A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice.

Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11α signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific Gq/11α inhibitor was delivered to the PVN; this provided evidence that a Gsα-independent signaling pathway, namely Gq/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11α may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects.

HIV prevalence among a retrospective clinical cohort of transgender women in Canada: Results of the Montreal-Toronto Trans study, collected 2018-2019.

BACKGROUND: HIV prevalence data among transgender (trans) people are not routinely collected in national estimates, including Canada, contributing to gender-based inequities. We examined HIV prevalence and associated factors among trans women in clinical care in two large Canadian cities. METHODS: Retrospective chart data of trans women aged 16+ were collected from six family medicine and/or HIV clinics in Montreal and Toronto, Canada, 2018-2019. Multinomial logistic regression was used to analyze factors associated with documented HIV positive or missing HIV status relative to documented HIV negative status. RESULTS: Among 1,059 patients, 7.5% were HIV positive, 54.4% HIV negative, and 38.1% missing HIV data. Findings showed lower odds of being HIV positive for those <30 years or 30-50 years (vs. >50 years); higher odds were seen for those: of Black race/ethnicity (vs. white), landed immigrant or refugee (vs. Canadian citizen), receiving social assistance (vs. not), and whom ever having used recreational drugs. CONCLUSIONS: Albeit high, the prevalence of HIV was lower than expected based on global estimates. Missing HIV status data suggest gaps in testing. Findings highlight socioeconomic and clinical realities among trans women in Canada and inform future HIV prevention and support.

A Saffron based Polyherbal Formulation DuK Prevents Hepatocellular Carcinoma in Male Wistar Rats.

BACKGROUND: Duk is a well-established traditional drug which has been used since time immemorial by Indian practitioners to cure various human ailments. OBJECTIVE: The purpose of this study was to explore the anti-cancer activity and the possible mechanism of Duk against diethylnitrosamine (DEN)-initiated hepatocarcinogenesis. METHODS & RESULTS: We administered Duk at 3 doses, viz., 75, 150, and 300 mg/kg/day, 2 weeks before the DEN and continued it for 16 weeks. After 1 week of DEN recovery, 2-aminoacetylflourine (2-AAF) was administered to promote hepatocarcinogenesis. We found that Duk significantly reduced the DEN and 2-AAF induced phenotypical changes in rats and restored the activities of serum markers. Furthermore, Duk counteracted the oxidative stress induced by carcinogens as observed by restoration in the levels of superoxide dismutase (SOD) and catalase (CAT). Duk significantly diminished the levels of malondialdehyde (MDA) in a dose dependent manner and restored the liver microarchitecture as assessed by histopathological studies. The results of immunohistochemical staining showed that Duk inhibited the DEN-induced decrease in the number of cells positive for Bid and Caspase-9. It also reduces the number of cells positive for Cyclin D. CONCLUSION: Duk significantly protects rat liver from hepatocarcinogenesis by regulating oxidative damage and restoring serum markers. The chemopreventive effect of Duk might be through induction of apoptosis.

Comparing Pharmacological Potential of Freshwater Microalgae Carotenoids Towards Antioxidant and Anti-proliferative Activity on Liver Cancer (HUH7) Cell Line.

Chemical-based carotenoids have large implications to health as they may cause adverse side effects. Naturally occurring carotenoids mainly from microalgal sources are emerging as excellent substitute to combat cancer diseases. Astaxanthin is the most powerful antioxidant that derived from selected established microalgae with limited yield. Microalgal bioprospecting may provide the high-yielding sources for astaxanthin production. Hence, in the present research, freshwater microalgae Monoraphidium sp. (NCM no. 5585) and Scenedesmus obliquus (NCM no. 5586) were chosen to explore the unique potential of producing astaxanthin. Identification of bioactive metabolites in extracted carotenoid was analyzed through HPLC. Astaxanthin is identified as a major bioactive metabolite in both carotenoid fraction and ß carotene only in Scenedesmus obliquus. Antioxidant potential of microalgal carotenoids was obtained by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric-reducing antioxidant power (FRAP) assay. The anti-proliferation activity of the extracted carotenoid from Monoraphidium sp. and Scenedesmus obliquus was evaluated against hepatocellular liver carcinoma cell line HUH7 by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) colorimetric assay. Higher astaxanthin in Monoraphidium sp. leads to boosted antioxidant and anti-proliferation activity contrary to Scenedesmus obliquus that possess both astaxanthin and ß carotene. Though freshwater microalgae have a huge potential to create beneficial metabolites like carotenoids, they are rarely studied in the pharmaceutical industry. This work was the first to investigate the anti-proliferative activity of Monoraphidium sp. and Scenedesmus obliquus carotenoid fraction on the HUH7 hepatocarcinoma cell line.

