Effectiveness of Botulinum Toxin Injection With Casting in Children With Spastic Cerebral Palsy: A Randomized Controlled Trial.

BACKGROUND: The most common form of movement disorder presented in children with cerebral palsy is spasticity, and dynamic equinus is the most common spastic ankle deformity. Botulinum toxin (BT) injection is now an established first-line treatment for focal spasticity. AIM: To assess the effects of BT injection with casting in the treatment of dynamic equinus in children diagnosed with cerebral palsy with spastic diplegia. SETTING AND DESIGN: A prospective randomized controlled trial was conducted among patients aged 2-12 years with cerebral palsy and spastic diplegia, attending the general outpatient department and admitted to the indoor facility of the Department of Physical Medicine and Rehabilitation and the Department of Pediatric Orthopedics at King George's Medical University, Lucknow. MATERIAL AND METHODS: Two groups of 19 patients each were formed. Group A received BT injection with casting, whereas in group B, only a cast was applied. Outcome measures including spasticity by Modified Ashworth Scale (MAS), Modified Tardieu Scale (MTS), range of motion (ROM), passive ankle dorsiflexion, and Gross Motor Function Measure (GMFM-66) (dimensions D and E) were assessed before and after the intervention. RESULTS: The participants in groups A and B were age-matched. A statistically significant difference was seen within group A and group B for MAS, passive ROM-dorsiflexion (PROM-DF), and passive ROM-plantarflexion (PROM-PF) at various follow-ups. In the 3rd week, MAS in each group was statistically insignificant (p-value> 0.05). CONCLUSION: There was a significant improvement in tone and a significant increase in the passive range of motion in both groups.

A Prodrug Strategy to Reposition Atovaquone as a Long-Acting Injectable for Malaria Chemoprotection.

Recent malaria drug discovery approaches have been extensively focused on the development of oral, smallmolecule inhibitors for disease treatment whereas parenteral routes of administration have been avoided due to limitations in deploying a shelf-stable injectable even though it could be dosed less frequently. However, an updated target candidate profile from Medicines for Malaria Venture (MMV) and stakeholders have advocated for long-acting injectable chemopreventive agents as an important interventive tool to improve malaria prevention. Here, we present strategies for the development of a long-acting, intramuscular, injectable atovaquone prophylactic therapy. We have generated three prodrug approaches that are contrasted by their differential physiochemical properties and pharmacokinetic profiles: mCBK068, a docosahexaenoic acid ester of atovaquone formulated in sesame oil, mCKX352, a heptanoic acid ester of atovaquone formulated as a solution in sesame oil, and mCBE161, an acetic acid ester of atovaquone formulated as an aqueous suspension. As a result, from a single 20 mg/kg intramuscular injection, mCKX352 and mCBE161 maintain blood plasma exposure of atovaquone above the minimal efficacious concentration for >70 days and >30 days, respectively, in cynomolgus monkeys. The differences in plasma exposure are reflective of the prodrug strategy, which imparts altered chemical properties that ultimately influence aqueous solubility and depot release kinetics. On the strength of the pharmacokinetic and safety profiles, mCBE161 is being advanced as a first-in-class clinical candidate for first-in-human trials.

Perioperative Immunosuppressive Factors during Cancer Surgery: An Updated Review.

Surgical excision of the primary tumor represents the most frequent and curative procedure for solid malignancies. Compelling evidence suggests that, despite its beneficial effects, surgery may impair immunosurveillance by triggering an immunosuppressive inflammatory stress response and favor recurrence by stimulating minimal residual disease. In addition, many factors interfere with the immune effectors before and after cancer procedures, such as malnutrition, anemia, or subsequent transfusion. Thus, the perioperative period plays a key role in determining oncological outcomes and represents a short phase to circumvent anesthetic and surgical deleterious factors by supporting the immune system through the use of synergistic pharmacological and non-pharmacological approaches. In line with this, accumulating studies indicate that anesthetic agents could drive both protumor or antitumor signaling pathways during or after cancer surgery. While preclinical investigations focusing on anesthetics' impact on the behavior of cancer cells are quite convincing, limited clinical trials studying the consequences on survival and recurrences remain inconclusive. Herein, we highlight the main factors occurring during the perioperative period of cancer surgery and their potential impact on immunomodulation and cancer progression. We also discuss patient management prior to and during surgery, taking into consideration the latest advances in the literature.

Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention.

In efforts towards eliminating malaria, a discovery program was initiated to identify a novel antimalarial using KAF156 as a starting point. Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment (∼40-106 mg) and one-month chemoprevention (∼96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156.

Factors affecting adherence to recommendations on pre-operative cardiac testing: A cohort study.

BACKGROUND: Cardiac risk evaluation prior to noncardiac surgery is fundamental to tailor peri-operative management to patient's estimated risk. Data on the degree of adherence to guidelines in patients at cardiovascular risk in Europe and factors influencing adherence are underexplored. OBJECTIVES: The aim of this analysis was to describe the degree of adherence to [2014 European Society of Cardiology (ESC)/European Society of Anaesthesiology (ESA) guidelines] recommendations on rest echocardiography [transthoracic echocardiography (TTE)] and to stress imaging prior to noncardiac surgery in a large European sample and to assess factors potentially affecting adherence. DESIGN: Secondary analysis of a multicentre, international, prospective cohort study (MET-REPAIR). SETTING: Twenty-five European centres of all levels of care that enrolled patients between 2017 and 2020. PATIENTS: With elevated cardiovascular risk undergoing in-hospital elective, noncardiac surgery. MAIN OUTCOME MEASURES: (Non)adherence to each pre-operative TTE and stress imaging recommendations classified as guideline-adherent, overuse and underuse. We performed descriptive analysis. To explore the impact of patients' sex, age, geographical region, and hospital teaching status, we conducted multivariate multinominal regression analysis. RESULTS: Out of 15 983 patients, 15 529 were analysed (61% men, mean age 72 ±â€Š8 years). Overuse (conduction in spite of class III) and underuse (nonconduction in spite of class I recommendation) for pre-operative TTE amounted to 16.6% (2542/15 344) and 6.6% (1015/15 344), respectively. Stress imaging overuse and underuse amounted to 1.7% (241/14 202) and 0.4% (52/14 202) respectively. Male sex, some age categories and some geographical regions were significantly associated with TTE overuse. Male sex and some regions were also associated with TTE underuse. Age and regions were associated with overuse of stress imaging. Male sex, age, and some regions were associated with stress imaging underuse. CONCLUSION: Adherence to pre-operative stress imaging recommendation was high. In contrast, adherence to TTE recommendations was moderate. Both patients' and geographical factors affected adherence to joint ESC/ESA guidelines. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03016936.

Anesthetic Management of Large Bronchogenic Cyst With Severe Tracheal Compression in Adults: A Case Report.

Bronchogenic cysts (BCs) are a congenital anomaly, forming fluid-filled sacs in the bronchial tree during fetal development, and are relatively rare in adults. Patients with large BCs in the mediastinum presenting with severe tracheal compression pose a significant challenge to anesthesiologists. The confined and narrow space of the mediastinum exacerbates the compression effect on surrounding structures, leading to potential respiratory or cardiovascular collapse during anesthesia and postoperatively. Herein, we report the stepwise anesthetic management of a patient with a BC in the paratracheal region of superior mediastinum, causing near-complete tracheal compression, scheduled for right posterolateral thoracotomy and tumor excision. The patient presented with dyspnea, chest pain, cough, and severe tracheal compression necessitating meticulous airway management. Utilizing awake fiberoptic intubation with a single-lumen endotracheal tube and one-lung ventilation facilitated by an EZ bronchial blocker, we successfully secured the airway, provided ideal surgical conditions through lung deflation, and ensured perioperative safety. This case underscores the crucial role of comprehending the underlying pathophysiology, anticipating complications, and meticulously planning, preparing, and executing strategies for airway management and perioperative care in patients with mediastinal masses leading to significant tracheal compression.

Low-dose radiation therapy for COVID-19 pneumonia: Comparison of dosimetry and life-time attributable risk of cancer with conventional AP-PA fields and bone marrow sparing VMAT.

