Deciphering Cathepsin K inhibitors: a combined QSAR, docking and MD simulation based machine learning approaches for drug design.

Cathepsin K (CatK), a lysosomal cysteine protease, contributes to skeletal abnormalities, heart diseases, lung inflammation, and central nervous system and immune disorders. Currently, CatK inhibitors are associated with severe adverse effects, therefore limiting their clinical utility. This study focuses on exploring quantitative structure-activity relationships (QSAR) on a dataset of CatK inhibitors (1804) compiled from the ChEMBL database to predict the inhibitory activities. After data cleaning and pre-processing, a total of 1568 structures were selected for exploratory data analysis which revealed physicochemical properties, distributions and statistical significance between the two groups of inhibitors. PubChem fingerprinting with 11 different machine-learning classification models was computed. The comparative analysis showed the ET model performed well with accuracy values for the training set (0.999), cross-validation (0.970) and test set (0.977) in line with OECD guidelines. Moreover, to gain structural insights on the origin of CatK inhibition, 15 diverse molecules were selected for molecular docking. The CatK inhibitors (1 and 2) exhibited strong binding energies of -8.3 and -7.2 kcal/mol, respectively. MD simulation (300 ns) showed strong structural stability, flexibility and interactions in selected complexes. This synergy between QSAR, docking, MD simulation and machine learning models strengthen our evidence for developing novel and resilient CatK inhibitors.

Nationwide precision oncology pilot study: KOrean Precision Medicine Networking Group Study of MOlecular profiling-guided therapy based on genomic alterations in advanced solid tumors (KOSMOS) KCSG AL-20-05.

BACKGROUND: Next-generation sequencing (NGS) has become widely available but molecular profiling-guided therapy (MGT) had not been well established in the real world due to lack of available therapies and expertise to match treatment. Our study was designed to test the feasibility of a nationwide platform of NGS-guided MGT recommended by a central molecular tumor board (cMTB) for metastatic solid tumors. PATIENTS AND METHODS: Patients with advanced or metastatic solid tumors with available NGS results and without standard treatment were enrolled. The cMTB interpreted the patients' NGS reports and recommended the following: (i) investigational medicinal products (IMPs) approved in other indications; (ii) alternative treatments; (iii) clinical trials. The primary variables were the proportion of patients with actionable genomic alterations and those receiving MGT as per cMTB recommendations. Others included treatment duration (TD), overall response rate (ORR), disease control rate (DCR), and safety. RESULTS: From February 2021 to February 2022, 193 cases [99 (51.3%) men; median age 58 years (range 24-88 years); median line of previous treatment 3 (range 0-9)] from 29 sites were enrolled for 60 cMTB sessions. The median time from case submission to cMTB discussion was 7 days (range 2-20 days), and to IMP treatment initiation was 28 days (range 14-90 days). Actionable genetic alterations were found in 145 patients (75.1%). A total of 89 (46.1%) patients received actual dosing of IMPs, and 10 (5.2%) were enrolled in cMTB-recommended clinical trials, achieving an MGT rate of 51.3%. ORR and DCR of IMPs were 10.1% and 72.5%, respectively. The median TD was 3.5 months [95% confidence interval (CI) 2.8-5.5 months], and the 4-month TD rate was 44.9%. The median overall survival of patients who received IMPs was 6.9 months (95% CI 5.2-10.0 months). CONCLUSION: KOSMOS confirmed the feasibility of MGT recommended by the cMTB, achieving a high MGT match rate and promising effectiveness in heavily pretreated advanced cancer patients.

Exposome Signatures of Gastrointestinal Disorders Among Active Duty Service Members.

