Clinical Importance Research Articles

Development of clinical decision support for patients older than 65 years with fall-related TBI using artificial intelligence modeling.

Older persons comprise most traumatic brain injury (TBI)-related hospitalizations and deaths and are particularly susceptible to fall-induced TBIs. The combination of increased frailty and susceptibility to clinical decline creates a significant ongoing challenge in the management of geriatric TBI. As the population ages and co-existing medical conditions complexify, so does the need to improve the quality of care for this population. Utilizing early hospital admission variables, this study will create and validate a multinomial decision tree that predicts the discharge disposition of older patients with fall-related TBI. From the National Trauma Data Bank, we retrospectively analyzed 11,977 older patients with a fall-related TBI (2017-2021). Clinical variables included Glasgow Coma Scale (GCS) score, intracranial pressure monitor use, venous thromboembolism (VTE) prophylaxis, and initial vital signs. Outcomes included hospital discharge disposition re-categorized into home, care facility, or deceased. Data were split into two sets, where 80% developed a decision tree, and 20% tested predictive performance. We employed a conditional inference tree algorithm with bootstrap (B = 100) and grid search options to grow the decision tree and measure discrimination ability using the area under the curve (AUC) and calibration plots. Our decision tree used seven admission variables to predict the discharge disposition of older TBI patients. Significant non-modifiable variables included total GCS and injury severity scores, while VTE prophylaxis type was the most important interventional variable. Patients who did not receive VTE prophylaxis treatment had a higher probability of death. The predictive performance of the tree in terms of AUC value (95% confidence intervals) in the training cohort for death, care, and home were 0.66 (0.65-0.67), 0.75 (0.73-0.76), and 0.77 (0.76-0.79), respectively. In the test cohort, the values were 0.64 (0.62-0.67), 0.75 (0.72-0.77), and 0.77 (0.73-0.79). We have developed and internally validated a multinomial decision tree to predict the discharge destination of older patients with TBI. This tree could serve as a decision support tool for caregivers to manage older patients better and inform decision-making. However, the tree must be externally validated using prospective data to ascertain its predictive and clinical importance.

PROTACs coupled with oligonucleotides to tackle the undruggable.

Undruggable targets account for roughly 85% of human disease-related targets and represent a category of therapeutic targets that are difficult to tackle with traditional methods, but their considerable clinical importance. These targets are generally defined by planar functional interfaces and the absence of efficient ligand-binding pockets, making them unattainable for conventional pharmaceutical strategies. The advent of oligonucleotide-based proteolysis-targeting chimeras (PROTACs) has instilled renewed optimism in addressing these challenges. These PROTACs facilitate the targeted degradation of undruggable entities, including transcription factors (TFs) and RNA-binding proteins (RBPs), via proteasome-dependent mechanisms, thereby presenting novel therapeutic approaches for diseases linked to these targets. This review offers an in-depth examination of recent progress in the integration of PROTAC technology with oligonucleotides to target traditionally undruggable proteins, emphasizing the design principles and mechanisms of action of these innovative PROTACs.

Prognostic Value of Ki-67 in the Invasive Zone of Oral Squamous Cell Carcinoma.

The molecular profile of cells within the tumor invasive zone, where tumor cells interact with surrounding non-tumor cells, plays a crucial role in defining tumor malignant characteristics, such as the pattern of invasion (POI). Therefore, evaluating the diagnostic value of the proliferation index molecule, Ki-67, in both tumor cells and adjacent non-tumor cells at the invasive zone with different POIs, holds significant clinical importance for oral squamous cell carcinoma (OSCC). This retrospective study included 133 primary OSCC samples, and the spatial pattern of Ki-67 in the tumor invasive zone was analyzed by immunohistochemistry (IHC). The prognostic value of tumor cells and stroma proliferative capacity in different POIs were assessed. Ki-67 was widely expressed in tumor cells and stroma cells within the invasive zone, and cells in high-invasiveness POIs exhibit higher proliferation. Elevated Ki-67 expression in tumor cells was associated with poor overall survival (OS) and disease-free survival (DFS) in patients, which is independent of POIs. In our study, we identified the expression level of Ki-67 in tumor cells across high-invasiveness POIs as an independent risk factor for OS and DFS in OSCC patiens. Additionally, Ki-67 expression in surrounding non-tumor cells did not significantly correlate with patient survival. The remarkable proliferation characteristic of tumor cells in high-invasiveness POIs of OSCC tumors plays a crucial role in the prognosis of patients.

