Pelvic Pseudotumor Associated With a Ceramic Bearing Total Hip.

Pseudotumors have been well documented to occur most frequently in metal-metal bearing total hip arthroplasties and less frequently in metal-polyethylene bearings. There are few cases in the literature of pseudotumors occurring in ceramic-ceramic articulations. We report a case of a large pelvic pseudotumor in a patient with a ceramic-ceramic bearing articulation in a 67-year-old man. In addition to the usual investigations, we did a detailed wear analysis of the ceramic implants and an examination of the soft tissues for particulate debris. The detailed wear analysis did show evidence of stripe wear; however, the volumetric wear was within the expected range. Synchrotron imaging identified strontium and zirconium debris arising from the ceramic surfaces. Although association does not mean causation, no other cause for the large pseudotumor could be identified and presumably represents an idiosyncratic reaction to ceramic debris.

Effects of the selective AMPA modulator NBI-1065845 on the pharmacokinetics of midazolam or ethinyl estradiol-levonorgestrel in healthy adults.

This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

CHD7 regulates craniofacial cartilage development via controlling HTR2B expression.

Mutations in the Chromodomain helicase DNA-binding protein 7 - coding gene (CHD7) cause CHARGE syndrome (CS). Although craniofacial and skeletal abnormalities are major features of CS patients, the role of CHD7 in bone and cartilage development remain largely unexplored. Here, using a zebrafish (Danio rerio) CS model, we show that chd7-/- larvae display abnormal craniofacial cartilage development and spinal deformities. The craniofacial and spine defects are accompanied by a marked reduction of bone mineralization. At the molecular level, we show that these phenotypes are associated with significant reduction in the expression levels of osteoblast differentiation markers. Additionally, we detected a marked depletion of collagen 2α1 in the cartilage of craniofacial regions and vertebrae, along with significantly reduced number of chondrocytes. Chondrogenesis defects are at least in part due to downregulation of htr2b, which we found to be also dysregulated in human cells derived from an individual with CHD7 mutation-positive CS. Overall, this study thus unveils an essential role for CHD7 in cartilage and bone development, with potential clinical relevance for the craniofacial defects associated with CS.

Patients with CHARGE syndrome exhibit skeletal defects. CHARGE syndrome is primarily caused by mutations in the chromatin remodeler-coding gene CHD7. To investigate the poorly characterized role of CHD7 in cartilage and bone development, here, we examine the craniofacial and bone anomalies in a zebrafish chd7-/- mutant model. We find that zebrafish mutant larvae exhibit striking dysmorphism of craniofacial structures and spinal deformities. Notably, we find a significant reduction in osteoblast, chondrocyte, and collagen matrix markers. This work provides important insights to improve our understanding of the role of chd7 in skeletal development.

INTERACT: a randomized phase 2 study of the DAAO inhibitor luvadaxistat in adults with schizophrenia.

Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational d-amino acid oxidase (DAAO) inhibitor that increases d-serine levels at NMDAR coagonist sites. INTERACT is a phase 2 randomized, placebo-controlled study that evaluated the efficacy and safety of three doses of luvadaxistat, covering a range of DAAO occupancy and d-serine levels, in patients with schizophrenia with persistent negative symptoms. The study included a 14-day, single-blinded placebo run-in period and a 12-week, double-blinded treatment period. The primary efficacy endpoint was the 12-week change from baseline in Positive and Negative Syndrome Scale-Negative Symptom Factor Score (PANSS NSFS). Secondary efficacy endpoints included the 12-week changes from baseline in Brief Assessment of Cognition in Schizophrenia (BACS) score and Schizophrenia Cognition Rating Scale (SCoRS) score. Safety endpoints included adverse event assessments. The full analysis set included all randomized patients (N = 256 [placebo, n = 87; luvadaxistat 50 mg, n = 58; 125 mg, n = 56; 500 mg, n = 55]); 228 patients completed the study. No significant improvements in PANSS NSFS were observed at any dose versus placebo at week 12. Improvements were observed with luvadaxistat 50 mg versus placebo in cognitive endpoints: BACS composite score (nominal one-sided p = 0.031) and SCoRS interviewer total score (nominal one-sided p = 0.011). Luvadaxistat did not significantly improve negative symptoms of schizophrenia. However, luvadaxistat 50 mg met the prespecified secondary endpoints for cognitive performance (BACS) and function (SCoRS), warranting further investigation in patients with cognitive impairment associated with schizophrenia. Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov: NCT03382639.

Mild Cognitive Impairment: Clinical Presentation and Short-Term Comparative Outcome of Patients With Potentially Modifiable and Nonmodifiable Risk Factors.