INTRODUCTION: We evaluated the risk factors associated with gastrointestinal disorders (GD) among the soldiers of the Army and Marine Aviation community (AMAC) using an exposomic approach. Specifically, we aimed to determine the medical and operational factors associated with reported GD in the Military Health System. METHODS: Longitudinal data were obtained from the Medical Assessment and Readiness System (MARS) housed at Womack Army Medical Center, Fort Liberty, NC, for a retrospective cohort study that included 79,249 active duty United States AMAC active duty service members (ADSMs) from October 2015 to December 2019. Multivariable mixed-effects logistic regression was used to assess the relationship between the incidence occurrence of GD and variables including rank, service time, deployment, Armed Forces Qualification Test score, education, tobacco use, alcohol use, age, gender, race, ethnicity, body mass index (BMI), and marital status. RESULTS: The incidence of GD included 22,813 person-years of observations with a rate of 2.2 per 100 person-years and a period prevalence of 3.2%. GD was independently associated with rank, service time, and deployment (all P < 0.05). CONCLUSION: The high-risk categories associated with GD in the AMAC included age, BMI, race (not ethnicity), marital status, and service time. Our data also show that deployment time, not geographical location, was associated with a higher risk of GD. Together, these analyses suggest that White ADSMs older than 33 years of age who have experienced marriage, longer service time, and deployments appear to have a higher risk of GDs. Our assessment shows the utility of using an exposomic approach to create a member-specific, big data-informed personalized clinical algorithm of health outcomes.

A phase II study of tepotinib in patients with advanced solid cancers harboring MET exon 14 skipping mutations or amplification (KCSG AL19-17).

BACKGROUND: We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification. PATIENTS AND METHODS: A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test. RESULTS: Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2. CONCLUSIONS: Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib.

Metataxonomic and metabolomic profiling revealed Pinus koraiensis cone essential oil reduced methane emission through affecting ruminal microbial interactions and host-microbial metabolism.

BACKGROUND: Pinus koraiensis cone essential oil (PEO) contains functional compounds such as monoterpene hydrocarbons, and the administration of PEO reduced methane (CH4) emissions during growing phase of goats. However, the mode of action of PEO driven CH4 reduction is not known, especially how the administration of PEO can affect rumen microbiota and host metabolism in goats during the fattening phase. This study aimed to elucidate the potential microbial and host responses PEO supplementation in goats using metataxonomics (prokaryotes and protozoa) and metabolomics (rumen fluid and serum). RESULTS: Ten fattening Korean native goats were divided into two dietary groups: control (CON; basal diet without additives) and PEO (basal diet + 1.5 g/d of PEO) with a 2 × 2 crossover design and the treatment lasted for 11 weeks. Administration of PEO reduced CH4 concentrations in the exhaled gas from eructation by 12.0-13.6% (P < 0.05). Although the microbial composition of prokaryotes (bacteria and archaea) and protozoa in the rumen was not altered after PEO administration. MaAsLin2 analysis revealed that the abundance of Selenomonas, Christensenellaceae R-7 group, and Anaerovibrio were enriched in the rumen of PEO supplemented goats (Q < 0.1). Co-occurrence network analysis revealed that Lachnospiraceae AC2044 group and Anaerovibrio were the keystone taxa in the CON and PEO groups, respectively. Methane metabolism (P < 0.05) was enriched in the CON group, whereas metabolism of sulfur (P < 0.001) and propionate (P < 0.1) were enriched in the PEO group based on microbial predicted functions. After PEO administration, the abundance of 11 rumen and 4 serum metabolites increased, whereas that of 25 rumen and 14 serum metabolites decreased (P < 0.1). Random forest analysis identified eight ruminal metabolites that were altered after PEO administration, among which four were associated with propionate production, with predictive accuracy ranging from 0.75 to 0.88. Additionally, we found that serum sarcosine (serum metabolite) was positively correlated with CH4 emission parameters and abundance of Methanobrevibacter in the rumen (|r|≥ 0.5, P < 0.05). CONCLUSIONS: This study revealed that PEO administration reduced CH4 emission from of fattening goats with altered microbial interactions and metabolites in the rumen and host. Importantly, PEO administration affected utilizes various mechanisms such as formate, sulfur, methylated amines metabolism, and propionate production, collectively leading to CH4 reduction. The knowledge is important for future management strategies to maintain animal production and health while mitigate CH4 emission.

Assessment of a continuous passive motion assistive device in dogs following stifle surgery.

