Browse Articles
Discover research articles across all indexed journals
Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice
There is no cure for Marinesco-Sjögren syndrome (MSS), a genetic multisystem disease linked to loss-of-function mutations in the SIL1 gene, encoding a BiP co-chaperone. Previously, we showed that the PERK kinase inhibitor GSK2606414 delays cerebellar Purkinje cell (PC) degeneration and the onset of ataxia in the woozy mouse model of MSS. However, GSK2606414 is toxic to the pancreas and does not completely rescue the woozy phenotype. The present study tested trazodone and dibenzoylmethane (DBM), which partially inhibit PERK signaling with neuroprotective effects and no pancreatic toxicity. We also tested the chemical chaperone tauroursodeoxycholic acid (TUDCA), which protects MSS patients’ cells from stress-induced apoptosis. Mice were chronically treated for five weeks, starting from a presymptomatic stage. Trazodone was given 40 mg/kg daily by intraperitoneal (ip) injection. DBM was given 0.5% in the diet ad libitum. TUDCA was given either 0.4% in the diet, or 500 mg/kg ip every three days. None of the treatments prevented motor dysfunction or PC degeneration in woozy mice, as assessed by beam walking, rotarod test, and calbindin immunohistochemistry. Only trazodone slightly boosted beam walking performance, but this effect was not related to inhibition of PERK signaling. Pharmacokinetic studies excluded that the lack of effect was due to altered drug metabolism in woozy mice. These results indicate that trazodone, DBM and TUDCA, at dosing regimens active in other neurodegenerative disease mouse models, have no disease-modifying effect in a preclinical model of MSS. This underscores the difficulty of translating neuroprotective strategies from other conditions to MSS, highlighting the need for more targeted therapeutic approaches.
Specialty palliative care use among cancer patients: A population-based study
Background Rigorous population-based assessments of the use of specialty palliative care (SPC) in the US are rare. Settings/subjects This study examined SPC use among cancer patients in a mid-sized metropolitan area in Southeast US. Measurements In this cancer decedent cohort study, data were acquired and linked from the state-wide cancer registry; state-wide hospital discharge dataset; and local SPC providers. Results 12,030 individuals with cancer were included in this study; only 2,958 (24.6%) used SPC. Of the 9,072 persons who did not use SPC, 3,877 (42.7%) went only to hospitals that did not offer SPC; and 3,517 (38.8%) went to hospitals that offered SPC but did not use it. About half of SPC recipients (1493; 50.5%) first received SPC in the final 30 days of life, including 768 (26.0%) in the final week of life. Characteristics associated with using SPC use included being in an socio-economic status quintile other than the lowest; being younger; being Black; having a solid (versus hematological) cancer; having a shorter survival with cancer; dying in the latter two years of the study; being from an area of low or complete rurality; having a hospital admission in the final 60 days prior to initiation of PC or death; having more days in hospital; and living within 15 miles of a hospital offering SPC. Conclusions In this population-based study, only one-quarter of cancer patients used SPC, and for half who did so, it came in the final 30 days of life.
Clinical course and neurological outcomes of cerebral venous sinus thrombosis: A single center retrospective observational study
Background Cerebral venous sinus thrombosis (CVST) is a rare type of thrombosis that affects the cerebral venous system. The data on neurological outcomes are limited. Objectives This study aimed to investigate the neurological outcomes of CVST, contributing factors, clinical presentation, treatment and mortality. Methods This was a single-center, retrospective study at a university-based referral hospital in Thailand. Consecutive patients diagnosed with CVST between January 2010 and December 2020 were included. Outcomes were neurological outcomes measured by modified Rankin Scale (mRS), anticoagulant treatment, recurrence, and mortality. Results One hundred and seven CVST patients were included with a mean age (± SD) of 42.7 ± 20.4 years. Following the treatment, neurological outcomes significantly improved, with the proportion of patients with mRS 0–1 increasing from 18.7% at diagnosis to 83.2% and 85.1% at three and six months, respectively (P < 0.001). Clinical variables were associated with residual neurological symptoms (mRS≥1) included age ≥ 50 years (OR 4.1, 95% CI; 1.7–9.4, P 0.001), male sex (OR 3.0, 95%CI; 1.4–6.6, P 0.006), the thrombus involvement in deep sinus system (OR 6.1, 95%CI; 1.1–76.9, P 0.04) and cerebral vein and dural sinus thrombosis (CVT) risk score ≥ 1 (OR 3.1, 95%CI; 1.3–7.5, P 0.014). Patients whose CVST was associated with hormonal therapy were found to have a lower risk of residual neurological symptoms (OR 0.2, 95%CI 0.1–0.6, P 0.004). Hormonal therapy was associated with anticoagulant discontinuation (OR 2.7, 95% CI 1.1–7.0; P = 0.04). The presence of malignancy increased the risk of bleeding (OR 5.8, 95% CI 1.4–24.1; P 0.016). Overall mortality was 2.8%. Of which 50% were related to major bleeding. Conclusions A significant improvement in neurological outcomes was observed at 3 and 6 months after diagnosis. Older age, male sex, thrombus involvement in deep sinus system were associated with residual neurological symptoms.
