Moving from stable standing to single-limb stance or an up-on-the-toes position: The importance of vision to dynamic balance control.

Understanding the contribution vision has to dynamic balance control may help in understanding where/why loss of balance occurs during everyday locomotion. The current study determined how body-centre-of-mass (BCoM) dynamics and postural stability when moving to and holding a single-limb-stance (SS) or an up-on-the-toes (UTT) position were affected by visual occlusion. From standing on a force platform, 18 adults (mean (SD) 26.7 (4.8) years; 1.73 (0.08) m; 84.0 (22.9) kg; 7 females) completed repeated trials (x3) with and without vision in which they moved to either a SS or an UTT position (order countered-balanced), and attempted to hold that position for 2 (SS) or 5 (UTT) seconds before returning to standing. UTT trials were also repeated at a fast speed, and SS trials were repeated using both the dominant and non-dominant limb. BCoM dynamics were assessed by analysing the displacement and peak velocity of the centre-of-pressure (CoP) when moving to and from the SS and UTT positions. Balance stability was the variability in the CoP displacement/velocity when holding these positions. Results indicate that under visual occlusion, the peak CoP velocity when moving to the SS or UTT position was reduced (ES, 0.67 and 0.68, respectively), suggesting greater caution. Both the variability in the CoP displacement/velocity when holding these positions and the peak CoP velocity when returning to flat-standing increased (SS: ES, 1.0 and 0.86, respectively; UTT: ES 1.26 and 0.66, respectively), suggesting, respectively, greater instability and poorer control. The poorer control in SS trials, occurred when returning to standing from the SS position held on the non-dominant limb, and correspondingly, the reduction in SS duration when vision was occluded was greater for the non-dominant limb trails (limb-vision interaction; p = 0.042). This suggests that movements initiated/controlled by the non-dominant limb are more reliant on visual feedback than those initiated/controlled by the dominant limb.

Efficacy and Accuracy of Diagnosing Septic Arthritis: How Effective are Current Methods for Timely Diagnosis of Septic Arthritis?

The diagnosis of septic arthritis requires a reliance on ancillary tests, including synovial fluid white blood cell count (jWBC), percentage of polymorphonuclear leukocytes (%PMN), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). This study evaluated these tests to determine their diagnostic utility in suspected septic arthritis. A retrospective chart review was performed on patients admitted to an urban hospital who underwent arthrocentesis. The authors evaluated the jWBC, %PMN, ESR, and CRP with receiver operating characteristic (ROC) curve analyses. Two hundred sixty-five patients met inclusion criteria. Sixty-three had a culture-positive aspirate. ROC curve analysis resulted in an area under the curve (AUC) of 0.80 for jWBC with cutoff point of 22,563 cells/mm3 and an AUC of 0.71 for %PMN with cutoff point of 90.5%. CRP and ESR had AUC values of 0.62 and 0.61, respectively. The culture-positive cohort had higher elevations in all assessed diagnostic tests. However, AUC data for ESR and CRP showed little diagnostic utility. Additionally, sensitivities and specificities of jWBC and %PMN were too low. Associated cutoff points would result in excessive unnecessary operative intervention. Further studies should incorporate synovial fluid biomarkers into the workup of a suspected septic joint. (Journal of Surgical Orthopaedic Advances 33(2):108-111, 2024).

Ongoing Implementation and Prospective Validation of Artificial Intelligence/Machine Learning Tools at an African Drug Discovery Center.

Artificial intelligence (AI) and machine learning (ML) are anticipated to accelerate drug discovery programs. Following our development of an end-to-end virtual screening cascade at the University of Cape Town (UCT) Holistic Drug Discovery and Development (H3D) Center, we report the ongoing implementation of open-source AI/ML tools for use in resource-constrained settings.

Predictors of the efficacy of His bundle pacing in patients with a prolonged PR interval: A stratified analysis of the HOPE-HF randomized controlled trial.