Canine rehabilitation optimizes recovery and the quality of life in dogs with musculoskeletal conditions or after surgery. Achieving proper range of motion (ROM) is vital post-stifle surgery, often accomplished through manual therapy and active exercises. We investigated the mechanical performance of a continuous passive motion (CPM) device for dogs and its potential use in canine rehabilitation therapy. In the ethical review process, our research was accepted to be evaluated in a sample of four dogs that had undergone left stifle surgery. Each dog underwent four sessions with the device at three different speeds. Results showed the device replicated extension angles close to goniometer measurements used in manual therapy. Flexion was also achieved, but not to the same extent. A force threshold stopped the device, avoiding discomfort in dogs with restricted ROM. Dog-specific factors like body position, opposition to movement, limb size, stage of recovery, haircoat, and discomfort, appeared to influence device operation. Mechanical improvements to allow for enhanced flexion are recommended in future CPM device designs, including a resistance threshold that could be adjusted for individual dogs and stages of healing. This study serves as a foundation for future advancements in canine rehabilitation systems. A canine CPM device may provide an affordable option to improve ROM. This could be beneficial for dog owners, who may not be comfortable with manual therapy, to assist with home rehabilitation exercises.

Non-cardiac comorbid health outcomes and prevalence after myocardial infarction: an umbrella review.

OBJECTIVE: There exists limited comprehensive evidence on the potential association between non-cardiac comorbidities and myocardial infarction (MI). Thus, we conducted an umbrella review of existing meta-analyses to provide a broad understanding of non-cardiac health outcomes associated with MI. MATERIALS AND METHODS: The primary focus on the prevalence of related health outcomes in patients with MI was systemically searched. Each original meta-analysis that was included had its methodological quality evaluated by a Measurement Tool Assessment Systematic Reviews 2 (AMSTAR2). To evaluate the certainty in the evidence for each outcome, we employed GRADE and the Joanna Briggs Institute Prevalence Critical Appraisal Tool. The protocol was registered in PROSPERO (CRD42023458642). RESULTS: We identified seven meta-analyses comprising 126 studies with 336,581 participants from 22 countries and five continents. The pooled prevalence of comorbidities in patients with MI was 39% anxiety [95% confidence interval (CI), 30-48; GRADE, very low certainty], 29% depression (95% CI, 23-36; very low certainty), 39% frailty (95% CI, 24-55; very low certainty), and 23% failure of returning to work (95% CI, 16-29; very low certainty). The diagnosis of MI was associated with an increased risk of cognitive impairment (odds ratio, 1.45; 95% CI, 1.10-1.92; moderate certainty). Among frail patients, MI was associated with an increased risk of major bleeding (relative risk, 1.93; 95% CI, 1.08-3.45; low certainty) and mortality (relative risk, 2.29; 95% CI, 1.48-3.53; moderate certainty). However, we did not find any evidence of cancer risk associated with the development of MI. CONCLUSIONS: Our umbrella meta-analysis provided comprehensive evidence of the association between MI and several non-cardiac health conditions. The robustness of our study is attributed to the integration of evidence across several studies, thus, these insights offer valuable treatment options for policymakers and physicians to develop personalized health strategies.

Human epididymis protein 4: Analysis of national health and nutrition examination survey data.

BACKGROUND: Human epididymis protein 4 (HE4) is a tumor marker overexpressed in ovarian cancer and is commonly utilized to aid with diagnosis of an adnexal mass. HE4 levels vary based on pregnancy, age, menopausal status, and tobacco use. OBJECTIVE(S): The objective of this study was to evaluate population-based data to examine factors that affect HE4 among adult women in the United States and stratify levels of HE4 by demographic and gynecologic factors. STUDY DESIGN: A retrospective analysis was conducted using data from 2,480 women aged 20 + who participated in the National Health and Nutrition Examination Survey (2001-2002). From these cross-sectional data, serum HE4 and cotinine, a marker of tobacco exposure, were combined with demographic and interview data. Estimated glomerular filtration rates (eGFR) were based on serum creatinine, age, sex, and race. Other variables of interest included menopausal status, pregnancy, and various gynecologic factors. Summary HE4 data are provided as geometric means with associated 95 % confidence intervals. RESULTS: HE4 levels were independently associated with age, renal function, and nicotine use, all p < 0.001. Pre-menopausal women with a history of endometriosis were found to have elevated HE4 levels compared to those without, p < 0.01; however, we found no such difference among post-menopausal women. Adjusting for age, no differences in HE4 were found based on race/ethnicity, p = 0.29. HE4 levels showed statistically significant associations with income level; however, these were small and clinically irrelevant. CONCLUSION: This study provides evaluation of HE4 levels among a data set representative of 98.5 million non-institutionalized women in the United States and gives insight into extraneous factors that may influence these levels.

