Individualized homeopathic medicines in preventing the progression from pre-diabetes to diabetes: A double-blind, randomized, placebo-controlled, parallel-arm trial.

CONTEXT: Pre-diabetes is a significant public health problem worldwide. India has a very high rate of progression from pre-diabetes to diabetes, 75-78 per thousand persons per year. OBJECTIVE: To study the efficacy of individualized homeopathic medicinal products (HMPs) against placebos in preventing the progression from pre-diabetes to diabetes. DESIGN: Six-month, double-blind, randomized (1:1), two parallel arms, placebo-controlled trial. SETTING: Outpatient departments of D. N. De Homoeopathic Medical College and Hospital, Kolkata, West Bengal, India. PATIENTS: Sixty participants with pre-diabetes. INTERVENTIONS: Verum: HMPs plus yoga therapy (YT; n = 30); control: identical-looking placebos plus YT (n = 30). MAIN OUTCOME MEASURES: The primary efficacy endpoint was the proportion of participants progressing from pre-diabetes to diabetes, measured after three and six months. Secondary outcomes comprised of fasting blood glucose (FBS), oral glucose tolerance test (OGTT), glycated hemoglobin percentage (HbA1c%), lipid profile, liver enzymes (alanine transaminase, aspartate transaminase), urea and creatinine, and Measure Yourself Medical Outcome Profile version 2 (MYMOP-2); all measured after 3 and 6 months. RESULTS: The proportion of participants converted from pre-diabetics to diabetics (n/N; n = diabetics, N = prediabetics) was significantly less in the verum group than control: HbA1C% (month 3: verum - 2/30 versus control - 11/30, p = 0.003; month 6: 3/30 vs. 2/30, p = 0.008), OGTT (month 3: 0/30 vs. 8/30, p = 0.015; month 6: 0/30 vs. 1/30, p = 0.008), but not according to FBS (month 3: 1/30 vs. 1/30, p = 0.779; month 6: 1/30 vs. 3/30, p = 0.469). Several secondary outcomes also revealed significant improvements in the verum group than in placebo: HbA1C% (p < 0.001), OGTT (p = 0.001), serum ALT (p = 0.031), creatinine (p = 0.012), and MYMOP-2 profile scores (p < 0.001). Sulphur, Bryonia alba, and Thuja occidentalis were the most frequently indicated medicines. Thus, HMPs outperformed placebos by successfully preventing the progression of pre-diabetes to diabetes. TRIAL REGISTRATION: Clinical Trials Registry - India CTRI/2022/04/042,026; UTN: U1111-1277-0021.

Individualized Homeopathic Medicines in the Treatment of Knee Osteoarthritis: Double-Blind, Randomized, Placebo-Controlled Feasibility Trial.

INTRODUCTION: This study aimed at examining the feasibility issues of comparing individualized homeopathic medicines (IHMs) with identical-looking placebos for treating knee osteoarthritis (OA). METHODS: Forty eligible patients participated in this double-blind, randomized (1:1), placebo-controlled feasibility trial in the outpatient clinics of a homeopathic hospital in West Bengal, India. Either IHMs or identical-looking placebos were administered, along with mutually agreed-upon concomitant care guidelines. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was the primary outcome measure, and derived Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores from KOOS, EQ-5D-5L questionnaire, and Visual Analog Scale (VAS) were the secondary outcomes; all measured at baseline and after 2 months. Group differences and effect sizes (Cohen's d) were estimated using an intention-to-treat approach. p-Values less than 0.05 (two-tailed) were considered statistically significant. RESULTS: Enrolment/screening and trial retention rates were 43% and 85% respectively. Recruitment was difficult owing to the coronavirus disease 2019 (COVID-19) lockdown. Group differences were statistically significant, favoring IHMs against placebos in all the KOOS sub-scales: symptoms (p < 0.001), pain (p = 0.002), activities of daily living (p < 0.001), sports or recreation (p = 0.016), and quality of life (p = 0.002). Derived WOMAC scores from KOOS favored IHMs against placebos: stiffness (p < 0.001) and pain (p < 0.001). The EQ-5D-5L questionnaire score (p < 0.001) and EQ-5D-5L VAS scores (p < 0.001) also yielded significant results, favoring IHMs over placebos. All the effect sizes ranged from moderate to large. Sulphur was the most frequently prescribed homeopathic medication. Neither group reported any harm or serious adverse events. CONCLUSION: Although recruitment was sub-optimal due to prevailing COVID-19 conditions during the trial, the action of IHMs was found to be superior to that of placebos in the treatment of knee OA. Larger and more definitive studies, with independent replications, are required to substantiate the findings. TRIAL REGISTRATION: CTRI/2021/02/031453.