Prevalence of neonatal sepsis and associated factors among neonates admitted in the neonatal intensive care unit at Lira Regional Referral Hospital, Northern Uganda
Background Sepsis is one of the leading causes of mortality and morbidity among neonates. An estimated 5.29–8.73 million Disability-adjusted life years (DALYs) are lost annually in SSA due to neonatal sepsis (NS). Uganda registered stagnated neonatal mortality of 27 deaths per 1000 live births in 2020 of which 12% was attributed to NS. Early risk factor identification and improved obstetric care are proven to reduce deaths due to NS, yet there is scanty literature on the LRRH. We, therefore, determined the prevalence of NS and identified its associated factors within the LRRH of northern Uganda. Methods A hospital-based, cross-sectional study with a retrospective chart review was conducted in the neonatal intensive care unit (NICU) at Lira Regional Referral Hospital (LRRH), in northern Uganda. 194 records of neonates admitted to the NICU from September 2022 to February 2023 were reviewed. The participant records were selected by systematic sampling technique and a structured data extraction tool was used to collect data. Using SPSS version 25 data entry and analysis were done. The univariable analysis gave a general description of the data. Logistic regression analysis was used to show associations and the statistical significance was declared at a P value of 0.05 after multivariable analysis. Results Among a total of 194 neonates whose charts were reviewed, 80 neonates had neonatal sepsis, giving a proportion of 0.412 and then prevalence of 41.2%. Age in days of the neonate (AOR = 4.212, 95% CI: [1.627-10.903]) for neonates of 1-3days of age, sex where males (AOR = 2.09, 95% CI: [1.123-3.887]), an APGAR score of 1-4 at birth (AOR = 0.309, 95% CI: [0.115-0.831]) and weight at birth <2500g (AOR = 2.543, 95% CI: [1.381-4.683]) were significantly related to it. Conclusions and recommendations The results found the prevalence of NS among neonates admitted to the NICU of LRRH high at 41.2%. Factors 1-3 days of age, male sex, a birth weight of <2500g, and an Apgar score of 1-4 at birth among all neonates were significant. Therefore, it was suggested that caregivers ensure safe newborn care, detect infections early, and use prophylactic antibiotics for high-risk babies after birth, to reduce NS. Further research will be conducted on the major causative agents and outcomes of NS in the NICU of LRRH.
Unexpected effects of pandemic-related changes on mental health: Evidence from a nationwide survey in South Korea
Background Substantial evidence indicates that the COVID-19 pandemic has adversely affected population mental health globally. However, most studies assumed a linear relationship where only negative pandemic-induced changes led to worse mental health outcomes, overlooking the complex relationship between COVID-19-related changes and mental health. This study examined how various types and magnitudes of pandemic-related changes relate to depression and suicidal thoughts in a large, nationwide adult population sample. Methods We analyzed data from the 2021 Korean Community Health Survey, a cross-sectional survey of 229,213 adults. The study examined the association between mental health outcomes and three types of pandemic-related changes: daily life impact (scored 0–100), economic activities (employment and income changes), and health behaviors (physical activity, instant food consumption, alcohol consumption, and smoking). Complex sample multiple logistic regression analysis was used to assess these associations, adjusting for sociodemographic factors. Results The relationship between pandemic-related changes and mental health showed non-linear patterns. Compared to those reporting moderate changes, individuals reporting either no change (depression: aOR 1.253, 95% CI 1.135–1.384; suicidal thoughts: aOR 1.355, 95% CI 1.236–1.486) or complete disruption (depression: aOR 1.895, 95% CI 1.667–2.155; suicidal thoughts: aOR 1.788, 95% CI 1.558–2.052) in daily life showed higher risks of poor mental health. Unexpectedly, positive changes such as improved working conditions (suicidal thoughts: aOR 1.419, 95% CI 1.200–1.677) and increased income (depression: aOR 1.304, 95% CI 1.139–1.493; suicidal thoughts: aOR 1.244, 95% CI 1.079–1.435) were also associated with adverse mental health outcomes. Conclusions This study reveals that both minimal and substantial changes in daily life, as well as both positive and negative changes in economic conditions and health behaviors, were associated with poor mental health outcomes during the pandemic. These findings suggest the need for comprehensive mental health interventions that consider various types and magnitudes of life changes during crisis situations.
Modeling maize aflatoxins and fumonisins in a Tanzanian smallholder system: Accounting for diverse risk factors improves mycotoxin models
Human exposure to mycotoxins is common and often severe in underregulated maize-based food systems. This study explored how monitoring of these systems could help to identify when and where outbreaks occur and inform potential mitigation efforts. Within a maize smallholder system in Kongwa District, Tanzania, we performed two food surveys of mycotoxin contamination at local grain mills, documenting high levels of aflatoxins and fumonisins in maize destined for human consumption. A farmer questionnaire documented diverse pre-harvest and post-harvest practices among smallholder farmers. We modeled maize aflatoxins and fumonisins as a function of diverse indicators of mycotoxin risk based on survey data, high-resolution geospatial environmental data (normalized difference vegetation index and soil quality), and proximal near-infrared spectroscopy. Interestingly, mixed linear models revealed that all data types explained some portion of variance in aflatoxin and fumonisin concentrations. Including all covariates, 2015 models explained 27.6% and 20.6% of variation in aflatoxin and fumonisin, and 2019 models explained 39.4% and 40.0% of variation in aflatoxin and fumonisin. This study demonstrates the value of using low-cost risk factors to model mycotoxins and provides a framework for designing and implementing mycotoxin monitoring within smallholder settings.
