Tricompartmental Microcarriers with Controlled Release for Efficient Management of Parkinson's Disease.

Parkinson's is a progressive neurodegenerative disease of the nervous system. It has no cure, but its symptoms can be managed by supplying dopamine artificially to the brain.This work aims to engineer tricompartmental polymeric microcarriers by electrohydrodynamic cojetting technique to encapsulate three PD (Parkinson's disease) drugs incorporated with high encapsulation efficiency (∼100%) in a single carrier at a fixed drug ratio of 4:1:8 (Levodopa (LD): Carbidopa(CD): Entacapone (ENT)). Upon oral administration, the drug ratio needs to be maintained during subsequent release from microparticles to enhance the bioavailability of primary drug LD. This presents a notable challenge, as the three drugs vary in their aqueous solubility (LD > CD > ENT). The equilibrium of therapeutic release was achieved using a combination of FDA-approved polymers (PLA, PLGA, PCL, and PEG) and the disc shape of particles. In vitro studies demonstrated the simultaneous release of all the three therapeutics in a sustained and controlled manner. Additionally, pharmacodynamics and pharmacokinetics studies in Parkinson's disease rats induced by rotenone showed a remarkable improvement in PD conditions for the microparticles-fed rats, thereby showing a great promise toward efficient management of PD.

The Gut Microbiota-Brain Axis: A New Frontier in Alzheimer's Disease Pathology.

Dr. Aloysius Alzheimer, a German neuropathologist and psychiatrist, recognized the primary instance of Alzheimer's disease (AD) for a millennium, and this ailment, along with its related dementias, remains a severe overall community issue related to health. Nearly fifty million individuals worldwide suffer from dementia, with Alzheimer's illness contributing to between 60 and 70% of the instances, estimated through the World Health Organization. In addition, 82 million individuals are anticipated to be affected by the global dementia epidemic by 2030 and 152 million by 2050. Furthermore, age, environmental circumstances, and inherited variables all increase the likelihood of acquiring neurodegenerative illnesses. Most recent pharmacological treatments are found in original hypotheses of disease, which include cholinergic (drugs that show affective cholinergic system availability) as well as amyloid-accumulation (a single drug is an antagonist receptor of Nmethyl D-aspartate). In 2020, the FDA provided approval on anti-amyloid drugs. According to mounting scientific data, this gut microbiota affects healthy physiological homeostasis and has a role in the etiology of conditions that range between obesity and neurodegenerative disorders like Alzheimer's. The microbiota-gut-brain axis might facilitate interconnection among gut microbes as well as the central nervous system (CNS). Interaction among the microbiota-gut system as well as the brain occurs through the "two-way" microbiota-gut-brain axis. Along this axis, the stomach as well as the brain develop physiologically and take on their final forms. This contact is constant and is mediated by numerous microbiota-derived products. The gut microbiota, for instance, can act as non-genetic markers to set a threshold for maintaining homeostasis or getting ill. The scientific community has conducted research and found that bowel dysbiosis and gastrointestinal tract dysregulation frequently occur in Alzheimer's disease (AD) patients. In this review, the effects of the microbiota- gut-brain axis on AD pathogenesis will be discussed.

What's Your Poison? Is Sitting Always Health Hindering and Moving Always Health Promoting?

The clear public messaging from international health authorities is that individuals should "sit less and move more." While it is acknowledged that this guidance needs to be tailored to the age of people and also to their health, and abilities, the guidance is not tailored to their current level of physical behaviors. This opinion piece aims to highlight that although people with excessive sitting and insufficient moderate-to-vigorous physical activity should sit more and move less, for other people their health would be promoted by sitting more and moving less. Thus, physical behaviors are not always "poison" or "medicine," but rather the health impact of changes in physical behaviors depends on people's initial levels. Policy, research, and practice implications of this realization are presented. Only tailoring messaging to age and health status could be far from optimal for people with very different current levels of physical behaviors. Policy, research, and practice will be enhanced when the potential for physical behaviors to be either health hindering or health promoting is adequately considered.