The use of antivirals in the treatment of human monkeypox outbreaks: a systematic review.

OBJECTIVES: Human monkeypox virus (MPXV) infection is a recently declared public health emergency of international concern by the World Health Organization. Besides, there is scant literature available on the use of antivirals in MPXV infection. This systematic review compiles all evidence of various antivirals used on their efficacy and safety and summarizes their mechanisms of action. METHODS: A review was done of all original studies mentioning individual patient data on the use of antivirals in patients with MPXV infection. RESULTS: Of the total 487 non-duplicate studies, 18 studies with 71 individuals were included. Tecovirimat was used in 61 individuals, followed by cidofovir in seven and brincidofovir (BCV) in three individuals. Topical trifluridine was used in four ophthalmic cases in addition to tecovirimat. Of the total, 59 (83.1%) were reported to have complete resolution of symptoms; one was experiencing waxing and waning of symptoms, only one (1.8%) had died, and the others were having a resolution of symptoms. The death was thought unrelated to tecovirimat. Elevated hepatic panels were reported among all individuals treated with BCV (leading to treatment discontinuation) and five treated with tecovirimat. CONCLUSION: Tecovirimat is the most used and has proven beneficial in several aggravating cases. No major safety concerns were detected upon its use. Topical trifluridine was used as an adjuvant treatment option along with tecovirimat. BCV and cidofovir were seldom used, with the latter often being used due to the unavailability of tecovirimat. BCV was associated with treatment discontinuation due to adverse events.

Noncommunicable Diseases and Gender Gap in Out-of-pocket Spending on Inpatient Health Care: An Investigation of Indian Elderly.

SUMMARY: The present study intends to examine whether there exists any gender gap in out-of-pocket spending on hospitalization between elderly men and elderly women. Data were drawn from the NSS 75th Round Health Care Survey (2017-2018) consisting of a total number of 45,299 elderly. Bivariate analysis and t-test were used to examine the disease burden and gender gap in health spending. The burden of noncommunicable diseases such as bone disease and anemia is considerably higher among elderly women than elderly men. There is a significant, positive gender gap in inpatient health spending, especially in the rural area across various diseases. Lower level of awareness, male dominance in health-related decision-making, and financial dependence are some possible factors for the gender gap. Generating awareness among households and particularly among women regarding health-care system, chronic diseases, and sources of health financing along with formulating disease-specific policy may reduce the gender gap in health spending.

Screening of organoids derived from patients with breast cancer implicates the repressor NCOR2 in cytotoxic stress response and antitumor immunity.

Resistance to antitumor treatment contributes to patient mortality. Functional proteomic screening of organoids derived from chemotherapy-treated patients with breast cancer identified nuclear receptor corepressor 2 (NCOR2) histone deacetylase as an inhibitor of cytotoxic stress response and antitumor immunity. High NCOR2 in the tumors of patients with breast cancer predicted chemotherapy refractoriness, tumor recurrence and poor prognosis. Molecular studies revealed that NCOR2 inhibits antitumor treatment by regulating histone deacetylase 3 (HDAC3) to repress interferon regulatory factor 1 (IRF-1)-dependent gene expression and interferon (IFN) signaling. Reducing NCOR2 or impeding its epigenetic activity by modifying its interaction with HDAC3 enhanced chemotherapy responsiveness and restored antitumor immunity. An adeno-associated viral NCOR2-HDAC3 competitor potentiated chemotherapy and immune checkpoint therapy in culture and in vivo by permitting transcription of IRF-1-regulated proapoptosis and inflammatory genes to increase IFN-γ signaling. The findings illustrate the utility of patient-derived organoids for drug discovery and suggest that targeting stress and inflammatory-repressor complexes such as NCOR2-HDAC3 could overcome treatment resistance and improve the outcome of patients with cancer.

