Nevin Manimala

Crit Care Explor. 2025 Jul 14;7(7):e1290. doi: 10.1097/CCE.0000000000001290. eCollection 2025 Jul 1.

ABSTRACT

IMPORTANCE: While corticosteroid administration in septic shock has been shown to reduce vasopressor requirements and accelerate shock reversal, the optimal discontinuation strategy remains unexplored.

OBJECTIVES: The purpose of this study was to assess whether rates of hemodynamic instability differ among patients with septic shock undergoing abrupt hydrocortisone discontinuation compared with gradual tapering.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study conducted in five medical and surgical ICUs at a tertiary care hospital, involving adult patients (≥ 18 yr) with septic shock who received at least 48 hours of stress-dose hydrocortisone (≥ 200 mg/d).

MAIN OUTCOMES AND MEASURES: The primary outcome was hemodynamic instability, defined as vasopressor reinitiation during tapering or within 72 hours of hydrocortisone discontinuation. Secondary outcomes included dysglycemia, duration of mechanical ventilation, ICU and hospital length of stay, and mortality.

RESULTS: Patients were grouped based on their hydrocortisone discontinuation strategy into abrupt and gradual tapering groups. A total of 414 patients were included in this evaluation. Gradual tapering was associated with higher rates of hemodynamic instability (29.2% vs. 12.9%; p < 0.001), more frequent dysglycemia (59.4% vs. 43.1%; p < 0.001), longer hydrocortisone use (9.9 vs. 4.1 d; p < 0.001), and extended mechanical ventilation (20 vs. 15 d; p = 0.014) and ICU stay (23 vs. 17 d; p = 0.008). Total hydrocortisone duration was the strongest independent predictor of post-discontinuation hemodynamic instability, regardless of strategy (adjusted odds ratio, 1.083; 95% CI, 1.025-1.145; p = 0.004).

CONCLUSIONS AND RELEVANCE: While abrupt hydrocortisone discontinuation was associated with fewer ICU-related adverse events, hydrocortisone duration was the primary factor influencing hemodynamic instability post-discontinuation among patients with septic shock. Prospective studies are needed to determine the optimal discontinuation strategy in septic shock.

PMID:40658883 | DOI:10.1097/CCE.0000000000001290

J Chem Inf Model. 2025 Jul 14. doi: 10.1021/acs.jcim.4c01652. Online ahead of print.

ABSTRACT

Breast cancer (BC) is the second most common cause of cancer in women and the most common kind of cancer diagnosed with a high mortality rate. This heterogeneous disease is classified into multiple subtypes based on the expression of key biomarkers, including human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). These biomarkers have significantly transformed breast cancer treatment and played a crucial role in improving the patient prognosis. Given the complexity of BC, there is a pressing need to develop additional therapeutic agents and pharmacological targets. To address this, network-based gene expression profiling has emerged as a valuable method for identifying potential therapeutic targets, as it considers various factors such as disease conditions, gene expression levels, and protein-protein interactions We began our analysis by employing statistical methods, including p-values and false discovery rates (FDR), to identify differentially expressed genes (DEGs) as potential biomarkers in breast cancer (BC). A total of 123 DEGs were identified, with 101 genes showing downregulation and 11 genes exhibiting upregulation. Survival and expression analyses indicated that each hub gene plays a crucial role in the initiation and progression of BC. An enrichment analysis revealed that most of these genes are integral components of various signaling networks. Additionally, we identified key kinases and transcription factors that regulate the proteins involved in protein-protein interactions (PPIs) associated with the DEGs. From this analysis, we also deduced potential pharmaceuticals that could interact with these hub genes. Notably, HMOX1 (Heme Oxygenase 1) emerged as a particularly promising hub gene based on our computational analysis. Promising novel compounds were investigated, resulting in high potency of binding affinities through docking and simulation investigation. The molecular dynamics simulation demonstrated significant stability of the anticipated compounds, especially the top2 complex system at the docked site. The significant binding affinity between the chemical and the binding pockets of HMOX1 complexes was confirmed by the calculation of binding free energies using MMPBSA and MMGBSA followed by hydrogen bond analysis. Hence, these findings significantly enhance our understanding of critical biomarkers in breast cancer.

PMID:40658875 | DOI:10.1021/acs.jcim.4c01652

Dent Med Probl. 2025 May-Jun;62(3):537-545. doi: 10.17219/dmp/174298.

ABSTRACT

BACKGROUND: The effect of the macrogeometry of dental implants with double trapezoidal threads on the probability of survival and the long-term success of oral rehabilitation is unclear.