PURPOSE: Low-dose radiation therapy (LDRT) to lungs did show encouraging results in COVID-19 patients in some clinical trials. However, there has been some concern regarding the long-term risk of radiation-induced cancer (RIC). Compared to the conventional AP-PA field technique, volumetric modulated arc therapy (VMAT) can potentially reduce the dose to the marrow and other organs at risk (OARs) and thus minimize the risk of cancer. We designed a dosimetry study to study if VMAT can reduce the exposure to the marrow and other OAR doses and curtail the estimated life-time attributable risk (LAR) of cancer. METHODS AND MATERIALS: We retrieved the computed tomography scan data of 10 patients (aged 40-60 years, median 48 years) who have been already treated for any malignancy in the region of the thorax. A dose of 1.0 Gy in single fraction was prescribed to both lungs. All the organs were delineated as per the established guidelines. The dosimetry achieved by the two plans was compared to find the difference. Mean OAR doses were used to estimate the LAR for both plans and compared. RESULTS: Planning target volume coverage parameters like conformity index and homogeneity index were significantly better with VMAT (P value < 0.05 for all). The mean dose to most OARs was significantly lower with VMAT (P value < 0.05 for all). The mean dose to the marrow was significantly lower with VMAT (59.05 vs 81.9 cGy with P value < 0.05). The overall LAR was significantly lower with VMAT as compared to the conventional plan (0.357% vs 0.398%, P value < 0.05). CONCLUSION: Compared to the conventional technique, VMAT provides better OAR dosimetry for lung irradiation (a prescription dose of 1.0 Gy or more) in COVID-19 pneumonia. VMAT significantly reduces the risk of RIC. We therefore suggest if lung LDRT is used for COVID-19 patients, VMAT is the preferred technique for a prescription dose of ≥1.0 Gy.

Bone Marrow Sparing by Intensity Modulated Proton Beam Therapy in Postoperative Irradiation of Gynecologic Malignancies.

Purpose: The aim of this matched-pair cohort study was to evaluate the potential of intensity-modulated proton therapy (IMPT) for sparring of the pelvic bone marrow and thus reduction of hematotoxicity compared to intensity-modulated photon radiotherapy (IMRT) in the setting of postoperative irradiation of gynaecological malignancies. Secondary endpoint was the assessment of predictive parameters for the occurrence of sacral insufficiency fractures (SIF) when applying IMPT. Materials and Methods: Two cohorts were analyzed consisting of 25 patients each. Patients were treated with IMPT compared with IMRT and had uterine cervical (n = 8) or endometrial cancer (n = 17). Dose prescription, patient age, and diagnosis were matched. Dosimetric parameters delivered to the whole pelvic skeleton and subsites (ilium, lumbosacral, sacral, and lower pelvis) and hematological toxicity were evaluated. MRI follow-up for evaluation of SIF was only available for the IMPT group. Results: In the IMPT group, integral dose to the pelvic skeleton was significantly lower (23.4GyRBE vs 34.3Gy; p < 0.001), the average V5Gy, V10Gy, and V20Gy were reduced by 40%, 41%, and 28%, respectively, compared to the IMRT group (p < 0.001). In particular, for subsites ilium and lower pelvis, the low dose volume was significantly lower. Hematotoxicity was significantly more common in the IMRT group (80% vs 32%; p = 0009), especially hematotoxicity ≥ CTCAE II (36% vs 8%; p = 0.037). No patient in the IMPT group experienced hematotoxicity > CTCAE II. In the IMPT cohort, 32% of patients experienced SIF. Overall SIF occurred more frequently with a total dose of 50.4 GyRBE (37.5%) compared to 45 GyRBE (22%). No significant predictive dose parameters regarding SIF could be detected aside from a trend regarding V50Gy to the lumbosacral subsite. Conclusion: Low-dose exposure to the pelvic skeleton and thus hematotoxicity can be significantly reduced by using IMPT compared to a matched photon cohort. Sacral insufficiency fracture rates appear similar to reported rates for IMRT in the literature.

Navigating the Complexities: Addressing the Challenges of Aneurysmal Atrial Septal Defects.

