Anemia and Iron Supplementation in Relation to Viral Load and Mortality among 70,442 People Living with Human Immunodeficiency Virus in Tanzania.

BACKGROUND: Anemia may be associated with poor clinical outcomes among people living with human immunodeficiency virus (HIV) (PLHIV) despite highly active antiretroviral therapy (HAART). There are concerns that iron supplementation may be unsafe to prevent and treat anemia among PLHIV. OBJECTIVE: The objective of the study was to evaluate the associations of anemia and iron supplementation with mortality and viral load among PLHIV in Tanzania. METHODS: We analyzed data from a cohort of 70,442 nonpregnant adult PLHIV in Tanzania conducted between 2015 and 2019. Regression models evaluated the relationships between anemia severity and iron supplement use with mortality and unsuppressed HIV-1 viral load among all participants and stratified by whether participants were initiating or continuing HAART. RESULTS: Anemia was associated with an increased risk of mortality and unsuppressed viral load for participants who initiated or continued HAART. Iron supplement use was associated with reduced mortality risk but also had a greater risk of an unsuppressed viral load among participants continuing HAART. There was no association of iron supplement use with mortality, and unsuppressed viral load among PLHIV that were initiating HAART. There was a stronger negative association between iron supplement use and the risk of having an unsuppressed viral load among participants with stage III/IV disease compared with stage I/II disease. CONCLUSIONS: Anemia is associated with increased risk of mortality and unsuppressed viral load, but the benefits and safety of iron supplements appear to differ for those initiating compared with continuing ART as well as by HIV disease severity.

Cardiology career satisfaction: a little academic activity goes a long way.

The professional landscape for clinical cardiologists and most physicians has changed dramatically in the last decade in the United States. By the end of 2020, 87% of cardiologists were integrated with a health system (employed or part of a professional services agreement). Physicians transitioning to a large employer are often dissatisfied with the lack of autonomy and the pressure from "one-size-fits-all" productivity targets. The results from physician surveys indicate that physicians practicing clinically in an academic environment have greater job satisfaction. Potentially even a modest amount of time comprising 10-20% of total effort spent on academic pursuits that are most meaningful to the individual physician can result in nearly a two-thirds lower risk of burnout compared with physicians who don't receive this time. The opportunity to participate in this special topic compendium by cardiovascular specialists at one regional integrated health system in the United States is an example of an opportunity to successfully incorporate meaningful professional academic opportunities into a clinical care environment.

Enhancing colistin efficacy against Salmonella infections with a quinazoline-based dual therapeutic strategy.

Colistin remains one of the last-resort therapies for combating infections caused by multidrug-resistant (MDR) Enterobacterales, despite its adverse nephro- and neuro-toxic effects. This study elucidates the mechanism of action of a non-antibiotic 4-anilinoquinazoline-based compound that synergistically enhances the effectiveness of colistin against Salmonella enterica. The quinazoline sensitizes Salmonella by deactivating intrinsic, mutational, and transferable resistance mechanisms that enable Salmonella to counteract the antibiotic impact colistin, together with an induced disruption to the electrochemical balance of the bacterial membrane. The attenuation of colistin resistance via the combined treatment approach also proves efficacious against E. coli, Klebsiella, and Acinetobacter strains. The dual therapy reduces the mortality of Galleria mellonella larvae undergoing a systemic Salmonella infection when compared to individual drug treatments. Overall, our findings unveil the potential of the quinazoline-colistin combined therapy as an innovative strategy against MDR bacteria.

Effects of gene dosage and development on subcortical nuclei volumes in individuals with 22q11.2 copy number variations.

The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in a total of 385 scans from 22qDel (n = 96, scans = 191, 53.1% female), 22qDup (n = 37, scans = 64, 45.9% female), and TD controls (n = 80, scans = 130, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the linear effects of 22q11.2 gene dosage and non-linear effects of age were characterized with generalized additive mixed models (GAMMs). Positive gene dosage effects (volume increasing with copy number) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age-related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

Perspective: Leveraging Electronic Health Record Data Within Food Is Medicine Program Evaluation: Considerations and Potential Paths Forward.

Government, health care systems and payers, philanthropic entities, advocacy groups, nonprofit organizations, community groups, and for-profit companies are presently making the case for Food is Medicine (FIM) nutrition programs to become reimbursable within health care services. FIM researchers are working urgently to build evidence for FIM programs' cost-effectiveness by showing improvements in health outcomes and health care utilization. However, primary collection of this data is costly, difficult to implement, and burdensome to participants. Electronic health records (EHRs) offer a promising alternative to primary data collection because they provide already-collected information from existing clinical care. A few FIM studies have leveraged EHRs to demonstrate positive impacts on biomarkers or health care utilization, but many FIM studies run into insurmountable difficulties in their attempts to use EHRs. The authors of this commentary serve as evaluators and/or technical assistance providers with the United States Department of Agriculture's Gus Schumacher Nutrition Incentive Program National Training, Technical Assistance, Evaluation, and Information Center. They work closely with over 100 Gus Schumacher Nutrition Incentive Program Produce Prescription FIM projects, which, as of 2023, span 34 US states and territories. In this commentary, we describe recurring challenges related to using EHRs in FIM evaluation, particularly in relation to biomarkers and health care utilization. We also outline potential opportunities and reasonable expectations for what can be learned from EHR data and describe other (non-EHR) data sources to consider for evaluation of long-term health outcomes and health care utilization. Large integrated health systems may be best positioned to use their own data to examine outcomes of interest to the broader field.