Campylobacter infection and the link with Irritable Bowel Syndrome: on the pathway towards a causal association.

OBJECTIVES: proving causality between an exposure and outcome can be difficult in humans. Here, we utilize the Bradford Hill (BH) criteria to summarize the causal relationship between Campylobacter infection and the development of Irritable Bowel Syndrome (IBS). METHODS: we utilized the BH criteria to assess the strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy of the current evidence linking Campylobacter to IBS. Through a consensus amongst all authors, the confidence of each criterion was graded as high, moderate, low, or very low. RESULTS: a total of four criteria (strength, temporality, plausibility, and analogy) were graded as high; four criteria (consistency, biological gradient, coherence, and experiment) were graded as moderate; and one criterion (specificity) was graded as low. Large-scale epidemiological studies report a risk ratio of 2.7-5.6 for developing IBS after campylobacter. In rodent models, Campylobacter jejuni 81-176 can cause loose stool months after the infection is cleared and share common pathophysiology as IBS patients such as elevated intestinal TLR-4 and IL-8, antibodies to CdtB and vinculin, increased intraepithelial lymphocytes, and small intestinal bacterial overgrowth. CONCLUSIONS: Campylobacter infection appear to cause IBS in a subset of patients. This may hold implication in risk factor identification, public health policy, and possibly treatment.

Magnitude and determinants of inpatient health expenditure among the elderly in India.

As India is experiencing both the epidemiological and demographic transition, the grey population is expected to incur huge expenditure on health care, especially hospitalization expenditure, in the coming decades. The present study, thus, examines the magnitude of different types of inpatient health expenditure (medical, non-medical, total and out-of-pocket expenditure) and factors affecting them among the Indian elderly, using a health expenditure model empirically tested by the World Health Organization. Data were drawn from the 75th Round of the Health Survey conducted by the National Sample Survey Office, Government of India. In addition to basic descriptive statistics, the study employs a two-stage least square and a generalized linear model with log-link and gamma distribution to conduct the econometric analysis. The study finds that higher income, education, and household size, diseases like cancer, treatment involving surgery, poor physical mobility, and the elderly opting for packages involve higher inpatient health spending, while both private and social health insurance tends to reduce the same. So, a thrust on insurance-financed health systems may reduce health spending among the elderly. In this context, the study suggests that a disease-specific policy is required for the elderly along with ensuring state-of-the-art treatment facilities for them in public hospitals for critical ailments.

Challenges and Limitations in Distributional Cost-Effectiveness Analysis: A Systematic Literature Review.

BACKGROUND: Cost-effectiveness is a tool to maximize health benefits and to improve efficiency in healthcare. However, efficient outcomes are not always the most equitable ones. Distributional cost-effectiveness analysis (DCEA) offers a framework for incorporating equity concerns into cost-effectiveness analysis. OBJECTIVE: This systematic review aims to outline the challenges and limitations in applying DCEA in healthcare settings. METHODS: We searched Medline, Scopus, BASE, APA Psych, and JSTOR databases. We also included Google Scholar. We searched for English-language peer-reviewed academic publications, while books, editorials and commentary papers were excluded. Titles and abstract screening, full-text screening, reference list reviews, and data extraction were performed by the main researcher. Another researcher checked every paper for eligibility. Details, such as study population, disease area, intervention and comparators, costs and health effects, cost-effectiveness findings, equity analysis and effects, and modelling technique, were extracted. Thematic analysis was applied, focusing on challenges, obstacles, and gaps in DCEA. RESULTS: In total, 615 references were identified, of which 18 studies met the inclusion criteria. Most of these studies were published after 2017. DCEA studies were mainly conducted in Europe and Africa and used quality health-adjusted measurements. In the included studies, absolute inequality indices were used more frequently than relative inequality indices. Every stage of the DCEA presented challenges and/or limitations. CONCLUSION: This review provides an overview of the literature on the DCEA in healthcare as well as the challenges and limitations related to the different steps needed to conduct the analysis. In particular, we found problems with data availability, the relative unfamiliarity of this analysis among policymakers, and challenges in estimating differences among socioeconomic groups.

