reintervention were compared between patients with high VTIMV/LVOT (≥2.5) and low (<2.5). Results: In total, 372 patients were included (mean age 78.7 ± 8.8 years, 68 % male, mean pre-TEER ejection fraction of 50.5 ± 14.7 %). Follow up TTEs were performed at a median of 37.5 (IQR 30-48) days post-procedure. Patients with high VTIMV/LVOT had significantly higher all-cause mortality (HR 2.10, p = 0.003), cardiac mortality (HR 3.03, p = 0.004) and heart failure admissions (HR 2.28, p < 0.001) at one-year post-procedure. There was no association between raised VTIMV/LVOT and subsequent MV reintervention. Conclusion: High VTIMV/LVOT has clinically significant prognostic value at one year post TEER. This tool could be used to select patients for consideration of repeat intervention.

Case report: A novel somatic SDHB variant in a patient with bladder paraganglioma.

Background: Paragangliomas (PGL) are rare neuroendocrine tumors derived from the autonomic nervous system paraganglia. Urinary bladder paragangliomas (UBPGL) originate from the sympathetic neurons of the urinary bladder wall and represent 0.7% of all paragangliomas and <0.05% of all bladder tumors. PGL and UBPGL can be associated with SDHB, SDHD, NF1, and VHL gene variants, with the most common germline alterations found in SDHB and VHL. Case report: We report a case of a 42-year-old woman who presented with menorrhagia/hematuria, uterine leiomyomas, as well as cardiac and bladder masses. The cardiac mass was favored to be a myxoma based on clinical findings, while the bladder mass was diagnosed as UBPGL. A novel SDHB mutation (c.642G>A, p Q214Q), detected in the UBPGL, was proven to be somatic. Although this variant was seemingly synonymous, it was predicted to have a loss of function due to the splice site effect, which was further supported by the immunohistochemical loss of SDHB. Conclusion: This case highlights the challenges of diagnosing an extremely rare entity, bladder paraganglioma, with an emphasis on the multidisciplinary approach to navigate various clinical and imaging findings that may initially be misleading. In addition, a novel loss of function SDHB variant that could have been overlooked as a synonymous variant is herein reported, while also illustrating the importance of both germline and somatic mutation testing.

Influence of egg density on larval development and adult body size of cat fleas (Ctenocephalides felis).

Fleas (Siphonaptera) are holometabolous insects with larval and adult stages that exhibit vastly different ecologies from each other. Adult fleas are parasitic and feed exclusively on the blood of a vertebrate host, whereas flea larvae do not live on hosts and consume dried faecal blood from adult fleas. Because flea larvae rely on adult flea faeces for food, excrement and eggs must fall in the same location; thus, larval density is likely high in these restricted habitats. However, the influence of larval density on the subsequent adult stage has not been examined. In the present study, we utilized egg density to investigate density-dependent effects on larval development and adult body size in the cat flea (Ctenocephalides felis Bouché) (Siphonaptera: Pulicidae). Specifically, eggs were collected to create three different larval densities (n = 50, 100 and 150 per 56.7 cm2), and hatched larvae from all groups were fed an excess amount of adult faecal pellets. Larval development was measured by recording the proportion of eggs that developed to the pupal stage and the proportion of eggs that reached adulthood (eclosion). The body size of eclosed adults was quantified for both sexes using head length and length of the total body. We found that the number of eggs had no effect on the proportion of larvae that pupated or the proportion of larvae that eclosed; however, higher egg densities resulted in larger body sizes for both sexes. Overall, these data yield significant insight into how the ecology of larval fleas impacts the biology of the resultant adults.

Once-daily oral small-molecule glucagon-like peptide-1 receptor agonist lotiglipron (PF-07081532) for type 2 diabetes and obesity: Two randomized, placebo-controlled, multiple-ascending-dose Phase 1 studies.

AIM: To investigate the effects of lotiglipron (PF-07081532), a once-daily, oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes (T2D) and/or obesity. MATERIALS AND METHODS: Two Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending-dose studies were conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of lotiglipron. RESULTS: Across the studies, 74 participants with T2D were treated for 28 or 42 days, and 26 participants with obesity without diabetes were treated for 42 days, following randomization to placebo or lotiglipron (target doses 10-180 mg/day, with dose titration to higher target doses). Most adverse events were mild (89.6%), with nausea the most frequently reported in both studies. There were no clinically meaningful adverse trends noted in safety laboratory tests, vital signs, or electrocardiogram parameters. In participants with T2D, lotiglipron resulted in dose-dependent reductions in mean daily glucose. The 180-mg dose was associated with least squares mean decreases from baseline in glycated haemoglobin (-1.61% [90% confidence interval {CI} -2.08, -1.14] vs. -0.61% [-1.56, 0.34] for placebo) and body weight (-5.10 kg [90% CI -6.62, -3.58] vs. -2.06 kg [90% CI -4.47, 0.36] for placebo) after 42 days; a similar magnitude of weight loss was seen in participants with obesity. The observed pharmacokinetic profile supported once-daily dosing. CONCLUSIONS: The profile of once-daily lotiglipron with doses up to 180 mg, as observed in these two Phase 1 studies, indicated a safety and tolerability profile consistent with the mechanism of action, with dose-dependent reductions in glycaemic indices (T2D) and body weight (both populations) after multiple doses. CLINICALTRIALS: gov identifier: NCT04305587, NCT05158244.

Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients.

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care.

Ancient mitogenomes from Pre-Pottery Neolithic Central Anatolia and the effects of a Late Neolithic bottleneck in sheep (Ovis aries).

Occupied between ~10,300 and 9300 years ago, the Pre-Pottery Neolithic site of Asikli Höyük in Central Anatolia went through early phases of sheep domestication. Analysis of 629 mitochondrial genomes from this and numerous sites in Anatolia, southwest Asia, Europe, and Africa produced a phylogenetic tree with excessive coalescences (nodes) around the Neolithic, a potential signature of a domestication bottleneck. This is consistent with archeological evidence of sheep management at Asikli Höyük which transitioned from residential stabling to open pasturing over a millennium of site occupation. However, unexpectedly, we detected high genetic diversity throughout Asikli Höyük's occupation rather than a bottleneck. Instead, we detected a tenfold demographic bottleneck later in the Neolithic, which caused the fixation of mitochondrial haplogroup B in southwestern Anatolia. The mitochondrial genetic makeup that emerged was carried from the core region of early Neolithic sheep management into Europe and dominates the matrilineal diversity of both its ancient and the billion-strong modern sheep populations.

Associations of humor, morale, and unit cohesion on posttraumatic stress disorder symptoms.

Military personnel experience many stressors during deployments that can lead to symptoms of posttraumatic stress disorder (PTSD). However, not all military personnel who are exposed to deployment stressors develop PTSD symptoms. Recent research has explored factors that contribute to military personnel resilience, a multifaceted and multidetermined construct, as a means to mitigate and prevent PTSD symptoms. Much of this research has focused on the effects of individual-level factors (e.g., use of coping strategies like humor, the morale of individual unit members), with some research focusing on unit-level factors (e.g., the cohesiveness of a unit). However, there is little research exploring how these factors relate to each other in mitigating or reducing PTSD symptoms. In this study, we examined the association between deployment stressors, perceived unit cohesion, morale, humor, and PTSD symptoms in a sample of 20,901 active-duty military personnel using structural equation modeling. Results indicated that perceived unit cohesion, humor, and morale were positively associated with each other and negatively associated with PTSD symptoms over and above the effect of deployment stressors. These findings highlight the influence of resilience factors on PTSD symptoms beyond their substantial overlap and have implications for future research as well as the potential development of interventions for military personnel.

Identifying the Causes of Unexplained Dyspnea at High Altitude Using Normobaric Hypoxia with Echocardiography.

Exposure to high altitude results in hypobaric hypoxia, leading to physiological changes in the cardiovascular system that may result in limiting symptoms, including dyspnea, fatigue, and exercise intolerance. However, it is still unclear why some patients are more susceptible to high-altitude symptoms than others. Hypoxic simulation testing (HST) simulates changes in physiology that occur at a specific altitude by asking the patients to breathe a mixture of gases with decreased oxygen content. This study aimed to determine whether the use of transthoracic echocardiography (TTE) during HST can detect the rise in right-sided pressures and the impact of hypoxia on right ventricle (RV) hemodynamics and right to left shunts, thus revealing the underlying causes of high-altitude signs and symptoms. A retrospective study was performed including consecutive patients with unexplained dyspnea at high altitude. HSTs were performed by administrating reduced FiO2 to simulate altitude levels specific to patients' history. Echocardiography images were obtained at baseline and during hypoxia. The study included 27 patients, with a mean age of 65 years, 14 patients (51.9%) were female. RV systolic pressure increased at peak hypoxia, while RV systolic function declined as shown by a significant decrease in the tricuspid annular plane systolic excursion (TAPSE), the maximum velocity achieved by the lateral tricuspid annulus during systole (S' wave), and the RV free wall longitudinal strain. Additionally, right-to-left shunt was present in 19 (70.4%) patients as identified by bubble contrast injections. Among these, the severity of the shunt increased at peak hypoxia in eight cases (42.1%), and the shunt was only evident during hypoxia in seven patients (36.8%). In conclusion, the use of TTE during HST provides valuable information by revealing the presence of symptomatic, sustained shunts and confirming the decline in RV hemodynamics, thus potentially explaining dyspnea at high altitude. Further studies are needed to establish the optimal clinical role of this physiologic method.