The "sweet- and sour-spot" of occupational physical activity for back pain: a prospective accelerometer study among eldercare workers.

OBJECTIVES: Both high and low levels of occupational physical activity are associated with back pain. Thus, there might be a "sweet- and sour-spot" of occupational physical activity for back pain. Our aim was to investigate if there exists an occupational physical activity "sweet- (lowest risk) and sour-spot" (highest risk) for back pain. METHODS: A total of 396 eldercare workers from 20 Danish nursing homes participated. Occupational physical activity was measured between 1-4 working days using thigh-worn accelerometry. Back pain intensity was reported monthly on a scale from 0-10 over 1-year. A zero-inflated mixed-effects model was developed regressing occupational physical activity against back pain, adjusted for confounders. The "sweet- and sour-spot" were defined as the occupational physical activity compositions (sitting, standing, light, and moderate-to-vigorous) associated with the 5% lowest and highest risk for back pain, respectively. RESULTS: The composition associated with the lowest risk of back pain - the "sweet-spot"- consisted of 71% worktime spent sitting, 18% spent standing, 5% spent on light physical activity and 6% spent on moderate-to-vigorous physical activity. The composition associated with highest risk for back pain -the "sour-spot"- consisted of 8% worktime spent sitting, 66% spent standing, 4% spent on light physical activity, and 21% spent on moderate-to-vigorous physical activity. CONCLUSIONS: The "sweet-spot" of occupational physical activity for back pain among eldercare workers involves more sitting and light physical activity time, while the "sour-spot" involves more standing and moderate-to-vigorous physical activity time. Research on the occupational physical activity "sweet- and sour-spot" is needed.

Feasibility and acceptability of a cohort study baseline data collection of device-measured physical behaviors and cardiometabolic health in Saudi Arabia: expanding the Prospective Physical Activity, Sitting and Sleep consortium (ProPASS) in the Middle East.

BACKGROUND: Physical behaviors such physical activity, sedentary behavior, and sleep are associated with mortality, but there is a lack of epidemiological data and knowledge using device-measured physical behaviors. PURPOSE: To assess the feasibility of baseline data collection using the Prospective Physical Activity, Sitting, and Sleep consortium (ProPASS) protocols in the specific context of Saudi Arabia. ProPASS is a recently developed global platform for collaborative research that aims to harmonize retrospective and prospective data on device-measured behaviors and health. Using ProPASS methods for collecting data to perform such studies in Saudi Arabia will provide standardized data from underrepresented countries. METHOD: This study explored the feasibility of baseline data collection in Saudi Arabia between November and December 2022 with a target recruitment of 50 participants aged ≥ 30 years. Established ProPASS methods were used to measure anthropometrics, measure blood pressure, collect blood samples, carry out physical function test, and measure health status and context of physical behaviors using questionnaires. The ActivPal™ device was used to assess physical behaviors and the participants were asked to attend two sessions at (LHRC). The feasibility of the current study was assessed by evaluating recruitment capability, acceptability, suitability of study procedures, and resources and abilities to manage and implement the study. Exit interviews were conducted with all participants. RESULT: A total of 75 participants expressed an interest in the study, out of whom 54 initially agreed to participate. Ultimately, 48 participants were recruited in the study (recruitment rate: 64%). The study completion rate was 87.5% of the recruited participants; 95% participants were satisfied with their participation in the study and 90% reported no negative feelings related to participating in the study. One participant reported experiencing moderate skin irritation related to placement of the accelerometer. Additionally, 96% of participants expressed their willingness to participate in the study again. CONCLUSION: Based on successful methodology, data collection results, and participants' acceptability, the ProPASS protocols are feasible to administer in Saudi Arabia. These findings are promising for establishing a prospective cohort in Saudi Arabia.

