Uncovering the hidden effects of repetitive subconcussive head impact exposure: A mega-analytic approach characterizing seasonal brain microstructural changes in contact and collision sports athletes.

Repetitive subconcussive head impacts (RSHI) are believed to induce sub-clinical brain injuries, potentially resulting in cumulative, long-term brain alterations. This study explores patterns of longitudinal brain white matter changes across sports with RSHI-exposure. A systematic literature search identified 22 datasets with longitudinal diffusion magnetic resonance imaging data. Four datasets were centrally pooled to perform uniform quality control and data preprocessing. A total of 131 non-concussed active athletes (American football, rugby, ice hockey; mean age: 20.06 ± 2.06 years) with baseline and post-season data were included. Nonparametric permutation inference (one-sample t tests, one-sided) was applied to analyze the difference maps of multiple diffusion parameters. The analyses revealed widespread lateralized patterns of sports-season-related increases and decreases in mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) across spatially distinct white matter regions. Increases were shown across one MD-cluster (3195 voxels; mean change: 2.34%), one AD-cluster (5740 voxels; mean change: 1.75%), and three RD-clusters (817 total voxels; mean change: 3.11 to 4.70%). Decreases were shown across two MD-clusters (1637 total voxels; mean change: -1.43 to -1.48%), two RD-clusters (1240 total voxels; mean change: -1.92 to -1.93%), and one AD-cluster (724 voxels; mean change: -1.28%). The resulting pattern implies the presence of strain-induced injuries in central and brainstem regions, with comparatively milder physical exercise-induced effects across frontal and superior regions of the left hemisphere, which need further investigation. This article highlights key considerations that need to be addressed in future work to enhance our understanding of the nature of observed white matter changes, improve the comparability of findings across studies, and promote data pooling initiatives to allow more detailed investigations (e.g., exploring sex- and sport-specific effects).

Clinically contextualised ECG interpretation: the impact of prior clinical exposure and case vignettes on ECG diagnostic accuracy.

BACKGROUND: ECGs are often taught without clinical context. However, in the clinical setting, ECGs are rarely interpreted without knowing the clinical presentation. We aimed to determine whether ECG diagnostic accuracy was influenced by knowledge of the clinical context and/or prior clinical exposure to the ECG diagnosis. METHODS: Fourth- (junior) and sixth-year (senior) medical students, as well as medical residents were invited to complete two multiple-choice question (MCQ) tests and a survey. Test 1 comprised 25 ECGs without case vignettes. Test 2, completed immediately thereafter, comprised the same 25 ECGs and MCQs, but with case vignettes for each ECG. Subsequently, participants indicated in the survey when last, during prior clinical clerkships, they have seen each of the 25 conditions tested. Eligible participants completed both tests and survey. We estimated that a minimum sample size of 165 participants would provide 80% power to detect a mean difference of 7% in test scores, considering a type 1 error of 5%. RESULTS: This study comprised 176 participants (67 [38.1%] junior students, 55 [31.3%] senior students, 54 [30.7%] residents). Prior ECG exposure depended on their level of training, i.e., junior students were exposed to 52% of the conditions tested, senior students 63.4% and residents 96.9%. Overall, there was a marginal improvement in ECG diagnostic accuracy when the clinical context was known (Cohen's d = 0.35, p < 0.001). Gains in diagnostic accuracy were more pronounced amongst residents (Cohen's d = 0.59, p < 0.001), than senior (Cohen's d = 0.38, p < 0.001) or junior students (Cohen's d = 0.29, p < 0.001). All participants were more likely to make a correct ECG diagnosis if they reported having seen the condition during prior clinical training, whether they were provided with a case vignette (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.24-1.71) or not (OR 1.58, 95% CI 1.35-1.84). CONCLUSION: ECG interpretation using clinical vignettes devoid of real patient experiences does not appear to have as great an impact on ECG diagnostic accuracy as prior clinical exposure. However, exposure to ECGs during clinical training is largely opportunistic and haphazard. ECG training should therefore not rely on experiential learning alone, but instead be supplemented by other formal methods of instruction.

Effectiveness of blended learning versus lectures alone on ECG analysis and interpretation by medical students.