AIMS: The randomized, double-blind, placebo-controlled HOPE-HF trial assessed the benefit of atrio-ventricular (AV) delay optimization delivered using His bundle pacing. It recruited patients with left ventricular ejection fraction ≤40%, PR interval ≥200 ms, and baseline QRS ≤140 ms or right bundle branch block. Overall, there was no significant increase in peak oxygen uptake (VO2max) but there was significant improvement in heart failure specific quality of life. In this pre-specified secondary analysis, we evaluated the impact of baseline PR interval, echocardiographic E-A fusion, and the magnitude of acute high-precision haemodynamic response to pacing, on outcomes. METHODS AND RESULTS: All 167 randomized participants underwent measurement of PR interval, acute haemodynamic response at optimized AV delay, and assessment of presence of E-A fusion. We tested the impact of these baseline parameters using a Bayesian ordinal model on VO2max, quality of life and activity measures. There was strong evidence of a beneficial interaction between the baseline acute haemodynamic response and the blinded benefit of pacing for VO2 (Pr 99.9%), Minnesota Living With Heart Failure (MLWHF) (Pr 99.8%), MLWHF physical limitation score (Pr 98.9%), EQ-5D visual analogue scale (Pr 99.6%), and exercise time (Pr 99.4%). The baseline PR interval and the presence of baseline E-A fusion did not have this reliable ability to predict the clinical benefit of pacing over placebo across multiple endpoints. CONCLUSIONS: In the HOPE-HF trial, the acute haemodynamic response to pacing reliably identified patients who obtained clinical benefit. Patients with a long PR interval (≥200 ms) and left ventricular impairment who obtained acute haemodynamic improvement with AV-optimized His bundle pacing were likely to obtain clinical benefit, consistent across multiple endpoints. Importantly, this gradation can be reliably tested for before randomization, but does require high-precision AV-optimized haemodynamic assessment to be performed.

Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. Cholesterol homeostasis was identified as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro, in mouse TNBC xenografts and in patient-derived, estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single agent or combination treatment with AKT inhibitor and pitavastatin, which was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels, and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. These findings support combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC. .

Evaluation of PVC and PTFE filters for direct-on-filter crystalline silica quantification by FTIR.

Direct-on-Filter (DoF) analysis of respirable crystalline silica (RCS) by Fourier Transform Infrared (FTIR) spectroscopy is a useful tool for assessing exposure risks. With the RCS exposure limits becoming lower, it is important to characterize and reduce measurement uncertainties. This study systematically evaluated two filter types (i.e., polyvinyl chloride [PVC] and polytetrafluoroethylene [PTFE]) for RCS measurements by DoF FTIR spectroscopy, including the filter-to-filter and day-to-day variability of blank filter FTIR reference spectra, particle deposition patterns, filtration efficiencies, and pressure drops. For PVC filters sampled at a flow rate of 2.5 L/min for 8 h, the RCS limit of detection (LOD) was 7.4 µg/m3 when a designated laboratory reference filter was used to correct the absorption by the filter media. When the spectrum of the pre-sample filter (blank filter before dust sampling) was used for correction, the LOD could be up to 5.9 µg/m3. The PVC absorption increased linearly with reference filter mass, providing a means to correct the absorption differences between the pre-sample and reference filters. For PTFE, the LODs were 12 and 1.2 µg/m3 when a designated laboratory blank or the pre-sample filter spectrum was used for blank correction, respectively, indicating that using the pre-sample blank spectrum will reduce RCS quantification uncertainty. Both filter types exhibited a consistent radially symmetric deposition pattern when particles were collected using 3-piece cassettes, indicating that RCS can be quantified from a single measurement at the filter center. The most penetrating aerodynamic diameters were around 0.1 µm with filtration efficiencies ≥ 98.8% across the measured particle size range with low-pressure drops (0.2-0.3 kPa) at a flow rate of 2.5 L/min. This study concludes that either the PVC or the PTFE filters are suitable for RCS analysis by DoF FTIR, but proper methods are needed to account for the variability of blank absorption among different filters.

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013-2023).

This Perspective is a continuation of our analysis of U.S. FDA-approved small-molecule drugs (1938-2012) containing nitrogen heterocycles. In this study we report drug structure and property analyses of 321 unique new small-molecule drugs approved from January 2013 to December 2023 as well as information about frequency of important heteroatoms such as sulfur and fluorine and key small nitrogen substituents (CN and NO2). The most notable change is an incredible increase in drugs containing at least one nitrogen heterocycle─82%, compared to 59% from preceding decades─as well as a significant increase in the number of nitrogen heterocycles per drug. Pyridine has claimed the #1 high-frequency nitrogen heterocycle occurrence spot from piperidine (#2), with pyrimidine (#5), pyrazole (#6), and morpholine (#9) being the big top 10 climbers. Also notable is high number of fused nitrogen heterocycles, apparently driven largely by newly approved cancer drugs.

Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer.

Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.

High variability in assays of blood markers of collagen turnover in cardiovascular disease: Implications for research and clinical practice.

