The evolution of non-small cell lung cancer metastases in TRACERx.

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.

Good performance in the management of acute heart failure in cardiogeriatric departments: the ICREX-94 experience.

CONTEXT: A growing number of elderly patients hospitalized for Acute Heart Failure (AHF) are being managed in cardiogeriatrics departments, but their characteristics and prognosis are poorly known. This study aimed to investigate the profile and outcome (rehospitalization at 90 days) of patients hospitalized for AHF in cardiogeriatrics departments in the Val-de-Marne area in the suburbs of Paris, and to compare them to AHF patients hospitalized in cardiology departments in the same area. METHODS: Observational study, ICREX-94, conducted in seven cardiology departments in France and three specific cardiogeriatrics departments in Val-de-Marne. RESULTS: A total of 308 patients were hospitalized for AHF between October 2017 and January 2019. During the 90 days following discharge, 29.6% patients were readmitted to the hospital. Compared with patients hospitalized in cardiology departments, patients in cardiogeriatrics departments were older (p < 0.001), less independent (living more often alone or in an institution) (p < 0.001), more often depressed (p < 0.001), had more often major neurocognitive disorder (p < 0.001), had a higher Human Development Index (HDI, p < 0.001), and were less often diagnosed with amyloidosis (p < 0.001). There was no difference in outcome whether patients were discharged from cardiology or cardiogeriatrics departments. The most frequent precipitating factors underlying AHF decompensation between the first and second hospitalization were arrhythmia and infection. CONCLUSION: AHF patients discharged from cardiogeriatrics departments, compared to cardiology departments, showed clinical differences but had the same prognosis regarding AHF rehospitalization at 90 days.

Practical Treatments Considering the Role of Sociocultural Factors on Problem Gambling.

Reviews of problem gambling (PG) literature increasingly recognize the ways in which different ethnic groups are affected by gambling behaviors, yet discourse, which considers sociocultural factors within PG, remains limited. Literature on this topic is influenced by large inconsistencies amongst research studies, overlapping terminology, and variability in the validity of research studies, making conclusions difficult to draw. Despite these discrepancies, this paper explores how sociocultural factors influence PG among diverse cultural groups and provides specific practical implications for treating PG disorders in culturally diverse populations. Notable factors that exacerbate PG behavior cross-culturally include substance abuse, low socioeconomic status, lack of social activities, and geographic location. Culturally sensitive treatment options such as Motivational Interviewing and Cognitive Behavioral Therapy have been identified as effective treatments for PG with culturally diverse populations. This paper extends current thought by providing practical treatment recommendations that consider the subtle nuances of diverse populations. It explains how treatment providers and behavioral addiction professionals can increase their understanding and skills when conceptualizing PG clients from a diverse background.

Comparing effectiveness of residential versus intensive virtual treatment for veterans with posttraumatic stress disorder.

OBJECTIVE: During the COVID-19 pandemic, restrictions imposed on residential treatment programs necessitated rapid implementation of virtual treatment delivery. Posttraumatic stress disorder (PTSD) Residential Rehabilitation Treatment Programs (P-RRTP) are a key mental health treatment for Veterans with PTSD who require more intensive interventions than outpatient care. During the pandemic, the W. G. (Bill) Hefner VA Healthcare System developed and implemented a Virtual Intensive Outpatient Program for PTSD (VIOPP) to meet the needs of the Veteran population. The purpose of this analysis was to compare the effectiveness of VIOPP to P-RRTP. METHOD: Analyses included N = 370 Veterans, n = 193 who completed P-RRTP between January 2018 to April 2020 and n = 177 who completed VIOPP between June 2020 and November 2022 and provided pre- and posttreatment scores. Pre- and posttreatment scores of the PTSD Checklist for DSM-5 (PCL-5) were available for all patients. Pre- and posttreatment depressive symptom scores from the Nine-item Patient Health Questionnaire (PHQ-9) were available for n = 254 Veterans. Paired and independent samples t tests evaluated differences in change scores overall and by treatment modality (residential vs. virtual). RESULTS: Results indicated a significant decrease in PCL-5 scores regardless of treatment modality, p < .001. Despite beginning VIOPP with significantly higher PCL-5 scores than P-RRTP, there were no significant differences in PCL-5 change scores between virtual (M = -16.94) and residential treatment (M = -17.10), p = .910. PHQ-9 scores also decreased significantly for both treatment groups. CONCLUSION: These analyses suggest that intensive virtual treatment has similar effectiveness to residential treatment for PTSD. This supports the development of intensive virtual interventions as viable alternatives to residential treatments and a valuable component within the continuum of PTSD care. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Internalizing and externalizing comorbidity and symptom burden in a VA ADHD specialty evaluation clinic.