Annual mpMRI surveillance: PI-RADS upgrading and increasing trend correlated with patients who harbor clinically significant disease.

INTRODUCTION: Prostate cancer screening has routinely identified men with very low- or low-risk disease, per the National Comprehensive Cancer Network guidelines. Current literature has demonstrated that the most appropriate management strategy for these patients is active surveillance (AS). The mainstay of AS includes periodic biopsies and biannual prostate-specific antigen tests. However, multiparametric magnetic resonance imaging (mpMRI) is uniquely posed to improve patient surveillance. This study aimed to evaluate the utility of an annual mpMRI in patients on AS, focusing on radiologic upgrading and Prostate Imaging-Reporting and Data System (PI-RADS) trends as indicators of clinically significant disease. METHODS: This prospective, single intuition, study enrolled 208 patients on AS who had at least two biopsies and 1 mpMRI with a median follow-up of 5.03 years. The main outcome variable was time to Gleason grade (GG) reclassification. RESULTS: After delineating patients on their initial PI-RADS score, men with score 3 and 5 lesions at first MRI had comparable GG reclassification-free survival to their counterparts. Conversely, men with initial PI-RADS 4 lesions showed a lower 5-year GG reclassification-free survival compared to those with PI-RADS score 1-2. The cohort was then subset to 70 patients who obtained ≥2 mpMRIs on protocol. Men experiencing uptrending mpMRI scores had an increased risk of GG reclassification, with a 35.4% difference in 5 year GG reclassification-free survival probability on the Kaplan-Meier curve analysis. CONCLUSION: In conclusion, this study demonstrates that for men on AS with stable recapitulated disease, an annual MRI may replace repeat biopsies after confirmatory sampling has been obtained. On the other hand, men who initiate AS with PI-RADS 4 and/or who display uptrending mpMRI scores require periodic biopsies along with repeat imaging. This study highlights the utility of integrating an annual MRI into AS protocols, thus promising a more effective approach to management.

Nutritional Criminology: Why the Emerging Research on Ultra-Processed Food Matters to Health and Justice.

There is mounting concern over the potential harms associated with ultra-processed foods, including poor mental health and antisocial behavior. Cutting-edge research provides an enhanced understanding of biophysiological mechanisms, including microbiome pathways, and invites a historical reexamination of earlier work that investigated the relationship between nutrition and criminal behavior. Here, in this perspective article, we explore how this emergent research casts new light and greater significance on previous key observations. Despite expanding interest in the field dubbed 'nutritional psychiatry', there has been relatively little attention paid to its relevancy within criminology and the criminal justice system. Since public health practitioners, allied mental health professionals, and policymakers play key roles throughout criminal justice systems, a holistic perspective on both historical and emergent research is critical. While there are many questions to be resolved, the available evidence suggests that nutrition might be an underappreciated factor in prevention and treatment along the criminal justice spectrum. The intersection of nutrition and biopsychosocial health requires transdisciplinary discussions of power structures, industry influence, and marketing issues associated with widespread food and social inequalities. Some of these discussions are already occurring under the banner of 'food crime'. Given the vast societal implications, it is our contention that the subject of nutrition in the multidisciplinary field of criminology-referred to here as nutritional criminology-deserves increased scrutiny. Through combining historical findings and cutting-edge research, we aim to increase awareness of this topic among the broad readership of the journal, with the hopes of generating new hypotheses and collaborations.

"Food faddists and pseudoscientists!": Reflections on the history of resistance to ultra-processed foods.

The term 'ultra-processed food' emerged in the 1980s, mostly used in reference to highly-processed convenience foods and snacks, often energy-dense, poor in nutrients, and inclusive of various synthetic additives such as emulsifiers, colors, artificial sweeteners, and/or flavor enhancers. Concern over such foods was part of the growing holistic and environmental health movements of the 1970-80s; yet, those who raised alarm about the encroachment of ultra-processed foods were often labeled, especially by industry and their powerful allies, as 'food faddists' and 'pseudoscientists'. Today, the topic of ultra-processed foods is generating massive personal, public, and planetary health interest. However, other than discussing the history of the NOVA food classification system, a useful tool that has allowed researchers to more accurately separate foods based on processing, most lay media and academic articles are ahistorical. That is, there is a tendency to present the term ultra-processed food(s) as a relatively new entrance into the lexicon, and by default, the idea that health-related pushback on ultra-processed foods is a relatively new phenomenon. This omission overlooks decades of determined advocacy and clinical work, much of it by pioneers within the holistic medicine (now integrative, functional, and lifestyle medicine) movement. Here in this reflection paper, the authors will use historical research and reporting to fill in the historical gap and articulate the saliency of why it matters.

Elevated CO2 interacts with nutrient inputs to restructure plant communities in phosphorus-limited grasslands.