Depression and Anxiety in Long-Term Care Residents During the COVID-19 Pandemic: The Influence of Telehealth Availability, Cognitive Status, and Trauma History.

OBJECTIVES: The present study investigates the impact of disrupted mental health services during the COVID-19 pandemic on depression and anxiety symptoms in long-term care (LTC) residents. METHODS: The study examined clinical data from 5,645 residents who received at least two psychological services in a long-term care (LTC) or assisted living (AL) setting between March 2019 and March 2021. A series of multiple regressions were run to explore the effects of the COVID-19 shutdown on depression and anxiety symptoms while examining the effects of COVID-19-related facility closure and facility telehealth capabilities. Follow-up regression analyses explored the impact of cognitive impairment and positive trauma history on depression and anxiety symptoms. RESULTS: Post-COVID levels of anxiety and depression were higher for residents with higher levels of pre-COVID anxiety and depression. The interaction between facility closure and availability of telehealth services and trauma history predicted self-report anxiety symptoms. Clinician-observed anxiety symptoms were predicted by cognitive impairment. Residents with a history of trauma had an increase in self-reported anxiety symptoms. CONCLUSIONS: Telehealth appeared to mitigate anxiety during the pandemic for residents with higher pre-COVID anxiety. CLINICAL IMPLICATIONS: For those individuals with severe anxiety, results suggest the importance of ensuring that mental health services are available to mitigate symptoms via telehealth when infection control disrupts the usual delivery of treatment.

The Society of Thoracic Surgeons General Thoracic Surgery Database: 2023 Update on Outcomes and Research.

The Society of Thoracic Surgeons General Thoracic Surgery Database (GTSD) continues its trajectory of growth and enhancement, solidifying its stature as a premier global thoracic surgical database. The past year witnessed a notable expansion with the inclusion of 10 additional participating sites, now totaling 287, augmenting the database's repository to more than 800,000 procedures. A significant stride was made in refining the data audit process, thereby elevating the accuracy and completeness metrics, a testament to the relentless pursuit of data integrity. The GTSD further broadened its research apparatus, with 15 scholarly publications, a 50% uptick from the preceding year. These publications underscore the database's instrumental role in advancing thoracic surgical knowledge. In a concerted effort to alleviate data entry exigencies, the GTSD Task Force also instituted streamlined data submission protocols, a move lauded by participant sites. This report delineates the recent advancements, volume trajectories, and outcome metrics and encapsulates the prolific research output emanating from the GTSD, reflecting a year of substantial progress and academic fecundity.

Using Augmented Mean Arterial Pressure to Identify High Mortality Risk Patients With Moderate Aortic Stenosis.

OBJECTIVE: To study the usefulness of a novel echocardiographic marker, augmented mean arterial pressure (AugMAP = [(mean aortic valve gradient + systolic blood pressure) + (2 × diastolic blood pressure)] / 3), in identifying high-risk patients with moderate aortic stenosis (AS). PATIENTS AND METHODS: Adults with moderate AS (aortic valve area, 1.0-1.5 cm2) at Mayo Clinic sites from January 1, 2010, through December 31, 2020, were identified. Baseline demographic, echocardiographic, and all-cause mortality data were retrieved. Patients were grouped into higher and lower AugMAP groups using a cutoff value of 80 mm Hg for analysis. Kaplan-Meier and Cox regression models were used to assess the performance of AugMAP. RESULTS: A total of 4563 patients with moderate AS were included (mean ± SD age, 73.7±12.5 years; 60.5% men). Median follow-up was 2.5 years; 36.0% of patients died. The mean ± SD left ventricular ejection fraction (LVEF) was 60.1%±11.4%, and the mean ± SD AugMAP was 99.1±13.1 mm Hg. Patients in the lower AugMAP group, with either preserved or reduced LVEF, had significantly worse survival performance (all P<.001). Multivariate Cox regression showed that AugMAP (hazard ratio, 0.962; 95% CI, 0.942 to 0.981 per 5-mm Hg increase; P<.001) and AugMAP less than 80 mm Hg (hazard ratio, 1.477; 95% CI, 1.241 to 1.756; P<.001) were independently associated with all-cause mortality. CONCLUSION: AugMAP is a simple and effective echocardiographic marker to identify high-risk patients with moderate AS independent of LVEF. It can potentially be used in the candidate selection process if moderate AS becomes indicated for aortic valve intervention in the future.