Brain volume, energy balance, and cardiovascular health in two nonindustrial South American populations.

Little is known about brain aging or dementia in nonindustrialized environments that are similar to how humans lived throughout evolutionary history. This paper examines brain volume (BV) in middle and old age among two indigenous South American populations, the Tsimane and Moseten, whose lifestyles and environments diverge from those in high-income nations. With a sample of 1,165 individuals aged 40 to 94, we analyze population differences in cross-sectional rates of decline in BV with age. We also assess the relationships of BV with energy biomarkers and arterial disease and compare them against findings in industrialized contexts. The analyses test three hypotheses derived from an evolutionary model of brain health, which we call the embarrassment of riches (EOR). The model hypothesizes that food energy was positively associated with late life BV in the physically active, food-limited past, but excess body mass and adiposity are now associated with reduced BV in industrialized societies in middle and older ages. We find that the relationship of BV with both non-HDL cholesterol and body mass index is curvilinear, positive from the lowest values to 1.4 to 1.6 SDs above the mean, and negative from that value to the highest values. The more acculturated Moseten exhibit a steeper decrease in BV with age than Tsimane, but still shallower than US and European populations. Lastly, aortic arteriosclerosis is associated with lower BV. Complemented by findings from the United States and Europe, our results are consistent with the EOR model, with implications for interventions to improve brain health.

Preservation of the heart in ancient Egyptian mummies: A computed tomography investigation with focus on the myocardium.

The ancient Egyptians considered the heart to be the most important organ. The belief that the heart remained in the body is widespread in the archeological and paleopathological literature. The purpose of this study was to perform an overview of the preserved intrathoracic structures and thoracic and abdominal cavity filling, and to determine the prevalence and computed tomography (CT) characteristics of the myocardium in the preserved hearts of ancient Egyptian mummies. Whole-body CT examinations of 45 ancient Egyptian mummies (23 mummies from the Ägyptisches Museum und Papyrussammlung, Berlin, Germany, and 22 mummies from the Museo Egizio, Turin, Italy) were systematically assessed for preserved intrathoracic soft tissues including various anatomical components of the heart (pericardium, interventricular septum, four chambers, myocardium, valves). Additionally, evidence of evisceration and cavity filling was documented. In cases with identifiable myocardium, quantitative (measurements of thickness and density) and qualitative (description of the structure) assessment of the myocardial tissue was carried out. Heart structure was identified in 28 mummies (62%). In 33 mummies, CT findings demonstrated evisceration, with subsequent cavity filling in all but one case. Preserved myocardium was identified in nine mummies (five male, four female) as a mostly homogeneous, shrunken structure. The posterior wall of the myocardium had a mean maximum thickness of 3.6 mm (range 1.4-6.6 mm) and a mean minimum thickness of 1.0 mm (range 0.5-1.7 mm). The mean Hounsfield units (HU) of the myocardium at the posterior wall was 61 (range, 185-305). There was a strong correlation between the HU of the posterior wall of the myocardium and the mean HU of the muscles at the dorsal humerus (R = 0.77; p = 0.02). In two cases, there were postmortem changes in the myocardium, most probably due to insect infestation. To our knowledge, this is the first study to investigate the myocardium systematically on CT scans of ancient Egyptian mummies. Strong correlations between the densities of the myocardium and skeletal muscle indicated similar postmortem changes of the respective musculature during the mummification process within individual mummies. The distinct postmortem shrinking of the myocardium and the collapse of the left ventriclular cavity in several cases did not allow for paleopathological diagnoses such as myocardial scarring.

Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease.

BACKGROUND: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. METHODS: Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. RESULTS: No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. CONCLUSIONS: Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

Prevalence of dementia and mild cognitive impairment in indigenous Bolivian forager-horticulturalists.