Factors affecting the choice of health care utilisation between private and public services among the elderly population in India.

India is experiencing rapid population ageing in recent years. One of the most concomitant issues is the choice of health care services among the elderly, leading to its impact on the magnitude of health expenditure. Applying Andersen's Health Behavioural Model, this study identifies the predictors of the choice of inpatient health care services among the Indian elderly between private and public services. It also examines the nature of interregional disparity in the choice of health care services. Using NSSO data, the results suggest that the elderly belonging to upper caste and having higher levels of education, higher incomes, larger family size, and needing surgery are likely to choose private health care, while those experiencing higher economic dependence, chronic diseases, and higher duration of hospitalisation tend to prefer public inpatient services. The magnitude and significance of these factors, however, vary across regions. The findings of the study provide an understanding of the preferences of the India's geriatric population over hospital services, which may help policymakers better understand their health care needs.

Distinct Interaction Modes of the Kinesin-13 Motor Domain with the Microtubule.

Kinesins-13s are members of the kinesin superfamily of motor proteins that depolymerize microtubules (MTs) and have no motile activity. Instead of generating unidirectional movement over the MT lattice, like most other kinesins, kinesins-13s undergo one-dimensional diffusion (ODD) and induce depolymerization at the MT ends. To understand the mechanism of ODD and the origin of the distinct kinesin-13 functionality, we used ensemble and single-molecule fluorescence polarization microscopy to analyze the behavior and conformation of Drosophila melanogaster kinesin-13 KLP10A protein constructs bound to the MT lattice. We found that KLP10A interacts with the MT in two coexisting modes: one in which the motor domain binds with a specific orientation to the MT lattice and another where the motor domain is very mobile and able to undergo ODD. By comparing the orientation and dynamic behavior of mutated and deletion constructs we conclude that 1) the Kinesin-13 class specific neck domain and loop-2 help orienting the motor domain relative to the MT. 2) During ODD the KLP10A motor-domain changes orientation rapidly (rocks or tumbles). 3) The motor domain alone is capable of undergoing ODD. 4) A second tubulin binding site in the KLP10A motor domain is not critical for ODD. 5) The neck domain is not the element preventing KLP10A from binding to the MT lattice like motile kinesins.

Structural model for tubulin recognition and deformation by kinesin-13 microtubule depolymerases.

To elucidate the structural basis of the mechanism of microtubule depolymerization by kinesin-13s, we analyzed complexes of tubulin and the Drosophila melanogaster kinesin-13 KLP10A by electron microscopy (EM) and fluorescence polarization microscopy. We report a nanometer-resolution (1.1 nm) cryo-EM three-dimensional structure of the KLP10A head domain (KLP10AHD) bound to curved tubulin. We found that binding of KLP10AHD induces a distinct tubulin configuration with displacement (shear) between tubulin subunits in addition to curvature. In this configuration, the kinesin-binding site differs from that in straight tubulin, providing an explanation for the distinct interaction modes of kinesin-13s with the microtubule lattice or its ends. The KLP10AHD-tubulin interface comprises three areas of interaction, suggesting a crossbow-type tubulin-bending mechanism. These areas include the kinesin-13 family conserved KVD residues, and as predicted from the crossbow model, mutating these residues changes the orientation and mobility of KLP10AHDs interacting with the microtubule.

Electronic structure and proton transfer in ground-state hexafluoroacetylacetone.

The ground electronic state (X(1)A(1)) of hexafluoroacetylacetone (HFAA) has been subjected to synergistic experimental and theoretical investigations designed to resolve controversies surrounding the nature of intramolecular hydrogen bonding for the enol tautomer. Cryogenic (93K) X-ray diffraction studies were conducted on single HFAA crystals grown in situ by means of the zone-melting technique, with the resulting electron density maps affording clear evidence for distinguishable O(1)-H and H...O(2) bonds that span an interoxygen distance of 2.680 +/- 0.003 A. Such laboratory findings have been corroborated by a variety of quantum chemical methods including Hartree-Fock (HF), density functional [DFT (B3LYP)], Møller-Plesset perturbation (MPn), and coupled cluster [CCSD, CCSD(T)] treatments built upon extensive sets of correlation-consistent basis functions. Geometry optimizations performed at the CCSD(T)/aug-cc-pVDZ level of theory predict an asymmetric (C(s)) equilibrium configuration characterized by an O...O donor-acceptor separation of 2.628 A. Similar analyses of the transition state for proton transfer reveal a symmetric (C(2v)) structure that presents a potential barrier of 21.29 kJ/mol (1779.7 cm(-1)) height. The emerging computational description of HFAA is in reasonable accord with crystallographic measurements and suggests a weakening of hydrogen-bond strength relative to that of the analogous acetylacetone molecule.