Comparative efficacy and acceptability of non-invasive neuromodulation technologies and botulinum toxin injections for post-stroke spasticity and motor function: a network meta-analysis of randomised controlled trials.

Non-invasive neuromodulation is a promising approach for improving spasticity and motor function after stroke. However, it is still unclear which type of non-invasive neuromodulation is effective and evidence of important differences between them and botulinum toxin (BoNT) injection is limited. We aimed to assess the comparative efficacy and acceptability of non-invasive neuromodulation technologies and BoNT for post-stroke spasticity and motor function. In this network meta-analysis, Cochrane Library, EMBASE, MEDLINE, Web of Science, Scopus, CNKI, and Wan Fang Data were searched from the earliest records to 8 October 2024. Randomised controlled trials that compared any type of non-invasive neuromodulation therapies, BoNT, and control treatments (including sham or no stimulation/injection) for post-stroke spasticity measured by modified Ashworth scale (MAS) were included. MAS, motor function, and acceptability were pooled using random-effects model with summary weighted mean difference (WMD) or risk ratios (RR) alongside 95% confidence interval (CI). Ranking probabilities of the treatments were estimated. Clinical importance was categorized as definite, probable, possible, or definitely not, considering the relationship between effect measures (95% CI) and minimal clinically important difference (1, 6, and 1.5 points for MAS, motor function, and acceptability, respectively). The quality of evidence was assessed using CINeMA online web. PROSPERO registration CRD42024543494. 6260 studies were identified and 185 trials (11,185 participants; 12 interventions) were included. Compared with control treatments, BoNT, high- and low-frequency repetitive transcranial magnetic stimulation (HFrTMS and LFrTMS), and anodal, cathodal, and dual transcranial direct current stimulation (atDCS, ctDCS, and dtDCS) significantly improved spasticity at short-term follow-up (WMD range-0.81 to-0.31), but did not achieve clinical importance. At mid-term, ctDCS (WMD=-2.00; 95% CI:-3.03,-0.97) and dtDCS (WMD=-1.62; 95% CI:-3.22,-0.02) were more efficacious than control treatments in reducing post-stroke spasticity with probable clinical importance. For motor function, atDCS, ctDCS, and dtDCS were more efficacious than control treatments (WMD range 6.29-13.00), with probable clinical importance, while BoNT, HFrTMS, and LFrTMS with possible clinical importance (WMD range 3.42-5.28). Various modalities have comparable acceptability to control treatments (RR range 0.48-1.46). Confidence in accordance with CINeMA ranged from high to low. Sensitivity and meta-regression analyses on limb measured, cointervention, and stroke stage confirmed the main findings of this study. Taken together with clinical importance, evidence available supports three forms of tDCS as effective treatments for post-stroke spasticity and/or motor impairments, whereas BoNT, HFrTMS, and LFrTMS for motor impairments. These modalities could be considered alongside rehabilitation interventions as core treatments for post-stroke spasticity and motor impairments. China Postdoctoral Science Foundation (2024M752230).

The tibiofibular mortise - anatomical controversies and their clinical importance: a historical and pictorial essay.

During 280 years of studies of the anatomy of the distal tibiofibular articulation, there have arisen many unclear issues regarding the description of individual structures and their terminology. These historical inaccuracies were subsequently reflected in the clinical practice. A literature search of original publications and historical sources was performed. The distal tibiofibular articulation is a synovial joint, rather than a syndesmosis, as it is an integral part of the ankle joint. The interosseous tibiofibular ligament (ITFL), described for the first time by a French anatomist Bichat in 1801, is the strongest ligament of the tibiofibular mortise. Unfortunately, this clinically important ligament is not recognized by the current international anatomical nomenclature. The terms anterior inferior (AITFL) and posterior inferior tibiofibular ligaments (PITFL) are historical remnants "reimported" from the American/British literature and should not be used, because the analogous superior ligaments do not exist. The intermalleolar ligament, first described by Weitbrecht in 1742, is a variable, but constant, structure reinforcing the posterior capsule of the ankle joint. The term inferior transverse ligament (IFT) denoting in the English literature the inferior part of the posterior tibiofibular ligament was originally used for the intermalleolar ligament. The IFT ligament is a part of the posterior tibiofibular ligament and there is no reason to stress its importance. The chaos in the anatomy, terminology and depiction of the articulation of the distal tibia and fibula, unparalleled in any other joint of the human body, is the result of historical development. A certain negative role was, in this respect, played also by Basiliensia Nomina Anatomica (1895), that eradicated ITFL and called the distal tibiofibular joint a syndesmosis.

