Ex-situ machine perfusion in clinical liver transplantation: Current practices and future directions.

Ex-situ machine perfusion of the liver has surmounted traditional limitations associated with static cold storage in the context of organ preservation. This innovative technology has changed the landscape of liver transplantation by mitigating ischemia perfusion injury, offering a platform for continuous assessment of organ quality, and providing an avenue for optimizing use of traditionally marginal allografts. This review summarizes the contemporary clinical applications of machine perfusion devices, and discusses potential future strategies for real-time viability assessment, therapeutic interventions, and modulation of organ function after recovery.

"Good Care Is Slow Enough to Be Able to Pay Attention": Primary Care Time Scarcity and Patient Safety.

BACKGROUND: There is growing, widespread recognition that expectations of US primary care vastly exceed the time and resources allocated to it. Little research has directly examined how time scarcity contributes to harm or patient safety incidents not readily capturable by population-based quality metrics. OBJECTIVE: To examine near-miss events identified by primary care physicians in which taking additional time improved patient care or prevented harm. DESIGN: Qualitative study based on semi-structured interviews. PARTICIPANTS: Twenty-five primary care physicians practicing in the USA. APPROACH: Participants completed a survey that included demographic questions, the Ballard Organizational Temporality Scale and the Mini-Z scale, followed by a one hour qualitative interview over video-conference (Zoom). Iterative thematic qualitative data analysis was conducted. KEY RESULTS: Primary care physicians identified several types of near-miss events in which taking extra time during visits changed their clinical management. These were evident in five types of patient care episodes: high-risk social situations, high-risk medication regimens requiring patient education, high acuity conditions requiring immediate workup or treatment, interactions of physical and mental health, and investigating more subtle clinical suspicions. These near-miss events highlight the ways in which unreasonably large patient panels and packed schedules impede adequate responses to patient care episodes that are time sensitive and intensive or require flexibility. CONCLUSIONS: Primary care physicians identify and address patient safety issues and high-risk situations by spending more time than allotted for a given patient encounter. Current quality metrics do not account for this critical aspect of primary care work. Current healthcare policy and organization create time scarcity. Interventions to address time scarcity and to measure its prevalence and implications for care quality and safety are urgently needed.

Three-dimensional telomere profiling predicts risk of progression in smoldering multiple myeloma.

Smoldering multiple myeloma (SMM) is a precursor stage that precedes multiple myeloma (MM). SMM is heterogenous with nearly 40% of patients progressing to MM in the first 5 years. The high rate of progression of SMM patients highlights the need for early intervention, which underscores the importance of identifying SMM patients with the highest risk of progression. Several risk stratification models showed utility in identifying high-risk SMM patients; however, these systems showed limited sensitivity. To date, identifying high-risk SMM patients remains an important clinical need. In this study, we present the 3-dimensional telomere profiling as a structural biomarker capable of stratifying SMM patients as a function of genomic instability. Quantifying telomere dysfunction using the TeloView technology showed utility in risk stratification of cancer patients, particularly hematological malignancies. In this study, we analyzed 168 SMM patients. We report an AUC in ROC analysis of 0.8 using a subset of the patients as a training dataset. We then conducted a blind validation on a different cohort and demonstrated a positive predictive value of 85% and negative predictive value of 73%, with sensitivity and specificity of 83% and 76%, respectively. We examined the correlation between the TeloView prediction and the 20-2-20 scoring system, and cytogenetic abnormalities. We report a correlation of 53% with the 20-2-20 scores and over 60% correlation with cytogenetic abnormalities. The result of this study presents the telomere profiling as an effective biomarker able to stratify SMM patients to their respective risk groups with high sensitivity and specificity.

Culturally Competent Approaches in Addressing Hypertension Control Disparities in African Americans: The Pharmacist's Perspective.

In the United States, cardiovascular disease (CVD) is the leading cause of death. Despite advancements in the identification of risk factors and management of CVD leading to improved mortality over the years, disparities in outcomes persist among racial/ethnic groups. In this commentary, we discuss the multifaceted nature of this issue, including structural barriers and historical injustices that lead to healthcare mistrust. Emphasizing culturally appropriate approaches, we explore the pharmacist's role in providing culturally competent care and propose policy recommendations to improve disparities in blood pressure outcomes. The paper underscores the importance of collaborative efforts among healthcare providers, policymakers, and communities to address this critical public health challenge.

Combination biologics or targeted synthetic disease-modifying anti-rheumatic drugs in the treatment of spondyloarthritis: a systematic literature review.