Variation in the anti-oxidant, anti-obesity, and anti-cancer potential of different polarity extracts of saffron petals.

The aim of the present study is to explore the anti-cancer, anti-oxidant, and anti-obesity potential of saffron petal extract (SPE) prepared through the hydro-alcoholic extraction method. Further partitioning was done with a series of polar and non-polar solvents to find out the most potent fraction of SPE against HCC. Organoleptic characterization depicted the color, odor, taste, and texture of the sub-fractions of SPE. Phytochemical, and pharmacognostic screening of these fractions revealed the presence of alkaloids, flavonoids, carbohydrates, glycosides, and phenols. The quantitative assessment demonstrated that the n-butanol fraction showed maximum phenolic (60.8 mg GAE eq./mg EW), and flavonoid (23.3 mg kaempferol eq./mg EW) content. The anti-oxidant study revealed that the n-butanol fraction exhibited the highest radical scavenging activity, as assessed through DPPH and FRAP assay. The results of the comparative cytotoxic potential also showed n-butanol as the best against liver cancer cells (Huh-7), as it has the least IC50 value (462.8 µg/ml). While other extracts viz., chloroform, n-hexane, ethyl acetate, and aqueous fractions have IC50 values as 1088, 733.9, 1043, and 1245 µg/ml, respectively. Additionally, the n-butanol fraction exerted the highest inhibitory potential against α-amylase (92.5%) and pancreatic lipase enzymes (78%), indicating its anti-adipogenesis property. Based on the current finding, we can deduce that the n-butanol fraction of SPE has better cytotoxic, anti-oxidant, and anti-obesity potential than the other fractions. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03669-x.

Anti-cancer activity of guggulsterone by modulating apoptotic markers: a systematic review and meta-analysis.