OBJECTIVES: The purpose of this in vitro study was to evaluate the effect of dental implant macrogeometry on the probability of survival, failure mode and strain distribution of an implant-abutment set.

MATERIAL AND METHODS: Dental implants were divided into 2 groups according to their macrogeometry (n = 21 per group): trapezoidal thread (control group); and double trapezoidal thread (test group). The macrogeometry analysis was performed with the use of computed microtomography (n = 1). The specimens were subjected to single load to failure (SLF) (n = 3), which permitted the step-stress profiles for design-based step-stress accelerated life testing (SSALT) (n = 18). The probability of survival and reliability for a mission of 50,000 cycles were calculated at 100 N and 150 N. The scanning electron microscope (SEM) was used to analyze the failure mode of the implant-abutment set. The digital image correlation (DIC) (n = 3) was performed using the implant-abutment set embedded in a polyurethane resin subjected to a static load of 250 N in axial and non-axial positions.

RESULTS: No statistically significant differences were observed between the groups with respect to the probability of survival. All groups showed a reliability level higher than 95% at 100 N, while a decrease in reliability was observed at 150 N. The Weibull modulus and characteristic resistance exhibited no significant differences between the groups. The β mean values (control = 0.66, test = 0.33) indicated that failures were dictated by material strength. The SEM revealed an abutment and implant body fracture, characterized by fracture initiation on the lingual surface that subsequently propagated to the opposing buccal side. In the context of non-axial loading, the test group exhibited a higher concentration of tensile strain in the cervical region (152.05 μs), while the control group exhibited a predominance of compression strain (-800.00 μs).

CONCLUSIONS: The macrogeometry of dental implants did not influence the failure mode and probability of survival, but modified the strain distribution of the implant-abutment set.

PMID:40658872 | DOI:10.17219/dmp/174298

Dent Med Probl. 2025 May-Jun;62(3):521-526. doi: 10.17219/dmp/166408.

ABSTRACT

BACKGROUND: Root resorption (RR) is usually a consequence of dental trauma, pulpal infection, primary occlusal pressure, or orthodontic tooth movement, leading to the loss of anatomical root formation. As a result of apical RR, the apical constriction is destroyed, and the determination of the working length (WL) may become difficult.

OBJECTIVES: The purpose of the present study was to evaluate the accuracy of 4 different electronic apex locators (EALs) – ProPex® II, Propex Pixi®, DentaPort ZX, and DTE DPEX V – in the determination of WL in teeth with natural apical RR in the presence of different irrigation solutions (ISs).

MATERIAL AND METHODS: A total of 36 teeth with natural apical RR were included in the study. The actual length (AL) was determined under a stereomicroscope at ×15 magnification. Afterward, the electronic length (EL) was established by using 4 different EALs in the presence of different ISs. The ISs used in the measurements were freshly prepared, and 6 groups were organized based on the solution used. The control group was marked as group 1. For groups 2-6, 1% sodium hypochlorite (NaOCl), 2.5% NaOCl, saline, 2% chlorhexidine (CHX), and 17% ethylenediaminetetraacetic acid (EDTA) were used, respectively. After each measurement, the roots were washed with 5 mL of distilled water and dried with paper points before the same teeth were used in the subsequent group. The absolute length was subtracted from EL for each tooth to calculate the difference. The data was analyzed statistically.

RESULTS: For each device, there were no significant differences in the success rates between the ISs used. In group 1, there were no significant differences among the 4 EALs. In group 2, DentaPort ZX was significantly more successful than DTE DPEX V (p = 0.037). There were no significant differences among EALs in groups 3-6.

CONCLUSIONS: The difference between DentaPort ZX and DTE DPEX V was statistically significant in group 2 (1% NaOCl).

PMID:40658871 | DOI:10.17219/dmp/166408

Proc Natl Acad Sci U S A. 2025 Jul 22;122(29):e2502691122. doi: 10.1073/pnas.2502691122. Epub 2025 Jul 14.

