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Neurodevelopmental Outcomes After Nitric Oxide During Cardiopulmonary Bypass for Open Heart Surgery: A Randomized Clinical Trial
No full textIMPORTANCE: Children with congenital heart defects who undergo cardiopulmonary bypass (CPB) surgery are at risk for delayed or impaired neurodevelopmental outcomes. Nitric oxide (NO) added to the CPB oxygenator may reduce systemic inflammation due to CPB and improve recovery from surgery, including improved neurodevelopmental outcomes. OBJECTIVE: To investigate neurodevelopment, health-related quality of life (HRQOL), and factors associated with impaired neurodevelopment at 12 months post surgery in infants who received CPB with NO or standard CPB. DESIGN, SETTING, AND PARTICIPANTS: This double-masked randomized clinical trial was conducted in 6 centers in Australia, New Zealand, and the Netherlands between July 19, 2017, and April 28, 2021, with a preplanned prospective follow-up 12 months postrandomization completed on August 5, 2022. The cohort included 1364 infants younger than 2 years who underwent open heart surgery with CPB for congenital heart disease. INTERVENTIONS: The intervention group received NO 20 ppm into the CPB oxygenator. The control group received standard CPB. MAIN OUTCOMES AND MEASURES: The primary outcome was neurodevelopment, defined as the Ages and Stages Questionnaire, Third Edition (ASQ-3) total score. Secondary outcomes were HRQOL and functional status as measured by Pediatric Quality of Life Inventory and modified Pediatric Overall Performance Category scores, respectively. Sensitivity analyses modeled the outcome for patients lost to follow-up. RESULTS: Of 1318 infants alive 12 months after randomization, follow-up was performed in 927, with 462 patients in the NO group and 465 in the standard care group (median [IQR] age at follow-up, 16.6 [13.7-19.8] months; median [IQR] time since randomization, 12.7 [12.1-13.9] months; 516 male [55.7%]). There were no differences between the NO and standard care groups in ASQ-3 total score (mean [SD], 196.6 [75.4] vs 198.7 [73.8], respectively; adjusted mean difference, -2.24; 95% CI, -11.84 to 7.36). There were no differences in secondary outcomes. Prematurity (gestational age \u3c37 weeks), univentricular lesions, congenital syndromes, and longer intensive care unit length of stay were associated with lower ASQ-3 total scores in adjusted multivariable analyses. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of infants with congenital heart disease, NO administered via the CPB oxygenator did not improve neurodevelopmental outcomes or HRQOL 12 months after open heart surgery. Further research should explore homogenous cohorts with higher surgical risk and higher-dose or alternative therapies. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12617000821392
Transient Viremia Among People with HIV Receiving Injectable Cabotegravir Plus Rilpivirine
No full textLong-acting injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) provides an effective treatment option for people with HIV (PWH). Studies suggest that PWH on LAI CAB/RPV may experience isolated episodes of transient viremia (HIV RNA \u3e 20 copies/mL) defined as virologic blips (VB). The risk factors for VB in PWH receiving LAI CAB/RPV are limited. We aimed to describe a cohort of PWH on LAI CAB/RPV and evaluate risk factors and time to VB following LAI CAB/RPV initiation. We obtained DC Cohort data from PWH who initiated LAI CAB/RPV prior to July 2023 and used Kaplan-Meier curves and Cox proportional hazards models to evaluate the association between participant demographics, HIV clinical factors, and time to VB. Among 98 PWH who initiated LAI CAB/RPV, 9 (9.2%) experienced at least one VB (median HIV RNA = 50 copies/mL; ranges 30-12,000 copies/mL) during a median follow-up period of five months (IQR: 2-10). The median CD4 count among PWH was 754 cells/µL (IQR: 598, 980) at the time of LAI CAB/RPV initiation. Having a high CD4 (≥ 500 cells/μL) at LAI CAB/RPV initiation was significantly associated with a lower hazard for VB when compared to baseline CD4 \u3c 200 cells/µL [hazard ratios (HR): 0.15 [95% confidence intervals (CI): 0.03, 0.77]; aHR: 0.07 (95% CI: 0.01, 0.50); log-rank p = .026]. No other characteristics were significantly associated with time to VB, and no participants experienced virologic failure. Considerations for baseline CD4 may be important when initiating a patient on LAI CAB/RPV, and future studies will help evaluate the VB occurrence and associated factors among PWH