Background: Guggulsterone (pregna-4,17-diene-3,16-dione; C21H28O2) is an effective phytosterol isolated from the gum resin of the tree Commiphora wightii (Family Burseraceae) and is responsible for many of the properties of guggul. This plant is widely used as traditional medicine in Ayurveda and Unani system of medicine. It exhibits several pharmacological activities, such as anti-inflammatory, analgesic, antibacterial, anti-septic and anticancer. In this article, the activities of Guggulsterone against cancerous cells were determined and summarized. Methods: Using 7 databases (PubMed, PMC, Google Scholar, Science Direct, Scopus, Cochrane and Ctri.gov), the literature search was conducted since conception until June 2021. Extensive literature search yielded 55,280 studies from all the databases. A total of 40 articles were included in the systematic review and of them, 23 articles were included in the meta-analysis.The cancerous cell lines used in the studies were for pancreatic cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, oesophageal adenocarcinoma, prostrate cancer, colon cancer, breast cancer, gut derived adenocarcinoma, gastric cancer, colorectal cancer, bladder cancer, glioblastoma, histiocytic leukemia, acute myeloid leukemia and non-small cell lung cancer. The reliability of the selected studies was assessed using ToxRTool. Results: Based on this review, guggulsterone significantly affected pancreatic cancer (MiaPaCa-2, Panc-1, PC-Sw, CD18/HPAF, Capan1, PC-3), hepatocellular carcinoma (Hep3B, HepG2, PLC/PRF/5R), head and neck squamous cell carcinoma (SCC4, UM-22b, 1483), cholangiocarcinoma (HuCC-T1, RBE, Sk-ChA-1, Mz-ChA-1) and oesophageal adenocarcinoma (CP-18821, OE19), prostrate cancer (PC-3), colon cancer (HT-29), breast cancer (MCF7/DOX), gut derived adenocarcinoma (Bic-1), gastric cancer (SGC-7901), colorectal cancer (HCT116), bladder cancer (T24, TSGH8301), glioblastoma (A172, U87MG, T98G), histiocytic leukemia (U937), acute myeloid leukemia (HL60, U937) and non-small cell lung cancer (A549, H1975) by inducing apoptotic pathways, inhibiting cell proliferation, and regulating the expression of genes involved in apoptosis. Guggulsterone is known to have therapeutic and preventive effects on various categories of cancers. It can inhibit the progression of tumors and can even reduce their size by inducing apoptosis, exerting anti-angiogenic effects, and modulating various signaling cascades. In vitro studies reveal that Guggulsterone inhibits and suppresses the proliferation of an extensive range of cancer cells by decreasing intrinsic mitochondrial apoptosis, regulating NF-kB/STAT3/ß-Catenin/PI3K/Akt/CHOP pathway, modulating the expression of associated genes/proteins, and inhibiting angiogenesis. Furthermore, Guggulsterone reduces the production of inflammatory markers, such as CDX2 and COX-2. The other mechanism of the Guggulsterone activity is the reversal of P-glycoprotein-mediated multidrug resistance. Twenty three studies were selected for meta-analysis following the PRISMA statements. Fixed effect model was used for reporting the odds ratio. The primary endpoint was percentage apoptosis. 11 of 23 studies reported the apoptotic effect at t = 24 h and pooled odds ratio was 3.984 (CI 3.263 to 4.865, p < 0.001). 12 studies used Guggulsterone for t > 24 h and the odds ratio was 11.171 (CI 9.148 to 13.643, 95% CI, p < 0.001). The sub-group analysis based on cancer type, Guggulsterone dose, and treatment effects. Significant alterations in the level of apoptotic markers were reported by Guggulsterone treatment. Conclusion: This study suggested that Guggulsterone has apoptotic effects against various cancer types. Further investigation of its pharmacological activity and mechanism of action should be conducted. In vivo experiments and clinical trials are required to confirm the anticancer activity.

Report: Council for Ayurveda Research - Industry Roundtable and Global Consortium for Collaborative Research in Ayurveda, 2021.

The Council for Ayurveda Research (CAR) organized a three-day international event titled 'Global Consortium for Collaborative Research in Ayurveda (GCCRA) from September 17 to 19, 2021. The Consortium event was preceded by a pre-conference Industry Round Table (IRT), on September 16, 2021. The IRT and GCCRA events hosted industry heads, Ayurveda and integrative scholars and subject matter experts from several countries. The event's main objective was to initiate, facilitate, and conduct classical and cutting-edge research in Ayurveda and identify current gaps in research and research methodologies. The idea was also to develop consensus on key research areas. It was decided to form a Council for Ayurveda Research-Industrial Conclave (CAR-IC) to foster and support research on the industry side, with regular periodic meetings to enable dialogs and exchange of information and thoughts. Similarly, a Council for Ayurveda Research-Global Consortium for Collaborative Research in Ayurveda (CAR-GCCRA) was incepted to lead the initiative for providing clear, contemporary, and futuristic directions to research in the practice side of Ayurveda.

Z-Guggulsterone Is a Potential Lead Molecule of Dawa-ul-Kurkum against Hepatocellular Carcinoma.

