Category: Nevin Manimala

ACS Pharmacol Transl Sci. 2025 Jul 20;8(8):2600-2611. doi: 10.1021/acsptsci.5c00195. eCollection 2025 Aug 8.

ABSTRACT

Targeted protein degradation (TPD) mediated by molecular glues is an innovative pharmaceutical paradigm. By binding to and modulating the surface of an E3-ligase component, molecular glue degraders can facilitate the recruitment of a specific target protein (or vice versa) and ultimately invoke target degradation. This mode of action results in specific challenges for the development of rational discovery strategies, and complex hit validation workflows may be required to reliably eliminate compounds that elicit nonspecific effects. With the aim to guide screening efforts, we optimized two orthogonal cell-based, target-centric assays for degrader discovery: (1) a time-resolved FRET assay directly quantifying the levels of a target protein and its degradation (signal inhibition) and (2) an assay coupling TPD to cell growth (signal rescue). To enable a deeper understanding of the individual assays’ strengths and limitations, we compared their statistical performance as well as respective hit populations by screening a specifically designed collection of about 1000 compounds containing well-annotated reference compounds and known frequent hitters (FHs). We found that the signal rescue format reliably and specifically captured active target degraders while efficiently filtering out interfering or FH compounds. Importantly, this format achieved to retrieve lower potency hits, which might be desirable in order to confidently include as many diverse chemical starting points as possible at the start of a drug discovery project.

PMID:40810141 | PMC:PMC12340641 | DOI:10.1021/acsptsci.5c00195

Equine Vet Educ. 2025 Jan 29. doi: 10.1111/eve.14109. Online ahead of print.

ABSTRACT

BACKGROUND: Meconium impaction/retention is a significant cause of colic in foals. Historically, limitations of both medical and surgical treatment are noted. Outcomes of meconium impaction/retention have not recently been reported.

OBJECTIVE: To describe case characteristics and outcomes in foals with meconium impaction/retention.

STUDY DESIGN: Retrospective, single referral hospital.

METHODS: Medical records from 2006 to 2024 were searched for foals ≤3 days old with a history of straining to defecate, abdominal distention, colic, weakness and/or tail flagging. Signalment, presenting complaint, treatment, outcome and comorbidities were summarised and compared between groups based on sex and survival. Associations between comorbidities and survival were evaluated by zero-inflated Poisson regression.

RESULTS: Forty-three foals met the inclusion criteria. Male foals dominated (30/43; 70%). All foals were managed with enemas; phosphate (11/43; 30%), water with soap/lube (25/43; 58%), not specified 9/43 (21%), multiple types (8; 19%), acetylcysteine retention (1; 2%). Forty foals (93%) survived to discharge, and three (7%) were humanely euthanised. Of surviving foals, 37/40 (93%) responded fully to medical treatment. Surgical treatment was required in 4 foals (9%); 3/4 (75%) survived. Comorbidities were common including sepsis (10/43; 23%), pneumonia (10/43; 23%), failure of passive transfer (6/43; 14%) and hypoxic-ischaemic encephalopathy (5/43; 12%). Non-survivors (3/43; 7%) were euthanised due to sepsis, limb malformation and pneumonia.

MAIN LIMITATIONS: Small sample size and low number of non-survivors prevented meaningful statistical analysis.

CONCLUSION: Medical management of meconium impaction/retention is successful in the great majority of cases. Prognosis depends on the comorbidities present.

PMID:40810138 | PMC:PMC12341383 | DOI:10.1111/eve.14109

Orthop J Sports Med. 2025 Aug 12;13(8):23259671251361488. doi: 10.1177/23259671251361488. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: Meniscal tears are a common knee injury in athletes, necessitating effective repair techniques. Despite the prevalence of meniscal tears, there is limited literature comparing the efficacy of the 2 primary suture methods-all-inside and inside-out-in the athletic population.

PURPOSE: To evaluate the postoperative outcomes and failure rates of the all-inside versus inside-out suture techniques in meniscal repairs among athletes.

STUDY DESIGN: Systematic review; Level of evidence, 4.

