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Background: Undiagnosed and untreated hypertension is a main driver of cardiovascular disease and disproportionately affects persons living with HIV (PLHIV) in low- and middle-income countries. Across sub-Saharan Africa, guideline application to screen and manage hypertension among PLHIV is inconsistent due to poor service readiness, low health worker motivation, and limited integration of hypertension screening and management within HIV care services. In Mozambique, where the adult HIV prevalence is over 13%, an estimated 39% of adults have hypertension. As the only scaled chronic care service in the county, the HIV treatment platform presents an opportunity to standardize and scale hypertension care services. Low-cost, multi-component systems-level strategies such as the Systems Analysis and Improvement Approach (SAIA) have been found effective at integrating hypertension and HIV services to improve the effectiveness of hypertension care delivery for PLHIV, reduce drop-offs in care, and improve service quality. To build off lessons learned from a recently completed cluster randomized trial (SAIA-HTN) and establish a robust evidence base on the effectiveness of SAIA at scale, we evaluated a scaled-delivery model of SAIA (SCALE SAIA-HTN) using existing district health management structures to facilitate SAIA across six districts of Maputo Province, Mozambique., Methods: This study employs a stepped-wedge design with randomization at the district level. The SAIA strategy will be "scaled up" with delivery by district health supervisors (rather than research staff) and will be "scaled out" via expansion to Southern Mozambique, to 18 facilities across six districts in Maputo Province. SCALE SAIA-HTN will be introduced over three, 9-month waves of intensive intervention, where technical support will be provided to facilities and district managers by study team members from the Mozambican National Institute of Health. Our evaluation of SCALE SAIA-HTN will be guided by the RE-AIM framework and will seek to estimate the budget impact from the payer's perspective., Discussion: SAIA packages user-friendly systems engineering tools to support decision-making by frontline health workers and to identify low-cost, contextually relevant improvement strategies. By integrating SAIA delivery into routine management structures, this pragmatic trial will determine an effective strategy for national scale-up and inform program planning., Trial Registration: ClinicalTrials.gov NCT05002322 (registered 02/15/2023)., (© 2024. The Author(s).)

Background: The rising prevalence of electronic cigarette (e-cigarette) and hookah use among youth raises questions about medical trainees' views of these products. We aimed to investigate medical trainees' knowledge and attitudes toward e-cigarette and hookah use., Methods: We used data from a large cross-sectional survey of medical trainees in Brazil, the United States, and India. We investigated demographic and mental health aspects, history of e-cigarettes and tobacco use, knowledge and attitudes toward e-cigarettes and hookah, and sources of information on e-cigarettes and hookah. Although all medical trainees were eligible for the original study, only senior students and physicians-in-training were included in the present analysis., Results: Of 2,036 senior students and physicians-in-training, 27.4% believed e-cigarette use to be less harmful than tobacco smoking. As for hookah use, 14.9% believed it posed a lower risk than cigarettes. More than a third of trainees did not acknowledge the risks of passive e-cigarette use (42.9%) or hookah smoking (35.1%). Also, 32.4% endorsed e-cigarettes to quit smoking, whereas 22.5% felt ill equipped to discuss these tobacco products with patients. Fewer than half recalled attending lectures on these topics, and their most common sources of information were social media (54.5%), Google (40.8%), and friends and relatives (40.3%)., Conclusions: Medical trainees often reported incorrect or biased perceptions of e-cigarettes and hookah, resorted to unreliable sources of information, and lacked the confidence to discuss the topic with patients. An expanded curriculum emphasis on e-cigarette and hookah use might be necessary because failing to address these educational gaps could risk years of efforts against smoking normalization., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2024 by Daedalus Enterprises.)