An ancient saffron-based polyherbal formulation, Dawa-ul-Kurkum (DuK), has been used to treat liver ailments and other diseases and was recently evaluated for its anticancer potential against hepatocellular carcinoma (HCC) by our research team. To gain further insight into the lead molecule of DuK, we selected ten active constituents belonging to its seven herbal constituents (crocin, crocetin, safranal, jatamansone, isovaleric acid, cinnamaldehyde, coumaric acid, citral, guggulsterone and dehydrocostus lactone). We docked them with 32 prominent proteins that play important roles in the development, progression and suppression of HCC and those involved in endoplasmic reticulum (ER) stress to identify the binding interactions between them. Three reference drugs for HCC (sorafenib, regorafenib, and nivolumab) were also examined for comparison. The in silico studies revealed that, out of the ten compounds, three of them-viz., Z-guggulsterone, dehydrocostus lactone and crocin-showed good binding efficiency with the HCC and ER stress proteins. Comparison of binding affinity with standard drugs was followed by preliminary in vitro screening of these selected compounds in human liver cancer cell lines. The results provided the basis for selecting Z-guggulsterone as the best-acting phytoconstituent amongst the 10 studied. Further validation of the binding efficiency of Z-guggulsterone was undertaking using molecular dynamics (MD) simulation studies. The effects of Z-guggulsterone on clone formation and cell cycle progression were also assessed. The anti-oxidant potential of Z-guggulsterone was analyzed through DPPH and FRAP assays. qRTPCR was utilized to check the results at the in vitro level. These results indicate that Z-guggulsterone should be considered as the main constituent of DuK instead of the crocin in saffron, as previously hypothesized.

Natural products and their derivatives as immune check point inhibitors: Targeting cytokine/chemokine signalling in cancer.

Cancer immunotherapy is the new generation and widely accepted form of tumour treatment. It is, however, associated with exclusive challenges which include organ-specific inflammation, and single-target strategies. Therefore, approaches that can enhance the efficiency of existing immunotherapies and expand their indications are required for the further development of immunotherapy. Natural products and medicines are stated to have this desired effect on cancer immunotherapy (adoptive immune-cells therapy, cancer vaccines, and immune-check point inhibitors). They refurbish the immunosuppressed tumour microenvironment, which is the primary location of interaction of tumour cells with the host immune system. Various immune cell subsets, via interaction with cytokine/chemokine receptors, are recruited into this microenvironment, and these subsets have roles in tumour progression and treatment responsiveness. This review summarises cytokine/chemokine signalling, types of cancer immunotherapy and the herbal medicine-derived natural products targeting cytokine/chemokines and immune checkpoints. These natural compounds possess immunomodulatory activities and exert their anti-tumour effect by either blocking the interaction or modulating the expression of the proteins linked with immune checkpoint signaling pathways. Some compounds also show a synergistic effect in combination with existing monoclonal antibody drugs to reverse the tumour microenvironment. Additionally, we have also reported some studies about the derivatives and formulations used to overcome the limitations of natural forms. This review can provide important insights for directing future research.

Development and assessment of a hospital-led, community-partnering COVID-19 testing and prevention program for homeless and congregate living services in Toronto, Canada: a descriptive feasibility study.

BACKGROUND: Outbreaks of SARS-CoV-2 in shelters and congregate living settings are a major concern because of overcrowding and because resident populations are often at high risk for infection. The objective of this study was to describe the development, implementation and assessment of the COVID-19 Community Response Team, a program that enabled Women's College Hospital in Toronto, Ontario, to work in partnership with shelters and congregate living settings to prevent outbreaks. METHODS: The Community Response Team, associated with Women's College Hospital, an academic ambulatory hospital, carried out mobile testing for SARS-CoV-2, supported outbreak management and prevention through ongoing onsite partnership with medical staff, and conducted infection prevention and control (IPC) training to shelter staff. We conducted a descriptive analysis of the sites supported by the program between Apr. 20, 2020, and Aug. 15, 2020. We also assessed the program's feasibility (number of completed needs assessments, mobile testing events and IPC training events, and median time from referral to service delivery), adoption (number of nasopharyngeal swabs, number of pre- and post-program outbreaks and IPC uptake) and acceptability or satisfaction. RESULTS: The Community Response Team supported 32 sites. Of those, 30 completed an intake needs assessment, 24 completed mobile testing for SARS-CoV-2 and 15 received IPC support. Mobile testing resulted in the collection of 1566 nasopharyngeal swabs, of which 64 were positive for SARS-CoV-2 infection. Three sites had confirmed outbreaks. The median time from referral to needs assessment was 4 days (interquartile range [IQR] 1-13 days), and the median time to the testing day was 9 days (IQR 1-49 days). The median time from referral to IPC staff training was 14 days (IQR 4-79 days), and 100% of respondents reported being pleased or very pleased with the training. During the follow-up period, the 3 facilities with outbreaks overcame those outbreaks. Three sites supported by the Community Response Team had further single cases, but no site reported subsequent or secondary outbreaks. INTERPRETATION: The Community Response Team program led to the transfer of IPC knowledge, allowed for the management and prevention of SARS-CoV-2 outbreaks, and demonstrated feasibility. Collaborative supports between hospitals and the community housing sector may serve as models for ongoing system integration beyond the COVID-19 pandemic.