METHODS: Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a comprehensive search was conducted across the PubMed, Cochrane, and Embase databases on July 26, 2023, yielding 245 studies, of which 7 were included in this review. Studies reporting postoperative outcomes and failure rates of both suture techniques were included. Failure was defined as the need for subsequent surgery due to a persistent meniscal tear. Outcome measures included the Tegner, Lysholm, and International Knee Documentation Committee scores. Differences between groups and subgroups were assessed using the Welch t test and the odds ratio. Wilcoxon tests were used as a sensitivity analysis to confirm the results of the Welch t tests. Heterogeneity was assessed with the I ² statistic and the Bartlett test. All statistical analyses were done using R.

RESULTS: Seven studies-published between 2009 and 2023-met the inclusion criteria, including 469 operations in 458 patients. A total of 199 operations used the all-inside technique, and 270 operations used the inside-out technique. Of the 469 operations, 377 had documentation on laterality (medial meniscal repair versus lateral meniscal repair), with 167 patients undergoing medial meniscal repair and 210 patients undergoing lateral meniscal repair. Each all-inside repair was done with the Fast-Fix device. The all-inside technique showed a statistically significant increase in failure rate compared with the inside-out technique (23.1% vs 12.2%; P = .003). This trend was exaggerated in all-inside repairs for the medial meniscus versus the lateral meniscus (58.1% vs 11.8%; P = 2.6 × 10^-5). When excluding all radial tears, the all-inside technique again had an increased rate of failure compared with the inside-out repairs (20.7% vs 8.3%; P = .01). No significant difference was found in postoperative Tegner scores between all-inside and inside-out repairs (5.9 vs 6.5; P = 0.45).

CONCLUSION: Our review demonstrated that medial meniscal repairs with the all-inside technique using the Fast-Fix device had a higher failure rate compared with those with the inside-out technique; this trend is not seen for lateral meniscal repairs. Based on the findings of this study, surgeons should consider the inside-out technique first for athletic patients presenting with medial meniscal tears who want to return to their sport. Given the limited scope of existing studies combined with more recent utilization of novel all-inside meniscal repair devices that may not be captured in the present study, additional high-quality, prospective studies in this area are needed to validate these findings.

PMID:40810129 | PMC:PMC12344347 | DOI:10.1177/23259671251361488

Orthop J Sports Med. 2025 Aug 12;13(8):23259671251360345. doi: 10.1177/23259671251360345. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: Flag football, a noncontact variant of American football, has gained significant interest in the United States and globally, which has been attributed to its accessibility, low cost, and perceived safety compared with traditional tackle football.

PURPOSE: To identify the trends, primary mechanisms, and distributions of American flag football injuries among female athletes to better inform prevention and safety measures.

STUDY DESIGN: Descriptive epidemiology study.

METHODS: Data analyzed in this study were extracted from the National Electronic Injury Surveillance System (NEISS), a public database representing approximately 100 US emergency departments (EDs) that provides national injury estimates. NEISS was queried for all flag football injuries in female patients from January 1, 2014, to December 31, 2023. Descriptive statistics were used to analyze the distribution of injury by age, mechanism, diagnosis, and body region. Linear regression was used to analyze changes in injury rates over time.

RESULTS: Across the study period, 605 female patients with flag football injuries were evaluated at US EDs, extrapolating to a national estimate (NE) of 22,666 injuries from 2014 to 2023. The highest frequency of injuries occurred in 2023 (NE = 3531; 15.6%) and the lowest in 2020 (NE = 436; 1.9%). The most common injury diagnosis was found to be strain/sprain (NE = 6835; 30.2%), with adolescents aged 11 to 20 years sustaining the greatest number of injuries across all diagnoses. The most commonly affected body part was the finger (NE = 137; 22.6%). When analyzing the mechanism of injury, the most common cause was fall, including fall on an outstretched hand (NE = 4321; 19.1%). In addition, the majority of patients were treated and released (NE = 22,253; 98.2%).

CONCLUSION: This study demonstrated that from 2014 to 2023, female flag football injuries reported to US EDs remained relatively stable, dropping in 2020 during the COVID-19 pandemic and peaking in 2023. The most common injuries sustained by female athletes playing flag football were strains/sprains and fractures. Given the high prevalence of injuries sustained in the adolescent population, the use of appropriate protective gear should be emphasized to prevent a precipitous rise in injuries as the sport continues to grow in popularity throughout the country.

