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Charlotte Sumner and colleagues report that mutations in the ankyrin repeat region of TRPV4 cause Charcot-Marie-Tooth disease type 2C. Their functional studies indicate that the mutations result in increased channel activity. Charcot-Marie-Tooth disease type 2C (CMT2C) is an autosomal dominant neuropathy characterized by limb, diaphragm and laryngeal muscle weakness. Two unrelated families with CMT2C showed significant linkage to chromosome 12q24.11. We sequenced all genes in this region and identified two heterozygous missense mutations in the TRPV4 gene, C805T and G806A, resulting in the amino acid substitutions R269C and R269H. TRPV4 is a well-known member of the TRP superfamily of cation channels. In TRPV4-transfected cells, the CMT2C mutations caused marked cellular toxicity and increased constitutive and activated channel currents. Mutations in TRPV4 were previously associated with skeletal dysplasias. Our findings indicate that TRPV4 mutations can also cause a degenerative disorder of the peripheral nerves. The CMT2C-associated mutations lie in a distinct region of the TRPV4 ankyrin repeats, suggesting that this phenotypic variability may be due to differential effects on regulatory protein-protein interactions.

Polyglutamine diseases include at least nine neurodegenerative disorders, each caused by a CAG repeat expansion in a different gene. Accumulation of mutant polyglutamine-containing proteins occurs in patients, and evidence from cell culture and animal experiments suggests the nucleus as a site of pathogenesis. To understand the consequences of nuclear accumulation, we created a cell culture system with nuclear-targeted polyglutamine. In our system, cell death can be mitigated by overexpression of full-length cAMP response element binding protein (CREB)-binding protein (CBP) or its amino-terminal portion alone. CBP is one of several histone acetyltransferases sequestered by polyglutamine inclusions. We found histone acetylation to be reduced in cells expressing mutant polyglutamine. Reversal of this hypoacetylation, which can be achieved either by overexpression of CBP or its amino terminus or by treatment with deacetylase inhibitors, reduced cell loss. These findings suggest that nuclear accumulation of polyglutamine can lead to altered protein acetylation in neurons and indicate a novel therapeutic strategy for polyglutamine disease.

The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by mutation of the telomeric survival motor neuron 1 (SMN1) gene with retention of the centromeric SMN2 gene. We sought to establish whether the potent and specific hydroxamic acid class of histone deacetylase (HDAC) inhibitors activates SMN2 gene expression in vivo and modulates the SMA disease phenotype when delivered after disease onset. Single intraperitoneal doses of 10 mg/kg trichostatin A (TSA) in nontransgenic and SMA model mice resulted in increased levels of acetylated H3 and H4 histones and modest increases in SMN gene expression. Repeated daily doses of TSA caused increases in both SMN2-derived transcript and SMN protein levels in neural tissues and muscle, which were associated with an improvement in small nuclear ribonucleoprotein (snRNP) assembly. When TSA was delivered daily beginning on P5, after the onset of weight loss and motor deficit, there was improved survival, attenuated weight loss, and enhanced motor behavior. Pathological analysis showed increased myofiber size and number and increased anterior horn cell size. These results indicate that the hydroxamic acid class of HDAC inhibitors activates SMN2 gene expression in vivo and has an ameliorating effect on the SMA disease phenotype when administered after disease onset.