Respiratory and chest wall mechanics in very preterm infants.

Data on static compliance of the chest wall (Ccw) in preterm infants are scarce. We characterized the static compliance of the lung (CL) and Ccw to determine their relative contribution to static compliance of the respiratory system (Crs) in very preterm infants at 36 wk postmenstrual age (PMA). We also aimed to investigate how these compliances were influenced by the presence of bronchopulmonary dysplasia (BPD) and impacted breathing variables. Airway opening pressure, esophageal pressure, and tidal volume (VT) were measured simultaneously during a short apnea evoked by the Hering-Breuer reflex. We computed tidal breathing variables, airway resistance (R), and dynamic lung compliance (CL,dyn), inspiratory capacity (IC), and Crs, CL, and Ccw. Functional residual capacity was assessed by the multiple breath washout technique (FRCmbw). Breathing variables, compliances, and lung volumes were adjusted for body weight. Twenty-three preterm infants born at 27.2 ± 2.0 wk gestational age (GA) were studied at 36.6 ± 0.6 wk PMA. Median and interquartile range (IQR) Crs/kg is 0.69 (0.6), CL/kg 0.95 (1.0), and Ccw/kg 3.0 (2.4). Infants with BPD (n = 11) had lower Crs/kg (P = 0.013), CL/kg (P = 0.019), and Ccw/kg (P = 0.027) compared with infants without BPD. Ccw/CL ratio was equal between groups. FRCmbw/kg (P = 0.044) and IC/kg (P = 0.005) were decreased in infants with BPD. Infants with BPD have reduced static compliance of the respiratory system, the lungs, and chest wall. Decreased Crs, CL, and Ccw in infants with BPD explain the lower FRC and IC seen in these infants.NEW & NOTEWORTHY Data on chest wall compliance in very preterm infants in the postsurfactant era are scarce. To our knowledge, we are the first group to report data on static respiratory system compliance (Crs), lung compliance (CL), and chest wall compliance (Ccw) in preterm infants with and without bronchopulmonary dysplasia (BPD) in the postsurfactant era.

Exposomic Signatures of Tinnitus and/or Hearing Loss.

INTRODUCTION: We evaluated the risk factors associated with tinnitus and/or hearing loss (THL) among active duty (AD) members of the U.S. Army and Marine Aviation Community (AMAC) using an exposomic approach. Specifically, we aimed to determine the factors associated with the reported THL in the Military Health System. METHODS: Longitudinal data were obtained from the Medical Assessment and Readiness System housed at Womack Army Medical Center, Fort Bragg, NC, for a retrospective cohort study that included 78,546 AD AMAC members from October 2015 to December 2019. Multivariable mixed-effects logistic regression was used to assess the relationship between THL and numerous variables to include rank, service time, deployment, tobacco use, alcohol use, age, gender, race, ethnicity, and body mass index. RESULTS: Our analysis included a total of 220,044 person-years of observations. The THL incidence rate was 6.7 per 100 person-years, with an 8.1% period prevalence. THL was associated with age, gender, body mass index, race, deployment, service time, marital status, and tobacco use (all P < .05). Service time greater than 16 years had the greatest odds ratio of THL (4.46, 95% CI: 3.58-5.55, P < .001). CONCLUSIONS: Our assessment shows the utility of using an exposomic approach to create member-specific personalized clinical algorithms for health outcomes. We examined individuals with THL diagnoses and identified a combination of risk factors from biomedical, lifestyle, environmental, and stochastic sources. Taken together, the risk factors identified across the four exposomic domains could help understand the etiology of THL. Our exposomic methodology could be the foundation for generating predictive models. Finally, a specific evaluation of occupational risk factors may provide insight into aspects not readily available from civilian literature. In upcoming years, as the Medical Assessment and Readiness System matures, we will expand our analyses to include prospective, untargeted metabolites and biomarker data.