PMID:40810127 | PMC:PMC12344343 | DOI:10.1177/23259671251360345

World J Oncol. 2025 Jul 26;16(4):331-341. doi: 10.14740/wjon2613. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause severe gastrointestinal immune-related adverse events (irAEs), often leading to treatment interruption and increased morbidity. Immune-mediated colitis (IMC) ranges from mild diarrhea to life-threatening colitis, sometimes requiring urgent intervention. While corticosteroids are the first-line treatment, selective immunosuppressive therapy (SIT) with either infliximab or vedolizumab is used for steroid-refractory or dependent cases. However, standardized practices are lacking, and treatment decisions are largely left to provider discretion. This study compares infliximab and vedolizumab for IMC, focusing on remission rates, recurrence, SIT dosing, and systemic steroid exposure duration.

METHODS: We identified six retrospective cohort studies that compared infliximab with vedolizumab in the treatment of IMC through a systematic search of PubMed, EMBASE, Cochrane Library, Scopus, CINAHL, Google Scholar, and Web of Science in English from inception until October 2024. From the identified literature, we extracted pertinent data such as remission and recurrence of IMC. Pooled analysis and heterogeneity analysis were performed using R Studio version 4.4.1. The risk of bias was assessed using the Newcastle-Ottawa Scale.

RESULTS: A total of six studies with 645 patients were included. In ICI-associated colitis, vedolizumab was associated with lower recurrence rates (odds ratio (OR): 0.29, 95% confidence interval (CI): 0.15 – 0.54) and shorter systemic steroid exposure (mean difference (MD): -16.88 days, 95% CI: -20.47 to -13.30) compared to infliximab. While vedolizumab showed improved remission, there was no statistically significant difference in remission rates between vedolizumab and infliximab monotherapy (OR: 3.16, 95% CI: 0.29 – 34.01). Remission was achieved with fewer doses of infliximab than vedolizumab (MD: 1.16, 95% CI: 0.09 – 2.22). The mean number of vedolizumab doses was 2.57 (raw mean score (MRAW): 2.57, 95% CI: 1.43 – 2.71), while the mean number of infliximab doses was 1.36 (MRAW: 1.36, 95% CI: 0.69 – 2.02).

CONCLUSIONS: Among patients with ICI-induced colitis, vedolizumab demonstrated superiority over infliximab by being associated with lower rates of colitis recurrence and decreased systemic steroid exposure, although it required a higher number of doses compared to infliximab.

PMID:40810084 | PMC:PMC12339259 | DOI:10.14740/wjon2613

World J Oncol. 2025 Jul 8;16(4):347-356. doi: 10.14740/wjon2583. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: The development of targeted next-generation sequencing (NGS) technologies has contributed to precision medicine, as evidenced by the growing interest in evaluating human epidermal growth factor receptor 2 (HER2) expression status to treat unresectable/metastatic HER2-low breast cancer (BC). However, the concordance between erb-b2 receptor tyrosine kinase 2 (ERBB2) copy number alteration (CNA) and HER2 immunohistochemistry (IHC) has never been determined. The aim of this study was to evaluate the utility of targeted NGS for determining HER2 status and optimizing targeted therapies for BC.

METHODS: ERBB2 CNAs were examined by targeted NGS in 41 formalin-fixed paraffin-embedded (FFPE) BC tissues. ERBB2 CNA was compared with HER2 status evaluated by IHC in tissue sections, which were identical to those subjected to targeted NGS, using the Ventana 4B5 antibody.

RESULTS: The median fold changes (FCs) for ERBB2 CNAs in tumors with an IHC score of 3+, 2+, 1+, and 0 were 4.81, 1.49, 1.00, and 1.00, respectively. The difference in the FC for ERBB2 CNA according to HER2 status was statistically significant (P < 0.001). An FC greater than 1.0 for ERBB2 CNA was established as the cutoff value to differentiate between tumors with an IHC score of 3+, 2+, or 1+ and tumors with an IHC score of 0, on the basis of receiver operating characteristic curve analysis. The overall percent agreement, positive percent agreement, negative percent agreement, and Cohen’s kappa between ERBB2 CNA and HER2 status were 68.3%, 57.7%, 86.7%, and 0.39, respectively. The numbers of patients with mutations in ERBB2, estrogen receptor 1 (ESR1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), serine/threonine kinase 1 (AKT1), and phosphatase and tensin homolog (PTEN) were 7, 3, 6, 1, and 5, respectively. Targeted NGS detected additional gene mutations and presented treatment options for seven of 22 patients (31.8%) with an FC of ERBB2 CNA = 1.00.