BACKGROUND: Most medical students lack confidence and are unable to accurately interpret ECGs. Thus, better methods of ECG instruction are being sought. Current literature indicates that the use of e-learning for ECG analysis and interpretation skills (ECG competence) is not superior to lecture-based teaching. We aimed to assess whether blended learning (lectures supplemented with the use of a web application) resulted in better acquisition and retention of ECG competence in medical students, compared to conventional teaching (lectures alone). METHODS: Two cohorts of fourth-year medical students were studied prospectively. The conventional teaching cohort (n = 67) attended 4 hours of interactive lectures, covering the basic principles of Electrocardiography, waveform abnormalities and arrhythmias. In addition to attending the same lectures, the blended learning cohort (n = 64) used a web application that facilitated deliberate practice of systematic ECG analysis and interpretation, with immediate feedback. All participants completed three tests: pre-intervention (assessing baseline ECG competence at start of clinical clerkship), immediate post-intervention (assessing acquisition of ECG competence at end of six-week clinical clerkship) and delayed post-intervention (assessing retention of ECG competence 6 months after clinical clerkship, without any further ECG training). Diagnostic accuracy and uncertainty were assessed in each test. RESULTS: The pre-intervention test scores were similar for blended learning and conventional teaching cohorts (mean 31.02 ± 13.19% versus 31.23 ± 11.52% respectively, p = 0.917). While all students demonstrated meaningful improvement in ECG competence after teaching, blended learning was associated with significantly better scores, compared to conventional teaching, in immediate (75.27 ± 16.22% vs 50.27 ± 17.10%, p <  0.001; Cohen's d = 1.58), and delayed post-intervention tests (57.70 ± 18.54% vs 37.63 ± 16.35%, p <  0.001; Cohen's d = 1.25). Although diagnostic uncertainty decreased after ECG training in both cohorts, blended learning was associated with better confidence in ECG analysis and interpretation. CONCLUSION: Blended learning achieved significantly better levels of ECG competence and confidence amongst medical students than conventional ECG teaching did. Although medical students underwent significant attrition of ECG competence without ongoing training, blended learning also resulted in better retention of ECG competence than conventional teaching. Web applications encouraging a stepwise approach to ECG analysis and enabling deliberate practice with feedback may, therefore, be a useful adjunct to lectures for teaching Electrocardiography.

Determining electrocardiography training priorities for medical students using a modified Delphi method.

BACKGROUND: Although electrocardiography is considered a core learning outcome for medical students, there is currently little curricular guidance for undergraduate ECG training. Owing to the absence of expert consensus on undergraduate ECG teaching, curricular content is subject to individual opinion. The aim of this modified Delphi study was to establish expert consensus amongst content and context experts on an ECG curriculum for medical students. METHODS: The Delphi technique, an established method of obtaining consensus, was used to develop an undergraduate ECG curriculum. Specialists involved in ECG teaching were invited to complete three rounds of online surveys. An undergraduate ECG curriculum was formulated from the topics of ECG instruction for which consensus (i.e. ≥75% agreement) was achieved. RESULTS: The panellists (n = 131) had a wide range of expertise (42.8% Internal Medicine, 22.9% Cardiology, 16% Family Medicine, 13.7% Emergency Medicine and 4.6% Health Professions Education). Topics that reached consensus to be included in the undergraduate ECG curriculum were classified under technical aspects of performing ECGs, basic ECG analysis, recognition of the normal ECG and abnormal rhythms and waveforms and using electrocardiography as part of a clinical diagnosis. This study emphasises that ECG teaching should be framed within the clinical context. Course conveners should not overload students with complex and voluminous content, but rather focus on commonly encountered and life-threatening conditions, where accurate diagnosis impacts on patient outcome. A list of 23 "must know" ECG diagnoses is therefore proposed. CONCLUSION: A multidisciplinary expert panel reached consensus on the ECG training priorities for medical students.

Improved Treatment Outcomes With Bedaquiline When Substituted for Second-line Injectable Agents in Multidrug-resistant Tuberculosis: A Retrospective Cohort Study.