INTRODUCTION: We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle. METHODS: Participants from population-based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini-Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans. RESULTS: Tsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age-standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia. DISCUSSION: The prevalence of dementia in this cohort is among the lowest in the world. Widespread intracranial medial arterial calcifications suggest a previously unrecognized, non-Alzheimer's disease (AD) dementia phenotype.

Implementation of Vancomycin Therapeutic Monitoring Guidelines: Focus on Bayesian Estimation Tools in Neonatal and Pediatric Patients.

BACKGROUND: The 2020 consensus guidelines for vancomycin therapeutic monitoring recommend using Bayesian estimation targeting the ratio of the area under the curve over 24 hours to minimum inhibitory concentration as an optimal approach to individualize therapy in pediatric patients. To support institutional guideline implementation in children, the objective of this study was to comprehensively assess and compare published population-based pharmacokinetic (PK) vancomycin models and available Bayesian estimation tools, specific to neonatal and pediatric patients. METHODS: PubMed and Embase databases were searched from January 1994 to December 2020 for studies in which a vancomycin population PK model was developed to determine clearance and volume of distribution in neonatal and pediatric populations. Available Bayesian software programs were identified and assessed from published articles, software program websites, and direct communication with the software company. In the present review, 14 neonatal and 20 pediatric models were included. Six programs (Adult and Pediatric Kinetics, BestDose, DoseMeRx, InsightRx, MwPharm++, and PrecisePK) were evaluated. RESULTS: Among neonatal models, Frymoyer et al and Capparelli et al used the largest PK samples to generate their models, which were externally validated. Among the pediatric models, Le et al used the largest sample size, with multiple external validations. Of the Bayesian programs, DoseMeRx, InsightRx, and PrecisePK used clinically validated neonatal and pediatric models. CONCLUSIONS: To optimize vancomycin use in neonatal and pediatric patients, clinicians should focus on selecting a model that best fits their patient population and use Bayesian estimation tools for therapeutic area under the -curve-targeted dosing and monitoring.

Voluntary collective isolation as a best response to COVID-19 for indigenous populations? A case study and protocol from the Bolivian Amazon.

Indigenous communities worldwide share common features that make them especially vulnerable to the complications of and mortality from COVID-19. They also possess resilient attributes that can be leveraged to promote prevention efforts. How can indigenous communities best mitigate potential devastating effects of COVID-19? In Bolivia, where nearly half of all citizens claim indigenous origins, no specific guidelines have been outlined for indigenous communities inhabiting native communal territories. In this Public Health article, we describe collaborative efforts, as anthropologists, physicians, tribal leaders, and local officials, to develop and implement a multiphase COVID-19 prevention and containment plan focused on voluntary collective isolation and contact-tracing among Tsimane forager-horticulturalists in the Bolivian Amazon. Phase 1 involves education, outreach, and preparation, and phase 2 focuses on containment, patient management, and quarantine. Features of this plan might be exported and adapted to local circumstances elsewhere to prevent widespread mortality in indigenous communities.

White matter microstructure among perinatally HIV-infected youth: a diffusion tensor imaging study.

We evaluated white matter microstructure integrity in perinatally HIV-infected (PHIV) youths receiving cART compared to age- and gender-matched healthy youths through DTI metrics using voxel-based morphometry (VBM). We investigated 14 perinatally HIV-infected patients (age 17.9 ± 2.5 years) on cART and 17 healthy youths (HC) (age 18.0 ± 3.0 years) using a 3T MRI scanner. Four DTI-derived metrics were fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Statistical analysis was done with voxel-based analysis of covariance (ANCOVA), with age and gender as covariates. Region-of-interest secondary analyses in statistically significant regions were also performed. Regional increases in FA in the PHIV youths were found in left middle frontal gyrus, right precuneus, right lingual gyrus, and left supramarginal gyrus. Increased MD was found in the right precentral gyrus while decreased MD was found in the white matter of the right superior parietal lobule and right inferior temporal gyrus/fusiform gyrus. Regions of increased/decreased RD overlapped with regions of increased/decreased MD. Both increased and decreased AD were found in three to four regions respectively. The regional FA, MD, RD, and AD values were consistent with the voxel-based analysis findings. The findings are mostly consistent with previous literature, but increased FA has not been previously reported for perinatally HIV-infected youths. Potentially early and prolonged therapy in our population may have contributed to this new finding. Both toxicity of antiretroviral therapy and indolent infection must be considered as causative factors in the DTI metric changes that we have observed.

Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study.

BACKGROUND: Conventional coronary artery disease risk factors might potentially explain at least 90% of the attributable risk of coronary artery disease. To better understand the association between the pre-industrial lifestyle and low prevalence of coronary artery disease risk factors, we examined the Tsimane, a Bolivian population living a subsistence lifestyle of hunting, gathering, fishing, and farming with few cardiovascular risk factors, but high infectious inflammatory burden. METHODS: We did a cross-sectional cohort study including all individuals who self-identified as Tsimane and who were aged 40 years or older. Coronary atherosclerosis was assessed by coronary artery calcium (CAC) scoring done with non-contrast CT in Tsimane adults. We assessed the difference between the Tsimane and 6814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). CAC scores higher than 100 were considered representative of significant atherosclerotic disease. Tsimane blood lipid and inflammatory biomarkers were obtained at the time of scanning, and in some patients, longitudinally. FINDINGS: Between July 2, 2014, and Sept 10, 2015, 705 individuals, who had data available for analysis, were included in this study. 596 (85%) of 705 Tsimane had no CAC, 89 (13%) had CAC scores of 1-100, and 20 (3%) had CAC scores higher than 100. For individuals older than age 75 years, 31 (65%) Tsimane presented with a CAC score of 0, and only four (8%) had CAC scores of 100 or more, a five-fold lower prevalence than industrialised populations (p≤0·0001 for all age categories of MESA). Mean LDL and HDL cholesterol concentrations were 2·35 mmol/L (91 mg/dL) and 1·0 mmol/L (39·5 mg/dL), respectively; obesity, hypertension, high blood sugar, and regular cigarette smoking were rare. High-sensitivity C-reactive protein was elevated beyond the clinical cutoff of 3·0 mg/dL in 360 (51%) Tsimane participants. INTERPRETATION: Despite a high infectious inflammatory burden, the Tsimane, a forager-horticulturalist population of the Bolivian Amazon with few coronary artery disease risk factors, have the lowest reported levels of coronary artery disease of any population recorded to date. These findings suggest that coronary atherosclerosis can be avoided in most people by achieving a lifetime with very low LDL, low blood pressure, low glucose, normal body-mass index, no smoking, and plenty of physical activity. The relative contributions of each are still to be determined. FUNDING: National Institute on Aging, National Institutes of Health; St Luke's Hospital of Kansas City; and Paleocardiology Foundation.

Is coronary calcium scoring too late? Total body arterial calcium burden in patients without known CAD and normal MPI.

BACKGROUND: Patients with normal myocardial perfusion imaging (MPI) have a good prognosis. However, pre-clinical coronary and extracoronary atherosclerosis may exist in the absence of myocardial ischemia. METHODS: 154 Egyptian patients (mean age 53 years) underwent whole-body non-contrast CT following normal MPI. RESULTS: Atherosclerosis in the form of calcification was observed in ≥1 vascular bed in 115 of 154 (75%) patients. This included the iliofemoral (62%), abdominal aorta (53%), thoracic aorta (47%), coronary (47%), and carotid (25%) vascular beds. Mean total body calcium score was 3172 ± 530 AU. Extracoronary atherosclerosis in patients with a zero coronary artery calcium (CAC) score was common, occurring in the above-listed beds 42%, 36%, 29%, and 7% of the time, respectively. CAC was rarely present without iliofemoral or abdominal aortic calcification. CONCLUSION: Quantitative assessment of calcification in different vascular beds demonstrates that extracoronary atherosclerosis is common in patients who have normal MPI. Atherosclerotic calcifications are most common in the iliofemoral arteries and abdominal aorta, which typically predate coronary calcifications. An imaging strategy to detect extracoronary atherosclerosis could lead to greater understanding of the natural history of atherosclerosis in its long pre-clinical phase and possibly to earlier preventive strategies.