CONCLUSIONS: Targeted NGS has the potential in distinguishing HER2 IHC 3+, 2+, and 1+ tumors from IHC 0 in patients with BC; however, differentiating between HER2 IHC 1+ and 0 remains challenging. Additionally, targeted NGS may aid in the identification of actionable mutations, thereby contributing to the selection of optimal treatment strategies in BC management.

PMID:40810081 | PMC:PMC12339287 | DOI:10.14740/wjon2583

Front Endocrinol (Lausanne). 2025 Jul 30;16:1624717. doi: 10.3389/fendo.2025.1624717. eCollection 2025.

ABSTRACT

OBJECTIVE: In this study, we aimed to investigate whether serum NGAL, MMP-9 and the MMP-9/NGAL ratio, which are inflammatory markers used for the diagnosis and follow-up of some diseases, can be used as diagnostic and follow-up markers for the diagnosis of endometriomas in infertile patients.

METHODS: Forty-five patients with unexplained infertility and 45 infertile patients with endometriomas were included in the study. Patients with endometriomas of at least 3 cm in size were included in the study. NGAL and MMP-9 levels in venous blood samples and the MMP-9/NGAL ratios of the unexplained infertility and endometrioma groups and the preoperative and postoperative results of the endometrioma group were compared.

RESULTS: The mean blood NGAL and MMP-9 levels in the endometrioma and unexplained groups were 22.0 ± 4.0 ng/ml and 25.4 ± 4.9 ng/ml and 43.7 ± 8.0 ng/ml and 39.3 ± 10.7 ng/ml, respectively, and all the results were statistically significant (p=0.001; p=0.012). The mean blood levels of NGAL and MMP-9 in endometriomas and the same patients at three months after surgery were 24.9 ± 4.9 ng/ml and 27.0 ± 4.9 ng/ml and 43.9 ± 7.3 ng/ml and 36.7 ± 8.7 ng/ml, respectively (p=0.179; p=0.006). The mean ratios of MMP-9/NGAL in the endometrioma, unexplained and postoperative groups were 2.0 ± 0.2, 1.5 ± 0.2 and 1.4 ± 0.2, respectively. All these results were significantly different between the endometrioma-unexplained group and the endometrioma-postoperative group (p=0.001; p=0.001). When we performed a ROC curve analysis for the presence of endometrioma, an MMP-9/NGAL ratio greater than 1.75 had 86.1% sensitivity and 84% specificity in indicating the presence of endometrioma (AUC=0.898). There was a positive correlation between the VAS score and the MMP-9/NGAL ratio.

CONCLUSIONS: Interestingly, the NGAL blood NGAL level was lower in the endometrioma group than in the control group. The MMP-9/NGAL ratio can be useful in the diagnosis of endometrioma, and this ratio reflects the clinical findings of the disease.

PMID:40810077 | PMC:PMC12343217 | DOI:10.3389/fendo.2025.1624717

Transplant Direct. 2025 Aug 13;11(9):e1843. doi: 10.1097/TXD.0000000000001843. eCollection 2025 Sep.

ABSTRACT

BACKGROUND: The transmission of undetected infections from organ donors to recipients is a persistent concern in transplantation medicine. Despite nucleic acid testing, some infections, especially those acquired recently, may evade detection. This study aimed to model the effects of critical care interval before screening on the residual risk of undetected infections in organ donors.

METHODS: We modeled the risk of blood-borne virus acquisition in donors using a Poisson process, assuming that the critical care interval carries negligible risk. A continuous probability function was developed using estimates of HIV, hepatitis C virus, and hepatitis B virus incidence, viral doubling rates, and assay performance characteristics from a commonly used triplex nucleic acid screening test.