A comprehensive analysis of the pyruvate kinase M1/2 (PKM) in human cancer.

Pyruvate Kinase Muscle Isozyme (PKM), as a member of the pyruvate kinase, is a key enzyme in glycolysis. Numerous tumors have demonstrated its oncogenic properties. There is, however, no pan-carcinogenic analysis for PKM. A thorough analysis of PKM across various types of cancer was carried out using bioinformatics resources like The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) database. This study involved analyzing the role of PKM in 33 various types of cancers, along with investigating gene expressions, survival rates, clinical importance, genetic changes, immune system presence, and related signaling pathways. Furthermore, we evaluated the effects of PKM knockdown on human colon carcinoma, and glioblastoma cell lines by in vitro experimentation. In most tumors, PKM expression was markedly increased and was associated with unfavorable overall survival (OS) in certain individuals. In addition, infiltration of macrophages was associated with PKM expression in various tumors. PKM was linked to glycolysis/gluconeogenesis, HIF-1 signaling, carbon metabolism, and NADPH regeneration in a mechanistic manner. Additionally, cell experiments showed that the knockdown of PKM could reduce the proliferation and migration abilities while promoting the apoptosis of Caco-2, and U-87 MG cells. PKM controls immune cell infiltration, impacts patient outcomes in various types of cancer, and plays an essential role in proliferation and migration in some tumor cells by affecting glycometabolism. The PKM molecule may serve as a potential prognostic biomarker and therapeutic target for human cancers.

How Should a Physician Respond to a Patient's Unexpected Pain During a Pelvic Examination When There Is Clinical Indication of Infection?

This commentary on a case considers how to navigate a pelvic exam in the context of a patient's personal experience and suggests the clinical and ethical importance of thoughtful, intentional action and consistent, clear communication in these clinical encounters.

Role of glutaminyl-peptide cyclo-transferase-like protein (QPCTL) in cancer: From molecular mechanisms to immunotherapy.

Glutaminyl-peptide cyclotransferase-like protein (QPCTL) is a newly discovered enzyme that has sparked interest owing to its possible role in cancer genesis and progression. Initially discovered as a post-translational modification regulator of protein maturation, QPCTL has emerged as a key participant in cancer biology. Recent research has linked QPCTL to numerous essential cancer-related processes, including cell proliferation, migration, invasion, and apoptosis. Furthermore, QPCTL expression changes have been seen in a variety of cancer types, underlining its potential as a diagnostic and prognostic marker. The molecular mechanisms behind QPCTL's participation in cancer will be examined in this review. We investigate its involvement in the control of signaling pathways and the modification of cellular activities that are important in cancer. We also examine the clinical importance of QPCTL, including as its relationship with tumor development, metastasis, and response to treatment. We also discuss the possible therapeutic implications of targeting QPCTL in cancer therapy. QPCTL is a prospective target for the development of innovative anticancer treatments due to its participation in several cancer-associated pathways.

51 Diagnostic lens: the clinical importance of early recognition of leukocoria

51 Diagnostic lens: the clinical importance of early recognition of leukocoria

Clinical importance of borderline proteinuria in nonazotemic cats and evaluation of other risk factors for the development of chronic kidney disease.

Borderline proteinuria is associated with decreased survival in cats with azotemic chronic kidney disease (CKD). Determine the clinical importance of borderline proteinuria in nonazotemic cats. A total of 201 healthy client-owned cats ≥7 years of age; 150 nonproteinuric (urinary protein : creatinine ratio [UPC] <0.2) and 51 borderline proteinuric (UPC 0.2-0.4). Prospective study. Cats were thoroughly screened and subsequently examined every 6 months for 2 years. Kaplan-Meier curves were compared between nonproteinuric and borderline proteinuric cats. Univariable and multivariable Cox models were fit to determine the relationship between development of renal disease and potential risk factors such as age, sex, breed, weight, dental disease, blood pressure, serum creatinine concentration (sCrea), serum symmetric dimethylarginine concentration (sSDMA), blood urea nitrogen concentration, urine specific gravity (USG), and UPC. Significantly more cats with borderline proteinuria at inclusion developed renal disease (International Renal Interest Society [IRIS] ≥ stage 2 CKD or renal proteinuria; log-rank P = .004) or died (log-rank P = .02) within 2 years, compared with nonproteinuric cats. In the multivariate analysis, IRIS stage 1 CKD (persistent USG <1.035 or sSDMA >14 μg/dL; hazard ratio [HR], 4.2; 95% confidence interval [CI], 2.0-8.8; P < .001), sCrea ≥1.6 mg/dL (≥140 μmol/L; HR, 2.6; 95% CI, 1.1-6.4; P = .04), borderline proteinuria (HR, 2.5; 95% CI, 1.2-5.2; P = .01), and age at inclusion (HR, 1.3; 95% CI, 1.2-1.5; P < .001) were significantly associated with diagnosis of renal disease 6 months later. Borderline proteinuria should receive more attention in healthy mature adult and senior cats because it is associated with renal disease and death.