ABSTRACT

Evaluating species’ roles in food webs is critical for advancing ecological theories on competition, coexistence, and biodiversity but is complicated by pronounced dietary variability within species and overlap across species. We combined dietary DNA metabarcoding, GPS tracking, and a machine-learning algorithm to cluster and compare dietary profiles within and among five migratory large-herbivore species from Yellowstone National Park. Interspecific niche partitioning was weak, but statistically significant (PERMANOVA: pseudo-F_4,498 = 14.7, R² = 0.11, P ≤ 0.001), such that some diet profiles from different species were as similar as those from within one species. Instead of affirming species’ identity as a primary determinant of diet composition, we found three statistically different clusters of diet profiles-one concentrated on graminoids and forbs, another on forbs and deciduous shrubs, and a third on gymnosperms-each including samples from all herbivore species. Clusters did not reflect traditional diet classification schemes such as the grazer-browser continuum that is often used to distinguish species by percent grass consumption or use of grassland habitat in African savannas. Instead, clusters in Yellowstone reflected seasonal dietary variation within species that often equaled or exceeded niche differences between species, contributing to our growing understanding of why environmental variability may favor generalist foraging strategies at temperate latitudes, whereas specialized grazer and browser guilds appear to predominate in tropical savannas. Data-driven strategies that untangle complex trophic networks without relying on a priori groupings can offer new insights into wildlife diets, with potential applications in resource management and environmental monitoring.

PMID:40658848 | DOI:10.1073/pnas.2502691122

J Leg Med. 2025 Jul 14:1-13. doi: 10.1080/01947648.2025.2524668. Online ahead of print.

ABSTRACT

INTRODUCTION: Medical-legal partnerships (MLP) improve the ability of healthcare professionals to address patients’ socioeconomic concerns. The Finger Lakes Legal Care Project (FLLC) is an MLP of LawNY, a nonprofit law firm that provides free legal assistance in western New York. This study aimed to assess for changes in self-reported health outcomes following receipt of legal aid.

MATERIALS AND METHODS: Patients who received legal assistance through the FLLC Project were administered the Short Form-12 Health Survey (SF-12) at the outset and conclusion of legal intervention. Demographic information was collected. Survey responses were analyzed using paired t-tests.

RESULTS: Four hundred and eight participants with an average age of 49 years completed the pre-legal intervention survey and 123 individuals completed the survey post legal intervention. The majority of participants were White, non-Hispanic (36%) or African American (31.3%). There were statistically significant differences in the mean scores of two of the SF-12 questions. Participants reported that their health was less likely to limit their ability to perform regular activities (p = .037) and they felt “calm and peaceful” more frequently (p = .032) following legal aid.

CONCLUSIONS: Standardized surveys in conjunction with qualitative measures are needed to assess the efficacy of MLP models and establish a framework for emerging MLPs.

PMID:40658806 | DOI:10.1080/01947648.2025.2524668

Hepatol Commun. 2025 Jul 14;9(8):e0734. doi: 10.1097/HC9.0000000000000734. eCollection 2025 Aug 1.

ABSTRACT

BACKGROUND: Alcohol associated liver disease (ALD) is a common condition that is a significant global cause of morbidity and mortality. Diabetes mellitus (DM) increases the risk of adverse outcomes in other types of steatotic liver disease. This retrospective study sought to explore the relationship between ALD and DM.

METHODS: The Worldwide Alcohol-related Liver Disease Outcomes (WALDO) study is an international multicenter cohort of patients with biopsy-proven ALD. The presence of DM at baseline or during follow-up was noted. Clinical events after index biopsy were noted, including death and liver-associated clinical events (LACE). Risks for adverse outcomes were assessed with Cox proportional hazard models with DM as a time-dependent variable to reflect periods of time without or with diabetes. All analyses were done in R.

RESULTS: In total, 712 patients with a median age of 52 years were followed up for a median of 4.8 years (IQR: 1.2-9.5). At baseline, DM was present in 113 patients (15.9%), and a further 56 patients (7.8%) developed DM in follow-up. During follow-up, 113 patients developed LACE. One hundred fifty-two patients died from liver disease, and 46 underwent liver transplantation. DM was significantly associated with liver-related mortality (HR: 1.77, 1.15-2.73, p=0.009) and incident LACE (HR: 1.90, 1.23-2.95, p=0.004). In multivariable analysis, DM remained significantly associated with liver-related mortality (HR=1.79, 1.30-2.48, p<0.001).

CONCLUSIONS: DM is a frequent comorbidity in persons with ALD and is associated with a higher risk of liver-related mortality. Patients’ diabetic status should be an important consideration for clinicians treating people with ALD.

PMID:40658799 | DOI:10.1097/HC9.0000000000000734

Hepatol Commun. 2025 Jul 14;9(8):e0740. doi: 10.1097/HC9.0000000000000740. eCollection 2025 Aug 1.