Aneurysmal atrial septal defects (ASDs) represent a rare subset of congenital cardiac anomalies, characterized by bulging of the interatrial septum. This condition poses unique challenges in diagnosis, management, and outcomes due to its variable clinical presentation and associated complications. While echocardiography remains the cornerstone of diagnosis, advanced imaging modalities such as cardiac magnetic resonance imaging (MRI) and computed tomography (CT) may provide additional insights. Optimal management strategies for aneurysmal ASDs require careful consideration of patient-specific factors, including the size and location of the defect, associated cardiovascular abnormalities, and the presence of pulmonary hypertension. Surgical repair, whether through conventional open-heart techniques or transcatheter interventions, remains the primary treatment modality; however, the approach may vary based on individual patient characteristics. Anesthetic considerations, including hemodynamic monitoring and perioperative care, are crucial in optimizing outcomes and reducing the risk of complications during surgical interventions. Long-term follow-up is essential to monitor potential complications such as residual shunting, arrhythmias, and the development of pulmonary vascular disease. Collaborative efforts among cardiologists, cardiothoracic surgeons, anesthesiologists, and other multidisciplinary specialists are paramount in providing comprehensive care for patients with aneurysmal ASDs.

Enhancing COVID-19 Vaccine Uptake among Tribal Communities: A Case Study on Program Implementation Experiences from Jharkhand and Chhattisgarh States, India.

Tribal populations in India have health care challenges marked by limited access due to geographical distance, historical isolation, cultural differences, and low social stratification, and that result in weaker health indicators compared to the general population. During the pandemic, Tribal districts consistently reported lower COVID-19 vaccination coverage than non-Tribal districts. We assessed the MOMENTUM Routine Immunization Transformation and Equity (the project) strategy, which aimed to increase access to and uptake of COVID-19 vaccines among Tribal populations in Chhattisgarh and Jharkhand using the reach, effectiveness, adoption, implementation, and maintenance framework. We designed a qualitative explanatory case study and conducted 90 focus group discussions and in-depth interviews with Tribal populations, community-based nongovernmental organizations that worked with district health authorities to implement the interventions, and other stakeholders such as government and community groups. The active involvement of community leaders, targeted counseling, community gatherings, and door-to-door visits appeared to increase vaccine awareness and assuage concerns about its safety and efficacy. Key adaptations such as conducting evening vaccine awareness activities, holding vaccine sessions at flexible times and sites, and modifying messaging for booster doses appeared to encourage vaccine uptake among Tribal populations. While we used project resources to mitigate financial and supply constraints where they arose, sustaining long-term uptake of project interventions appears dependent on continued funding and ongoing political support.

Efficacy of Triglyceride Glucose Index-Neck Circumference and Triglyceride Glucose Index-Neck-to-Height Ratio in the Diagnosis of Cardiovascular Diseases and Metabolic Syndrome.

BACKGROUND: A group of characteristics known as metabolic syndrome raises the chance of developing diabetes and cardiovascular disease. Insulin resistance (IR) and obesity are regarded as critical metabolic syndrome pathophysiology. OBJECTIVES: The diagnostic accuracy of IR indicators, triglyceride (TG) glucose index-neck circumference (TyG-NC), and TG glucose index-neck-to-height ratio (TyG-NHtR) to be evaluated for the detection of cardiovascular diseases and metabolic syndrome in nondiabetic individuals. MATERIALS AND METHODS: A cross-sectional study was conducted and passed by the Ethics Committee of the institute. The age should be 18 years or older, and subjects should not have diabetes. Each patient's clinical information was gathered, and lab tests were run. The study was done for a period of 1 year. RESULTS: The study has 100 participants. Around 74% of the group was women. Only 26.5% of the group had an obesity diagnosis. Poor fasting plasma glucose levels were found in 19.4% of the research team. Receiver operating characteristic (ROC)-area under the curve (AUC) testing revealed that all examined IR indices can differentiate individuals with metabolic syndrome from those who are healthy. Our analysis laid out the soaring high area under the ROC curve for TyG index and the low stunted area under the ROC curve for TyG-NC. For obesity, all indices showed appreciable diagnostic efficacy, indicating the maximum achieved area under the ROC curve for TyG index and the minimum recorded metabolic score for IR. The AUC in the case of the metabolic score for IR (METS-IR) male sample population was found to be not statistically compelling. CONCLUSION: The exploration of indirect indices, the proposed ones, namely TyG-NC and TyG-NHtR, emphasized an intricate link between cardiovascular diseases and metabolic syndrome.

Design and Fabrication of Broad-Spectrum Antimicrobial Porous Metallo-Polymeric Microsphere for Water Disinfection.