Excellent Reliability for an Instrumented Test of Ankle Plantarflexion Force

Background/Purpose The assessment of ankle plantarflexion force is commonly required in athletic performance and clinical rehabilitation settings to assess the integrity of the calf and lower limb musculature. The force generating capacity of the soleus muscle is thought to be important in many aspects of sporting and everyday function. Unfortunately, there are only a few reliable tests describing the assessment of the strength of the soleus muscle, especially in dorsiflexion greater than plantar grade/neutral which mimics ankle joint positions associated with higher ground contact forces. Accordingly, the purpose of this study is to describe the reliability, feasibility, and clinimetrics of a novel test of plantarflexion force in a clinical setting Methods Test-retest reliability of a seated isometric plantar flexion strength test performed a minimum of one day apart (maximum of six) using the maximum value of four trials was investigated using a force plate and custom apparatus in 61 volunteer adults (of varying activity levels (Tegner one to ten). Inter-rater reliability (ICC2,1), Bland-Altman, and minimal detectable change values were estimated. Results Sixty-one subjects were tested (49 male, 12 female, 39.6±12.6 years, 81.1±13.8kg). Excellent test-retest reliability was demonstrated (ICC2,1)=0.976 [0.97 to 0.98], p&lt;0.001; and minimal detectable change (MDC) was found to be 118N. Conclusion Excellent test-retest reliability and a minimal detectable change of 118N (14.8% bodyweight) were demonstrated for this measure of plantar flexion force. MDC data can inform clinical progression and between-limb differences in healthy and injured individuals. Further, these results can be used to explore the clinical importance of the measurement using the instrumentation. Level of Evidence 3b

Maternal shift work during pregnancy and cardiovascular health impacts on mother and offspring.

Cardiovascular disease (CVD) is the leading cause of death for women worldwide. One of the risk factors for CVD in women is complications during pregnancy. Pregnancy complications include a wide arena of pathologies, including hypertension, preeclampsia, gestational diabetes, preterm delivery and miscarriage. Interestingly, increased evidence in recent years highlights a novel link between maternal shift work during pregnancy and increased risk for pregnancy complications, specifically hypertension and diabetes, while knowledge on other CVDs, such heart failure, atherosclerosis, ischemic heart disease, and stroke in pregnant shift working mothers is still scarce. Notably, shift work during pregnancy results in significant changes to the circadian rhythm of both the mother and fetus, therefore, engaging into shift work during pregnancy may adversely affect the cardiovascular health of both the mother and offspring, and carry into adulthood. Herein, we highlight the novel relationship between maternal shift work during pregnancy and the increased risk for pregnancy complications that may increase risk for CVD later in life. Furthermore, we provide mechanistic insights of the hemodynamic processes that are disrupted in response to maternal shift work and may explain the increased risk for cardiovascular disease. Understanding how shift work during pregnancy influences the prevalence for heart disease is of paramount clinical importance for minimizing the risk for cardiovascular disease for both the mother and offspring.

The role and molecular mechanism of GDF5 in regulating cell migration and angiogenesis via the Hippo-YAP signaling pathway in colorectal cancer.