INTRODUCTION: The advent of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have transformed the management of immune-mediated rheumatic diseases, including spondylarthritis (SpA). However, the data about combining b/ts DMARDs in the treatment of SpA are scarce. The study objectives were to assess the efficacy and safety of combination b/tsDMARD in SpA. METHODS: We conducted systematic literature review (PubMed and Medline) with two independent reviewers, one adjudicator, exploring the efficacy and safety of combination b/tsDMARDs in the treatment of SpA. Inclusion criteria were studies published in last 20 years, English language, interventions included use of two b/tsDMARDs, and minimal three-month follow-up. RESULTS: Out of 1936 initial hits, 28 manuscripts fulfilled the inclusion criteria. Two were randomized controlled trials, and the remaining were retrospective cohort studies or case series. Combination of apremilast with bDMARD, or TNF inhibitor plus IL12/23 inhibitor were the commonest and reported good efficacy with no increased safety signal. CONCLUSIONS: There is not enough data to fully evaluate efficacy and safety of combination b/tsDMARDs in SpA treatment. Limited information shows apremilast plus bDMARD, or TNF inhibitor plus IL12/23 inhibitor combination to be efficacious and safe. Randomized controlled trials and larger cohort with a longer follow-up are required.

Circulating Cell Free DNA and DNA Double-Strand Breakage in Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that is characterized by memory loss and multiple cognitive impairments. AD is pathologically characterized by age-dependent accumulation of amyloid-ß protein and the phosphorylation of tau protein in the brains of patients with AD. Clinically, manifestations of AD include cognitive decline, dementia, alterations of high-order brain functions, and movement disorders. Double-stranded DNA breaks are a lethal form of DNA damage and are typically repaired via non-homologous end joining and homologous recombination. However, in AD brain, repair mechanism is disrupted, leading to a cascade of events, cognitive dysfunction, organ failure and reduced lifespan. Increased circulating cell-free DNA in the blood, cerebrospinal fluid, and urine in patients with AD, can be used as early detectable biomarkers for AD. The purpose of our article is to explore the potential uses of cell-free DNA and double-stranded DNA breaks as prognostic markers for AD and examine the recent research on the application of these markers in studies.

Reproductive planning and infertility: Training the next generation of surgeons.

BACKGROUND: Female surgeons face increased rates of fertility challenges compared to the general population. We aim to understand surgical trainees' understanding and perspectives on family planning. METHODS: A 35-question survey was emailed to program directors at all US surgical residency programs for distribution to residents. Descriptive analyses were performed to evaluate resident understanding and perspectives on family planning and fertility treatments. RESULTS: A total of 121 residents responded to the survey. Most were female (n â€‹= â€‹78; 65 â€‹%). Responders indicated the need to postpone pregnancy during training (female: n â€‹= â€‹48, 64 â€‹% vs male n â€‹= â€‹18, 45 â€‹%; p â€‹= â€‹0.09). Potential negative career consequences (n â€‹= â€‹50; 42 â€‹%), limited leave benefits (n â€‹= â€‹47; 39 â€‹%), and lack of childcare (n â€‹= â€‹45; 38 â€‹%) were primary reasons for postponing pregnancy. Only nine responders (8 â€‹%) received fertility-preservation education. CONCLUSION: Surgical trainees delay pregnancy for career and social support concerns and are interested in reproductive preservation. Fertility education could provide needed support for trainees.

Primary Care Physicians' Experiences With and Adaptations to Time Constraints.

Importance: The primary care workforce shortage is significant and persistent, with organizational and policy leaders urgently seeking interventions to enhance retention and recruitment. Time constraints are a valuable focus for action; however, designing effective interventions requires deeper understanding of how time constraints shape employees' experiences and outcomes of work. Objective: To examine how time constraints affect primary care physicians' work experiences and careers. Design, Setting, and Participants: Between May 1, 2021, and September 31, 2022, US-based primary care physicians who trained in family or internal medicine were interviewed. Using qualitative analysis of in-depth interviews, this study examined how participants experience and adapt to time constraints during a typical clinic day, taking account of their professional and personal responsibilities. It also incorporates physicians' reflections on implications for their careers. Main Outcomes and Measures: Thematic analysis of in-depth interviews and a measure of well-being (American Medical Association Mini-Z survey). Results: Interviews with 25 primary care physicians (14 [56%] female and 11 [44%] male; median [range] age, 43 [34-63] years) practicing in 11 US states were analyzed. Two physicians owned their own practice, whereas the rest worked as employees. The participants represented a wide range of years in practice (range, 1 to ≥21), with 11 participants (44%) in their first 5 years. Physicians described that the structure of their work hours did not match the work that was expected of them. This structural mismatch between time allocation and work expectations created a constant experience of time scarcity. Physicians described having to make tradeoffs between maintaining high-quality patient care and having their work overflow into their personal lives. These experiences led to feelings of guilt, disillusionment, and dissatisfaction. To attempt to sustain long-term careers in primary care, many sought ways to see fewer patients. Conclusions and Relevance: These findings suggest that organizational leaders must align schedules with work expectations for primary care physicians to mitigate physicians' withdrawal from work as a coping mechanism. Specific strategies are needed to achieve this realignment, including incorporating more slack into schedules and establishing realistic work expectations for physicians.

The Interplay between Mycobacterium tuberculosis and Human Microbiome.