Exposomic Signatures of Cervical Pain.

INTRODUCTION: We evaluated risk factors associated with cervical pain (CP) among officers and enlisted members of the U.S. Army and Marine Aviation community using an exposomic approach. Specifically, we aimed to determine the factors associated with reported CP. MATERIALS AND METHODS: This is a retrospective cohort study that utilized the Medical Assessment and Readiness System housed at Womack Army Medical Center to evaluate the longitudinal data taken from medical and workforce resources. This study included 77,864 active duty AMAC members during October 2015-December 2019. Multivariable mixed-effects logistic regression was used to assess the relationship between the independent variables of rank, service time, deployment, Armed Forces Qualification Test score, tobacco use, alcohol use, age, gender, race, ethnicity, body mass index, marital status, and education level and the dependent variable, incidence occurrence of CP. RESULTS: The total analysis included 77,864 individuals with 218,180 person-years of observations. The incidence rate of CP was 18.8 per 100 person-years, with a 12% period prevalence. Cervical pain was independently associated with rank, service time, Armed Forces Qualification Test score, and alcohol use (all P < .05). CONCLUSIONS: Our longitudinal exposomic signatures-based approach aims to complement the outcomes of data science and analytics from Medical Assessment and Readiness System with validations of objective biochemical indicator species observed in Army and Marine Aviation community members suffering from CP. This initial approach using parallel track complementarity has the potential of substantiating the underlying mechanisms foundational to design prospective personalized algorithms that can be used as a predictive model. Finally, a specific evaluation of occupational risk factors may provide insight into factors not readily ascertained from the civilian literature.

Imaging findings of granular cell tumours of the head and neck.

AIM: To review the imaging characteristics of granular cell tumours in the head and neck and assess their associations with pathological findings. MATERIALS AND METHODS: Eleven patients (10 [91%] women, mean age 43 years) with histopathologically confirmed granular cell tumours were included in this study. Preoperative imaging studies were performed, including computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound. The location of the tumours, their imaging features, and histopathological findings were analysed. RESULTS: Among the 11 granular cell tumours, four (36%), three (27%), and two (18%) tumours were found in the submucosal layer, subcutaneous layer, and intramuscular area, respectively. On CT, all tumours exhibited homogeneous iso-attenuating enhancement compared with adjacent muscle, and nine out of the 11 tumours (81%) demonstrated well-defined margins. On T2-weighted imaging (T2WI), four out of five tumours (80%) demonstrated iso-signal intensity compared with adjacent muscles, and four tumours (80%) exhibited homogeneous signal intensity. The apparent diffusion coefficient (ADC) values ranged from 0.68-0.81 × 10-3 mm2/s. Histopathological examination revealed densely packed tumour cells with variable amounts of fibrous stroma. CONCLUSION: Granular cell tumours were characterised by well-defined and iso-signals on T2WI and low mean ADC values, and were predominantly located in the submucosal, subcutaneous, or intramuscular areas in middle-aged women. The characteristic locations, demographic characteristics, and imaging findings can help to differentiate granular cell tumours from other soft-tissue tumours in the head and neck.

National prevalence and socioeconomic factors associated with the acceptance of COVID-19 vaccines in South Korea: a large-scale representative study in 2021.