Objective: To estimate the prevalence and study the clinical presentation of mild cognitive impairment (MCI), assess its outcome in terms of cognition and quality of life, identify factors for reversion to baseline, and compare these factors in the modifiable and nonmodifiable risk factor groups.Methods: Individuals aged >50 years with memory/cognitive complaint(s) were screened using the Mini-Cog over 1 year (August 2018-August 2019). Those meeting the DSM-5 criteria for MCI were enrolled, and risk factors (modifiable and nonmodifiable) were noted. Assessments were done using the Hindi version of the Montreal Cognitive Assessment (H-MoCA), the Clinical Dementia Rating (CDR)-Hindi version, and the World Health Organization Quality of Life-Brief Hindi version. Treatment outcome was assessed at 6 months and compared between the risk factor groups. Factors for reversion of MCI were assessed.Results: A total of 124 patients (22.1% of 561 with cognitive complaints) had MCI, and 100 patients (50 patients from the modifiable group and 50 patients from the nonmodifiable group) completed the study. Depression (52%) and hypertension (48%) were common risk factors. End point cognition scores were similar in both groups, with quality of life better in the modifiable group (P = .023). Age was negatively correlated with cognition in total patients and the nonmodifiable group (r =0.283-0.420; P = .002-.004). In total patients, cognition moderately correlated with education and somewhat with quality of life; 31% and 57% reverted to normal on the MoCA and CDR scales, respectively, while 1 progressed to dementia. Reverters had higher baseline H-MoCA scores (odds ratio [OR] = 6.996; P < .001) and were treated with cholinesterase inhibitors + vitamin E (OR = 28.999; P = .007).Conclusion: Short-term outcome for both the modifiable and nonmodifiable risk factor groups was favorable. Higher education positively correlated with cognition, which itself predicted a better quality of life. Reverters of MCI had better baseline cognition and were treated with cholinesterase inhibitors + vitamin E.Prim Care Companion CNS Disord 2024;26(4):24m03708. Author affiliations are listed at the end of this article.

A Comprehensive Analysis of Clinical, Biochemical, and Polysomnographic Characteristics in Patients With Type 2 Diabetes Mellitus With and Without Obstructive Sleep Apnea.

BACKGROUND: Obstructive sleep apnea (OSA) has been a significant contributor to mortality all across the globe. The most attributing factors to pathogenesis are metabolic syndrome, obesity, diabetes, and so on, but the indicators of its early detection are still elusive. OBJECTIVE: The study aimed to compare the clinical, biochemical, and polysomnographic characteristics of type 2 diabetes patients with and without OSA. DESIGN AND METHODS: This cross-sectional study was conducted at the Department of Medicine and Endocrinology Unit of Dayanand Medical College and Hospital, Ludhiana. A total of 584 patients with type 2 diabetes were assessed using the Berlin questionnaire, with 302 fulfilling the criteria for a high risk of OSA. Out of 302 patients who met the criteria for the high-risk category, 110 patients underwent a sleep study. RESULTS:  Three hundred and two patients satisfying the inclusion and exclusion criteria were enrolled in the study. A total of 110 patients underwent a sleep study, of which 68 (61.8%) had evidence of OSA. The waist-to-hip ratio was considerably higher in the OSA patients than in the non-OSA group (1.09 vs 0.930, p = 0.001). HbA1c >7% was found in 58.8% of OSA patients contrary to 38.1% of non-OSA patients. Fasting plasma glucose levels (>126 mg/dl) were identified in a substantially larger proportion of OSA patients than the non-OSA patients (64.7% vs 45.2%, p = 0.04). Similarly, peripheral neuropathy was found more commonly in the OSA patients than in the non-OSA patients (47% vs. 26.1%, p = 0.02). Prevalence of retinopathy, nephropathy, coronary artery disease, stroke, heart failure, and peripheral vascular disease did not differ significantly between the two groups. CONCLUSIONS: OSA frequently occurs among individuals diagnosed with type 2 diabetes mellitus. The prompt identification of OSA within this demographic is imperative to pinpoint those at an elevated risk of succumbing to conditions such as peripheral neuropathy, the exacerbation of glycemic control, and the onset of unmanaged hypertension. Moreover, there exists a positive correlation between the waist-to-hip ratio and the prevalence of OSA in persons with type 2 diabetes mellitus, highlighting the critical role of waist-to-hip ratio assessments in this patient population.

GeneAI 3.0: powerful, novel, generalized hybrid and ensemble deep learning frameworks for miRNA species classification of stationary patterns from nucleotides.