RESULTS: Our quarantine-adjusted window period model showed that longer critical care intervals resulted in a decreased quarantine-adjusted residual risk of undetected infections. This relationship was linear for most assay window periods. For example, a typical critical care interval of 2.7 d reduces the residual risk by 43.5% for hepatitis C virus, 22.9% for HIV, and 7.4% for hepatitis B virus. In some clinical situations, the critical care quarantine effect may outweigh intragroup variations in risk behavior. The model also enabled comparisons of different blood collection times.

CONCLUSIONS: The quarantine-adjusted window period model indicates that the critical care interval further reduces the risk of undetected infections in deceased organ donors. This supports and quantifies the impact of screening organ donors as close to retrieval surgery as possible, rather than delaying surgery solely based on the risk of residual infection.

PMID:40810059 | PMC:PMC12348399 | DOI:10.1097/TXD.0000000000001843

Yonago Acta Med. 2025 Jul 9;68(3):187-196. doi: 10.33160/yam.2025.08.003. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: A survey was conducted to determine the demand for the use of digital health content for health promotion, both among those interested in using digital tools and those interested in health promotion.

METHODS: This study targeted smartphone owners who attended a class on how to use a smartphone (CS) and/or a class on advancements in health (CH) held in Nanbu Town. The main questionnaire items included questions on age, gender, frailty, subjective cognitive decline (SCD), smartphone usage, and interest in health promotion using digital technology. An analysis was conducted on 33 participants in the CS and 33 participants from the CH who provided complete responses to the questionnaire.

RESULTS: The percentages of interest in using smartphones for accessing content on exercise, cognitive training, and nutrition management were 97.0%, 97.0%, and 87.9%, respectively, among CS participants and 69.7%, 78.8%, and 81.8%, respectively, among CH participants. The percentage of responses regarding interest in exercise content was significantly different between the two groups. Furthermore, some individuals responded that they were interested but concerned about how to use the services. No statistically significant differences were found with respect to the comparison of the percentages of responses by age group, frailty determination results, and SCD determination results among the participants of the CS and CR groups.

CONCLUSION: Regardless of age or the risk of developing health problems, there is demand for content related to health promotion using digital tools for those who want to master digital tools and who want to improve their health. However, support should be provided to them to ensure that they correctly use those tools. Notably, some individuals who want to improve their health are not interested in using digital tools.

PMID:40810047 | PMC:PMC12343190 | DOI:10.33160/yam.2025.08.003

bioRxiv [Preprint]. 2025 Jul 22:2025.07.18.665559. doi: 10.1101/2025.07.18.665559.

ABSTRACT

Background Our previous work demonstrated that in young adults, 61% of gait speed variance was attributable to instruction type. However, no study has investigated whether verbal instructions differentially influence older adults.

RESEARCH QUESTION: This study investigated how walking prompts contribute to gait speed variability across age groups.

METHODS: Thirty-four young adults (21±2 years) and twenty-eight older adults (70±5 years) performed walking trials responding to 24 different instructions.

RESULTS: Average walking speed was 1.23±0.30 m/s. Between-subject variance accounted for 25.3% of the total variance, while between subject and instruction variance components accounted for 76.1% of the total variance. When analyzed separately, variance due to instructions accounted for similar amounts of total variance within older adults (56.9%) and young adults (55.7%), a statistically non-significant difference (p = 0.85). A significant age-instruction interaction (χ ² =76.84, df = 23. p<0.001) revealed that the age differences between average gait speed depended on which instruction was given. Complex instructions elicited the largest between group differences (β:-0.24 to -0.32 m/s), while simple tasks showed minimal differences (β:-0.03 to -0.06 m/s).

SIGNIFICANCE: Instructions explain similar variance within each age group (~56%), but the model treating instructions as fixed effects captures how different age groups respond to the same instructions. These findings highlight the critical importance of instruction standardization in gait assessment protocols, as systematic age-related differences in instruction interpretation can significantly impact measured outcomes. Instructions that produce minimal between-group differences may be most appropriate for standardized clinical assessments, while those showing larger age effects may be valuable for detecting age-related changes in gait control.

PMID:40810011 | PMC:PMC12346562 | DOI:10.1101/2025.07.18.665559