An expedient and efficient approach is used to synthesize a new class of metallo-polymeric microspheres (MPMs) as antimicrobials to succumb the wide range of bacteria from water. Three types of MPMs, that is, poly[Silver (I)-methacrylate-co-methylmethacrylate] (pAgMA), poly[Copper (II)-methacrylate-co-methyl methacrylate] (pCuMA), and poly[Nickel (II)-methacrylate-co-methylmethacrylate] (pNiMA), are prepared via radical suspension polymerization technique in 3D shape with porous texture. The structural and morphological characterization of the prepared microspheres are examined by analytical techniques. The antimicrobial potentialities of prepared MPMs are investigated at the laboratory scale study, revealing that the MPMs exhibit strong antibacterial activity (≈99.9% killing) against Gram-negative and Gram-positive bacteria [Enterobacter hormaechei (EH), Bacillus megatarium (BM), and Bacillus bataviensis (BB)]. The MacConkey agar medium test reveals that MPMs have substantial biocidal efficacy against broad-spectrum Gram-negative bacteria present in tap water. The MPMs exhibit significant antimicrobial efficacy via contact killing owe to the presence of integrated biocidal metal moiety, which represents that the MPMs are safe for water disinfection.

Dosimetric comparison of O-ring versus conventional C-arm linear accelerator for volumetric modulated arc therapy (VMAT) of head and neck cancer and carcinoma cervix patients.

The objective of this study is dosimetric comparison between the O-ring Halcyon and C-arm Clinac iX linac for volumetric modulated arc therapy (VMAT) plans for head & neck (H&N) cancer and carcinoma cervix patients. Total 60 patients of H&N cancer and carcinoma cervix were enrolled prospectively from March 2021 to March 2023. VMAT plans with 6 MV photons for Halcyon and Clinac iX were generated and compared for each patient by dose volume histogram for planning target volume coverage and organ at risk (OAR) sparing. There were no differences in between both the linacs for PTV D2% and D98%, homogeneity index, conformity index, Dmax (maximum dose) and Dmean (mean dose) of OAR. Halcyon had significantly shorter treatment time compared to Clinac iX. Halcyon delivered higher integral dose and monitor units. O-ring Halcyon produces VMAT plans comparable to other C-arm linacs for H&N and carcinoma cervix patients.

Revolutionizing cancer treatment in India: Evaluating the unmet need, economics, and a roadmap for project implementation of particle therapy.

INTRODUCTION: This study aims to quantitatively assess eligible patients and project the demand for particle therapy facilities in India from 2020 to 2040. In addition, an economic analysis evaluates the financial feasibility of implementing this technology. The study also examines the prospective benefits and challenges of adopting this technology in India. METHODOLOGY: Cancer incidence and projected trends were analyzed for pediatric patients using the Global Childhood Cancer microsimulation model and adult patients using the Globocan data. Economic cost evaluation is performed for large-scale combined particle (carbon and proton-three room fixed-beam), large-scale proton (one gantry and two fixed-beam), and small-scale proton (one gantry) facility. RESULTS: By 2040, the estimated number of eligible patients for particle therapy is projected to reach 161,000, including approximately 14,000 pediatric cases. The demand for particle therapy facilities is projected to rise from 81 to 97 in 2020 to 121 to 146 by 2040. The capital expenditure is estimated to be only 3.7 times that of a standard photon linear accelerator over a 30-year period. Notably, the treatment cost can be reduced to USD 400 to 800 per fraction, substantially lower than that in high-income countries (USD 1000 to 3000 per fraction). CONCLUSION: This study indicates that, in the Indian scenario, all particle therapy models are cost-beneficial and feasible, with large-scale proton therapy being the most suitable. Despite challenges such as limited resources, space, a skilled workforce, referral systems, and patient affordability, it offers substantial benefits. These include the potential to treat many patients and convenient construction and operational costs. An iterative phased implementation strategy can effectively overcome these challenges, paving the way for the successful adoption of particle therapy in India. PLAIN LANGUAGE SUMMARY: In India, the number of eligible patients benefiting from high-precision particle therapy technology is projected to rise till 2040. Despite high upfront costs, our study finds the long-term feasibility of all particle therapy models, potentially offering a substantial reduction in treatment cost compared to high-income countries. Despite challenges, India can succeed with an iterative phased approach.