ADAR RNA editing in human disease; more to it than meets the I.

We review the structures and functions of ADARs and their involvements in human diseases. ADAR1 is widely expressed, particularly in the myeloid component of the blood system, and plays a prominent role in promiscuous editing of long dsRNA. Missense mutations that change ADAR1 residues and reduce RNA editing activity cause Aicardi-Goutières Syndrome, a childhood encephalitis and interferonopathy that mimics viral infection and resembles an extreme form of Systemic Lupus Erythmatosus (SLE). In Adar1 mouse mutant models aberrant interferon expression is prevented by eliminating interferon activation signaling from cytoplasmic dsRNA sensors, indicating that unedited cytoplasmic dsRNA drives the immune induction. On the other hand, upregulation of ADAR1 with widespread promiscuous RNA editing is a prominent feature of many cancers and particular site-specific RNA editing events are also affected. ADAR2 is most highly expressed in brain and is primarily required for site-specific editing of CNS transcripts; recent findings indicate that ADAR2 editing is regulated by neuronal excitation for synaptic scaling of glutamate receptors. ADAR2 is also linked to the circadian clock and to sleep. Mutations in ADAR2 could contribute to excitability syndromes such as epilepsy, to seizures, to diseases involving neuronal plasticity defects, such as autism and Fragile-X Syndrome, to neurodegenerations such as ALS, or to astrocytomas or glioblastomas in which reduced ADAR2 activity is required for oncogenic cell behavior. The range of human disease associated with ADAR1 mutations may extend further to include other inflammatory conditions while ADAR2 mutations may affect psychiatric conditions.

Increases in regional brain volume across two native South American male populations.

Industrialized environments, despite benefits such as higher levels of formal education and lower rates of infections, can also have pernicious impacts upon brain atrophy. Partly for this reason, comparing age-related brain volume trajectories between industrialized and non-industrialized populations can help to suggest lifestyle correlates of brain health. The Tsimane, indigenous to the Bolivian Amazon, derive their subsistence from foraging and horticulture and are physically active. The Moseten, a mixed-ethnicity farming population, are physically active but less than the Tsimane. Within both populations (N = 1024; age range = 46-83), we calculated regional brain volumes from computed tomography and compared their cross-sectional trends with age to those of UK Biobank (UKBB) participants (N = 19,973; same age range). Surprisingly among Tsimane and Moseten (T/M) males, some parietal and occipital structures mediating visuospatial abilities exhibit small but significant increases in regional volume with age. UKBB males exhibit a steeper negative trend of regional volume with age in frontal and temporal structures compared to T/M males. However, T/M females exhibit significantly steeper rates of brain volume decrease with age compared to UKBB females, particularly for some cerebro-cortical structures (e.g., left subparietal cortex). Across the three populations, observed trends exhibit no interhemispheric asymmetry. In conclusion, the age-related rate of regional brain volume change may differ by lifestyle and sex. The lack of brain volume reduction with age is not known to exist in other human population, highlighting the putative role of lifestyle in constraining regional brain atrophy and promoting elements of non-industrialized lifestyle like higher physical activity.

Testosterone is positively associated with coronary artery calcium in a low cardiovascular disease risk population.