AIMS: Fibrosis is a common feature of many chronic diseases, including heart failure, which can have deleterious effects on cardiac structure and function that are associated with adverse outcomes. By-products of collagen synthesis and degradation, such as carboxy- and amino-terminal pro- or telo-peptides of collagen type I and III (PICP, PINP, PIIINP, and CITP) have been extensively investigated as markers of fibrosis. Although the majority of studies report on the reproducibility of their assay results, there is no a comparison of biomarker assays across studies. Therefore, we conducted a systematic review adhering to PRISMA guidelines. METHODS AND RESULTS: The search terms employed in Medline were: 'collagen AND cardiac' or 'collagen AND heart'. This query yielded a total of 1049 articles. Thereafter, specific search criteria were applied: (i) original English-language papers; (ii) human studies; (iii) in-vivo investigations; and (iv) blood/serum/plasma samples. Overall, 89 studies were identified (42 on PIIINP, 32 on PICP, 29 on CITP, and 17 on PINP). The range of reported values for PIIINP was between 0.06 to 11 800 µg/l; for PICP 0.006 to 1265 µg/l; for CITP 0.3 to 5450 µg/l; for PINP 0.15 to 80 µg/l. Extreme variations in values for fibrosis biomarkers were observed across studies, especially when different assays were used, but also with the same assays. CONCLUSIONS: Our findings show that it is challenging to ascertain normal ranges or compare studies for the measurement of fibrosis biomarkers. Given the potential implications for clinical practice and current lack of awareness of these issues, this subject warrants comprehensive acknowledgement and understanding.

Outcomes Following the Use of Extracellular Matrix Cartilage Allograft for the Management of Osteochondral Lesions of the Talus: A Systematic Review.

Extracellular matrix cartilage allograft (EMCA) is a novel biological strategy utilized to augment the repair of osteochondral lesions of the talus (OLTs). However, there is no consensus on the precise role and outcomes following its use in the treatment of OLTs. The purpose of this systematic review was to evaluate the clinical and radiological outcomes following the use of EMCA for the treatment of OLT. During July 2023, the PubMed, Embase, and Cochrane Library databases were systematically reviewed to identify clinical studies examining outcomes following EMCA for the management of OLTs. In total, 162 patients (162 ankles) across five studies received EMCA as part of their surgical procedure at a weighted mean follow-up time of 23.8±4.2 months. Across all five studies, there were improvements in subjective clinical outcomes following the use of EMCA, regardless of the clinical scoring tool utilized. Two studies demonstrated superior postoperative magnetic resonance observation of cartilage repair tissue (MOCART) scores in the EMCA cohort compared to the bone marrow stimulation (BMS) cohort alone. In the EMCA-BMS cohort, there were seven complications (9%) and three failures (4.1%). In the autologous osteochondral transplantation (AOT) cohort, there were 10 complications (38.5%), zero failures, and six secondary surgical procedures (23.1%). In the EMCA alone cohort, there were zero complications and three failures (4.3%), all of which underwent an unspecified revision procedure. This current systematic review demonstrated improvements in both clinical and radiological outcomes following the use of EMCA for the treatment of OLTs. Further prospective comparative studies with longer follow-up times are warranted to determine the precise role of EMCA in the management of OLT.

Outcomes following minimally invasive dorsal cheilectomy for hallux rigidus: A systematic review.

BACKGROUND: Cheilectomy of the 1st metatarsophalangeal joint (MTPJ) is one of the most common procedures for the management of hallux rigidus. However, there is no consensus regarding outcomes following minimally invasive dorsal cheilectomy (MIDC) for the management of hallux rigidus. AIM: To evaluate outcomes following MIDC for the management of hallux rigidus. METHODS: During November 2023, the PubMed, EMBASE and Cochrane Library databases were systematically reviewed to identify clinical studies examining outcomes following MIDC for the management of hallux rigidus. RESULTS: Six studies were included. In total, 348 patients (370 feet) underwent MIDC for hallux rigidus at a weighted mean follow-up of 37.9 ± 16.5 months. The distribution of patients by Coughlin and Shurna's classification was recorded in 4 studies as follows: I (58 patients, 27.1%), II (112 patients, 52.3%), III (44 patients, 20.6%). Three studies performed an additional 1st MTPJ arthroscopy and debridement following MIDC. Retained intra-articular bone debris was observed in 100% of patients in 1 study. The weighted mean American orthopedic foot and ankle society score improved from a preoperative score of 68.9 ± 3.2 to a postoperative score of 87.1. The complication rate was 8.4%, the most common of which was persistent joint pain and stiffness. Thirty-two failures (8.7%) were observed. Thirty-three secondary procedures (8.9%) were performed at a weighted mean time of 8.6 ± 3.2 months following the index procedure. CONCLUSION: This systematic review demonstrated improvements in subjective clinical outcomes together with a moderate complication rate following MIDC for the management of hallux rigidus at short-term follow-up. A moderate re-operation rate at short-term follow-up was recorded. The marked heterogeneity between included studies and paucity of high quality comparative studies limits the generation of any robust conclusions.

Can Patients With Narcissistic Personality Disorder Change? A Case Series.