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead.

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent in primary cells) and human in vitro clearance (>4× better microsomal clearance and >10× better hepatocyte clearance), with good in vitro-to-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

Alleviating summer heat stress in cowpea-baby corn intercropping with stress-reducing chemicals and fertility variations.

Over the past century, the average surface temperature and recurrent heatwaves have been steadily rising, especially during the summer season, which is affecting the yield potential of most food crops. Hence, diversification in cropping systems with suitable fertilizer management is an urgent need to ensure high yield potential during the summer season. Since intercropping has emerged as an important strategy to increase food production, the present study comprises five intercropping systems in the main plot (sole cowpea, sole baby corn, cowpea + baby corn in 2:1, 3:1, and 4:1 row ratio), three levels of fertilizer viz. 100 (N20 P40), 125 (N25 P50), and 150% (N30 P60) recommended dose of fertilizer (RDF) in the subplot, along with two stress-mitigating chemicals (0.5% CaCl2 and 1% KNO3) in the sub-sub plots. A split-split plot system with four replications was established to carry out the field experiment. The effect of intercropping, fertilizer levels, and stress-mitigating chemicals on crop growth rate (CGR), relative growth rate (RGR), plant temperature, relative water content (RWC) and chlorophyll content of cowpea and baby corn, as well as cowpea equivalent yield (CEY), was investigated during the summer seasons of 2019 and 2020. The experiment was conducted at Agriculture University, Kota (Rajasthan), India. Results showed that CGR, RGR, RWC and chlorophyll content of both crops and CEY were maximum under intercropping of cowpea and baby corn in a 2:1 row ratio compared to other intercropping systems. However, the plant temperature of both crops was significantly lower under this system. CEY, CGR, RGR, and chlorophyll content were considerably greater in the subplots with a fertilizer application of 150% RDF compared to lower levels of fertilizer (100 and 125% RDF). Our findings further show that foliar application of CaCl2 0.5% at the flowering and pod-developing stages of cowpea dramatically boosted CEY, CGR, RGR, RWC, and chlorophyll content of both crops and lowered the plant temperature.

Pathological findings associated with the updated European Society of Cardiology 2022 guidelines for preoperative cardiac testing: an observational cohort modelling study.

BACKGROUND: In 2022, the European Society of Cardiology updated guidelines for preoperative evaluation. The aims of this study were to quantify: (1) the impact of the updated recommendations on the yield of pathological findings compared with the previous guidelines published in 2014; (2) the impact of preoperative B-type natriuretic peptide (NT-proBNP) use for risk estimation on the yield of pathological findings; and (3) the association between 2022 guideline adherence and outcomes. METHODS: This was a secondary analysis of MET-REPAIR, an international, prospective observational cohort study (NCT03016936). Primary endpoints were reduced ejection fraction (EF<40%), stress-induced ischaemia, and major adverse cardiovascular events (MACE). The explanatory variables were class of recommendations for transthoracic echocardiography (TTE), stress imaging, and guideline adherence. We conducted second-order Monte Carlo simulations and multivariable regression. RESULTS: In total, 15,529 patients (39% female, median age 72 [inter-quartile range: 67-78] yr) were included. The 2022 update changed the recommendation for preoperative TTE in 39.7% patients, and for preoperative stress imaging in 12.9% patients. The update resulted in missing 1 EF <40% every 3 fewer conducted TTE, and in 4 additional stress imaging per 1 additionally detected ischaemia events. For cardiac stress testing, four more investigations were performed for every 1 additionally detected ischaemia episodes. Use of NT-proBNP did not improve the yield of pathological findings. Multivariable regression analysis failed to find an association between adherence to the updated guidelines and MACE. CONCLUSIONS: The 2022 update for preoperative cardiac testing resulted in a relevant increase in tests receiving a stronger recommendation. The updated recommendations for TTE did not improve the yield of pathological cardiac testing.

RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial.

Importance: Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis. Objective: To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens. Design, Setting, and Participants: This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized. Interventions: Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months. Main Outcomes and Measures: The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP. Results: Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients. Conclusions and Relevance: In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3. Trial Registration: ClinicalTrials.gov Identifier: NCT04936035.