Background: In industrialized populations, low male testosterone is associated with higher rates of cardiovascular mortality. However, coronary risk factors like obesity impact both testosterone and cardiovascular outcomes. Here, we assess the role of endogenous testosterone on coronary artery calcium in an active subsistence population with relatively low testosterone levels, low cardiovascular risk and low coronary artery calcium scores. Methodology: In this cross-sectional community-based study, 719 Tsimane forager-horticulturalists in the Bolivian Amazon aged 40+ years underwent computed tomography (49.8% male, mean age 57.6 years). Results: Coronary artery calcium levels were low; 84.5% had no coronary artery calcium. Zero-inflated negative binomial models found testosterone was positively associated with coronary artery calcium for the full sample (Incidence Rate Ratio [IRR] = 1.477, 95% Confidence Interval [CI] 1.001-2.170, P = 0.031), and in a male-only subset (IRR = 1.532, 95% CI 0.993-2.360, P = 0.053). Testosterone was also positively associated with clinically relevant coronary atherosclerosis (calcium >100 Agatston units) in the full sample (Odds Ratio [OR] = 1.984, 95% CI 1.202-3.275, P = 0.007) and when limited to male-only sample (OR = 2.032, 95% CI 1.118-4.816, P = 0.024). Individuals with coronary artery calcium >100 had 20% higher levels of testosterone than those with calcium <100 (t = -3.201, P = 0.007). Conclusions and Implications: Among Tsimane, testosterone is positively associated with coronary artery calcium despite generally low normal testosterone levels, minimal atherosclerosis and rare cardiovascular disease (CVD) events. Associations between low testosterone and CVD events in industrialized populations are likely confounded by obesity and other lifestyle factors.

Case Report: Indocyanine Green-Based Angiography for Real-Time Assessment of Superficial Brachialis Axial Pattern Flap Vascularization in Two Dogs.

This case report describes the method and feasibility of near-infrared angiography (NIRA) to improve the surgical procedure of two superficial brachial axial pattern flaps intraoperatively using two camera systems. Two client-owned dogs were treated for tumors on their antebrachia with wide surgical excision. The defects were closed with a superficial brachial flap in both cases. A different NIRA camera system was used for each case to identify the perforator vessel and flap margins accordingly. Case 1 developed a seroma and healed without further complications. Case 2 developed partial flap necrosis, underwent revision surgery, and healed by secondary intent. NIRA proved useful intraoperatively in identifying the perforator vessel and determining flap margins. As these are only two cases, caution should be used in extrapolating the results.

In vitro reconstitution of Escherichia coli divisome activation.

The actin-homologue FtsA is essential for E. coli cell division, as it links FtsZ filaments in the Z-ring to transmembrane proteins. FtsA is thought to initiate cell constriction by switching from an inactive polymeric to an active monomeric conformation, which recruits downstream proteins and stabilizes the Z-ring. However, direct biochemical evidence for this mechanism is missing. Here, we use reconstitution experiments and quantitative fluorescence microscopy to study divisome activation in vitro. By comparing wild-type FtsA with FtsA R286W, we find that this hyperactive mutant outperforms FtsA WT in replicating FtsZ treadmilling dynamics, FtsZ filament stabilization and recruitment of FtsN. We could attribute these differences to a faster exchange and denser packing of FtsA R286W below FtsZ filaments. Using FRET microscopy, we also find that FtsN binding promotes FtsA self-interaction. We propose that in the active divisome FtsA and FtsN exist as a dynamic copolymer that follows treadmilling filaments of FtsZ.

Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (rhu GM-CSF) as Adjuvant Therapy for Invasive Fungal Diseases.