BACKGROUND: Bedaquiline is used as a substitute for second-line injectable (SLI) intolerance in the treatment of multidrug-resistant (MDR) tuberculosis, but the efficacy and safety of this strategy is unknown. METHODS: In this retrospective cohort study adults receiving bedaquiline substitution for MDR tuberculosis therapy, plus a matched control group who did not receive bedaquiline, were identified from the electronic tuberculosis register in the Western Cape Province, South Africa. The primary outcome measure was the proportion of patients with death, loss to follow-up, or failure to achieve sustained culture conversion at 12 months of treatment. RESULTS: Data from 162 patients who received bedaquiline substitution and 168 controls were analyzed; 70.6% were infected with human immunodeficiency virus. Unfavorable outcomes occurred in 35 of 146 (23.9%) patients in the bedaquiline group versus 51 of 141 (36.2%) in the control group (relative risk, 0.66; 95% confidence interval, .46 -.95). The number of patients with culture reversion was lower in those receiving bedaquiline (1 patient; 0.8%) than in controls (12 patients; 10.3%; P = .001). Delayed initiation of bedaquiline was independently associated with failure to achieve sustained culture conversion (adjusted odds ratio for every 30-day delay, 1.5; 95% confidence interval, 1.1-1.9). Mortality rates were similar at 12 months (11 deaths in each group; P = .97). CONCLUSIONS: Substituting bedaquiline for SLIs in MDR tuberculosis treatment resulted in improved outcomes at 12 months compared with patients who continued taking SLIs, supporting the use of bedaquiline for MDR tuberculosis treatment in programmatic settings.

Granulomatous interstitial nephritis on renal biopsy in human immunodeficiency virus positive patients: Prevalence and causes in Cape Town, South Africa.

South Africa continues to be burdened by human immunodeficiency virus (HIV) and tuberculosis (TB). In Cape Town, the epidemic of HIV-TB co-infection is as high as 70%. Granulomatous interstitial nephritis (GIN) has increased in frequency on renal biopsy. This study aimed to determine GIN prevalence and causes in HIV-positive patients as well as renal outcomes, patient survival and associated factors. This observational cohort study reviewed HIV-positive renal biopsies for GIN from 2005 to 2012. Causes of GIN (medications, TB, fungal and other), and baseline characteristics were analysed. A comparison of baseline data, renal function and survival was made between GIN and non-GIN cohorts. There were 45/316 biopsies demonstrating GIN. TB was the likely cause of GIN in 27 (60%) and 9 (20%) were due to a drug. Low estimated glomerular filtration rate was a statistically significant factor associated with mortality in both GIN (P = 0.045) and non-GIN cohorts (P < 0.000). In the GIN group, there were 12 (26.7%) deaths. Mortality for all patients was greatest in the first 6 months (P = 0.057). TB co-infection in both cohorts was associated with a higher mortality. The multivariate logistic regression demonstrated that a higher urine protein/creatinine ratio (uPCR) and lower estimated glomerular filtration rate were statistically associated with death. GIN is common in HIV-positive renal biopsies in Cape Town. TB-GIN was the commonest cause and associated with a high early mortality. GIN should be considered in HIV-positive patients with acute kidney injury, its presence conveys a survival benefit. There is a need for improved diagnostic accuracy and treatment strategies of TB-GIN.

The effects of add-on corticosteroids on renal outcomes in patients with biopsy proven HIV associated nephropathy: a single centre study from South Africa.

BACKGROUND: The aim of this study was to assess, the efficacy and safety of add-on corticosteroids to antiretroviral therapy [ART] in patients with biopsy proven HIV associated nephropathy. METHODS: All included patients had histological evidence of either collapsing or non-collapsing focal segmental glomerulosclerosis (FSGS) or podocyte and/or parietal cell hypertrophy or hyperplasia. All patients had evidence of tubulointerstitial inflammation with microcysts. Patients were randomized to ART with the addition of 1 mg/kg of corticosteroids [ART+C] or remained in the group [ART Alone] and followed for 2 years. A repeat biopsy was performed at 6 months. RESULTS: Twenty-one patients were randomized to [ART+C] and 17 to [ART Alone]. The baseline estimated glomerular filtration rate (eGFR) was significantly lower in the [ART+C] vs. [ART Alone] group [35mls/min/1.73m2 vs. 47 mls/min/1.73m2, p = 0.015]. The [ART+C] cohort had a statistically significant improvement in median (eGFR) from baseline to last follow up compared with [ART Alone] i.e. [Δ = 25mls/min (IQR: 15;51) vs 9 mls/min (IQR: 0-24), p = 0.008]. There were no statistically significant differences between the groups when proteinuria and histology were analyzed. There were 8 deaths during the trial period, 7 from [ART+C] (Log rank p = 0.071). CONCLUSIONS: In the [ART+C] cohort there was a significant improvement in eGFR over 2-years with increased mortality. Routine corticosteroid use cannot currently be recommended. Further investigation to define which subgroup of this cohort would safely benefit from the positive effects is required. TRIAL REGISTRATION: ISRCTN study ID ( 56112439 ] was retrospectively registered on the 5 September 2018.