Cost-Effectiveness of Ibrutinib for Chronic Lymphocytic Leukemia Treatment in India: Is Evidence Really at Crossroads?

In recent years, newer drugs, such as ibrutinib, have shown promising improvements in the survival of patients with chronic lymphocytic leukemia (CLL). Despite their effectiveness, concerns about their cost have arisen, prompting the need for an evaluation of their cost-effectiveness. However, recent assessments of ibrutinib's cost-effectiveness for treating CLL in India reveal divergent conclusions. The discord centers on divergent cost-effectiveness thresholds, comparator regimens, cost calculations, and outcome valuation approaches. Such discrepancies affect public health decisions and patient care. The recommendation calls for adherence to methodological guidelines by future studies, fostering consistent findings to empower policy makers and clinicians in leveraging economic evidence for informed decision making in CLL treatment strategies.

Taxonomic discordance of immersive realities in dentistry: A systematic scoping review.

OBJECTIVES: This review aimed to map taxonomy frameworks, descriptions, and applications of immersive technologies in the dental literature. DATA: The Preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) guidelines was followed, and the protocol was registered at open science framework platform (https://doi.org/10.17605/OSF.IO/H6N8M). SOURCES: Systematic search was conducted in MEDLINE (via PubMed), Scopus, and Cochrane Library databases, and complemented by manual search. STUDY SELECTION: A total of 84 articles were included, with 81 % between 2019 and 2023. Most studies were experimental (62 %), including education (25 %), protocol feasibility (20 %), in vitro (11 %), and cadaver (6 %). Other study types included clinical report/technique article (24 %), clinical study (9 %), technical note/tip to reader (4 %), and randomized controlled trial (1 %). Three-quarters of the included studies were published in oral and maxillofacial surgery (38 %), dental education (26 %), and implant (12 %) disciplines. Methods of display included head mounted display device (HMD) (55 %), see through screen (32 %), 2D screen display (11 %), and projector display (2 %). Descriptions of immersive realities were fragmented and inconsistent with lack of clear taxonomy framework for the umbrella and the subset terms including virtual reality (VR), augmented reality (AR), mixed reality (MR), augmented virtuality (AV), extended reality, and X reality. CONCLUSIONS: Immersive reality applications in dentistry are gaining popularity with a notable surge in the number of publications in the last 5 years. Ambiguities are apparent in the descriptions of immersive realities. A taxonomy framework based on method of display (full or partial) and reality class (VR, AR, or MR) is proposed. CLINICAL SIGNIFICANCE: Understanding different reality classes can be perplexing due to their blurred boundaries and conceptual overlapping. Immersive technologies offer novel educational and clinical applications. This domain is fast developing. With the current fragmented and inconsistent terminologies, a comprehensive taxonomy framework is necessary.

Utilization of Probiotics Among Dental Students: A KAP Study.

Aim: The aim of the study is to know about the awareness of probiotics among undergraduate dental students. Materials and Methods: We conducted cross-sectional research where we had distributed a questionnaire consisting of ten open-ended questions, among 150 dental students through emails. The questions were based on the utilization of probiotics in dentistry. The data obtained was statistically analyzed with the help of Chi-square test. Results: In our study, we noted that most of the participants were aware of the term probiotics and had general ideas but were not fully aware of its pathogenesis. Around 83.2% of the participants were aware of probiotics and general concepts. We also noted that only 42.5% of the students agreed that probiotics can be used in the management of halitosis as well as periodontitis. Conclusion: We concluded that most of the dental students had a lack of awareness as well as were not familiar with the usage of probiotics in dentistry.

Genital Surgery Outcomes Using an Individualized Algorithm for Hormone Management in Transfeminine Individuals.