ABSTRACT: The study was set out to establish the potential for psychotherapy to effect improvements in patients with narcissistic personality disorder (NPD). Eight patients with NPD who improved in treatment were identified. Consensus clinician/investigator diagnostic scores from before and after the psychotherapies were retroactively established on the Diagnostic Interview for Narcissism (DIN) and the Diagnostic Statistic Manual for Psychiatric Disorders, 5th Edition (DSM-5) Personality Disorder Section II criteria. Psychosocial functioning (work or school, romantic relationships) before and after the psychotherapies was retroactively evaluated as well. At the completion of the therapies after 2.5 to 5 years, all patients had improved, no longer met DIN or DSM-5 criteria for NPD, and showed better psychosocial functioning. Symptomatic improvements were associated with large effect sizes. In conclusion, changes in NPD can occur in treatment after 2.5 to 5 years. Future research should identify patient characteristics, interventions, and common processes in such improved cases that could help with development of treatments.

From mundane to surprising nonadditivity: drivers and impact on ML models.

Nonadditivity (NA) in Structure-Activity and Structure-Property Relationship (SAR) data is a rare but very information rich phenomenon. It can indicate conformational flexibility, structural rearrangements, and errors in assay results and structural assignment. While purely ligand-based conformational causes of NA are rather well understood and mundane, other factors are less so and cause surprising NA that has a huge influence on SAR analysis and ML model performance. We here report a systematic analysis across a wide range of properties (20 on-target biological activities and 4 physicochemical ADME-related properties) to understand the frequency of various different phenomena that may lead to NA. A set of novel descriptors were developed to characterize double transformation cycles and identify trends in NA. Double transformation cycles were classified into "surprising" and "mundane" categories, with the majority being classed as mundane. We also examined commonalities among surprising cycles, finding LogP differences to have the most significant impact on NA. A distinct behavior of NA for on-target sets compared to ADME sets was observed. Finally, we show that machine learning models struggle with highly nonadditive data, indicating that a better understanding of NA is an important future research direction.

Impact of the US Food and Drug Administration warning regarding increased risk of aortic aneurysms or aortic dissections on fluoroquinolone prescribing trends.

BACKGROUND: The US Food and Drug Administration (FDA) issued a warning in December 2018 regarding an increased risk of aortic aneurysms and aortic dissections associated with fluoroquinolone (FQ) use. This warning specifically targeted older adults and patients with conditions such as hypertension, Marfan syndrome, Ehlers-Danlos syndrome, atherosclerosis, peripheral vascular disease and history of aneurysms. OBJECTIVE: To evaluate the impact of the safety warning on prescribing trends of FQs in the targeted population. METHODS: This cross-sectional study with an interrupted time series (ITS) analysis (January 2018-December 2019) used a 25% random sample of IQVIA PharMetrics® Plus for Academics health plan claims database. The impact of the warning on FQ utilisation was quantified among the targeted population and a non-targeted population. RESULTS: From 2018 to 2019, both study populations saw a decrease in the year-over-year percent change of FQ prescriptions per 100 000 beneficiaries (-11%, from 14 227 to 12 662, targeted; -15%, from 5227 to 4446, non-targeted) and proportion of FQ use versus other antibiotics (from 15.6% to 13.8%, targeted; from 9.4% to 8%, non-targeted). In the targeted population, the ITS analysis did not show a significant trend change, a change in level or postwarning trend in the monthly rate of FQ prescriptions per 1000 beneficiaries. A positive trend change was observed in the non-targeted population (0.07, <0.01-0.13), but there were no significant changes in level or post-warning trend. CONCLUSION: We did not find a change in FQ prescription rates after the warning. The utility of safety advisories as a primary tool for mitigating FQ use in high-risk populations should be revisited.

Host cell CRISPR genomics and modelling reveal shared metabolic vulnerabilities in the intracellular development of Plasmodium falciparum and related hemoparasites.

Parasitic diseases, particularly malaria (caused by Plasmodium falciparum) and theileriosis (caused by Theileria spp.), profoundly impact global health and the socioeconomic well-being of lower-income countries. Despite recent advances, identifying host metabolic proteins essential for these auxotrophic pathogens remains challenging. Here, we generate a novel metabolic model of human hepatocytes infected with P. falciparum and integrate it with a genome-wide CRISPR knockout screen targeting Theileria-infected cells to pinpoint shared vulnerabilities. We identify key host metabolic enzymes critical for the intracellular survival of both of these lethal hemoparasites. Remarkably, among the metabolic proteins identified by our synergistic approach, we find that host purine and heme biosynthetic enzymes are essential for the intracellular survival of P. falciparum and Theileria, while other host enzymes are only essential under certain metabolic conditions, highlighting P. falciparum's adaptability and ability to scavenge nutrients selectively. Unexpectedly, host porphyrins emerge as being essential for both parasites. The shared vulnerabilities open new avenues for developing more effective therapies against these debilitating diseases, with the potential for broader applicability in combating apicomplexan infections.