Reduced brain glutamine in female varsity rugby athletes after concussion and in non-concussed athletes after a season of play.

The purpose of this study was to use non-invasive proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) to monitor changes in prefrontal white matter metabolite levels and tissue microstructure in female rugby players with and without concussion (ages 18-23, n = 64). Evaluations including clinical tests and 3 T MRI were performed at the beginning of a season (in-season) and followed up at the end of the season (off-season). Concussed athletes were additionally evaluated 24-72 hr (n = 14), three months (n = 11), and six months (n = 8) post-concussion. Reduced glutamine at 24-72 hr and three months post-concussion, and reduced glutamine/creatine at three months post-concussion were observed. In non-concussed athletes (n = 46) both glutamine and glutamine/creatine were lower in the off-season compared to in-season. Within the MRS voxel, an increase in fractional anisotropy (FA) and decrease in radial diffusivity (RD) were also observed in the non-concussed athletes, and correlated with changes in glutamine and glutamine/creatine. Decreases in glutamine and glutamine/creatine suggest reduced oxidative metabolism. Changes in FA and RD may indicate neuroinflammation or re-myelination. The observed changes did not correlate with clinical test scores suggesting these imaging metrics may be more sensitive to brain injury and could aid in assessing recovery of brain injury from concussion.

Factors associated with loss to follow-up after occupational HIV exposure in Cape Town, South Africa: a retrospective cohort study.

BACKGROUND: There is limited data on factors associated with loss to follow-up (LTFU) of health care workers (HCWs) following occupational exposure to HIV, and most studies were conducted in an era when poorly tolerated antiretrovirals like zidovudine were used. METHODS: A retrospective cohort study was conducted of HCWs attending a referral hospital's Occupational Health Clinic in Cape Town, South Africa for post-exposure prophylaxis (PEP) during a period when tenofovir was available. Our primary outcome was LTFU at the 3-month visit. We selected seven variables a priori for our logistic regression model and ensured there were at least 10 outcome events per variable to minimize bias. RESULTS: Two hundred and ninety-three folders were evaluated for descriptive analysis. LTFU worsened with successive visits: 36% at 6 weeks, 60% at 3 months, and 72% at 6 months. In multivariate analysis at the 3-month visit LTFU was associated with age (adjusted odds ratio (aOR), 0.6 per 10-year increase [95% CI, 0.5-0.9]), HCW category of doctor (aOR 2.7 [95% CI, 1.3-5.5]), and time from exposure to receiving PEP of more than 24 h (aOR 5.9 [95% CI, 1.3-26.9]). CONCLUSION: We identified factors associated with LTFU of HCWs after occupational HIV exposure, which could be used to target interventions to improve follow-up.

Isoflurane induces dose-dependent alterations in the cortical connectivity profiles and dynamic properties of the brain's functional architecture.

Despite their widespread use, the effect of anesthetic agents on the brain's functional architecture remains poorly understood. This is particularly true of alterations that occur beyond the point of induced unconsciousness. Here, we examined the distributed intrinsic connectivity of macaques across six isoflurane levels using resting-state functional MRI (fMRI) following the loss of consciousness. The results from multiple analysis strategies showed stable functional connectivity (FC) patterns between 1.00% and 1.50% suggesting this as a suitable range for anesthetized nonhuman primate resting-state investigations. Dose-dependent effects were evident at moderate to high dosages showing substantial alteration of the functional topology and a decrease or complete loss of interhemispheric cortical FC strength including that of contralateral homologues. The assessment of dynamic FC patterns revealed that the functional repertoire of brain states is related to anesthesia depth and most strikingly, that the number of state transitions linearly decreases with increased isoflurane dosage. Taken together, the results indicate dose-specific spatial and temporal alterations of FC that occur beyond the typically defined endpoint of consciousness. Future work will be necessary to determine how these findings generalize across anesthetic types and extend to the transition between consciousness and unconsciousness.