CONTEXT: Transgender and gender diverse (TGD) individuals have greater access to genital surgery (GS) with improved insurance coverage and access to trained surgeons and interdisciplinary gender affirming providers. OBJECTIVE: To determine perioperative medical and behavioral health outcomes in transfeminine (TF) individuals undergoing GS with use of a specific gender-affirming hormone therapy (GAHT) algorithm based on individualized risk factor assessment. DESIGN: Retrospective observational cohort study from 2017-2022. Pre- and post-operative data collected included clinical and biochemical assessment, GAHT regimens, validated behavioral health measures, and post-operative complications. SETTING: Single-center tertiary referral center. PATIENTS: 183 TF individuals, grouped into estradiol continued (Group 1) vs estradiol temporarily discontinued for 2-6 weeks preoperatively (Group 2). MAIN OUTCOME MEASURE(S): Venous thromboembolism (VTE) incidence, non-VTE postoperative complication incidence, and change in behavioral health assessments. RESULTS: The majority of individuals continued estradiol perioperatively [Group 1; 138 (75.4%)]. Individuals who temporarily held estradiol preoperatively [Group 2; 45 (24.6%)] were statistically older (p < 0.01), had higher incidence of cardiometabolic comorbidities (p < 0.01), and higher Caprini scores (p < 0.01). Group 1 was statistically more likely to use oral estradiol (p < 0.01). One episode (0.05%) of VTE occurred (Group 1). There was no significant difference in postoperative complications or behavioral health measures between groups. CONCLUSION: An individualized algorithm for preoperative hormone management for TF GS resulted in perioperative continuation of GAHT for the majority of individuals without significantly increasing the risk for post-operative surgical complications while maintaining stable behavioral health measures perioperatively.

A Case of Metastatic Choriocarcinoma-Related Paraneoplastic Thyroid Storm.

Thyroid storm due to gestational trophoblastic disease (GTD) with metastatic choriocarcinoma is a rare but potentially life-threatening endocrine emergency. We report on a woman with molar pregnancy and metastatic choriocarcinoma who presented with thyroid storm (Burch-Wartofsky point scale of 45) a few weeks after the evacuation of GTD. She was initially managed with intravenous hydrocortisone, oral propylthiouracil (PTU), and esmolol infusion. After stabilization in the intensive care unit, 10 cycles of chemotherapy with etoposide, methotrexate, leucovorin, dactinomycin, and cyclophosphamide (EMA-CO) were initiated for stage 4 choriocarcinoma with brain and lung metastases. She underwent a hysterectomy soon after completing chemotherapy and received an additional 3 cycles of chemotherapy after the hysterectomy. As human chorionic gonadotropin (hCG) levels normalized, thyroid function reverted to normal as well. At the last follow-up, the patient was asymptomatic, euthyroid (without antithyroid medication), had a normal hCG titer of 1.7 mIU/mL (normal nonpregnant reference is < 5 mIU/mL), and the lung and brain lesions had resolved entirely. Management of thyroid storm in the presence of untreated metastatic choriocarcinoma requires a high index of suspicion and a multidisciplinary team approach to prevent complications and improve survival.

Health-related quality of life and its determinants among cancer patients: evidence from 12,148 patients of Indian database.