The increased use of E-cigarettes and hookah among young consumers represents a public health concern. This study aimed to investigate the frequency and patterns of use of E-cigarettes and hookah among medical trainees. This cross-sectional multinational online survey included medical students, residents, and fellows in Brazil, the U.S., and India between October 2020 and November 2021. Information on sociodemographics; mental health; and E-cigarettes, hookah, tobacco, marijuana, and alcohol use were collected. Generalized structural equation models were used in 2022 to explore the factors associated with current vaping and current hookah use (ongoing monthly/weekly/daily use). People reporting previous sporadic/frequent use or those who never used/only tried it once were the reference group. Overall, 7,526 participants were recruited (Brazil=3,093; U.S.=3,067; India=1,366). The frequency of current vaping was 20% (Brazil), 11% (U.S.), and <1% (India), and current hookah use was 10% (Brazil), 6% (U.S.), and 1% (India). Higher family income (OR=6.35, 95% CI=4.42, 9.12), smoking cigarettes (OR=5.88, 95% CI=4.88, 7.09) and marijuana (OR=2.8, 95% CI=2.35, 3.34), and binge drinking (OR=3.03, 95% CI=2.56, 3.59) were associated with current vaping. The same was true for hookah use: higher family income (OR=2.69, 95% CI=1.75, 4.14), smoking cigarettes (OR=3.20, 95% CI=2.53, 4.06), smoking marijuana (OR=4.17, 95% CI=3.35, 4.19), and binge drinking (OR=2.42, 95% CI=1.96, 2.99). In conclusion, E-cigarettes and hookah were frequently used by Brazilian and American trainees, sharply contrasting with data from India. Cultural aspects and public health policies may explain the differences among countries. Addressing the problems of hookah and E-cigarette smoking in this population is relevant to avoid the renormalization of smoking., (Copyright © 2023 American Journal of Preventive Medicine. All rights reserved.)

Primary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) encompasses the timely diagnosis and adequate treatment of the superficial group A Streptococcus (GAS) infections pharyngitis and impetigo. GAS is the only known inciting agent in the pathophysiology of the disease. However, sufficient evidence indicates that the uptake and delivery of primary prevention approaches in RHD-endemic regions are significantly suboptimal. This report presents expert deliberations on priority research and implementation opportunities for primary prevention of ARF/RHD that were developed as part of a workshop convened by the US National Heart, Lung, and Blood Institute in November 2021. The opportunities identified by the Primary Prevention Working Group encompass epidemiological, laboratory, clinical, implementation and dissemination research domains and are anchored on five pillars including: (A) to gain a better understanding of superficial GAS infection epidemiology to guide programmes and policies; (B) to improve diagnosis of superficial GAS infections in RHD endemic settings; (C) to develop scalable and sustainable models for delivery of primary prevention; (D) to understand potential downstream effects of the scale-up of primary prevention and (E) to develop and conduct economic evaluations of primary prevention strategies in RHD endemic settings. In view of the multisectoral stakeholders in primary prevention strategies, we emphasise the need for community co-design and government engagement, especially in the implementation and dissemination research arena. We present these opportunities as a reference point for research organisations and sponsors who aim to contribute to the increasing momentum towards the global control and prevention of RHD., Competing Interests: Competing interests: ABeaton, AS, CSY and NS received funding support from the National Institutes of Health. ABeaton, AS and MEE received funding support from American Heart Association. ABeaton received funding support from Leducq Foundation, Edwards Lifesciences—Every Heartbeat Matters, The Philips Foundation and Thrasher Pediatric Research Fund. CSY received consultation fees from the WHO. JD received consulting fees from Variation Biotechnology. MEE received funding support from South African Research Council. ABowen receives funding support from the National Health and Medical Research Council of Australia., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: • Neurology trainees and program directors recognized a lack of structured breaking bad news training. • Program directors reported that many factors hinder the implementation of breaking bad news education. • Trainees felt capable of breaking bad news, but most did not have lectures, simulations, nor feedback. • Trainees acknowledged negative feelings when breaking bad news, including sadness and helplessness. We aimed to evaluate how breaking bad news training was implemented in neurology residency programs in Brazil and to assess the perception and preparedness of trainees and program directors., Methods: We performed a cross-sectional descriptive study. Neurology trainees and program directors were recruited from the Brazilian Academy of Neurology registry through convenience sampling. Participants answered a survey evaluating the breaking bad news training at their institution and their preparedness and perception towards the topic., Results: We collected 172 responses from 47 neurology institutions from all five socio-demographic regions of Brazil. More than 77% of trainees were dissatisfied with their breaking bad news training, and around 92% of program directors believed their programs required substantial improvement. Approximately 31% of neurology trainees reported never having a lecture about communicating bad news, 66% reported never having a simulated training, and nearly 61% never received feedback regarding their communication abilities. Moreover, 59% of program directors acknowledged that feedback was not a standard practice and nearly 32% reported the absence of any specific training., Conclusion: This study suggested that the breaking bad news training in neurology residencies across Brazil is deficient and highlighted challenges to achieve this core competency. Program directors and trainees recognized the importance of the topic, and program directors acknowledged that many factors hinder the ability to implement formal training. Given the relevance of such a skill to patient care, every effort should be made to provide structured training opportunities during residency.