Mechanism and inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase.

The non-mevalonate or 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway is responsible for generating isoprenoid precursors in plants, protozoa, and bacteria. Because this pathway is absent in humans, its enzymes represent potential targets for the development of herbicides and antibiotics. 1-Deoxy-d-xylulose (DXP) reductoisomerase (DXR) is a particularly attractive target that catalyzes the pathway's first committed step: the sequential isomerization and NADPH-dependent reduction of DXP to MEP. This article provides a comprehensive review of the mechanistic and structural investigations on DXR, including its discovery and validation as a drug target, elucidation of its chemical and kinetic mechanisms, characterization of inhibition by the natural antibiotic fosmidomycin, and identification of structural features that provide the molecular basis for inhibition of and catalysis.

Windows of Opportunity: How Age and Sex Shape the Influence of Prenatal Depression on the Child Brain.

Maternal prenatal depression can affect child brain and behavioral development. Specifically, altered limbic network structure and function is a likely mechanism through which prenatal depression impacts the life-long mental health of exposed children. While developmental trajectories are influenced by many factors that exacerbate risk or promote resiliency, the role of child age and sex in the relationship between prenatal depression and the child brain remains unclear. Here, we review studies of associations between prenatal depression and brain structure and function, with a focus on the role of age and sex in these relationships. After exposure to maternal prenatal depression, altered amygdala, hippocampal, and frontal cortical structure, as well as changes in functional and structural connectivity within the limbic network, are evident during the fetal, infant, preschool, childhood, and adolescent stages of development. Sex appears to play a key role in this relationship, with evidence of differential findings particularly in infants, with males showing smaller and females larger hippocampal and amygdala volumes following prenatal depression. Longitudinal studies in this area have only begun to emerge within the last 5 years and will be key to understanding critical windows of opportunity. Future research focused on the role of age and sex in this relationship is essential to further inform screening, policy, and interventions for children exposed to prenatal depression, interrupt the intergenerational transmission of depression, and ultimately support healthy brain development.

Prenatal depressive symptoms are associated with altered structural brain networks in infants and moderated by infant sleep.

BACKGROUND: The prevalence of prenatal depressive symptoms has more than doubled during the COVID-19 pandemic, raising substantial concerns about child outcomes including sleep problems and altered brain development. The objective of this work was to determine relationships between prenatal depressive symptoms, infant brain network structure, and infant sleep. METHODS: Pregnant individuals were recruited as part of the Pregnancy during the Pandemic (PdP) study. Maternal depressive symptoms were measured in pregnancy and postpartum. When infants of those participants were 3 months of age (n=66; 26 females), infants underwent diffusion magnetic resonance imaging and infant sleep was evaluated. Using tractography, we calculated structural connectivity matrices for the default mode (DMN) and limbic networks. We examined associations between graph theory metrics of infant brain networks and prenatal maternal depressive symptoms, with infant sleep as a moderator. RESULTS: Prenatal depressive symptoms were negatively related to average DMN clustering coefficient and local efficiency in infant brains. Infant sleep duration was related to DMN global efficiency and moderated the relationship between prenatal depressive symptoms and density of limbic connections such that infants who slept less had a more negative relationship between prenatal depressive symptoms and local brain connectivity. CONCLUSIONS: Prenatal depressive symptoms appear to impact early topological development in brain networks important for emotion regulation. In the limbic network, sleep duration moderated this relationship, suggesting sleep may play a role in infant brain network development.

The Evolving Spectrum of Kidney Histology in HIV-Positive Patients in South Africa.