Birth Defects and Adverse Pregnancy Outcomes in Hospital-based Birth Surveillance in Eswatini
No full textBACKGROUND: The Botswana Tsepamo study identified an initial neural tube defect (NTD) safety signal with dolutegravir antiretroviral therapy (ART) exposure at conception. We conducted similar surveillance in 5 hospitals in Eswatini from September 2021 to September 2023 to evaluate the prevalence of birth defects and adverse pregnancy outcomes by maternal HIV status and ART regimen/timing. METHODS: Routine pregnancy history and HIV/ART status were collected from clinic records. Women of live or stillborn infants with birth defects consented for interviews and photographs of defects. A medical geneticist reviewed blinded interview data and photographs. RESULTS: Of 45,836 women with live-born or stillborn infants, 13,577 (29.6%) were living with HIV; 11,581 (86.0%) were receiving ART at conception (84.1% dolutegravir). Overall, birth defects were confirmed in 387 (0.8%) women. Comparing women with and without HIV, there were no significant differences in major defects (0.48% vs. 0.38%) or NTD (0.10% vs. 0.08%). In women with HIV, there were no significant differences between those on dolutegravir versus non-dolutegravir at conception for major defects (0.53% vs. 0.49%) or NTD (0.08% vs. 0.22%). Stillbirths were significantly higher in women with HIV than those without (2.6% vs. 1.9%, P \u3c 0.001), as was low birthweight and preterm delivery (11.8% vs. 10.4%, P \u3c 0.001; 12.5% vs. 10.7%, P \u3c 0.001, respectively). There were no significant differences in outcomes by ART regimen. CONCLUSIONS: While these data from sub-Saharan Africa further strengthen the lack of a NTD safety signal in women with HIV on ART, there remained elevated adverse birth outcomes despite treatment compared to women without HIV
Sex Differences in the In-Hospital Outcomes of Left Ventricular Assist Device Implantation: A Population-Based National Inpatient Sample Study From 2015 to 2021
No full textBACKGROUND: Left ventricular assist device (LVAD) implantation can be used to manage advanced heart failure. Debates over sex differences in postoperative outcomes of LVAD implantation remain contentious; there is limited evidence available from the continuous-flow era, particularly following the introduction of third-generation devices. This study aimed to conduct a comprehensive, contemporary, and population-based analysis of the sex difference in the in-hospital outcomes following LVAD implantations. METHODS: Patients who underwent LVAD implantation were selected from National Inpatient Sample from Q4 2015-2021. Multivariable logistic regression was used to compare in-hospital outcomes between females and males, where demographics, socioeconomic status, primary payer status, hospital characteristics, comorbidities, and transfer/admission status were adjusted. RESULTS: There were 1201 (23.6%) female and 3881 (76.4%) male patients who underwent LVAD implantation. Females and males had comparable in-hospital mortality, MACE, and stroke. However, females had higher diaphragmatic paralysis (aOR = 7.94, 95 CI = 1.46-43.48, p = 0.02). Meanwhile, females had lower cardiogenic shock (aOR = 0.85, 95 CI = 0.73-0.98, p = 0.02), renal complications (aOR = 0.72, 95 CI = 0.62-0.84, p \u3c 0.01), and infection (aOR = 0.70, 95 CI = 0.58-0.86, p \u3c 0.01). Females also had longer hospital length of stay (44.1 ± 40.0 vs. 38.8 ± 30.6 days, p = 0.01) and higher total hospital charges (1293779.0 ± 1182139.0 vs. 1172780.0 ± 917544.0 US dollars, p = 0.04). CONCLUSION: In the contemporary era with the introduction of third-generation devices, in-hospital mortality and stroke after LVAD implantation continued to decrease and were comparable in both sexes. However, there are still notable sex-based differences in the complications of LVAD implantation, which underscores the need for sex-specific preoperative risk assessments and tailored perioperative management