Staudinger Reaction-Responsive Coacervates for Cytosolic Antibody Delivery and TRIM21-Mediated Protein Degradation
Physicians’ experiences with pharmacists as new members of the interprofessional emergency department team. A qualitative study
Pharmacists in emergency departments (EDs) can alleviate physicians’ workload by handling medication-related tasks and offer valuable contributions in interprofessional teams. We aimed to explore physicians’ experiences working with pharmacists in EDs, and their perspectives on future permanent collaboration. We conducted semi-structured interviews with twenty physicians from two EDs and analyzed the data using thematic analysis. Four main themes emerged, comprising twelve subthemes that highlighted both challenges and motivations. Theme 1: time addressed physicians’ time constraints, and the potential for time reallocation with assistance from pharmacists. Theme 2: various roles of pharmacists focused on the diverse roles of pharmacists who supported patient care and junior physicians, but faced challenges like availability and space constraints. Theme 3: teamwork concerned how pharmacists were trusted, brought valuable insights, and enhanced patient safety, yet there were ambiguous views on responsibility and cultural differences. Theme 4: future perspectives focused on how physicians favored a permanent inclusion of pharmacists in the ED, suggesting that they could independently conduct MedRec. Our findings suggest that pharmacists should be permanently integrated in ED teams. However, there is a need to address challenges related to space and legal regulations to enhance interprofessional collaboration.
Key Interaction Changes Determine the Activation Process of Human Parathyroid Hormone Type 1 Receptor
Moderate-intensity interval exercise exacerbates cardiac lipotoxicity in high-fat, high-calories diet-fed mice
Challenges and opportunities for high-quality battery production at scale
Abstract As the world electrifies, global battery production is expected to surge. However, batteries are both difficult to produce at the gigawatt-hour scale and sensitive to minor manufacturing variation. As a result, the battery industry has already experienced both highly-visible safety incidents and under-the-radar reliability issues—a trend that will only worsen if left unaddressed. Here we highlight both the challenges and opportunities to enable battery quality at scale. We first describe the interplay between various battery failure modes and their numerous root causes. We then discuss how to manage and improve battery quality during production. We hope our perspective brings greater visibility to the battery quality challenge to enable safe global electrification.
Impact of age-related changes in buccal epithelial cells on pediatric epigenetic biomarker research
Neuronal dynamics of cerebellum and medial prefrontal cortex in adaptive motor timing
Abstract Precise temporal control of sensorimotor coordination and adaptation is a fundamental basis of animal behavior. How different brain regions are involved in regulating the flexible temporal adaptation remains elusive. Here, we investigated the neuronal dynamics of the cerebellar interposed nucleus (IpN) and the medial prefrontal cortex (mPFC) neurons during temporal adaptation between delay eyeblink conditioning (DEC) and trace eyeblink conditioning (TEC). When mice were trained for either DEC or TEC and subsequently subjected to a new paradigm, their conditioned responses (CRs) adapted virtually instantaneously. Changes in the activity of the IpN neurons related to CR timing were prominent during DEC-to-TEC adaptation, but less so during TEC-to-DEC adaptation. In contrast, mPFC neurons could rapidly alter their modulation patterns during both adaptation paradigms. Accordingly, silencing the mPFC completely blocked the adaptation of CR timing. These results illustrate how cerebral and cerebellar mechanisms may play different roles during adaptive control of associative motor timing.
Proteomic signature of HIV-associated subclinical left atrial remodeling and incident heart failure
Integration of clinical, pathological, radiological, and transcriptomic data improves prediction for first-line immunotherapy outcome in metastatic non-small cell lung cancer
Abstract Immunotherapy is improving the survival of patients with metastatic non-small cell lung cancer (NSCLC), yet reliable biomarkers are needed to identify responders prospectively and optimize patient care. In this study, we explore the benefits of multimodal approaches to predict immunotherapy outcome using multiple machine learning algorithms and integration strategies. We analyze baseline multimodal data from a cohort of 317 metastatic NSCLC patients treated with first-line immunotherapy, including positron emission tomography images, digitized pathological slides, bulk transcriptomic profiles, and clinical information. Testing multiple integration strategies, most of them yield multimodal models surpassing both the best unimodal models and established univariate biomarkers, such as PD-L1 expression. Additionally, several multimodal combinations demonstrate improved patient risk stratification compared to models built with routine clinical features only. Our study thus provides evidence of the superiority of multimodal over unimodal approaches, advocating for the collection of large multimodal NSCLC datasets to develop and validate robust and powerful immunotherapy biomarkers.