The purpose of this study was to evaluate psychiatric diagnosis and symptom comorbidity in veterans diagnosed with attention-deficit/hyperactivity disorder (ADHD). Study design was retrospective chart review from an ADHD evaluation clinic at a Veterans Affairs hospital. Participants were 227 military veterans who completed a standardized ADHD assessment and produced valid Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) profiles. There were no differences in rates of internalizing or externalizing psychiatric conditions diagnosed in inattentive compared to combined ADHD presentations. However, compared to a subsample with no psychiatric diagnoses, individuals diagnosed with ADHD endorsed significantly more internalizing symptom burden, with combined ADHD veterans also endorsing significantly greater levels of negative emotions and neuroticism. Base rates of comorbid classes of psychiatric diagnoses were not increased in individuals with ADHD, though higher rates of trauma disorders were seen in the combined group compared to the inattentive group. Multivariate base rates of MMPI-2-RF Restructured Clinical scales across various subgroups are presented. There was evidence for differential phenotypes of psychiatric symptoms across ADHD presentations in clinically referred veterans, predominantly related to higher rates of internalizing symptoms.

Prescription, Compliance, and Burden Associated with Salt-Restricted Diets in Heart Failure Patients: Results from the French National OFICSel Observatory.

(1) Background: There is much debate about the use of salt-restricted diet for managing heart failure (HF). Dietary guidelines are inconsistent and lack evidence. (2) Method: The OFICSel observatory collected data about adults hospitalised for HF. The data, collected using study-specific surveys, were used to describe HF management, including diets, from the cardiologists' and patients' perspectives. Cardiologists provided the patients' clinical, biological, echocardiography, and treatment data, while the patients provided dietary, medical history, sociodemographic, morphometric, quality of life, and burden data (burden scale in restricted diets (BIRD) questionnaire). The differences between the diet recommended by the cardiologist, understood by the patient, and the estimated salt intake (by the patient) and diet burden were assessed. (3) Results: Between March and June 2017, 300 cardiologists enrolled 2822 patients. Most patients (90%) were recommended diets with <6 g of salt/day. Mean daily salt consumption was 4.7 g (standard deviation (SD): 2.4). Only 33% of patients complied with their recommended diet, 34% over-complied, and 19% under-complied (14% unknown). Dietary restrictions in HF patients were associated with increased burden (mean BIRD score of 8.1/48 [SD: 8.8]). (4) Conclusion: Healthcare professionals do not always follow dietary recommendations, and their patients do not always understand and comply with diets recommended. Restrictive diets in HF patients are associated with increased burden. An evidence-based approach to developing and recommending HF-specific diets is required.

Novel pyrrolidine melanin-concentrating hormone receptor 1 antagonists with reduced hERG inhibition.

We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition.

Effect of lipid head groups on double-layered two-dimensional crystals formed by aquaporin-0.

Aquaporin-0 (AQP0) is a lens-specific water channel that also forms membrane junctions. Reconstitution of AQP0 with dimyristoyl phosphatidylcholine (DMPC) and E. coli polar lipids (EPL) yielded well-ordered, double-layered two-dimensional (2D) crystals that allowed electron crystallographic structure determination of the AQP0-mediated membrane junction. The interacting tetramers in the two crystalline layers are exactly in register, resulting in crystals with p422 symmetry. The high-resolution density maps also allowed modeling of the annular lipids surrounding the tetramers. Comparison of the DMPC and EPL bilayers suggested that the lipid head groups do not play an important role in the interaction of annular lipids with AQP0. We now reconstituted AQP0 with the anionic lipid dimyristoyl phosphatidylglycerol (DMPG), which yielded a mixture of 2D crystals with different symmetries. The different crystal symmetries result from shifts between the two crystalline layers, suggesting that the negatively charged PG head group destabilizes the interaction between the extracellular AQP0 surfaces. Reconstitution of AQP0 with dimyristoyl phosphatidylserine (DMPS), another anionic lipid, yielded crystals that had the usual p422 symmetry, but the crystals showed a pH-dependent tendency to stack through their cytoplasmic surfaces. Finally, AQP0 failed to reconstitute into membranes that were composed of more than 40% dimyristoyl phosphatidic acid (DMPA). Hence, although DMPG, DMPS, and DMPA are all negatively charged lipids, they have very different effects on AQP0 2D crystals, illustrating the importance of the specific lipid head group chemistry beyond its mere charge.

False positive GI bleed on Tc-99m RBC scintigraphy due to ileal varices.

Tc-99m labeled RBC scintigraphy is commonly employed in the evaluation of acute gastrointestinal bleeding. On Tc-99m RBC studies gastrointestinal bleeding is seen as an initial focus of increased radiotracer activity that on subsequent images increases in intensity and changes position in a pattern that conforms to segments of bowel. We report a case of a patient with multiple episodes of hematochezia that presented with lower gastrointestinal hemorrhage. A Tc-99m labeled RBC scan was performed and the findings suggested a GI bleed. However, subsequent angiography revealed prominent ileal varices simulating an acute bleed. Although most varices fill promptly and should not be misinterpreted as a focus of hemorrhage, slow filling varices can simulate an acute bleed and lead to a false positive interpretation.