292 Background: Distant metastasis is a leading cause of poor prognosis and mortality in colorectal cancer (CRC) patients, with angiogenesis playing a crucial role in tumor progression. The TGF-β superfamily has been shown to significantly influence tumor angiogenesis, yet the biological function and molecular mechanism of Growth Differentiation Factor 5 (GDF5), a member of this superfamily, remain unexplored in CRC. Given that the efficacy of current anti-angiogenic therapies is limited to a subset of patients, identifying new therapeutic targets involved in tumor angiogenesis is of great clinical importance. GDF5, with its potential role in angiogenesis regulation, presents a promising candidate to bridge this therapeutic gap. Methods: In this study, we analyzed GDF5 expression in CRC tissue samples using both the TCGA dataset and samples from our center, revealing significantly lower GDF5 expression in tumors compared to adjacent normal tissues. Moreover, GDF5 downregulation correlated with lymph node metastasis and disease recurrence. Functional assays in vitro demonstrated that GDF5 overexpression reduced tumor cell migration and invasion, while its knockdown produced the opposite effect. Co-culture assays showed that GDF5 knockdown significantly enhanced endothelial cell migration and angiogenesis, whereas overexpression diminished these effects. Additionally, F-actin cytoskeletal staining indicated that GDF5 overexpression led to cytoskeletal remodeling in endothelial cells. Mechanistically, we found that GDF5 overexpression in tumor cells downregulated the epithelial-mesenchymal transition (EMT) marker Slug and upregulated E-cadherin, while downregulating N-cadherin. In endothelial cells, GDF5 inhibited the Hippo-YAP signaling pathway, increasing YAP phosphorylation and reducing nuclear YAP levels. Conversely, GDF5 knockdown suppressed YAP phosphorylation and promoted its nuclear translocation. Results: Our findings demonstrate that GDF5 functions as a tumor suppressor in CRC by regulating cell migration and angiogenesis. This study reveals that GDF5 exerts its anti-cancer effects by modulating both EMT in tumor cells and cytoskeletal changes in endothelial cells, leading to the inhibition of the Hippo-YAP signaling pathway and reduced angiogenic potential. These results identify GDF5 as a promising new target for anti-angiogenic therapy in CRC, offering potential avenues for improving treatment strategies in patients resistant to current therapies. Conclusions: GDF5 acts as a tumor suppressor in colorectal cancer by inhibiting cell migration and angiogenesis through modulation of the Hippo-YAP signaling pathway, making it a promising therapeutic target for anti-angiogenic treatment in patients resistant to current therapies.

The Global Epidemiology of Scleritis: A Systematic Review and Meta-analysis.

Scleritis, a severe inflammatory condition of the sclera, causes significant ocular pain and potential tissue damage. Often linked with systemic diseases, scleritis can be either infectious or noninfectious. Despite its clinical importance, the global incidence and detailed epidemiology of scleritis are poorly understood due to its heterogeneity and rarity. This systematic review and meta-analysis aim to elucidate the worldwide incidence and epidemiological trends of scleritis, examining variations across geographic regions, etiologies, and time periods. Systematic Review and Meta-analysis CLINICAL RELEVANCE: Understanding scleritis epidemiology is crucial for enhancing diagnostic accuracy and treatment, especially concerning systemic illnesses commonly associated with this condition. Identifying epidemiological trends can inform healthcare policies and resource allocation, improving patient outcomes. We systematically reviewed literature across databases, including Embase, PubMed, Virtual Health Library, The Cochrane Library, and medRxiv. Population-based, cohort, case-control, cross-sectional, and claims database studies reporting the frequency, prevalence, or incidence of scleritis diagnosed through clinical or imaging techniques, were included. The screening was based on titles and abstracts, followed by a full-text review. We assessed the risk of bias using standardized tools and systematically extracted data for both qualitative and quantitative synthesis. This review is registered with PROSPERO (CRD42022330948). Our review included 74 studies with 169,871 scleritis patients. The incidence was 2.67 per 100,000 in ophthalmological centers and 1.38 per 100,000 in broader population-based studies, both showing a decreasing trend over time. The patient population was predominantly female (67.24%), with an average age of 48.3 years. Epidemiological patterns were significantly influenced by etiology, geographic region, and publication period, with idiopathic cases being the most common. Scleritis was notably associated with systemic diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, Sjögren's syndrome, sarcoidosis, and infectious agents like Mycobacterium tuberculosis and herpes virus. This is the largest study on scleritis to date, providing comparative insights across geographic regions, age groups, and genders. Our meta-analysis highlights significant regional differences in scleritis incidence, reflecting variations in medical practice, access to care, and potential environmental factors. These findings underscore the need for further research to explore these patterns and their global health implications.