OBJECTIVE: Among the global efforts toward preventing the COVID-19 pandemic, vaccines are a pivotal factor in ending the pandemic. Thus, through a large-scale population-based study, we investigated the individual-, social-, and family-associated factors affecting the acceptance of COVID-19 vaccines in South Korea. PATIENTS AND METHODS: Data were obtained from a nationwide representative study (Korea Community Health) conducted in 2021. To determine the individual-, social-, and family-associated variables for COVID-19 vaccination acceptance, we investigated data from 225,319 individuals. RESULTS: In the total sample (n=225,319), 184,529 COVID-19-vaccinated people and 40,790 non-vaccinated people were evaluated. The factors related to the acceptance of COVID-19 vaccination were significantly associated with the demographic factors, namely, older age group, female sex, and a history of influenza vaccination, as well as medical conditions such as diabetes, hypertension, and depression. Socioeconomic conditions influencing the acceptance of COVID-19 vaccination were significantly associated with low-income families and blue-collar workers. Health-related risk factors were high in the obese group. However, a noteworthy negative association was found between the acceptance of vaccination and smoking habits and alcohol consumption. Conversely, a positive association was observed between academic level and vaccination acceptance. CONCLUSIONS: Our findings suggest that old age, female sex, a history of influenza vaccination, medical conditions, such as diabetes, hypertension, and depression, low-income families, blue-collar workers, and health-related risk factors, such as obesity, were associated with the acceptance of COVID-19 vaccination. Additionally, a high academic level, absence of smoking habits, and non-current alcohol use were positively associated with vaccine acceptance.

National prevalence and determinants of COVID-19 vaccine hesitancy during the initial phase pandemic.

OBJECTIVE: Although previous studies have explored the causes of COVID-19 vaccine hesitancy during the pandemic, there is a lack of generality and reproducibility in these studies. Therefore, we aimed to comprehensively identify the determinants of COVID-19 vaccine hesitancy through a representative nationwide cross-sectional study conducted in South Korea. SUBJECTS AND METHODS: We used a nationwide, representative, and large-scale dataset from the 2021 Community Health Survey. By analyzing 193,495 participants, we investigated the nationwide incidence of COVID-19 vaccine hesitancy and the various causes thereof. RESULTS: The national prevalence of COVID-19 vaccine hesitancy was 5.7% (95% CI, 5.5-5.8). COVID-19 vaccine hesitancy was associated with an increased incidence of the following factors: (1) demographic factors including early-middle adulthood [vs. late; odds ratio (OR), 1.51; 95% CI, 1.38-1.65] and male sex (vs. female sex; OR, 1.08; 95% CI, 1.01-1.14); (2) physically healthy subjects; (3) lower socio-economic status (vs. high household income; OR, 1.28; 95% CI, 1.19-1.38); (4) having mental illness (vs. normal mental status; OR, 1.25; 95% CI, 1.13-1.38); and (5) unhealthy habits such as current smoking (vs. non-smoking; OR, 1.22; 95% CI, 1.13-1.31); and insufficient physical activity (vs. sufficient; OR, 1.08; 95% CI, 1.01-1.17). Common reasons for vaccine hesitancy were concerns about side effects (41.34%), health problems (24.60%), and inability to select the type of vaccine (14.13%). CONCLUSIONS: This representative large-scale nationwide study conducted in South Korea investigated the nationwide prevalence and determinants of vaccine hesitancy. Our results provide useful public health information, especially on novel aspects of vaccination strategies, for policymakers to improve the acceptance of COVID-19 vaccines.

Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m2 paclitaxel on day 1 every 3 weeks, intravenously. All patients received six cycles of the combination treatment and continued to receive trastuzumab-pkrb maintenance until disease progression, unacceptable toxicity, or for up to 2 years. HER2 positivity (based on immunohistochemistry analysis) was determined according to the 2013 American Society of Clinical Oncology /College of American Pathologists HER2 testing guidelines. The primary endpoint was objective response rate (ORR); the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. RESULTS: Twenty-six patients were evaluated via primary endpoint analysis. The ORR was 48.1% (1 complete and 12 partial responses) and the duration of response was 6.9 months [95% confidence interval (CI) 4.4-9.3 months]. With a median follow-up of 10.5 months, the median PFS and OS were 8.4 months (95% CI 6.2-8.8 months) and 13.5 months (95% CI 9.8 months-not reached), respectively. The most common treatment-related adverse event (TRAE) of any grade was peripheral neuropathy (88.9%). The most common grade 3/4 TRAEs were neutropenia (25.9%), thrombocytopenia (7.4%), and anemia (7.4%). CONCLUSIONS: Trastuzumab-pkrb plus paclitaxel demonstrates promising efficacy with manageable toxicity profiles in patients with HER2-positive recurrent or metastatic UC.