Background: Although the use of video-assisted thoracoscopic surgery (VATS) for resection of lung metastases has increased, surgeons still advocate for open resection as it permits palpation of lesions that may be missed on imaging. This study aimed to compare the utilization of open thoracotomy versus VATS over time and determine if the use of VATS changes perioperative outcomes. Methods: Using the Kids' Inpatient Database (2006, 2009, 2012, 2016), we identified children (age ≤20) with a diagnosis of secondary lung cancer with either lobectomy or sublobar resection coded during the same admission. Utilization was compared across years for the overall cohort and for patients with primary bone and connective tissue (PBCT) cancers. We defined prolonged length of stay (LOS) as LOS ≥75th percentile (LOS ≥7 days). Univariable and multivariable analyses compared in-hospital complication rates and LOS for open and VATS approaches. Results: Of the 1316 children (539 female) undergoing pulmonary resection, VATS was utilized in 374 (28.4%). Utilization increased rapidly from 2006 to 2009 ( P  < .001 for trend), but stabilized thereafter ( P  = .622). Metastatic PBCT cancers were the most common indication for resection ( n  = 496, 38%), but open and VATS approaches were used nearly equally ( P  = .368). Overall, 352 (26%) patients had complications. On multivariable analysis, the open approach remained independently associated with increased complications (odds ratio [OR] 1.48, 95% confidence interval [CI] [1.04-2.11]). Median LOS increased for open cases (5 versus 3 days, P  < .001). Furthermore, open metastasectomy was associated with prolonged LOS (OR 1.50, [1.07-2.10]) after controlling for age, sex, primary cancer, reporting year, resection extent, obesity, complications, and nonoperative intubation. Conclusion: VATS approach to pulmonary metastasectomy resulted in fewer complications and shorter LOS in a nationwide sample of children. Despite these advantages, the use of VATS has plateaued. While this study cannot comment on oncologic safety or long-term outcomes, future studies should evaluate whether indications for VATS pulmonary metastasectomy can be expanded.

Introduction: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) often leads to mortality. Outcomes of patients with COVID-19-related ARDS compared to ARDS unrelated to COVID-19 is not well characterized., Areas Covered: We performed a systematic review of PubMed, Scopus, and MedRxiv 11/1/2019 to 3/1/2021, including studies comparing outcomes in COVID-19-related ARDS (COVID-19 group) and ARDS unrelated to COVID-19 (ARDS group). Outcomes investigated were duration of mechanical ventilation-free days, intensive care unit (ICU) length-of-stay (LOS), hospital LOS, and mortality. Random effects models were fit for each outcome measure. Effect sizes were reported as pooled median differences of medians (MDMs), mean differences (MDs), or odds ratios (ORs)., Expert Opinion: Ten studies with 2,281 patients met inclusion criteria (COVID-19: 861 [37.7%], ARDS: 1420 [62.3%]). There were no significant differences between the COVID-19 and ARDS groups for median number of mechanical ventilator-free days (MDM: -7.0 [95% CI: -14.8; 0.7], p = 0.075), ICU LOS (MD: 3.1 [95% CI: -5.9; 12.1], p = 0.501), hospital LOS (MD: 2.5 [95% CI: -5.6; 10.7], p = 0.542), or all-cause mortality (OR: 1.25 [95% CI: 0.78; 1.99], p = 0.361). Compared to the general ARDS population, results did not suggest worse outcomes in COVID-19-related ARDS.