Background: Sargramostim (yeast-derived, glycosylated recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) augments innate and adaptive immune responses and accelerates hematopoietic recovery of chemotherapy-induced neutropenia. However, considerably less is known about its efficacy as adjunctive immunotherapy against invasive fungal diseases (IFDs). Methods: The clinical courses of 15 patients with pediatric malignancies and IFDs treated adjunctively with sargramostim at a single institution were analyzed in a retrospective cohort review. Further, a systematic review of published reports of rhu GM-CSF for IFDs was also conducted. Results: Among 65 cases, 15 were newly described pediatric patients and 50 were previously published cases of IFDs treated with rhu GM-CSF. Among the newly reported pediatric patients, IFDs were caused by Candida spp., Trichosporon sp., and molds (Aspergillus spp., Rhizopus sp., Lichtheimia sp., and Scedosporium sp). Twelve (80%) were neutropenic at baseline, and 12 (80%) were refractory to antifungal therapy. Among 12 evaluable patients, the overall response rate was 92% (8 [67%] complete responses, 3 [25%] partial responses, and 1 [8%] stable). Treatment is ongoing in the remaining 3 patients. Among 50 published cases (15 Candida spp., 13 Mucorales, 11 Aspergillus spp., 11 other organisms), 20 (40%) had baseline neutropenia and 36 (72%) were refractory to standard therapy before rhu GM-CSF administration. Consistent with responses in the newly reported patients, the overall response rate in the literature review was 82% (40 [80%] complete responses, 1 [2%] partial response, and 9 [18%] no response). Conclusions: Sargramostim may be a potential adjunctive immunomodulator for selected patients with hematological malignancies and refractory IFDs.

Effectiveness of varicella vaccine in children infected with HIV.

Although varicella vaccine is given to clinically stable human immunodeficiency virus (HIV)-infected children, its effectiveness is unknown. We assessed its effectiveness by reviewing the medical records of closely monitored HIV-infected children, including those receiving highly active antiretroviral therapy (HAART) between 1989 and 2007. Varicella immunization and development of varicella or herpes zoster were noted. Effectiveness was calculated by subtracting from 1 the rate ratios for the incidence rates of varicella or herpes zoster in vaccinated versus unvaccinated children. The effectiveness of the vaccine was 82% (95% confidence interval [CI], 24%-99%; P = .01) against varicella and was 100% (95% CI, 67%-100%; P < .001) against herpes zoster. When the analysis was controlled for receipt of HAART, vaccination remained highly protective against herpes zoster.

Occupational Safety of Municipal Police Officers: Assessing the Vulnerability and Riskiness of Police Officers' Work.

The municipal police agencies increase the safety of a municipality's citizens and thus increase their quality of life. When performing interventions, municipal police officers may endanger their safety and health. This paper deals with the analysis of the riskiness of municipal police officers working in the Slovak Republic and the Czech Republic from 2004 to 2019 and the assessment of their occupational safety. The risk analysis was carried out on the basis of a risk matrix and calculations of the probability of attack and injury to municipal police officers. Using the Pearson correlation coefficient, the dependence between the selected variables was investigated. The reliability of this dependence was examined by the determination coefficient. The main result of the paper is the determination of the riskiness category of municipal police officer work based on the assessment of the occupational health protection of officers through statistical indicators of their activities and risk matrix. The results will serve as part of the explanatory memorandum for the proposal of legislative changes in order to increase the occupational health protection of municipal police officers.

White matter of perinatally HIV infected older youths shows low frequency fluctuations that may reflect glial cycling.

In perinatally HIV-infected (PHIV) children, neurodevelopment occurs in the presence of HIV-infection, and even with combination antiretroviral therapy (cART) the brain can be a reservoir for latent HIV. Consequently, patients often demonstrate long-term cognitive deficits and developmental delay, which may be reflected in altered functional brain activity. Our objective was to examine brain function in PHIV on cART by quantifying the amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo). Further, we studied ALFF and ReHo changes with neuropsychological performance and measures of immune health including CD4 count and viral loads in the HIV-infected youths. We found higher ALFF and ReHo in cerebral white matter in the medial orbital lobe for PHIV (N = 11, age mean ± sd = 22.5 ± 2.9 years) compared to controls (N = 16, age = 22.5 ± 3.0 years), with age and gender as co-variates. Bilateral cerebral white matter showed increased spontaneous regional activity in PHIV compared to healthy controls. No brain regions showed lower ALFF or ReHo in PHIV compared to controls. Higher log10 viral load was associated with higher ALFF and ReHo in PHIV in bilateral cerebral white matter and right cerebral white matter respectively after masking the outcomes intrinsic to the brain regions that showed significantly higher ALFF and ReHo in the PHIV compared to the control. Reductions in social cognition and abstract thinking in PHIV were correlated with higher ALFF at the left cerebral white matter in the left medial orbital gyrus and higher ReHo at the right cerebral white matter in the PHIV patients. Although neuroinflammation and associated neuro repair were not directly measured, the findings support their potential role in PHIV impacting neurodevelopment and cognition.