BACKGROUND: Cancer survivors experience a decrement in health-related quality of life (HRQoL) resulting from the disease as well as adverse effects of therapy. We evaluated the HRQoL of cancer patients, stratified by primary cancer site, stage, treatment response and associated adverse events, along with its determinants. METHODS: Data were collected from 12,148 patients, sampled from seven purposively chosen leading cancer hospitals in India, to elicit HRQoL using the EuroQol questionnaire comprising of 5-dimensions and 5-levels (EQ-5D-5L). Multiple linear regression was used to determine the association between HRQoL and various socio-demographic as well as clinical characteristics. RESULTS: Majority outpatients (78.4%) and inpatients (81.2%) had solid cancers. The disease was found to be more prevalent among outpatients (37.5%) and inpatients (40.5%) aged 45-60 years and females (49.3-58.3%). Most patients were found to be in stage III (40-40.6%) or stage IV (29.4-37.3%) at the time of recruitment. The mean EQ-5D-5 L utility score was significantly higher among outpatients [0.630 (95% CI: 0.623, 0.637)] as compared to inpatients [0.553 (95% CI: 0.539, 0.567)]. The HRQoL decreased with advancing cancer stage among both inpatients and outpatients, respectively [stage IV: (0.516 & 0.557); stage III (0.609 & 0.689); stage II (0.677 & 0.713); stage I (0.638 & 0.748), p value < 0.001]. The outpatients on hormone therapy (B = 0.076) showed significantly better HRQoL in comparison to patients on chemotherapy. However, palliative care (B=-0.137) and surgery (B=-0.110) were found to be associated with significantly with poorer HRQoL paralleled to chemotherapy. The utility scores among outpatients ranged from 0.305 (bone cancer) to 0.782 (Leukemia). Among hospitalized cases, the utility score was lowest for multiple myeloma (0.255) and highest for testicular cancer (0.771). CONCLUSION: Older age, lower educational status, chemotherapy, palliative care and surgery, advanced cancer stage and progressive disease were associated with poor HRQoL. Our study findings will be useful in optimising patient care, formulating individualized treatment plan, improving compliance and follow-up.

Cost-Effectiveness Analysis of Denosumab in the Prevention of Skeletal-Related Events Among Patients With Breast Cancer With Bone Metastasis in India.

PURPOSE: Denosumab is clinically superior to zoledronic acid (ZA) for preventing and delaying time to first and subsequent skeletal-related events (SREs) among patients with breast cancer (BC) with bone metastases. We evaluated the cost and health benefits of denosumab and ZA (once every 4 weeks and once every 12 weeks) among four different molecular subtypes of BC with bone metastases in India. MATERIALS AND METHODS: A Markov model was developed in Microsoft Excel to estimate lifetime health consequences and resulting costs among cohort of 1,000 patients with BC with bone metastasis, for three intervention scenarios, namely denosumab (once every 4 weeks), ZA (once every 4 weeks), and ZA (once every 12 weeks). The health outcomes were measured in terms of SREs averted and quality-adjusted life-years (QALYs) gained. The cost of each intervention scenario was measured using both the health system and the patient's perspectives. Indirect costs because of lost productivity were not included. The future costs and outcomes were discounted at the standard rate of 3%. RESULTS: Over a lifetime, the incremental number of SREs averted with use of denosumab once every 4 weeks (compared with ZA once every 4 weeks and once every 12 weeks) among patients with luminal A, luminal B, human epidermal growth factor receptor 2-enriched, and triple negative breast cancer were estimated as 0.39, 0.26, 0.25, and 0.19, respectively. The number of QALYs lived were slightly higher in the denosumab arm (1.45-2.80) compared with ZA once every 4 weeks and once every 12 weeks arms (1.44-2.78). However, denosumab once every 4 weeks was not found to be a cost-effective alternative for either of the four molecular subtypes of breast cancer. ZA once every 12 weeks was found to be a cost-effective option with an average cost-effectiveness ratio ranging between ₹68,254 and ₹73,636. CONCLUSION: ZA once every 12 weeks is the cost-effective treatment option for BC with bone metastases in India. The present study findings hold significance for standard treatment guidelines under India's government-funded health insurance program.

Cost-Effectiveness of Novel Agent Regimens for Transplant-Eligible Newly Diagnosed Multiple Myeloma Patients in India.