Introduction: Sub-Saharan Africa remains challenged by the highest burden of human immunodeficiency virus (HIV), an epidemic of tuberculosis (TB), and increasing number of people with HIV (PWH) on antiretroviral therapy (ART), all of which may result in kidney injury. Methods: This observational cohort study describes the spectrum of kidney disease in PWH in South Africa, between 2005 and 2020. Kidney biopsies were analyzed in 4 time periods as follows: early ART rollout (2005-2009), tenofovir disoproxil (TDF) introduction (2010-2012), TDF-based fixed dose combination (2013-2015), and ART at HIV diagnosis (2016-2020). Logistic regression was used to identify factors associated with HIV-associated nephropathy or focal segmental glomerulosclerosis (HIVAN/FSGS) and tubulointerstitial disease (TID). Results: We included 671 participants (median age 36, interquartile range, 21-44 years; 49% female; median CD4 cell count 162 [interquartile range, 63-345] cells/mm3). Over time, ART (31%-65%, P < 0.001), rate of HIV suppression (20%-43%, P < 0.001), nonelective biopsies (53%-72%, P < 0.001), and creatinine at biopsy (242-449 µmol/l, P < 0.001) increased. A decrease in HIVAN (45%-29% P < 0.001) was accompanied by an increase in TID (13%-33%, P < 0.001). Granulomatous interstitial nephritis accounted for 48% of TID, mostly because of TB. Exposure to TDF was strongly associated with TID (adjusted odds ratio 2.99, 95% confidence interval 1.89-4.73 P < 0.001). Conclusion: As ART programs intensified and increasingly used TDF, the spectrum of kidney histology in PWH evolved from a predominance of HIVAN in the early ART era to TID in recent times. The increase in TID is likely due to multiple exposures that include TB, sepsis, and TDF as well as other insults.

Outcomes of patients undergoing lung resection for drug-resistant TB and the prognostic significance of pre-operative positron emission tomography/computed tomography (PET/CT) in predicting treatment failure.

Background: Surgery remains an adjunctive treatment for drug-resistant tuberculosis (DR-TB) treatment failure despite the use of bedaquiline. However, there are few data about the role of surgery when combined with newer drugs. There are no outcome data from TB endemic countries, and the prognostic significance of pre-operative PET-CT remains unknown. Methods: We performed a prospective observational study of 57 DR-TB patients referred for surgery at Groote Schuur Hospital between 2010 and 2016. PET-CT was performed if there was nodal disease or disease outside the area of planned resection but did not influence treatment decisions. 24-month treatment success post-surgery (cure or treatment completion), including all-cause mortality, was determined. Findings: 35/57 (61.4%) patients (median age 40 years; 26% HIV-infected) underwent surgery and 22/57 (38.6%) did not (11 patients were deemed unsuitable due to bilateral cavitary disease and 11 patients declined surgery). Treatment failure was significantly lower in those who underwent surgery compared to those eligible but declined surgery [15/35 (43%) versus 11/11 (100%); relative risk 0.57 (0.42-0.76); p < 0.01). In patients treated with surgery, a post-operative regimen containing bedaquiline was associated with a lower odds of treatment failure [OR (95%CI) 0.06 (0.00-0.48); p = 0.007]. Pre-operative PET-CT (n = 25) did not predict treatment outcome. Interpretation: Resectional surgery for DR-TB combined with chemotherapy was associated with significantly better outcomes than chemotherapy alone. A post-operative bedaquiline-containing regimen was associated with improved outcome; however, this finding may have been confounded by higher use of bedaquiline and less loss to follow-up in the surgical group. However, PET-CT had no prognostic value. These data inform clinical practice in TB-endemic settings. Funding: This work was supported by the South African MRC (RFA-EMU-02-2017) and the EDCTP (TMA-2015SF-1043 & TMA- 1051-TESAII).

Highly precise measurement of kinetic isotope effects using 1H-detected 2D [13C,1H]-HSQC NMR spectroscopy.

A new method is presented for measuring kinetic isotope effects (KIEs) by (1)H-detected 2D [(13)C,(1)H]-heteronuclear single quantum coherence (HSQC) NMR spectroscopy. The high accuracy of this approach was exemplified for the reaction catalyzed by glucose-6-phosphate dehydrogenase by comparing the 1-(13)C KIE with the published value obtained using isotope ratio mass spectrometry. High precision was demonstrated for the reaction catalyzed by 1-deoxy-D-xylulose-5-phosphate reductoisomerase from Mycobacterium tuberculosis. 2-, 3-, and 4-(13)C KIEs were found to be 1.0031(4), 1.0303(12), and 1.0148(2), respectively. These KIEs provide evidence for a cleanly rate-limiting retroaldol step during isomerization. The high intrinsic sensitivity and signal dispersion of 2D [(13)C,(1)H]-HSQC offer new avenues to study challenging systems where low substrate concentration and/or signal overlap impedes 1D (13)C NMR data acquisition. Moreover, this approach can take advantage of highest-field spectrometers, which are commonly equipped for (1)H detection with cryogenic probes.