P-1554. Impact of High Predicted Risk of Antimicrobial Resistance on Empiric Treatment Failure in US Females with Uncomplicated Urinary Tract Infections

Abstract Background Antibiotic (ABX) treatment of uncomplicated urinary tract infection (uUTI) is often prescribed empirically which may lead to treatment failure (TF) and antimicrobial resistance (AMR). Suspected AMR may be assessed using a published AMR risk categorization framework. This study aimed to investigate the impact of high predicted risk of AMR on TF in female outpatients with uUTI. Methods Female outpatients aged ≥ 12 years with a uUTI diagnosis (Dx) between Jan 2018 and Sep 2022 were assessed retrospectively using Optum’s de-identified Electronic Health Record dataset. TF was defined as having a second oral ABX prescription (Rx), intravenous ABX, or emergency department/inpatient stay with a primary Dx of UTI ≤ 28 days after the first empiric oral ABX Rx for the uUTI Dx. Four validated AMR risk predictive models categorized patients as low or moderate (L/M) or high risk of isolate non-susceptibility to each of nitrofurantoin, sulfamethoxazole-trimethoprim, fluoroquinolones, and β-lactams, separately. Patients predicted to have high risk of isolate non-susceptibility to ≥ 1 ABX class were categorized as high AMR risk. Risk ratios (RRs) with 95% confidence intervals (CIs) were used to compare TF in patients with L/M AMR risk vs high AMR risk and the effect of recurrent uUTI history on TF in high AMR risk patients was explored. Results Of 376,004 female outpatients with uUTI, 121,802 (32.4%) were categorized as high AMR risk (Table 1). Risk of TF was higher in patients with high AMR risk vs L/M AMR risk (21% vs 15%, adjusted RR [95% CI] = 1.21 [1.20–1.23]; p&amp;lt; 0.001; Table 2). TF risk increased with number of predicted high risk ABX classes, as patients with 1, 2, 3, and 4 predicted high risk ABX classes had unadjusted TF RRs of 1.23, 1.37, 1.71, and 2.01, respectively, vs those with L/M AMR risk (all p&amp;lt; 0.001; Table 2). TF rates were higher in patients with high AMR risk and recurrent UTI history vs L/M AMR risk and non-recurrent UTI (23.1% vs 14.6%, unadjusted RR [95% CI] = 1.58 [1.55–1.62]; Table 3). Conclusion Female uUTI outpatients with high predicted AMR risk to ≥ 1 oral ABX had a significantly greater risk of TF vs those with L/M predicted risk of AMR. These findings underscore the clinical importance of suspected AMR and history of UTI recurrence in empiric treatment decision-making for uUTI. Funding GSK study 219500 Disclosures Debra L. Fromer, MD, GSK: Advisor/Consultant|Johnson &amp; Johnson/Janssen Pharmaceuticals: Advisor/Consultant Meghan Luck, PharmD, BCPS, GSK: Employee|GSK: Stocks/Bonds (Private Company) Malena Mahendran, MS, Analysis Group, Inc.: Employee of Analysis Group, Inc., a consulting company that received funding from GSK to conduct this study Rose Chang, ScD, Analysis Group, Inc.: Employee of Analysis Group, Inc., a consulting company that received funding from GSK to conduct this study Megan Pinaire, MPH, Analysis Group, Inc.: Employee of Analysis Group, Inc., a consulting company that received funding from GSK to conduct this study Dar Alon, MS, Analysis Group, Inc.: Employee of Analysis Group, Inc., a consulting company that received funding from GSK to conduct this study Mei Sheng Duh, MPH, ScD, Analysis Group, Inc.: Employee of Analysis Group, Inc., a consulting company that received funding from GSK to conduct this study Madison T. Preib, MPH, GSK: Employee|GSK: Stocks/Bonds (Public Company) Jeffrey J. Ellis, PharmD, MS, GSK: Employee|GSK: Stocks/Bonds (Public Company)

P-443. Outcomes in Pneumocystis Pneumonia Hospitalizations in Patients with HIV: A County Hospital Study 2015-2022