BACKGROUND: Survival outcomes for multiple myeloma have improved dramatically since the introduction of novel therapeutic agents. While these drugs are highly effective in improving survival outcomes and quality of life in patients with multiple myeloma, they come at a significant cost. We assessed the cost-effectiveness of bortezomib-based triplet or quadruplet drug regimens in isolation and followed by autologous hematopoietic stem cell transplantation (AHSCT) for the treatment of newly diagnosed multiple myeloma (NDMM) in the Indian context. METHODS: A Markov model was developed to assess the health and economic outcomes of novel drug regimens with and without AHSCT for the treatment of NDMM in India. We estimated the lifetime quality-adjusted life-years (QALYs) and costs in each scenario. The incremental cost-effectiveness ratios (ICERs) were computed and compared against the current willingness-to-pay threshold of a one-time per capita gross domestic product of ₹146,890 (US$1,927.70) for India. Parameter uncertainty was assessed through Monte Carlo probabilistic sensitivity analysis. RESULTS: Among seven treatment sequences, the VCd (bortezomib, cyclophosphamide, dexamethasone) alone arm has the lowest cost and health benefits as compared to four treatment sequences, namely VTd (bortezomib, thalidomide, dexamethasone) alone, VRd (bortezomib, lenalidomide, dexamethasone) alone, VRd plus AHSCT and DVRd (Daratumumab, bortezomib, lenalidomide, dexamethasone) plus AHSCT. It was found that VTd plus AHSCT and VCd plus AHSCT arms were extendedly dominated (ED) by combination of two alternative treatments. Among the five non-dominated strategies, VRd has a lowest incremental cost of ₹ 2,20,093 (US$2,888) per QALY gained compared to VTd alone followed by VRd plus AHSCT [₹3,14,530 (US$4,128) per QALY gained] in comparison to VRd alone. None of the novel treatment sequences were found to be cost-effective at the current WTP threshold of ₹1,46,890 (US$1,927.7). CONCLUSION: At the current WTP threshold of one-time per capita GDP (₹ 146,890) of India, VRd alone and VRd plus AHSCT has 38.1% and 6.9% probability to be cost-effective, respectively. Reduction in current reimbursement rates of novel drugs, namely VRd, lenalidomide, and pomalidomide plus dexamethasone under national insurance program and societal cost of transplant by 50%, would make VRd plus AHSCT and VTd plus AHSCT cost-effective at an incremental cost of ₹40,671 (US$34) and ₹97,639 (US$1,281) per QALY gained, respectively.

Understanding the Potential of mRNA as Biomarker to Revolutionize Diagnosis of Colorectal Cancer.

MicroRNA as potential biomarker for early diagnosis, differentiating various stages, interpreting the success of postoperative curative surgery and predicting early relapse of Colorectal cancer.In the realm of medical research, the quest to find effective biomarkers for various diseases has always been a top priority. Colorectal cancer (CRC), one of the leading causes of cancer-related deaths worldwide, is no exception. The emergence of microRNA (mRNA) as a potential biomarker for CRC has sparked immense interest among scientists and clinicians alike. mRNA, a molecule responsible for translating genetic information into functional proteins, presents a promising avenue for early detection and personalized treatment of this deadly disease. By analyzing the specific patterns and levels of mRNA expression in CRC cells, researchers have the ability to identify signatures that can aid in accurate diagnosis, predict patient prognosis, and even guide targeted therapies. This breakthrough in molecular biology not only enhances our understanding of CRC but also holds the potential to revolutionize the field of cancer diagnostics and treatment. In this article, we will delve deeper into the potential of mRNA as a biomarker for CRC, exploring its benefits and challenges in the field of cancer research.

Economic Evaluation of Targeted Therapies for Anaplastic Lymphoma Kinase- and ROS1 Fusion-Positive Non-Small Cell Lung Cancer in India.