Pain management is a crucial component of patient care that promotes relaxation, lowers complications, improves quality of life, and shortens hospital stays. Several studies assessed the nurses' pain management practices in Ethiopia. However, the findings of these studies are highly variable and inconsistent. Therefore, the study aims to determine the overall prevalence of pain management practice and associated factors among nurses working in Ethiopia. The study included all observational quantitative research articles conducted among nurses in Ethiopia. We used Google Scholar, PubMed, Cochrane Library, and Scopus searching databases. The Newcastle-Ottawa Scale was used to check the study quality. Then I2 statistics and Cochran's Q test were used to evaluate heterogeneity. The Funnel, Egger's test, and non-parametric trim and fill effect tests were used to check publication bias by using a random effect model. Finally, we conducted subgroup analysis and sensitivity tests to evaluate statistical heterogeneity and the presence or absence of any influential study. In the final analysis, we included eighteen studies, and 4,213 nurses participated. The overall pooled prevalence of nurses with good pain management practice was 43.79% (95% CI: 38.52, 49.06%). In-service training AOR; 95% CI 3.21 (1.87, 4.54), good knowledge AOR; 95% CI 2.44 (1.78, 3.09), positive attitudes AOR; 95% CI 2.84 (1.24, 4.44), and pain management guidelines in health facilities AOR; 95% CI 3.46 (1.48, 5.44) were the significant associated factors with pain management practice among nurses in Ethiopia. This study found that over half of Ethiopian nurses had poor pain management practices. Knowledge, attitude, training, and pain management guidelines in health facilities were significant factors. Therefore, health managers and stakeholders should prioritize pain management awareness, attitudes, availability of guidelines, and in-service training to improve patient care and outcomes.

Lost to follow-up (LTFU), defined as interrupting anti-TB treatment for ≥ 8 consecutive weeks or missing anti-retroviral therapy (ART) appointments for > 90 days, is a barrier to TB/HIV coinfection management. Poor treatment adherence, a driver of multidrug resistance in TB/HIV, poses critical challenges to case management. Overestimating effect sizes when considering mutually exclusive events, like LTFU from ART and anti-TB treatment, can occur if sources of error are not properly accounted for in competing events. However, studies estimating the effect sizes of predictors of time to LTFU using competing risk analysis are scarce. Hence, this study aimed to investigate the predictors of time to LTFU among adults with TB/HIV coinfection. We conducted a multicenter facility-based retrospective follow-up study. We randomly selected 471 TB/HIV coinfected adults. Data were extracted using standardised checklists. The LTFUs from ART and anti-TB treatment were events of interest and competing events, respectively, and others were censored. The data were entered into Epi data and then exported to Stata and Rstudio. Statistical differences were tested by Gray’s test, and the cumulative incidence of each event was estimated by a cumulative incidence function. Bivariable and multivariable competing risk regression models were fitted, and variables with p values < 0.05 were considered significant predictors. Incidence rates of LTFU for ART and TB treatment were 3.90 and 19.17 per 1000 person-months of observation (PMOs), respectively. The predictors of ART LTFU included rural residence (adjusted subdistribution hazard ratio (SDHR): 3.39), WHO stage IV (SDHR: 2.88), haemoglobin < 11 g/dl (SDHR: 3.56), and opportunistic infections (OIs) (SDHR: 3.65). For TB treatment LTFU, significant predictors were rural residence (SDHR: 0.11), divorced (SDHR: 2.81), widowed (SDHR: 5.92), BMI < 18.5 (SDHR: 0.41), ambulatory functional status (SDHR: 2.59), adverse drug effects (SDHR: 2.87), and poor ART adherence (SDHR: 5.72). Considering errors in competing events, ART LTFU was higher among rural dwellers, individuals with advanced disease, nutritional deficits, or adverse drug effects requiring prioritised, multifaceted interventions. Targeted strategies such as intensified monitoring, adherence counselling, nutritional support, proactive management of drug-related side effects, marital instability, OIs and poor ART adherence should be integrated into the existing ART/TB program to mitigate LTFU.