Cardiovascular disease in adults with osteogenesis imperfecta: clinical characteristics, care recommendations, and research priorities identified using a modified Delphi technique
No full textOsteogenesis imperfecta (OI) is a multisystem disorder most often caused by pathogenic variants in genes that encode type I collagen. Type I collagen is abundant not only in bone but also in multiple tissues including skin, tendons, cornea, blood vessels, and heart. Thus, OI can be expected to affect cardiovascular system, and there are numerous reports of cardiovascular disease (CVD) in people with OI. However, there is no consensus on how CVD in OI should be assessed or managed. To fill this gap, a multidisciplinary group was convened to develop clinical guidance. The work included a systematic review of the available literature and, using a modified Delphi approach, the development of a series of statements summarizing current knowledge. Fourteen clinical recommendations were developed to guide clinicians, patients, and stakeholders about an approach for CVD in adults with OI. This paper describes how the work was conducted and provides the background and rationale for each recommendation. Furthermore, we highlight knowledge gaps and suggest research priorities for the future study of CVD in OI
Pharmacokinetics, safety and efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in children with HIV aged from 2 years and weighing at least 14 kg
No full textINTRODUCTION: Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) was efficacious and well tolerated in children/adolescents with HIV (aged ≥6 years, weighing ≥25 kg) in a Phase 2/3 study. Here, we report data from children aged ≥2 years and weighing ≥14-\u3c25 kg. METHODS: This is an analysis of data from the youngest cohort in an open-label, multicentre, multi-cohort, single-group, international study of children/adolescents with HIV. Participants in this cohort were children aged ≥2 years, weighing ≥14-\u3c25 kg at screening and able to swallow tablets, on stable antiretroviral therapy with virologic suppression (HIV-1 RNA \u3c50 copies/ml for ≥6 consecutive months) and a CD4 count ≥400 cells/µl. Eligible participants received low-dose E/C/F/TAF (90/90/120/6 mg) once daily through Week 48. The study included pharmacokinetic evaluation of the low-dose E/C/F/TAF tablet at Week 2. Safety, efficacy, palatability and acceptability were also evaluated. RESULTS: Between 16 January and 25 November 2019, 27 participants were enrolled with a median (quartile [Q]1, Q3) age of 6 (4, 8) years, body weight of 19.3 (17.0, 20.5) kg, CD4 count of 1061 (895, 1315) cells/µl and CD4 cell percentage of 37.4 (30.6, 40.3). Most (92.6%) participants acquired HIV through vertical transmission. On 6 October 2020 (data-cut), median (Q1, Q3) exposure to E/C/F/TAF was 48.3 (48.0, 60.1) weeks. Pharmacokinetic parameters were within the safe and efficacious range of previous data in adult and paediatric populations. Drug-related treatment-emergent adverse events occurred in 4/27 (15%) participants. There were no Grade 3/4 adverse events, or adverse events leading to E/C/F/TAF discontinuation. One participant experienced a serious treatment-emergent adverse event (Grade 2 pneumonia not considered E/C/F/TAF related). Virologic suppression (US FDA Snapshot algorithm) was maintained by 26/27 (96%) participants at Weeks 24 and 48. At Week 48, most children reported positive palatability (84.6%) and acceptability (96.2%). CONCLUSIONS: These data support the use of single-tablet E/C/F/TAF (90/90/120/6 mg) regimen for the treatment of HIV in children aged ≥2 years and weighing ≥14-\u3c25 kg. CLINICAL TRIAL NUMBER: NCT01854775
Calcium Phosphate-Induced Injury in Kidney Tubular Cells-Supersaturated Solution vs Preformed Crystals