A novel eIF4G homolog, Off-schedule, couples translational control to meiosis and differentiation in Drosophila spermatocytes.

During spermatogenesis, cells coordinate differentiation with the meiotic cell cycle to generate functional gametes. We identified a novel gene, which we named off-schedule (ofs), as being essential for this coordinated control. During the meiotic G(2) phase, Drosophila ofs mutant germ cells do not reach their proper size and fail to execute meiosis or significant differentiation. The accumulation of four cell cycle regulators--Cyclin A, Boule, Twine and Roughex--is altered in these mutants, indicating that ofs reveals a novel branch of the pathway controlling meiosis and differentiation. Ofs is homologous to eukaryotic translation initiation factor eIF4G. The level of ofs expression in spermatocytes is much higher than for the known eIF4G ortholog (known as eIF-4G or eIF4G), suggesting that Ofs substitutes for this protein. Consistent with this, assays for association with mRNA cap complexes, as well as RNA-interference and phenotypic-rescue experiments, demonstrate that Ofs has eIF4G activity. Based on these studies, we speculate that spermatocytes monitor G(2) growth as one means to coordinate the initiation of meiotic division and differentiation.

The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60.

The c-MYC oncoprotein functions as a sequence-specific transcription factor. The ability of c-MYC to activate transcription relies in part on the recruitment of cofactor complexes containing the histone acetyltransferases mammalian GCN5 (mGCN5)/PCAF and TIP60. In addition to acetylating histones, these enzymes have been shown to acetylate other proteins involved in transcription, including sequence-specific transcription factors. This study was initiated in order to determine whether c-MYC is a direct substrate of mGCN5 and TIP60. We report here that mGCN5/PCAF and TIP60 acetylate c-MYC in vivo. By using nanoelectrospray tandem mass spectrometry to examine c-MYC purified from human cells, the major mGCN5-induced acetylation sites have been mapped. Acetylation of c-MYC by either mGCN5/PCAF or TIP60 results in a dramatic increase in protein stability. The data reported here suggest a conserved mechanism by which acetyltransferases regulate c-MYC function by altering its rate of degradation.

Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling.

Transcriptional regulation of the mdm2 oncogene by p53 requires TRRAP acetyltransferase complexes.

The p53 tumor suppressor regulates the cellular response to genetic damage through its function as a sequence-specific transcription factor. Among the most well-characterized transcriptional targets of p53 is the mdm2 oncogene. Activation of mdm2 is critical in the p53 pathway because the mdm2 protein marks p53 for proteosome-mediated degradation, thereby providing a negative-feedback loop. Here we show that the ATM-related TRRAP protein functionally cooperates with p53 to activate mdm2 transcription. TRRAP is a component of several multiprotein acetyltransferase complexes implicated in both transcriptional regulation and DNA repair. In support of a role for these complexes in mdm2 expression, we show that transactivation of the mdm2 gene is augmented by pharmacological inhibition of cellular deacetylases. In vitro analysis demonstrates that p53 directly binds to a TRRAP domain previously shown to be an activator docking site. Furthermore, transfection of cells with antisense TRRAP blocks p53-dependent transcription of mdm2. Finally, using chromatin immunoprecipitation, we demonstrate direct p53-dependent recruitment of TRRAP to the mdm2 promoter, followed by increased histone acetylation. These findings suggest a model in which p53 directly recruits a TRRAP/acetyltransferase complex to the mdm2 gene to activate transcription. In addition, this study defines a novel biochemical mechanism utilized by the p53 tumor suppressor to regulate gene expression.