Tuberculosis (TB), a respiratory disease caused by Mycobacterium tuberculosis (Mtb), is a significant cause of mortality worldwide. The lung, a breeding ground for Mtb, was once thought to be a sterile environment, but has now been found to host its own profile of microbes. These microbes are critical in the development of the host immune system and can produce metabolites that aid in host defense against various pathogens. Mtb infection as well as antibiotics can shift the microbial profile, causing dysbiosis and dampening the host immune response. Additionally, increasing cases of drug resistant TB have impacted the success rates of the traditional therapies of isoniazid, rifampin, pyrazinamide, and ethambutol. Recent years have produced tremendous research into the human microbiome and its role in contributing to or attenuating disease processes. Potential treatments aimed at altering the gut-lung bacterial axis may offer promising results against drug resistant TB and help mitigate the effects of TB.

Changes in Illicit Drug Use Among High School Students in Southeastern U.S. States-2009 to 2019.

To determine if decreasing lifetime use of methamphetamines, cocaine, ecstasy, and inhalants among high school students occurring from 2009 to 2019 in the U.S. also occurred in five southeastern states, Youth Risk Behavior Survey data representative of high school students in grades 9-12 in 2009 and 2019 were analyzed. In a classroom setting, lifetime use of methamphetamines, cocaine, ecstasy, and inhalants were self-reported. Students nationwide (n = 30,087) were compared to students in Alabama, Georgia, Louisiana, Mississippi, and South Carolina (n = 18,237). Lifetime methamphetamine use significantly increased from 4.8% in 2009 to 6.2% in 2019 in the southeast but decreased from 4.1 to 2.2% nationwide. Use of cocaine, ecstasy, and inhalants remained stable in the southeast while decreasing significantly nationwide from 2009 to 2019. During a period when use of methamphetamines, cocaine, ecstasy, and inhalants among high school students in the U.S. decreased, use in southeastern states did not change. Culturally specific programs and interventions may be needed to prevent illicit drug use in communities of southeastern states where youth remain at risk.

Consumption of 100% Fruit Juice and Body Weight in Children and Adults: A Systematic Review and Meta-Analysis.

Importance: Concerns have been raised that frequent consumption of 100% fruit juice may promote weight gain. Current evidence on fruit juice and weight gain has yielded mixed findings from both observational studies and clinical trials. Objective: To synthesize the available evidence on 100% fruit juice consumption and body weight in children and adults. Data Sources: MEDLINE, Embase, and Cochrane databases were searched through May 18, 2023. Study Selection: Prospective cohort studies of at least 6 months and randomized clinical trials (RCTs) of at least 2 weeks assessing the association of 100% fruit juice with body weight change in children and adults were included. In the trials, fruit juices were compared with noncaloric controls. Data Extraction and Synthesis: Data were pooled using random-effects models and presented as ß coefficients with 95% CIs for cohort studies and mean differences (MDs) with 95% CIs for RCTs. Main Outcomes and Measures: Change in body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was assessed in children and change in body weight in adults. Results: A total of 42 eligible studies were included in this analysis, including 17 among children (17 cohorts; 0 RCTs; 45 851 children; median [IQR] age, 8 [1-15] years) and 25 among adults (6 cohorts; 19 RCTs; 268 095 adults; median [IQR] age among cohort studies, 48 [41-61] years; median [IQR] age among RCTs, 42 [25-59]). Among cohort studies in children, each additional serving per day of 100% fruit juice was associated with a 0.03 (95% CI, 0.01-0.05) higher BMI change. Among cohort studies in adults, studies that did not adjust for energy showed greater body weight gain (0.21 kg; 95% CI, 0.15-0.27 kg) than studies that did adjust for energy intake (-0.08 kg; 95% CI, -0.11 to -0.05 kg; P for meta-regression <.001). RCTs in adults found no significant association of assignment to 100% fruit juice with body weight but the CI was wide (MD, -0.53 kg; 95% CI, -1.55 to 0.48 kg). Conclusion and Relevance: Based on the available evidence from prospective cohort studies, in this systematic review and meta-analysis, 1 serving per day of 100% fruit juice was associated with BMI gain among children. Findings in adults found a significant association among studies unadjusted for total energy, suggesting potential mediation by calories. Further trials of 100% fruit juice and body weight are desirable. Our findings support guidance to limit consumption of fruit juice to prevent intake of excess calories and weight gain.

Dissecting quantitative trait nucleotides by saturation genome editing.

Genome editing technologies have the potential to transform our understanding of how genetic variation gives rise to complex traits through the systematic engineering and phenotypic characterization of genetic variants. However, there has yet to be a system with sufficient efficiency, fidelity, and throughput to comprehensively identify causal variants at the genome scale. Here we explored the ability of templated CRISPR editing systems to install natural variants genome-wide in budding yeast. We optimized several approaches to enhance homology-directed repair (HDR) with donor DNA templates, including donor recruitment to target sites, single-stranded donor production by bacterial retrons, and in vivo plasmid assembly. We uncovered unique advantages of each system that we integrated into a single superior system named MAGESTIC 3.0. We used MAGESTIC 3.0 to dissect causal variants residing in 112 quantitative trait loci across 32 environmental conditions, revealing an enrichment for missense variants and loci with multiple causal variants. MAGESTIC 3.0 will facilitate the functional analysis of the genome at single-nucleotide resolution and provides a roadmap for improving template-based genome editing systems in other organisms.