Due to the intricate relationship between the small non-coding ribonucleic acid (miRNA) sequences, the classification of miRNA species, namely Human, Gorilla, Rat, and Mouse is challenging. Previous methods are not robust and accurate. In this study, we present AtheroPoint's GeneAI 3.0, a powerful, novel, and generalized method for extracting features from the fixed patterns of purines and pyrimidines in each miRNA sequence in ensemble paradigms in machine learning (EML) and convolutional neural network (CNN)-based deep learning (EDL) frameworks. GeneAI 3.0 utilized five conventional (Entropy, Dissimilarity, Energy, Homogeneity, and Contrast), and three contemporary (Shannon entropy, Hurst exponent, Fractal dimension) features, to generate a composite feature set from given miRNA sequences which were then passed into our ML and DL classification framework. A set of 11 new classifiers was designed consisting of 5 EML and 6 EDL for binary/multiclass classification. It was benchmarked against 9 solo ML (SML), 6 solo DL (SDL), 12 hybrid DL (HDL) models, resulting in a total of 11 + 27 = 38 models were designed. Four hypotheses were formulated and validated using explainable AI (XAI) as well as reliability/statistical tests. The order of the mean performance using accuracy (ACC)/area-under-the-curve (AUC) of the 24 DL classifiers was: EDL > HDL > SDL. The mean performance of EDL models with CNN layers was superior to that without CNN layers by 0.73%/0.92%. Mean performance of EML models was superior to SML models with improvements of ACC/AUC by 6.24%/6.46%. EDL models performed significantly better than EML models, with a mean increase in ACC/AUC of 7.09%/6.96%. The GeneAI 3.0 tool produced expected XAI feature plots, and the statistical tests showed significant p-values. Ensemble models with composite features are highly effective and generalized models for effectively classifying miRNA sequences.

The attitude of medical undergraduate students from North India toward transgender and change thereafter by educational intervention.

Background: There is a widespread gap among medical professionals about transgender, and it needs to be addressed through proper educational intervention to inculcate positive attitudes toward transgender people. Aim: This study aimed to assess the attitude of medical undergraduate students toward transgender and change thereafter by educational intervention. Materials and Methods: A total of 169 final-year undergraduate students (aged 22-25 years; 50.3% males; all having heterosexual orientation) were assessed for their attitudes toward transgender people using the Genderism and Transphobia Scale (GTS) and Attitude toward Transgender Individuals Scale (ATTIS). Subsequently, an educational intervention was conducted. The attitude scores were again evaluated immediately and after one month of post-intervention. A paired t-test, independent-samples t-test, and analysis of variance (ANOVA) were used to compare the data. Results: Mean ATTIS and GTS scores before intervention were 67.02 ± 9.20 and 80.84 ± 26.07, respectively. After the educational intervention, these scores were 79.27 ± 7.18 and 63.20 ± 12.11, respectively, thus showing a significant change in both scores. The change in GTS score was significantly higher in males than in females (P < 0.001) and in urban than in rural residents (P = 0.017). No significant association of demographic factors was observed concerning the change in ATTIS scores. On evaluating the recall value, no significant decline in GTS or ATTIS scores was observed following a one month of interval. Conclusion: There is a need to positively reinforce these changes brought about by educational intervention in the attitude of undergraduate medical students toward transgender people. Such cognitive gains are achievable in developing a humanistic society.

Acute Pancreatitis: Clinical Profile of 60 Patients.

Introduction  Acute pancreatitis (AP) is a common differential diagnosis of acute pain abdomen and cannot be considered self-limiting as it has serious early and long-term impacts. Depending on severity, AP is divided into mild, moderately severe, and severe AP. Management of AP involves accurate diagnosis, high-quality supportive care, monitoring for early detection and treatment of complications, and prevention of relapse. Aim To assess the etiological risk factors, clinical profile, and complications in patients with AP. Methods The present study was conducted on 60 eligible patients admitted to the Department of Medicine, Government Medical College, and Hospital of Northern India. A diagnosis of AP was established based on the revised Atlanta classification (2012) for the classification of AP, and relevant data were collected and statistically analyzed. Results Most of the AP patients were in the 21-40 year age group. The majority were males (88.3%). Alcohol was the most common etiological factor in 76.7% of patients followed by cholelithiasis in 10% of patients. Pain abdomen was the most common presenting clinical feature occurring in 96.7% of patients and vomiting in 65% of the patients. Acute fluid collection was the most common pancreatic complication occurring in 26.7% of the patients, pancreatic edema was seen in 21.7%, and pancreatic necrosis in 15%. Among extrapancreatic complications, ascites was most commonly seen in 50% of patients followed by pleural effusion in 15%, shock in 15%, multiple organ dysfunction syndrome (MODS) in 15%, and hypocalcemia in 11.7% of patients. Conclusion AP should be one of the differentials for patients presenting with pain abdomen, especially when probable risk factors such as alcohol abuse and cholelithiasis are present. A high index of suspicion to diagnose AP is needed as timely management may prevent systematic complications, thus improving the outcome. Poor prognostic indicators are raised levels of total serum bilirubin, raised serum lipase, reduced serum albumin, and low platelet count among AP patients.