Apigenin in cancer prevention and therapy: A systematic review and meta-analysis of animal models.

BACKGROUND: Apigenin is being increasingly recognized as a cancer chemopreventive agent. We aimed to investigate the anticancer effects of Apigenin in in-vivo studies to know its present research status and how close or how far it is from the clinics. METHODS: Several electronic databases such as PubMed, Springer, Cochrane, and ctri.gov.in were searched to fetch the relevant articles. We focused only on published animal studies that reported the anticancer effects of Apigenin against various cancers. Two reviewers independently assessed the risk of bias for each analysis, and the conflicting views were resolved later by consensus. RESULTS: A total of 25 studies focused on the anticancer effects of Apigenin on various cancer types, including liver, prostate, pancreatic, lung, nasopharyngeal, skin, colon, colorectal, colitis-associated carcinoma, head and neck squamous cell carcinoma, leukemia, renal cell carcinoma, Ehrlich ascites carcinoma, and breast cancer were included. Overall, Apigenin reduces tumor volume (SMD=-3.597, 95% CI: -4.502 to -2.691, p < 0.001), tumor-weight (SMD=-2.213, 95% CI: -2.897 to -1.529, p < 0.001), tumor number (SMD=-1.081, 95% CI: -1.599 to -0.563, p < 0.001) and tumor load (SMD=-1.556, 95% CI: -2.336 to -0.776, p < 0.001). Further, it has no significant effect on the animal's body-weight (SMD=-0.345, 95% CI: -0.832 to 0.143, p = 0.165). Apigenin exerts anti-tumor effects mainly by inducing apoptosis/cell-cycle arrest. CONCLUSIONS: Our analysis suggests that Apigenin has potential anticancer effects against various cancers. However, the poor symmetry of the funnel plot suggested publication bias. Thus, it warrants further research to evaluate the potential of Apigenin alone or as an adjuvant for cancer treatment.

Short report: Characterizing HIV care among a clinical sample of transgender women living with HIV.

INTRODUCTION: This study aimed to characterize and identify factors associated with HIV care among transgender (trans) women living with HIV (TWLWH) in two urban centres in Canada. METHODS: Retrospective data were collected from clinic charts of TWLWH aged 16 years and older across seven family medicine, endocrinology and/or HIV clinics in Montreal and Toronto, Canada, from 2018 to 2019 (n = 86). We assessed the proportion of individuals being ever engaged in HIV care [defined as having any recorded antiretroviral therapy (ART) regimen and/or viral load], current ART use, and most recent viral load (suppressed [<200 copies/ml] vs. unsuppressed) overall and compared across subgroups using χ2 tests. RESULTS: All TWLWH in our sample [100.0%, 95% confidence interval (CI): 95.8-100.0%] were engaged in HIV care; most (93.0%, 95% CI: 85.4-97.4%) were currently using ART and most (93.4%, 95% CI: 85.3-97.8%) with complete data (n = 71/76) were virally suppressed. A higher proportion of trans women of colour (100.0%) reported current ART use compared with white trans women (76.9%, p = 0.017). A higher proportion of those with no documented history of injection drug use (IDU; 96.6%) were virally suppressed compared with those with a history of IDU (66.7%, p = 0.022). Although not statistically significant, 96.2% of those currently reporting feminizing hormone use were virally suppressed, compared with 85.0% of those not reporting use (p = 0.202). CONCLUSIONS: Once engaged in HIV care, TWLWH in Canada appear to have excellent ART use and viral suppression. Findings can be leveraged to identify target populations to enhance HIV care and to further explore the relationship between gender-affirming medical care and HIV care.

Women-centred HIV care: a scoping review to understand the current state of service delivery for women living with HIV globally.