PURPOSE: Targeted therapies, such as crizotinib and ceritinib, have shown promising results in treating non-small cell lung cancer (NSCLC) with specific oncogenic drivers like anaplastic lymphoma kinase (ALK), c-ros (ROS1) oncogene, etc. This study aims to assess the cost-effectiveness of these therapies for patients with NSCLC in India. METHODS: The Markov model consisted of three health states: progression-free survival, progressive disease, and death. Lifetime costs and consequences were estimated for three treatment arms: crizotinib, ceritinib, and chemotherapy for patients with ALK- and ROS1-positive NSCLC. Incremental cost per quality-adjusted life-year (QALY) gained with crizotinib and ceritinib was compared to chemotherapy and assessed using a willingness-to-pay threshold of one-time per capita gross domestic product in India. RESULTS: The total lifetime cost per patient for ALK-positive NSCLC was ₹332,456 ($4,054 US dollars [USD]), ₹1,284,100 ($15,659 USD), and ₹2,337,779 ($28,509 USD) in the chemotherapy, crizotinib, and ceritinib arms, respectively. The mean QALYs lived per patient were 1.20, 2.21, and 3.34, respectively. For patients with ROS1-positive NSCLC, the total cost was ₹323,011 ($3,939 USD) and ₹1,763,541 ($21,507 USD) for chemotherapy and crizotinib, with mean QALYs lived per patient of 1.16 and 2.73, respectively. Nearly 92% and 81% reduction in the price of ceritinib and crizotinib is required to make it a cost-effective treatment option for ALK- and ROS1-positive NSCLC, respectively. CONCLUSION: Our study findings suggest that the prices of ceritinib and crizotinib need to be reduced significantly to justify their value for inclusion in India's publicly financed health insurance scheme for treatment of patients with locally advanced/metastatic ALK- and ROS1-positive NSCLC, respectively.

Apolipoprotein L1 (APOL1) renal risk variant-mediated podocyte cytotoxicity depends on African haplotype and surface expression.

Homozygous Apolipoprotein L1 (APOL1) variants G1 and G2 cause APOL1-mediated kidney disease, purportedly acting as surface cation channels in podocytes. APOL1-G0 exhibits various single nucleotide polymorphisms, most commonly haplotype E150K, M228I and R255K ("KIK"; the Reference Sequence is "EMR"), whereas variants G1 and G2 are mostly found in a single "African" haplotype background ("EIK"). Several labs reported cytotoxicity with risk variants G1 and G2 in KIK or EIK background haplotypes, but used HEK-293 cells and did not verify equal surface expression. To see if haplotype matters in a more relevant cell type, we induced APOL1-G0, G1 and G2 EIK, KIK and EMR at comparable surface levels in immortalized podocytes. G1 and G2 risk variants (but not G0) caused dose-dependent podocyte death within 48h only in their native African EIK haplotype and correlated with K+ conductance (thallium FLIPR). We ruled out differences in localization and trafficking, except for possibly greater surface clustering of cytotoxic haplotypes. APOL1 surface expression was required, since Brefeldin A rescued cytotoxicity; and cytoplasmic isoforms vB3 and vC were not cytotoxic. Thus, APOL1-EIK risk variants kill podocytes in a dose and haplotype-dependent manner (as in HEK-293 cells), whereas unlike in HEK-293 cells the KIK risk variants did not.

Longitudinal Associations between 24-h Movement Behaviors and Cardiometabolic Biomarkers: A Natural Experiment over Retirement.