Abstract Background Therapy related complications, morbidity and mortality are still problematic in treating pneumocystis jirovecii pneumonia (PJP) in persons living with HIV (PWH) on antiretroviral therapy (ART). Our study aims to outline patient demographics and hospital outcomes among PWH in a safety-net hospital during the contemporary ART era. Methods We retrospectively reviewed and extracted data from inpatient encounters with HIV and PJP between 2015-2022 at a safety-net hospital in Los Angeles County, California Results We identified 55 PWH (58 admissions) with confirmed or presumed PJP. Only 6.9% had a known HIV diagnosis and linked to care the prior year. 37.9% had concurrent opportunistic infections (OIs), and 20.7% had prior OI history. Treatment with trimethoprim-sulfamethoxazole (TMP-SMX) was used in 84.5% of cases in whom 48% had treatment related adverse effects. 62.1% received steroids. At one-year post-hospitalization, 63.8% were linked to care and 27.6% were lost to follow up or out of network. Inpatient mortality was 5.2%, and 10.3% died at 1-year. Higher oxygen requirements predicted a higher 1-year mortality (OR 2.68, 95%CI = 1.28 – 5.64, p = &amp;lt; 0.01), as did necessity of TMP-SMX alternatives (OR 18.8, p = 0.003, 95% CI 2.72 – 129.73). Conclusion A total of 32.8% of patients failed TMP-SMX. These patients also had higher 12-month mortality rate, likely reflecting underlying host comorbidities and disease severity. Atovaquone is inferior to TMP-SMX and primaquine-clindamycin is non-inferior to TMP-SMX, however, only in mild-moderate disease. There is a paucity of data for alternative treatments for severe disease. Concurrent OI were found in 37.9%, of whom 81.8% had no prior history of OI. Of the three inpatient mortalities, two had concurrent OIs, emphasizing the clinical importance of screening for other OI in patients who present with PJP. In-hospital mortality was 5.2%, compared to 9 -17% in other studies; 1-year mortality was 10.3% compared to estimates of 37-53% during early ART period, suggesting a positive trend compared to both pre- and early ART outcomes. The one-year follow-up mortality of 10.3% and having only 63.8% successfully linked with in-network HIV care underscores an opportunity to improve linkage and retention strategies for PWH. Disclosures All Authors: No reported disclosures

Abnormal left ventricular and left atrial mechanics in patients with resistant hypertension

Abstract Introduction Patients with resistant hypertension (RH) suffer from a high rate of cardiovascular (CV) complications and have poor prognosis. Given the poor prognosis in RH patients, early identification of subclinical myocardial abnormalities is of clinical importance to allow for timely preventive therapeutic interventions. Speckle tracking echocardiography (STE) is a valuable technique to detect subclinical myocardial dysfunction in hypertensive patients and, therefore, could assist in clinical risk stratification and provide important therapeutic implications. Purpose The study aimed to investigate whether left ventricular (LV) and left atrial (LA) myocardial mechanics are impaired in patients with RH compared to controlled hypertension (CH) patients and normotensive controls (NC). Methods This was a prospective cross-sectional study in which 54 age and sex-matched participants: 17 with RH (mean age 60.5±12.4 years), 18 with CH (57.7±12.2 years), and 19 NC (54.7±11.9 years) were consecutively recruited. Clinical and conventional echocardiographic measurements were obtained, followed by a two-dimensional STE analysis to assess LV and LA strain. Stepwise multivariable linear regression analysis was performed to identify independent predictors of LV and LA strain indices. Results The demographical characteristics were similar across the three groups (Table 1). Patients with RH had elevated BP readings and pronounced cardiac remodelling compared to CH and NC (p&amp;lt;0.001). Peak systolic global longitudinal strain (GLS) was lower in RH and CH groups compared to NC (RH: -16.7±1.9% and CH: -19.8±1.4% vs NC: -21.4±1.3%; p&amp;lt;0.001 and p=0.005, respectively), and being lower in RH compared to CH (p&amp;lt;0.001). Peak systolic global circumferential strain (GCS) was lower between RH and NC (RH: -18.3±3.6% vs NC: -21.7±2.2%, p=0.004) but not between RH and CH (RH: -18.3±3.6% vs CH: -20.3±2.9%, p=0.13). Peak systolic global radial strain (GRS) was lower in RH than in CH and NC (RH: 32.8±8.1% vs CH: 45.0±8.9% and NC: 49.1±5.2%, p&amp;lt;0.001 for all). LV twist was similar amongst the three groups (p&amp;gt;0.05). For the LA longitudinal strain indices, patients with RH had significantly lower reservoir, conduit, and pump strains than NC (p&amp;lt;0.001, p&amp;lt;0.001 and p=0.04, respectively) and CH (p=0.01, p=0.02 and p=0.02, respectively). Of note, the presence of RH remained independently associated with worse GLS (β=3.1, p&amp;lt;0.001), GRS (β= -8.6, p&amp;lt;0.001), LA reservoir (β= -6.0, p=0.005) and pump strains (β=3.5, p=0.007) after adjusting for demographical and clinical variables (Table 2). Conclusion Patients with RH show evidence of greater cardiac remodelling with subclinical impairment of their LV and LA mechanics when compared to CH and NC. The subclinical identification of myocardial abnormalities in patients with RH may provide a therapeutic window of opportunity for their reversal and potentially mitigate the occurrence of accompanied CV complications.