Women living with HIV (WLWH) face unique barriers and require specialized, integrated care that focuses on women's specific needs. We conducted a scoping review to examine factors important for a women-centred HIV care (WCHC) approach. We included published peer-reviewed articles which featured WCHC services as their central focus; included study populations of girls and WLWH aged 14 years of age or older; and contributed to the understanding of WCHC for WLWH. Seven databases were reviewed and yielded 15,332 references, of which 21 fit our inclusion criteria for the scoping review. Research findings were categorized into characteristics of the study, recommendations, and target audiences. Findings revealed WCHC as care which includes the involvement of WLWH in decisions; person-centred integrated care; integrated services including mental health; sexual and reproductive health services; trauma-informed and safe space practices; healthcare provider training; and women's care self-management. In general, current systems of care do not meet the unique needs of WLWH.

MicroRNAs: Regulators of immunological reactions in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third prominent cause of cancer mortality, with increasing prevalence and poor survival worldwide. Being diagnosed at an advanced stage, HCC frequently results in poor prognosis, treatment failure, and recurrence. Post-treatment reactivation and recurrence often amplify the immunosuppressed state induced by HCC pathogenesis. Therefore, stimulating the immune system may be a potential therapy measure for the treatment of HCC. Immune responses of the body may be potentiated by modulation of various effector cells such as B-cells, T-cells, Treg cells, natural killer cells, dendritic cells, cytotoxic T-lymphocytes, and other antigen-presenting cells. microRNAs (small non-coding RNAs) are the regulators of gene expression via translational inhibition or mRNA degradation. Various activities and developmental stages of the immune system are governed by miRNAs and they have a regulative impact on innate and adaptive immune cells in both, healthy and diseased conditions. Their misexpression has been associated with the initiation, development, and metastasis of various cancer types, including HCC. This review summarizes the functional impact of these immuno-miRNAs in the improvement of tumor conditions.

Hypoxia Drives Centrosome Amplification in Cancer Cells via HIF1α-dependent Induction of Polo-Like Kinase 4.

Centrosome amplification (CA) has been implicated in the progression of various cancer types. Although studies have shown that overexpression of PLK4 promotes CA, the effect of tumor microenvironment on polo-like kinase 4 (PLK4) regulation is understudied. The aim of this study was to examine the role of hypoxia in promoting CA via PLK4. We found that hypoxia induced CA via hypoxia-inducible factor-1α (HIF1α). We quantified the prevalence of CA in tumor cell lines and tissue sections from breast cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, and prostate cancer and found that CA was prevalent in cells with increased HIF1α levels under normoxic conditions. HIF1α levels were correlated with the extent of CA and PLK4 expression in clinical samples. We analyzed the correlation between PLK4 and HIF1A mRNA levels in The Cancer Genome Atlas (TCGA) datasets to evaluate the role of PLK4 and HIF1α in breast cancer and PDAC prognosis. High HIF1A and PLK4 levels in patients with breast cancer and PDAC were associated with poor overall survival. We confirmed PLK4 as a transcriptional target of HIF1α and demonstrated that in PLK4 knockdown cells, hypoxia-mimicking agents did not affect CA and expression of CA-associated proteins, underscoring the necessity of PLK4 in HIF1α-related CA. To further dissect the HIF1α-PLK4 interplay, we used HIF1α-deficient cells overexpressing PLK4 and showed a significant increase in CA compared with HIF1α-deficient cells harboring wild-type PLK4. These findings suggest that HIF1α induces CA by directly upregulating PLK4 and could help us risk-stratify patients and design new therapies for CA-rich cancers. IMPLICATIONS: Hypoxia drives CA in cancer cells by regulating expression of PLK4, uncovering a novel HIF1α/PLK4 axis.

New Antibiotic Prescription Pattern in Critically Ill Patients ("Ant-critic"): Prospective Observational Study from an Indian Intensive Care Unit.