ABSTRACT

BACKGROUND: HEV is an important cause of morbidity in solid organ transplant (SOT) recipients. However, the total burden of hepatitis E, including subclinical infections in this group, is not well defined. We compared hepatitis E exposures in SOT recipients to non-transplant controls. We also examined the prevalence of rat HEV (rHEV), an emerging hepatitis agent, in this population.

METHODS: This study was conducted in the main SOT center in Hong Kong. Quantitative HEV IgG, RT-PCR, IgM, and IgG avidity assays were used to measure conventional HEV and rHEV exposures in 669 SOT recipients and 667 non-transplant hospitalized controls. Follow-up samples from a subset of SOT recipients were assessed to measure longitudinal HEV exposures.

RESULTS: Age-adjusted HEV IgG seroprevalence in SOT recipients (236/669; 35.3%) was significantly higher than non-transplant controls (185/667; 27.7%; p=0.001). Across baseline and follow-up samples, 25 (3.7%) SOT recipients had viremia (n=3) or serological evidence (n=22) of recent hepatitis E. The latter had IgM positivity (n=5), IgG seroconversion (n=16), or a 5-fold increase in longitudinal HEV IgG concentrations (n=1). Chronic hepatitis occurred in all 3 viremic individuals, while transient hepatitis was observed in 10/22 (45.4%) SOT recipients with serological evidence of recent hepatitis E. rHEV IgG levels were similar between SOT recipients and controls (p=0.424), but 2 viremic infections in the SOT group were due to rHEV and both turned chronic.

CONCLUSIONS: SOT recipients have higher hepatitis E seroprevalence than the non-transplant population. Increased exposure is driven by viremic infections and a significant burden of subclinical infections in Hong Kong. rHEV is an important cause of chronic hepatitis E in SOT recipients.

PMID:40658785 | DOI:10.1097/HC9.0000000000000740

Ethics Hum Res. 2025 Jul-Aug;47(4):18-28. doi: 10.1002/eahr.60010.

ABSTRACT

Nominal cash and gift card incentives provided to research participants have immediate financial benefits but make no lasting improvements to participants’ lives or social inequities they might experience. Our study examined the acceptability of offering a nonmonetary educational incentive as an added option to research participants as a potential to advance antiracism and address social inequities. Community members (n = 128) completed a quantitative survey; nine of whom also participated in a qualitative interview. Focus group discussions occurred with 11 researchers. Survey data were analyzed to obtain descriptive statistics. Qualitative data were analyzed using an iterative process guided by template analysis. Survey participants’ mean age was 45 years; 39% were white and 30% were Hispanic/Latinx; 80% were male; 39% had completed some college; 45% had a degree; and 71% reported previous paid participation in a research or community program. Of this group, 80% preferred cash or gift card incentives; 16% preferred an educational incentive; and 88% were likely to extremely likely to use educational incentives. Qualitative data indicated that educational incentives were acceptable but should not replace cash incentives; successful implementation would require organizational support. Noncash educational incentives may be acceptable to research participants and researchers and would help address social inequities. Successful implementation would require further research.

PMID:40658773 | DOI:10.1002/eahr.60010

PLoS Comput Biol. 2025 Jul 14;21(7):e1013227. doi: 10.1371/journal.pcbi.1013227. Online ahead of print.

ABSTRACT

Chlamydia is an intracellular bacterium that reproduces via an unusual developmental cycle that only occurs within a eukaryotic host cell. A replicating form of the bacterium (RB) repeatedly divides to produce about a thousand progeny, which convert in a delayed and asynchronous manner into the infectious form (EB). The regulatory mechanisms that control this developmental switch are unknown, but they could potentially include extrinsic signals from the host cell or other chlamydiae, or an intrinsic signal such as chlamydial cell size. In this paper, we investigated the regulation of RB-to-EB conversion by developing and analyzing three mathematical models, each based on a different regulatory mechanism. To test these models, we derived statistical evidence from parameters, including number, size and location of RBs and EBs, obtained from experimental measurements and model fitting. All three models successfully reproduced the experimentally measured timing of RB-to-EB conversion and growth curves of the developmental forms in an infected cell. However, only the size control model, which postulates that RB size is an intrinsic signal that regulates the timing of RB-to-EB conversion, reproduced two additional statistical properties of the intracellular infection. These properties are a positive correlation between the number of RBs and EBs throughout the developmental cycle and the monotonic evolution of the coefficient of variation of EB number. This analysis thus provides support for the size control model.

PMID:40658728 | DOI:10.1371/journal.pcbi.1013227