Anatomical Study of the Palmaris Longus Muscle and Its Clinical Importance

Background: The palmaris longus (PL) is a long, thin muscle in the forearm’s flexor compartment, known for its variations. The present study aimed to study the PL muscle in Omani medical students and its correlation with grip strength. Methods: A cross-sectional prospective study was conducted among 240 medical students (120 males, 120 females) at Sultan Qaboos University, comprising 480 upper limbs. Participants were between 18 and 25 years old and had no history of forearm surgery. We considered 480 upper limbs irrespective of left or right side, and our main aim was to compare the grip strength according to the presence or absence of PL. We assessed the presence of the PL muscle using Schaeffer’s Test and Pushpakumar’s test and measured the grip strength using the CAMRY digital hand dynamometer. The data were analyzed using descriptive statistics, Chi-square tests, and independent t-tests. Results: The PL was present in 92.50% of the subjects (irrespective of side), with a higher prevalence in the females. The PL was absent in 24 (10.00%) males and 12 (5.00%) females, respectively. Average grip strength was 21.4 ± 5.25 kg in females and 40.92 ± 7.79 kg in males without considering PL presence or absence. If PL was present, then the mean grip strength was 30.84 ± 11.71 kg, and if the PL was absent, then the mean grip strength was 35.05 ± 12.44 kg. However, the p-value did not show any significant differences (p = 0.057). Conclusions: The PL is highly prevalent, especially in females, and its absence does not significantly affect grip strength. Hence, PL may be used for successful reconstructive surgeries without affecting hand function.

Haemophilia Infants Gross Motor Development: Comparisons With Full-Term and Preterm Infants of the Same Nationality.

Infants with haemophilia, due to parental overprotection, have difficulty developing their full motor repertoire of typical gross motor development. It is of great clinical importance to evaluate the motor development of these infants with a standardized assessment tool. To study the gross motor development in infants with haemophilia, using the Alberta Infant Motor Scale (AIMS) and compare it with full-term (FT) and preterm infants (PT). Fifteen FT infants with severe or moderate haemophilia A and B were assessed with the AIMS (Group D). The scale is already standardized in FT Greek infants (Group A). Two groups of PT infants were also included, with gestational age >32weeks and ≤32weeks, Groups B and C, respectively. The mean Z-scores were tested with the ANOVA procedure, followed by post hoc pairwise comparisons with Bonferroni correction. The four groups had significantly different mean Z-scores. Infants in Group A had a mean Z-score of 0±1. Infants in Group B lagged significantly behind by one standard deviation. Preterm infants in Group C had a mean Z-score significantly lower than Group B. Infants in Group D had a mean Z-score significantly lower than Group C. Motor development in infants with haemophilia significantly lags behind both FT and PT infants. Differences in AIMS scores could be attributed to the reduction of movement activity, since infants with haemophilia are often deprived of certain positions, being held and carried in the parents' arms, as well as from free play time on the floor.

Composition and liquid-to-solid maturation of protein aggregates contribute to bacterial dormancy development and recovery

Recalcitrant bacterial infections can be caused by various types of dormant bacteria, including persisters and viable but nonculturable (VBNC) cells. Despite their clinical importance, we know fairly little about bacterial dormancy development and recovery. Previously, we established a correlation between protein aggregation and dormancy in Escherichia coli. Here, we present further support for a direct relationship between both. Our experiments demonstrate that aggregates progressively sequester proteins involved in energy production, thereby likely causing ATP depletion and dormancy. Furthermore, we demonstrate that structural features of protein aggregates determine the cell’s ability to exit dormancy and resume growth. Proteins were shown to first assemble in liquid-like condensates that solidify over time. This liquid-to-solid phase transition impedes aggregate dissolution, thereby preventing growth resumption. Our data support a model in which aggregate structure, rather than cellular activity, marks the transition from the persister to the VBNC state.