Introduction: This study aimed to address the issue of antibiotic prescription processes in an Indian Intensive care unit (ICUs). Materials and methods: In a prospective longitudinal study, all adult patients admitted in the ICU for 24 hours or above between 01 June 2020 and 31 July 2021 were screened for any new antibiotic prescription throughout their ICU stay. All new antibiotic prescriptions were assessed for baseline variables at prescription, any modifications during the course, and the outcome of antibiotic prescription. Results: A total of 1014 patients fulfilled entry criteria; 59.2 and 7.2% of days they were on a therapeutic and prophylactic antibiotic(s). Patients, who were prescribed therapeutic antibiotic(s), had worse ICU outcomes. A total of 49.5% of patients (502 of 1,014) received a total of 552 new antibiotic prescriptions during their ICU stay. About 92.13% of these prescriptions were empirical and blood or other specimens were sent for culture in 78.81 and 60.04% of instances. A total of 31.7% of episodes were microbiologically proven and were more likely to be prescribed by an ICU consultant. A total of 169 modifications were done in 142 prescription episodes; 73 of them after sensitivity results. Thus, the overall rate of de-escalation was 13.95%. Apart from the negative culture result (36.05%), an important reason for a relatively low rate of de-escalation was the absence of sampling (12.32%). Longer ICU stay before antibiotic prescription, underlying chronic liver disease (CLD), worse organ dysfunction, and septic shock were independently associated with unfavorable treatment outcomes. No such independent association was observed between antibiotic appropriateness and patient outcome. Conclusion: Future antibiotic stewardship strategies should address issues of high empirical prescription and poor microbiological sampling hindering the de-escalation process. How to cite this article: Ghosh S, Salhotra R, Singh A, Lyall A, Arora G, Kumar N, et al. New Antibiotic Prescription Pattern in Critically Ill Patients ("Ant-critic"): Prospective Observational Study from an Indian Intensive Care Unit. Indian J Crit Care Med 2022;26(12):1275-1284.

Implementation of a Revised Montpellier Bundle on the Outcome of Intubation in Critically Ill Patients: A Quality Improvement Project.

Introduction: The feasibility of implementing a revised Montpellier intubation bundle incorporating recent evidences was tested in a quality-improvement project. It was hypothesized that this "Care Bundle" implementation would reduce intubation-related complications. Materials and methods: The project was conducted in an 18-bedded multidisciplinary intensive care unit (ICU). Baseline data for intubations were collected over 3-month "Control Period". During the 2-month "Interphase", a revised intubation bundle was developed, and staff members involved in the intubation process were extensively trained on different aspects of intubation with emphasis on bundle components. Various components of the bundle were pre-intubation fluid loading, pre-oxygenation with NIV plus PS, positive-pressure ventilation post-induction, succinylcholine as a first-line induction agent, routine use of stylet, and lung recruitment within 2 minutes of intubation. Intubation data were collected again in the 3-month "Intervention Period". Results: Data were collected for 61 and 64 intubations, respectively, during control and intervention periods. There was significant improvement in compliance to five of six-bundle components; improvement in pre-intubation fluid loading during the intervention period did not reach statistical significance. Overall, at least 3 components of the bundle were complied within over 92% of intubations in the intervention period. However, whole-bundle compliance was limited to 14.3%. Incidences of major complications were reduced significantly in the intervention period (23.8% vs 45.9%, p = 0.01). There was significant reduction in profound hypotension (21.77% vs 29.51%, p = 0.04) and a nonsignificant 11.89% reduction in profound hypoxemia. There were no differences in minor complications. Conclusion: Implementation of an evidence-based revised Montpellier intubation bundle is feasible and it reduces major complications related to endotracheal intubation. How to cite this article: Ghosh S, Salhotra R, Arora G, Lyall A, Singh A, Kumar N, et al. Implementation of a Revised Montpellier Bundle on the Outcome of Intubation in Critically Ill Patients: A Quality Improvement Project. Indian J Crit Care Med 2022;26(10):1106-1114.

Medicinal Plants and Natural Products: More Effective and Safer Pharmacological Treatment for the Management of Obesity.