Introduction: Because active cells present higher abundance of ribosomal RNA (rRNA) than rDNA (rRNA genes), data obtained with rDNA-based quantitative polymerase chain reaction (qPCR) and rRNA-based qPCR (RT-qPCR) were correlated to search for active bacteria after chemomechanical procedures (CMP). In addition, the ability of both assays to detect bacteria in endodontic samples was evaluated., Methods: Samples were taken from 40 teeth with primary endodontic infections before (S1) and after CMP (S2). DNA and cDNA (synthetized from RNA) were used as templates for qPCR using universal primers for bacteria and species-specific primers for Bacteroidaceae sp. HOT-272, Cutibacterium acnes, Selenomonas spp., and Enterococcus faecalis., Results: After CMP, there was a drastic reduction in the number of total bacteria, Selenomonas spp., and E. faecalis, whereas no significant difference was observed for the levels of Bacteroidaceae sp. HOT-272 and C. acnes. The concentration of rRNA copies in S2 samples was significantly higher than the corresponding levels of rDNA for assays targeting total bacteria, Bacteroidaceae sp. HOT-272, and C. acnes (P < .05), indicating persistence of active bacteria. The rDNA-based qPCR presented low sensitivity and high specificity when compared with RT-qPCR. For most assays, samples positive for rDNA were also positive for rRNA (positive predictive value = 100%)., Conclusions: CMP was effective in reducing levels but not the metabolic activity of total bacteria. Bacteroidaceae sp. HOT-272 and C. acnes were active members of the persistent community. Although less sensitive than RT-qPCR, most rDNA-based qPCR assays had a low risk of providing false-positive results in postinstrumentation samples., (Copyright © 2020 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

New tools for activating endodontic irrigants have evolved, yet their impact on root canal disinfection, in comparison to the passive placing of an inter-visit medication, have not yet been fully elucidated. The use of DNA- and rRNA-based methods may cast some new light on this issue, as they allow a comparison to be made between microbial presence and activity. Therefore, the aim of this single-arm intervention trial is to evaluate the antibacterial effect of endodontic procedures using both molecular methods. Root canal samples were obtained from 20 patients with asymptomatic apical periodontitis after each treatment step: access cavity, chemo-mechanical preparation, adjunctive procedures (XP-endo Finisher file and passive ultrasonic irrigation), calcium hydroxide medication, and 2nd-visit root canal preparation. DNA and cDNA from the samples were subjected to quantitative polymerase chain reaction with universal primers for the bacterial 16S rRNA gene. Chemo-mechanical preparation promoted a drastic reduction in bacterial levels and activity, whereas the adjunctive procedures did not make a significant contribution to further disinfection. At the 2nd visit, bacteria were active after the use of calcium hydroxide medication; however, they were significantly reduced after a 2nd-visit preparation. Consequently, the lowest bacterial levels were found at the end of the treatment. This clinical trial, which used an rRNA and rDNA combined approach, confirmed previous studies showing that root canal preparation represents the main strategy for root canal disinfection.

Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

The polymorphism of new and old active pharmaceutical ingredients (APIs) is of great importance due to performance, stability and processability aspects. The objective of this study was to investigate the polymorphism of deflazacort (DEF), a glucocorticoid discovered >40 years ago, since this phenomenon has not been previously investigated for this API. Using different methods for solid form screening, it was determined for the first time that DEF is able to exist as three forms: a crystalline (DEF-1); a hydrated X-ray amorphous (DEF-t-bw) and an anhydrous amorphous phase (DEF-g) obtained from manually grinding DEF-1. The in vitro and in vivo dissolution rates (DRs) of DEF-1 and DEF-t-bw, which were measured using the rotating disk method in water at 37 °C and the pellet implantation technique in rats, respectively, indicated that DEF-t-bw exhibited slightly faster in vitro and in vivo DRs than those of the crystalline form, but the values were not significantly different. In addition, it was determined that DEF-t-bw devitrifies to DEF-1 by the effect of pressure, humidity and heat. It was concluded that DEF is glucorticoid with low tendency to exhibit different crystalline forms and that DEF-t-bw has no advantages over DEF-1 in terms of solubility, DRs and solid-state stability.

Aim: To investigate the association between vasculopathy and survival during experimental cerebral malaria (ECM), and to determine whether targeting the endothelin-1 (ET-1) pathway alone or in combination with the anti-malaria drug artemether (a semi-synthetic derivative of artemisinin) will improve microvascular hemorrhage and survival., Main Methods: C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were randomly assigned to four groups: no treatment, artemether treated, ET(A) receptor antagonist (HJP-272) treated, or HJP-272 and artemether treated. The uninfected control mice were treated with HJP-272 and artemether. We analyzed survival, cerebral hemorrhage, weight change, blood glucose levels and parasitemia., Key Findings: Our studies demonstrated decreased brain hemorrhage in PbA-infected (ECM) mice treated when HJP-272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one novel ET(A) receptor antagonist synthesized by our group, is used in conjunction with artemether, an anti-malarial agent. In addition, despite adversely affecting parasitemia and weight in non-artemether treated infected mice, HJP-272, seemed to confer some survival benefit when used as adjunctive therapy, though this did not reach significance., Significance: Previous studies demonstrate that the endothelin pathway is associated with vasculopathy, neuronal injury and inflammation in ECM. As demonstrated here, components of the ET-1 pathway may be important targets for adjunctive therapy in ECM, and may help in preventing hemorrhage and in improving survival when used as adjunctive therapy during malaria infection. The data presented suggest that our novel agent, HJP-272, may ameliorate alterations in the vasculature which can potentially lead to inflammation, neurological dysfunction, and subsequent death in mice with ECM., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Neurological and cognitive impairment persist in more than 20% of cerebral malaria (CM) patients long after successful anti-parasitic treatment. We recently reported that long term memory and motor coordination deficits are also present in our experimental cerebral malaria model (ECM). We also documented, in a murine model, a lack of obvious pathology or inflammation after parasite elimination, suggesting that the long-term negative neurological outcomes result from potentially reversible biochemical and physiological changes in brains of ECM mice, subsequent to acute ischemic and inflammatory processes. Here, we demonstrate for the first time that acute ECM results in significantly reduced activation of protein kinase B (PKB or Akt) leading to decreased Akt phosphorylation and inhibition of the glycogen kinase synthase (GSK3β) in the brains of mice infected with Plasmodium berghei ANKA (PbA) compared to uninfected controls and to mice infected with the non-neurotrophic P. berghei NK65 (PbN). Though Akt activation improved to control levels after chloroquine treatment in PbA-infected mice, the addition of lithium chloride, a compound which inhibits GSK3β activity and stimulates Akt activation, induced a modest, but significant activation of Akt in the brains of infected mice when compared to uninfected controls treated with chloroquine with and without lithium. In addition, lithium significantly reversed the long-term spatial and visual memory impairment as well as the motor coordination deficits which persisted after successful anti-parasitic treatment. GSK3β inhibition was significantly increased after chloroquine treatment, both in lithium and non-lithium treated PbA-infected mice. These data indicate that acute ECM is associated with abnormalities in cell survival pathways that result in neuronal damage. Regulation of Akt/GSK3β with lithium reduces neuronal degeneration and may have neuroprotective effects in ECM. Aberrant regulation of Akt/GSK3β signaling likely underlies long-term neurological sequelae observed in ECM and may yield adjunctive therapeutic targets for the management of CM.