Infliximab versus second intravenous immunoglobulin for treatment of resistant Kawasaki disease in the USA (KIDCARE): a randomised, multicentre comparative effectiveness trial.

BACKGROUND: Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease, 10-20% of patients have recrudescent fever as a sign of persistent inflammation and require additional treatment. We aimed to compare infliximab with a second infusion of IVIG for treatment of resistant Kawasaki disease. METHODS: In this multicentre comparative effectiveness trial, patients (aged 4 weeks to 17 years) with IVIG resistant Kawasaki disease and fever at least 36 h after completion of their first IVIG infusion were recruited from 30 hospitals across the USA. Patients were randomly assigned (1:1) to second IVIG (2 g/kg over 8-12 h) or intravenous infliximab (10 mg/kg over 2 h without premedication), by using a randomly permuted block randomisation design with block size of two or four. Patients with fever 24 h to 7 days following completion of first study treatment crossed over to receive the other study treatment. The primary outcome measure was resolution of fever at 24 h after initiation of study treatment with no recurrence of fever attributed to Kawasaki disease within 7 days post-discharge. Secondary outcome measures included duration of fever from enrolment, duration of hospitalisation after randomisation, and changes in markers of inflammation and coronary artery Z score. Efficacy was analysed in participants who received treatment and had available outcome values. Safety was analysed in all randomised patients who did not withdraw consent. This clinical trial is registered with ClinicalTrials.gov, NCT03065244. FINDINGS: Between March 1, 2017, and Aug 31, 2020, 105 patients were randomly assigned to treatment and 103 were included in the intention-to-treat population (54 in the infliximab group, 49 in the second IVIG group). Two patients randomised to infliximab did not receive allocated treatment. The primary outcome was met by 40 (77%) of 52 patients in the infliximab group and 25 (51%) of 49 patients in the second IVIG infusion group (odds ratio 0·31, 95% CI 0·13-0·73, p=0·0076). 31 patients with fever beyond 24 h received crossover treatment: nine (17%) in the infliximab group received second IVIG and 22 (45%) in second IVIG group received infliximab (p=0·0024). Three patients randomly assigned to infliximab and two to second IVIG with fever beyond 24h did not receive crossover treatment. Mean fever days from enrolment was 1·5 (SD 1·4) for the infliximab group and 2·5 (2·5) for the second IVIG group (p=0·014). Mean hospital stay was 3·2 days (2·1) for the infliximab group and 4·5 days (2·5) for the second IVIG group (p<0·001). There was no difference between treatment groups for markers of inflammation or coronary artery outcome. 24 (44%) of 54 patients in the infliximab group and 33 (67%) of 49 in the second IVIG group had at least one adverse event. A drop in haemoglobin concentration of at least 2g/dL was seen in 19 (33%) of 58 patients who received IVIG as either their first or second study treatment (three of whom required transfusion) and in three (7%) of 43 who received only infliximab (none required transfusion; p=0·0028). Haemolytic anaemia was the only serious adverse events deemed definitely or probably related to study treatment, and was reported in nine (15%) of 58 patients who received IVIG as either their first or second study treatment and none who received infliximab only. INTERPRETATION: Infliximab is a safe, well tolerated, and effective treatment for patients with IVIG resistant Kawasaki disease, and results in shorter duration of fever, reduced need for additional therapy, less severe anaemia, and shorter hospitalisation compared with second IVIG infusion. FUNDING: Patient Centered Outcomes Research Institute.