The use of brachiobasilic arteriovenous fistulae for haemodialysis: a single-centre descriptive study.

AIM: The main aim of the study was to report on our local experience with the use of brachiobasilic arteriovenous fistulae (BBAVF) and to encourage wider local acceptance of the procedure in accordance with international guidelines. The primary aim was to report on access patency. The secondary aims were to report on functional outcomes and complications. METHODS: This was a retrospective, descriptive study of 41 consecutive haemodialysis patients who underwent BBAVF creation. RESULTS: The primary patency rates at 30 days, and one and three years were 95.1, 48.8 and 19.5%, respectively. Assisted primary patency rates at 30 days, and one and three years were 100, 67.7 and 24.3%, respectively. Secondary patency rates at 30 days, and one and three years were 100, 70.3 and 27%, respectively. CONCLUSION: BBAVF creation can successfully be performed in a resource-constrained environment by surgeons with limited prior experience with the technique. However, careful monitoring, well-established referral pathways for dysfunctional fistulae and access to surgical and endovascular revision seem to be key factors in ensuring long-term patency.

Multimodal brain features at 3 years of age and their relationship with pre-reading measures 1 year later.

Pre-reading language skills develop rapidly in early childhood and are related to brain structure and functional architecture in young children prior to formal education. However, the early neurobiological development that supports these skills is not well understood. Here we acquired anatomical, diffusion tensor imaging (DTI) and resting state functional MRI (rs-fMRI) from 35 children at 3.5 years of age. Children were assessed for pre-reading abilities using the NEPSY-II subtests 1 year later (4.5 years). We applied a data-driven linked independent component analysis (ICA) to explore the shared co-variation of gray and white matter measures. Two sources of structural variation at 3.5 years of age demonstrated relationships with Speeded Naming scores at 4.5 years of age. The first imaging component involved volumetric variability in reading-related cortical regions alongside microstructural features of the superior longitudinal fasciculus (SLF). The second component was dominated by cortical volumetric variations within the cerebellum and visual association area. In a subset of children with rs-fMRI data, we evaluated the inter-network functional connectivity of the left-lateralized fronto-parietal language network (FPL) and its relationship with pre-reading measures. Higher functional connectivity between the FPL and the default mode and visual networks at 3.5 years significantly predicted better Phonological Processing scores at 4.5 years. Together, these results suggest that the integration of functional networks, as well as the co-development of white and gray matter brain structures in early childhood, support the emergence of pre-reading measures in preschool children.

Retrospective Review of ART Regimens in HIV-Positive to HIV-Positive Kidney Transplant Recipients.

Introduction: The management of complex interactions between antiretroviral therapy (ART) and calcineurin inhibitor (CNI) immunosuppression regimens in HIV-positive to HIV-positive renal transplant recipients can be challenging. Literature describing ART regimens and indications for regimen switching in these patients is limited. Methods: This retrospective review included 53 HIV-positive to HIV-positive renal transplant recipients. Data on ART regimens, reasons for ART switching, and timing of switches were described from day of transplant to study endpoint (end of study date, death, or graft failure). The association between rejection and ART regimen (protease inhibitor [PI] -based vs. non-PI-based regimen) was analyzed using negative binomial regression. Results: There were a total of 46 switches in 31 of 53 patients (58%). Protocol switches (n = 17 of 46, 37%) accounted for most switches, of which the majority were from non-nucleoside reverse transcriptase inhibitors (NNRTIs) to PIs. Other common reasons for switching include cytochrome P450 enzyme induction from efavirenz (EFV) (9 of 46, 20%), tenofovir disoproxil fumarate (TDF) nephrotoxicity (8 of 46, 17%) or side effects (6 of 46, 13%). Of the 46 switches, nearly half (n = 21, 46%) occurred during the transplant admission period, and approximately two-thirds (n = 28, 62%) were during the first year post-transplantation. There was an association between rejection and being maintained on a PI-based regimen (incidence rate ratio 2.77 (95% confidence interval 1.03-7.48), P = 0.044). Conclusion: Despite frequent switching of ART regimens, HIV viral loads remained supressed and graft function remained stable in most HIV-positive kidney transplant recipients in our cohort. There was however a concerning signal for increased rejection rates in those on a PI-based regimen.