Pericardial diverticulum arising from the right lateral superior aortic recess: a mimicker of cystic anterior mediastinal mass.

AIM: To report the prevalence of pericardial diverticulum of the right lateral superior aortic recess (RSAR) on computed tomography (CT), to analyse the structural CT findings of whether or not the structure is large enough to be seen on chest radiographs, and to describe changes in size and shape of RSAR on follow-up CT. MATERIALS AND METHODS: A well-circumscribed, fluid-attenuation lesion in the anterior mediastinum with the following CT features was defined as a pericardial diverticulum of the RSAR: no enhancing wall, communication with the RSAR, abutment to the heart with an acute angle, and moulding by adjacent structures. Chest CT images of 31 patients with the diverticulum were evaluated, including four selected from 1,130 consecutive patients (0.4%). RESULTS: The diverticulum projected ventrally from the RSAR and its largest size on axial CT ranged between 12-56 mm. Although the RSAR and the largest diverticular portion were usually seen on the same axial image (n=19), the latter sometimes lay above (n=1) or below (n=11) the former. On sagittal images, the last 11 diverticula resembled teardrops hanging from the RSAR by small stems. All of the 24 patients, each with 1-31 follow-up CT examinations, showed size fluctuations ranging between 1-46 mm (mean, 16 mm) during a follow-up period of 0.5-172 months (mean, 65 months). The diverticulum was not identifiable in five cases and was identifiable but did not show a connection with the RSAR in three cases when the diverticulum was smallest in size. CONCLUSIONS: In cases of cystic anterior mediastinal mass, a deliberate search for its connection with the RSAR on all available CT images including previous studies is necessary for the diagnosis of pericardial diverticulum of the RSAR.

Cortisol/glucocorticoid receptor: a critical mediator of the ovulatory process and luteinization in human periovulatory follicles.

STUDY QUESTION: Do cortisol/glucocorticoid receptors play an active role in the human ovary during ovulation and early luteinization? SUMMARY ANSWER: The ovulatory hCG stimulation-induced glucocorticoid receptor signaling plays a crucial role in regulating steroidogenesis and ovulatory cascade in human periovulatory follicles. WHAT IS KNOWN ALREADY: Previous studies reported an increase in cortisol levels in the human follicular fluid after the LH surge or ovulatory hCG administration. However, little is known about the role of cortisol/glucocorticoid receptors in the ovulatory process and luteinization in humans. STUDY DESIGN, SIZE, DURATION: This study was an experimental prospective clinical and laboratory-based study. An in vivo experimental study was accomplished utilizing the dominant ovarian follicles from 38 premenopausal women undergoing laparoscopic sterilization. An in vitro experimental study was completed using the primary human granulosa/lutein cells (hGLC) from 26 premenopausal women undergoing IVF. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted in a private fertility clinic and academic medical centers. Dominant ovarian follicles were collected before the LH surge and at defined times after hCG administration from women undergoing laparoscopic sterilization. Primary hGLC were collected from women undergoing IVF. hGLC were treated without or with hCG in the absence or presence of RU486 (20 µM; dual antagonist for progesterone receptor and glucocorticoid receptor) or CORT125281 (50 µM; selective glucocorticoid receptor antagonist) for 12 or 36 h. The expression of genes involved in glucocorticoid receptor signaling, steroidogenesis, and ovulatory cascade was studied with RT-quantitative PCR and western blotting. The production of cortisol, corticosterone, and progesterone was assessed by hormone assay kits. MAIN RESULTS AND THE ROLE OF CHANCE: hCG administration upregulated the expression of hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1), nuclear receptor subfamily 3 group C member 1 (NR3C1), FKBP prolyl isomerase 5 (FKBP5), and FKBP prolyl isomerase 4 (FKBP4) in human ovulatory follicles and in hGLC (P < 0.05). RU486 and CORT125281 reduced hCG-induced increases in progesterone and cortisol production in hGLC. The expression of genes involved in glucocorticoid receptor signaling, steroidogenesis, and the key ovulatory process was reduced by RU486 and/or CORT125281 in hGLC. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The role of cortisol/glucocorticoid receptors demonstrated using the hGLC model may not fully reflect their physiological roles in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Successful ovulation and luteinization are essential for female fertility. Women with dysregulated cortisol levels often suffer from anovulatory infertility. Deciphering the functional role of glucocorticoid receptor signaling in human periovulatory follicles enhances our knowledge of basic ovarian physiology and may provide therapeutic insights into treating infertility in women. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by P01HD71875 (to M.J., T.E.C., and M.B.) and R01HD096077 (to M.J.) from the Foundation for the National Institutes of Health and the BTPSRF of the University of Kentucky Markey Cancer Center (P30CA177558). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Risk factors for musculoskeletal-related occupational disability among US Army soldiers.