Introduction Gestational trophoblastic neoplasia (GTN) is the most curable gynecologic malignancy. However, resistance to first-line chemotherapy remains common, and mortality is high in developing countries. Objective To evaluate remission, relapse, survival, and associated factors among GTN patients in northwest Ethiopia. Methods A hospital-based, multi-center retrospective cohort study was conducted on 205 patients treated between August 1, 2019, and July 31, 2024. Data were collected from medical charts and phone interviews. Logistic regression identified factors affecting remission. Kaplan–Meier analysis was used to estimate the overall survival (OS) probabilities. Prognostic factors were determined using Cox regression. Results were interpreted as adjusted odds (AOR) and adjusted hazard ratios (AHR) with 95% confidence intervals. Statistical significance was declared at P ≤ .05. Results The overall remission rate was 62.4%, with 41.0% of low-risk GTN patients developing resistance to monotherapy. Chemo-resistance was independently associated with FIGO/WHO scores of 5-6 (AOR = 2.4, 95% CI: 1.2-5.6), disease duration ≥4 months (AOR = 1.7, 95% CI: 1.0-3.3), metastases (AOR = 2.2, 95% CI: 1.1-4.6), and choriocarcinoma histology (AOR = 3.0, 95% CI: 1.3-6.7). The 5-year OS was 77%, with metastases independently predicting poor survival (AHR = 4.1, 95% CI: 1.0-15.9). Choriocarcinoma and high-risk GTN were associated with increased relapse. Conclusion Chemoresistance was notably high among low-risk GTN patients. Particularly, patients with metastasis, choriocarcinoma histology, a WHO-FIGO risk score of 5-6, and longer disease duration may benefit from early combination therapy. In addition, GTN patients have shown relatively low survival rates. Metastases significantly affect survival. These findings highlight the importance of early detection, risk-adapted therapy, and therapeutic advancements to improve outcomes in resource-limited settings. Plain Language Summary Gestational trophoblastic neoplasia (GTN) is a rare cancer that usually develops after a pregnancy. Although it is highly curable with proper treatment, many women in low-resource settings face delays in diagnosis and challenges in getting the right medicines. In this study, we followed 205 women with GTN who were treated at three major hospitals in Northwest Ethiopia. We found that women with low-risk GTN had lower chances of complete recovery compared to what is reported in other countries. The chance of treatment not working was higher if the cancer had lasted four months or longer, had spread to other parts of the body, or was a specific type called choriocarcinoma. Patients with very high scores were also more likely to have the cancer come back after treatment. Our findings suggest that some patients might benefit from starting stronger treatment earlier and being monitored more closely. Improving follow-up care and tailoring treatment to each patient could help more women fully recover and live healthy lives.

Rheumatoid arthritis is a chronic autoimmune inflammatory joint condition that progressively becomes devastating. Patient satisfaction with treatment is a predictor of medication adherence. Not only this, but it also affects the correct use of medication. Findings in this area are insufficient and contradictory. Therefore, this study aimed to assess treatment satisfaction and associated factors among patients with rheumatoid arthritis in northwest Ethiopia in 2024. A multi-center cross-sectional study was conducted among 393 rheumatoid arthritis patients attending the rheumatoid follow-up clinic of five comprehensive specialized hospitals in northwest Ethiopia from June 21 to September 20, 2024. A systematic random sampling technique was used to collect data. The Treatment Satisfaction with Medicines Questionnaire was used to determine treatment satisfaction. Face-to-face interviews with respondents from selected hospitals were used to gather data. Multiple linear regression was done to identify associated factors. Statistical significance was declared as p-value < 0.05. 393 participants were included in the study. The mean age was 52.28 (SD, 13.43). Around 75.6% were female, and 56.5% were married. Around 42.7% of patients had moderate disease activity, and 53.9% had comorbidities. The overall scores of treatment satisfaction were 52.8 (SD, 10.5). Treatment satisfaction was negatively associated with not taking therapeutic education (β =  − 0.14, 95% CI (− 6.12, − 1.54), p = 0.001), high disease activity (β =  − 0.31, 95% CI (− 12.64, − 0.45), p = 0.035), unavailability of medication (β =  − 0.13, 95% CI (− 6.22, − 1.09), p = 0.005), ≥ 5-year duration of disease (β =  − 0.16, 95% CI (− 7.01, − 1.45), p = 0.003). The present study revealed that overall treatment satisfaction was good. Duration of disease, disease activity, unavailability of medication and therapeutic education were factors affecting treatment satisfaction. Therefore, it is essential to prioritize therapeutic education and medication availability for patients with extended disease durations and high disease activity to improve treatment satisfaction.