Obesity is a major lifestyle disorder, and it is correlated with several ailments. The prevalence of obesity has elevated over the years, and it has become a global health problem. The drugs presently used for managing obesity have several side effects, such as diarrhea, leakage of oily stools, etc. On the contrary, herbal plants and natural products are considered safe for use because they have lesser side effects. New compounds isolated from medicinal plants are screened and identified to determine their effectiveness and potential in preventing abnormal weight gain. In this review, the medicinal plants and natural materials are surveyed across the literature to cover those that have the potential for managing and controlling weight gain. Furthermore, their mechanism of action, active components, and experimental methodologies are also reviewed. These herbal products can be developed as formulations for therapeutic use in obesity. The herbal plants mentioned in the review are classified based on their mechanism of action, inhibition of pancreatic lipase, and appetite suppression activities. The ability to inhibit pancreatic lipase enzyme has been used to determine the effectiveness of herbal products for the prevention of abnormal weight gain because of its action on dietary fat and suppression of appetite. This review is an attempt to summarize the herbal plants and natural products that can be used to develop formulations effective in controlling weight gain and obesity.

Changes in renal and metabolic indices after switching from tenofovir disoproxil fumarate- to tenofovir alafenamide-containing ART among individuals with HIV in Canada: A retrospective study.

We assessed renal and metabolic changes associated with switching from tenofovir disoproxil fumarate (TDF)- to tenofovir alafenamide (TAF)-containing regimens among patients with HIV at the Maple Leaf Medical Clinic, Toronto, Canada. Using an electronic medical records retrospective chart review from July 2005 to December 2019, 651 patients aged ≥16 years taking TDF-containing regimens for ≥6 months who switched to TAF-containing regimens for ≥6 months were included. Change in estimated glomerular filtration rate (eGFR) was examined at 12-month follow-up. Secondary outcomes included change in urine albumin-to-creatinine ratio, serum phosphate, alkaline phosphatase (ALP), cholesterol markers, HbA1C, and weight. After 12 months, eGFR increased in 63% of the baseline eGFR <60 mL/min/1.73 m2 group (mean change [SD] = +5.1 [10.8], p = 0.002), 52% for the baseline eGFR = 60-90 mL/min/1.73 m2 group (+0.5 [10.4], p = 0.490), and 26% for baseline eGFR >90 mL/min/1.73 m2 group (-7.2 [11.2], p <0.001). The multivariable generalized estimating equations model showed a significant reduction in eGFR after 12 months. Advanced age, HCV coinfection, and being switched to or on integrase inhibitors were significantly associated with reduced eGFR. Among secondary outcomes, ALP significantly decreased, while high-density lipoprotein, low-density lipoprotein, and weight significantly increased. Our findings suggest that TDF-to-TAF switching was beneficial for those with preexisting renal impairment (eGFR <60 mL/min/1.73 m2).

Centrosome amplification: a quantifiable cancer cell trait with prognostic value in solid malignancies.

Numerical and/or structural centrosome amplification (CA) is a hallmark of cancers that is often associated with the aberrant tumor karyotypes and poor clinical outcomes. Mechanistically, CA compromises mitotic fidelity and leads to chromosome instability (CIN), which underlies tumor initiation and progression. Recent technological advances in microscopy and image analysis platforms have enabled better-than-ever detection and quantification of centrosomal aberrancies in cancer. Numerous studies have thenceforth correlated the presence and the degree of CA with indicators of poor prognosis such as higher tumor grade and ability to recur and metastasize. We have pioneered a novel semi-automated pipeline that integrates immunofluorescence confocal microscopy with digital image analysis to yield a quantitative centrosome amplification score (CAS), which is a summation of the severity and frequency of structural and numerical centrosome aberrations in tumor samples. Recent studies in breast cancer show that CA increases across the disease progression continuum, while normal breast tissue exhibited the lowest CA, followed by cancer-adjacent apparently normal, ductal carcinoma in situ and invasive tumors, which showed the highest CA. This finding strengthens the notion that CA could be evolutionarily favored and can promote tumor progression and metastasis. In this review, we discuss the prevalence, extent, and severity of CA in various solid cancer types, the utility of quantifying amplified centrosomes as an independent prognostic marker. We also highlight the clinical feasibility of a CA-based risk score for predicting recurrence, metastasis, and overall prognosis in patients with solid cancers.