INTRODUCTION: Minimising temporary and permanent disability associated with musculoskeletal conditions (MSK-D) is critical to the mission of the US Army. Prior research has identified potentially actionable risk factors for overall military disability and its MSK-D subset, including elevated body mass index, tobacco use and physical fitness. However, prior work does not appear to have addressed the impact of these factors on MSK-D when controlling for a full range of factors that may affect health behaviours, including aptitude scores that may serve as a proxy for health literacy. Identifying risk factors for MSK-D when providing control for all such factors may inform efforts to improve military readiness. METHODS: We studied 494 757 enlisted Army soldiers from 2014 to 2017 using a combined medical and administrative database. Leveraging data from the Army's digital 'eProfile' system of duty restriction records, we defined MSK-D as the first restriction associated with musculoskeletal conditions and resulting in the inability to deploy or train. We used multivariable Cox proportional hazards regression to assess the associations between incident MSK-D and selected risk factors including aptitude scores, physical fitness test scores, body mass index and tobacco use. RESULTS: Among the subjects, 281 278 (45.14%) experienced MSK-D. In the MSK-D hazards model, the highest effect size was for failing the physical fitness test (adjusted HR=1.63, 95% CI 1.58 to 1.67, p<0.001) compared with scoring ≥290 points. CONCLUSIONS: The analysis revealed the strongest associations between physical fitness and MSK-D. Additional efforts are warranted to determine potential mechanisms for the observed associations between selected factors and MSK-D.

Rates of Lapidus Procedures in the US Military Before and After the Advent of and Advocacy for Tri-Plane Lapidus Corrective Surgery.

Tri-plane corrective Lapidus surgery has been described as advantageous with respect to its anatomic basis and outcomes. Because the procedure has been broadly publicized, changes in overall Lapidus procedure rates due to increased numbers of patients opting for the tri-plane approach could have occurred. Data supporting this possibility appears lacking. We employed official personnel and health records of the total active-duty US military to conduct a retrospective cohort study of Lapidus surgery rates before and after the advent of the tri-plane corrective Lapidus procedure. Least-squares and locally-weighted scatterplot smoother regression functions were used to confirm time trends. Sociodemographic and occupational traits of Lapidus patients were compared using 2-sided t tests and chi square tests. Lapidus surgery rates among hallux valgus patients decreased during 2014 to 2016 and increased during 2017 to 2021. While multiple factors might explain these trends, they coincide with the advent of and advocacy for tri-plane Lapidus surgery. The results support the possibility that its rise influenced overall Lapidus rates in this population. As these findings represent limited evidence of such an influence, further research is required to confirm a causal link. If such a link is found, and if the ongoing research suggests that superior outcomes are associated with tri-plane Lapidus surgery, substantial implications could exist for this population. Benefits might include enhanced medical readiness due to the importance of lower extremity function during military duties. Additional research is needed to confirm the impact of the procedure and to determine whether Lapidus surgery rate patterns in civilian populations mirror these findings.