The study examined the physical and chemical characteristics of Kafa Biosphere Reserve Forest coffees, collecting 54 georeferenced samples from various zones and plots within the forests. Samples were processed, cleaned, and ground, and chemical contents were determined using high-performance liquid chromatography. Analysis of variance, descriptive statistics, principal component, multiple factors, and hierarchical cluster analysis were applied to the data collected in a three-stage balanced nested design. The district difference did not significantly affect bean physical and chemical contents, but it did affect fruit physical qualities. Forest zonation did not affect these attributes. The effect of forest plotting was significant on the chlorogenic acid content, fruit width and thickness, and seed length. The descriptive statistics results revealed significant variations in coffee chemical compounds across different sampling locations. The principal component analysis revealed that 61.97% of variation in forest coffee chemical and physical attributes is influenced by factors like chlorogenic acid content and fruit and seed width. Multiple-factor analysis showed a tendency for a relationship to be observed between the elevation gradient with nicotinic acid and the measured physical attributes of coffee samples. Nicotinic acid tends to increase with elevation, whereas coffee fruit and seed sizes become larger with reduced nicotinic acid content at a decreasing elevation. Cluster analysis categorizes the samples into three major clusters. The study confirms that the chemical and physical properties of coffee fruit and beans vary more significantly in smaller sampling categories, suggesting further investigation.

Background Tuberculosis (TB) is the leading killer of people living with HIV (PLHIV). Many of these deaths occur in developing countries. This study aimed at determining the incidence and predictors of tuberculosis among PLHIV. Methods A five year retrospective follow up study was conducted among adult PLHIV. The Cox proportional hazards model was used to identify predictors. Results A total of 470 patients were followed and produced 1724.13 Person-Years (PY) of observation, and 136 new TB cases occurred during the follow up period. The overall incidence density of TB was 7.88 per 100 PY. It was high (95.9/100PY) in the first year of enrolment. The cumulative proportion of TB- free survivals was 79% and 67% at the end of the first and fifth years, respectively. Baseline WHO clinical stage III (AHR = 2.88, 95% CI = 1.53-5.43), WHO clinical stage IV (AHR = 3.82, 95% CI = 1.86-7.85), CD4 count <50 cell/ul (AHR = 2.13, 95% CI = 1.28-3.53) and ambulatory or bed ridden functional status (AHR = 1.64, 95%CI = 1.13-2.38) were predictors of time to TB occurrence. Conclusions TB incidence rate among PLHIV, especially in the first year of enrollment was high. Advanced WHO clinical stage, limited functional status, and low CD4 count (<50 cell cell/ul) were found to be the independent predictors of TB occurrence. Early care seeking and initiation of HAART to improve the CD4 count and functional status are important to reduce the risk of TB infection.

A comprehensive examination of the physical and cup quality of Kafa Biosphere Reserve coffees was essential to identify the inherent qualities of the coffees in connection with the area’s soil physical and chemical characteristics. As a result, preliminary coffee quality data was acquired from bean physical and cup quality examination of coffees derived through a three-stage nested design combining districts (Gimbo, Gawata, and Decha), coffee production systems (forest, semiforest, and garden), and coffee processing methods (wet, semiwet, and dry). Representative soil samples were collected according to the sampling structure and analyzed following the standard procedures. Multiple factor analysis and Pearson’s correlation coefficient analysis were applied to the collected data. According to the results of multiple factor analysis, the Gimbo and Decha districts are not significantly different from each other in terms of coffee quality. However, they are substantially different from the Gawata district in terms of coffee quality. Similarly, within each district, there are no clear differences in coffee production systems. However, the production systems of districts varied significantly. The coffee processing method had a pronounced effect on the overall quality and preliminary grade, physical and raw quality variables of coffee. Screen retention (14) was correlated with soil iron, but it was related negatively to boron and sodium contents. A significant and positive relationship was observed between green coffee bean moisture content and soil potassium, calcium, magnesium, boron, sodium, organic carbon, silicon content, and soil pH. A positive and significant relationship between soil molybdenum and the coffee quality variable was observed across the studied districts whereas most soil micronutrients, specifically, zinc, sulfur, and manganese, were significantly and negatively related to the organoleptic qualities of the coffees. Further investigation that includes the effects of elevation is recommended in future studies.