We evaluated the beneficial effect of treatment with bone marrow mononuclear cells(BMMC) in a rat model of focal ischemia induced by thermocoagulation of the blood vessels in the left sensorimotor cortex. BMMC were obtained from donor rats and injected into the femoral vein one day after ischemia. BMMC-treated animals received approx. 3×10⁷ cells and control animals received PBS. Animals were evaluated for functional sensorimotor recovery weekly with behavioral tests and for changes in neurodegeneration and structural plasticity with histochemical and immunostaining techniques, respectively. The BMMC-treated group showed a significant recovery of function in the cylinder test 14, 21 and 28 days after ischemia. In the beam test, both groups showed improvement, with a tendency for faster recovery in the BMMC-treated group. In the adhesive test, both groups did not show significant recovery of function. FJC+ cell counting revealed significant decrease in the neurodegeneration in the periphery of the lesion in the BMMC-treated group. The analyses by immunoblotting revealed no significant difference in the expression of GAP-43 and synaptophysin between the groups. Thus, our results showed beneficial effects of the treatment with BMMC, which promoted significant functional recovery and decreased neurodegeneration. These results suggest that the therapy with BMMC is effective and might be a protocol of treatment for stroke in humans, alternative to the therapy proposed with the bone marrow-derived mesenchymal stem cells.

This study compared the noninvasive assessment of left ventricular function with radionuclide angiography with that obtained with ultrasonic sonomicrometry. Left ventricular ejection fraction and rate of ventricular ejection (dV/dt) were measured with both techniques over a wide range of ventricular function. Six dogs were prepared with epicardial crystals across the major and minor axes of the left ventricle, paired transmural wall thickness crystals and a left ventricular catheter. The animals were studied while awake after they had recovered from operation. Left ventricular volume was calculated from the ultrasonic sonomicrometric dimension measurements and the equation for a prolate ellipsoid; dV/dt was calculated from the stroke volume and ejection time. Radionuclide angiograms were performed using technetium-99m--labeled red blood cells and an Anger camera with a converging collimator interfaced to a computer programmed for multigated acquisition. A wide range of ventricular function was produced with sequential infusion of isoproterenol, propranolol, phenylephrine and sodium thiamylal. Ejection fraction and dV/dt were measured simultaneously during each intervention using the time-activity curves of the multigated radionuclide angiogram and ultrasonic sonomicrometric dimensions. Regression analyses demonstrated a close correlation between the simultaneous measurements of ejection fraction (r values ranged from 0.95 to 0.99) and dV/dt (r values ranged from 0.87 to 0.99). These data indicate that noninvasive multigated radionuclide angiography accurately assesses changes in ejection fraction and dV/dt over a wide range of ventricular function.

Serial 99mTc pyrophosphate scintigrams were obtained 7 hr to 15 days after experimental acute myocardial infarction produced by permanent or transient coronary occlusion. Scintigrams were interpreted visually and the increased radioactivity in the precordial image was quantitated and compared to extent of infarction found histologically. Results of these studies indicate: 1) 99mTc pyrophosphate imaging is an extremely sensitive for detection of acute myocardial infarction, i.e., infarction in excess of 1% of the left ventricular mass was detected. 2) Early detection of acute infarction is a function of blood flow since 7 hr after infarction scans were negative after permanent occlusion but were strongly positive after transient occlusion. 3) Radioactivity in the precordial image was inversely related to extent of infarction after permanent occlusion and directly related to extent of infarction after transient occlusion. 4) 99mTc pyrophosphate localized in areas with significant histologic infarction but the distribution of radioactivity was not proportional to extent of infarction.