INTRODUCTION: Physical activity, sedentary behavior, and sleep, that is, 24-h movement behaviors, often change in the transition from work to retirement, which may affect cardiometabolic health. This study investigates the longitudinal associations between changes in 24-h movement behaviors and cardiometabolic biomarkers during the retirement transition. METHODS: Retiring public sector workers ( n = 212; mean (SD) age, 63.5 (1.1) yr) from the Finnish Retirement and Aging study used a thigh-worn Axivity accelerometer and filled out a diary to obtain data on daily time spent in sedentary behavior (SED), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA), and sleep before and after retirement (1 yr in-between). Cardiometabolic biomarkers, including LDL-cholesterol, HDL-cholesterol, total/HDL-cholesterol ratio, triglycerides, C-reactive protein, fasting glucose, and insulin, were measured. Associations between changes in 24-h movement behaviors and cardiometabolic biomarkers were analyzed using compositional robust regression and isotemporal substitution analysis. RESULTS: Increasing LPA in relation to remaining behaviors was associated with an increase in HDL-cholesterol and decrease in total/HDL-cholesterol ratio ( P < 0.05 for both). For instance, reallocation of 30 min from sleep/SED to LPA was associated with an increase in HDL-cholesterol by 0.02 mmol·L -1 . Moreover, increasing MVPA in relation to remaining behaviors was associated with a decrease in triglycerides ( P = 0.02). Reallocation of 30 min from SED/sleep to MVPA was associated with 0.07-0.08 mmol·L -1 decrease in triglycerides. Findings related to LDL-cholesterol, C-reactive protein, fasting glucose, and insulin were less conclusive. CONCLUSIONS: During the transition from work to retirement, increasing physical activity at the expense of passive behaviors was associated with a better lipid profile. Our findings suggest that life transitions like retirement could be utilized more as an optimal time window for promoting physical activity and health.

Convection-enhanced Diffusion: A Novel Tactics to Crack the BBB.

Although the brain is very accessible to nutrition and oxygen, it can be difficult to deliver medications to malignant brain tumours. To get around some of these issues and enable the use of therapeutic pharmacological substances that wouldn't typically cross the blood-brain barrier (BBB), convection-enhanced delivery (CED) has been developed. It is a cutting-edge strategy that gets beyond the blood-brain barrier and enables targeted drug administration to treat different neurological conditions such as brain tumours, Parkinson's disease, and epilepsy. Utilizing pressure gradients to spread the medicine across the target area is the main idea behind this diffusion mechanism. Through one to several catheters positioned stereotactically directly within the tumour mass, around the tumour, or in the cavity created by the resection, drugs are given. This method can be used in a variety of drug classes, including traditional chemotherapeutics and cutting-edge investigational targeted medications by using positive-pressure techniques. The drug delivery volume must be optimized for an effective infusion while minimizing backflow, which causes side effects and lowers therapeutic efficacy. Therefore, this technique provides a promising approach for treating disorders of the central nervous system (CNS).

Visual outcome and postoperative complications of cataract surgery in patients with ocular surface disorders.

PURPOSE: To determine the visual outcome and postoperative complications of cataract surgery in patients with ocular surface disorders (OSDs). SETTING: Tertiary eyecare center in North India. DESIGN: Retrospective observational study. METHODS: Patients with various OSDs with stabilized ocular surfaces who underwent cataract surgery during this period and had a minimum postoperative follow-up of 6 weeks were included. The primary outcome measures were postoperative corrected distance visual acuity (CDVA) at 6 weeks, best CDVA achieved, and postoperative complications. RESULTS: The study included 20 men and 24 women. A total of 55 eyes were evaluated: Stevens-Johnson syndrome (SJS) 35 eyes, ocular cicatricial pemphigoid (OCP) 4 eyes, 8 eyes with dry eye disease (DED), 6 eyes with chemical injury and 2 eyes with vernal keratoconjunctivitis (VKC). The mean duration of OSD was 33.9 ± 52.17 months. The median preoperative CDVA was 2.0 (interquartile range [IQR], 1.45 to 2.0). The median CDVA ever achieved was 0.50 (IQR, 0.18 to 1.45) at 2 months and the median CDVA at 6 weeks was 0.6 (IQR, 0.3 to 1.5). Maximum improvement in CDVA was noted in patients with DED and SJS and the least in OCP. Phacoemulsification was performed in 47.27% eyes with intraoperative complications noted in 9% eyes. Postoperative surface complications occurred in 12 (21.82%) eyes. Other postoperative complications occurred in 9 (16%) eyes. CONCLUSIONS: Cataract surgery outcome can be visually rewarding in patients with OSDs provided ocular surface integrity is adequately maintained preoperatively and postoperatively.