No full textCrystalline nephropathy (CN) is characterized by deposition of microcrystals within the kidney tubular microstructure, specifically in the renal tubular cells. Nephropathic conditions have been observed in kidney stone patients as nephrocalcinosis, resulting from the deposition of calcium phosphate (CaP) microcrystals mainly within the renal tubule. CaP microcrystals trigger nephrotoxicity and cell death leading to acute and chronic kidney disease and in some cases end stage renal disease. Although supersaturation of calcium (Ca)- and phosphate (PO ) ions in the urine was described as a main factor the precise mechanism of cell death by distinguishing the impact of supersaturated solution vs the crystalline substances is unclear. Here we show the differential effect of CaP solution vs preformed crystal (as crystalline CaP) on the nephrotoxicity and the degree and type of cell death using a murine kidney tubular cell line, LLCPK1. We examined the cellular [cell viability, lactate dehydrogenase (LDH) and HO releases and Annexin+ propidium iodide (PI) staining] and molecular events [gene expressions, oxidative and endoplasmic reticular (ER) stress] towards understanding the mechanism of CN. The results of the study demonstrated that CaP in solution exerts injury effect on LLCPK1 cells. The addition of CaP solution showed stronger necrosis than the preformed crystals as shown by PI staining and the releases of LDH and HO. Overall, the results in the study revealed a novel mechanism differentiating the kidney cell injury between the insult mediated by supersaturated CaP solution and preformed CaP crystals
Increased sound levels in the cardiac ICU are associated with an increase in heart rate, blood pressure, and sedation
No full textBACKGROUND: Several organizations including the Environmental Protection Agency, World Health Organization and American Academy of Pediatrics recommend that hospital sound levels not exceed 45 decibels. Yet, several studies across multiple age groups have observed higher than recommended levels in the intensive care setting. Elevated sound levels in hospitals have been associated with disturbances in sleep, patient discomfort, delayed recovery, and delirium. METHODS: We measured sound levels in a pediatric cardiac intensive care unit and collected vital signs data, sedation dosing and delirium scores. During a 5-week study period, sound levels for 68 patients in 22 private and 4 semi-private rooms were monitored. RESULTS: Sound levels were consistently above stated recommendations with an average daytime level of 50.6 decibels (maximum, 76.9 decibels) and an average nighttime level of 49.5 decibels (maximum, 69.6 decibels). An increase in average and maximum sound levels increased the probability of sedation administration the following hour (p-value \u3c 0.001 and 0.01, respectively) and was predictive of an increase in heart rate and blood pressure (p-value \u3c 0.001). CONCLUSION: Sound levels in the CICU were consistently higher than recommended. An increase in heart rate, blood pressure and sedation utilization may suggest a stress response to persistent and sudden loud sounds. Given known negative impacts of excessive noise on stress, sleep, and brain development, as well as the similar adverse effects from the related use of sedative medications, reducing excessive and sudden noise may provide an opportunity to improve short- and long-term hemodynamic and neurodevelopmental outcomes in the pediatric cardiac intensive care unit
Global Neurosurgery: A Path Forward Through Health System Strengthening
No full textThe future of global neurosurgery should focus on addressing the unmet neurosurgical need from a health system approach should we hope to achieve sustainable and ethical change. In this article, we review the global building blocks, as defined by the World Health Organization, and use this framework to propose strategies to strengthen neurosurgical care on the global frontier. The targets for Universal Healthcare Coverage by 2030, as outlined by the United Nations Sustainable Development Goals, are reviewed, and the role of neurosurgeons in addressing the global targets is discussed. Surgical indicators according to the Lancet Commission on Global Surgery are also reviewed, and neurosurgical indicators are proposed according to the 6 surgical indicators of the commission. The execution of these global targets and indicators within the context of health system strengthening will be a persistent challenge, given the complexity of health system and its components. The neurosurgical community must continue to support, promote, and diversify collaborations, especially among deserts of neurosurgical care across the world. Innovative technology and education are essential to this global dilemma