Globally pervasive increases in atmospheric CO2 and nitrogen (N) deposition could have substantial effects on plant communities, either directly or mediated by their interactions with soil nutrient limitation. While the direct consequences of N enrichment on plant communities are well documented, potential interactions with rising CO2 and globally widespread phosphorus (P) limitation remain poorly understood. We investigated the consequences of simultaneous elevated CO2 (eCO2 ) and N and P additions on grassland biodiversity, community and functional composition in P-limited grasslands. We exposed soil-turf monoliths from limestone and acidic grasslands that have received >25 years of N additions (3.5 and 14 g m-2 year-1 ) and 11 (limestone) or 25 (acidic) years of P additions (3.5 g m-2 year-1 ) to eCO2 (600 ppm) for 3 years. Across both grasslands, eCO2 , N and P additions significantly changed community composition. Limestone communities were more responsive to eCO2 and saw significant functional shifts resulting from eCO2 -nutrient interactions. Here, legume cover tripled in response to combined eCO2 and P additions, and combined eCO2 and N treatments shifted functional dominance from grasses to sedges. We suggest that eCO2 may disproportionately benefit P acquisition by sedges by subsidising the carbon cost of locally intense root exudation at the expense of co-occurring grasses. In contrast, the functional composition of the acidic grassland was insensitive to eCO2 and its interactions with nutrient additions. Greater diversity of P-acquisition strategies in the limestone grassland, combined with a more functionally even and diverse community, may contribute to the stronger responses compared to the acidic grassland. Our work suggests we may see large changes in the composition and biodiversity of P-limited grasslands in response to eCO2 and its interactions with nutrient loading, particularly where these contain a high diversity of P-acquisition strategies or developmentally young soils with sufficient bioavailable mineral P.

Thalamo-cortical evoked potentials during stimulation of the dentato-rubro-thalamic tract demonstrate synaptic filtering.

Essential tremor DBS targeting the ventral intermediate nucleus (Vim) of the thalamus and its input, the dentato-rubro-thalamic tract (DRTt), has proven to be an effective treatment strategy. We examined thalamo-cortical evoked potentials (TCEPs) and cortical dynamics during stimulation of the DRTt. We recorded TCEPs in primary motor cortex during clinical and supra-clinical stimulation of the DRTt in ten essential tremor patients. Stimulation was varied over pulse amplitude (2-10 â€‹mA) and pulse width (30-250 â€‹µs) to allow for strength-duration testing. Testing at clinical levels (3 â€‹mA, 60 â€‹µs) for stimulation frequencies of 1-160 â€‹Hz was performed and phase amplitude coupling (PAC) of beta phase and gamma power was calculated. Primary motor cortex TCEPs displayed two responses: early and all-or-none (<20 â€‹ms) or delayed and charge-dependent (>50 â€‹ms). Strength-duration curve approximation indicates that the chronaxie of the neural elements related to the TCEPs is <200 â€‹µs. At the range of clinical stimulation (amplitude 2-5 â€‹mA, pulse width 30-60 â€‹µs), TCEPs were not noted over primary motor cortex. Decreased pathophysiological phase-amplitude coupling was seen above 70 â€‹Hz stimulation without changes in power spectra and below the threshold of TCEPs. Our findings demonstrate that DRTt stimulation within normal clinical bounds does not excite fibers directly connected with primary motor cortex but that supra-clinical stimulation can excite a direct axonal tract. Both clinical efficacy and phase-amplitude coupling were frequency-dependent, favoring a synaptic filtering model as a possible mechanism of action.

Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy.

BACKGROUND: The World Health Organization recommends 1500 to 2000 mg of calcium daily as supplementation, divided into three doses, for pregnant persons in populations with low dietary calcium intake in order to reduce the risk of preeclampsia. The complexity of the dosing scheme, however, has led to implementation barriers. METHODS: We conducted two independent randomized trials of calcium supplementation, in India and Tanzania, to assess the noninferiority of a 500-mg daily dose to a 1500-mg daily dose of calcium supplementation. In each trial, the two primary outcomes were preeclampsia and preterm birth, and the noninferiority margins for the relative risks were 1.54 and 1.16, respectively. RESULTS: A total of 11,000 nulliparous pregnant women were included in each trial. The cumulative incidence of preeclampsia was 3.0% in the 500-mg group and 3.6% in the 1500-mg group in the India trial (relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03) and 3.0% and 2.7%, respectively, in the Tanzania trial (relative risk, 1.10; 95% CI, 0.88 to 1.36) - findings consistent with the noninferiority of the lower dose in both trials. The percentage of live births that were preterm was 11.4% in the 500-mg group and 12.8% in the 1500-mg group in the India trial (relative risk, 0.89; 95% CI, 0.80 to 0.98), which was within the noninferiority margin of 1.16; in the Tanzania trial, the respective percentages were 10.4% and 9.7% (relative risk, 1.07; 95% CI, 0.95 to 1.21), which exceeded the noninferiority margin. CONCLUSIONS: In these two trials, low-dose calcium supplementation was noninferior to high-dose calcium supplementation with respect to the risk of preeclampsia. It was noninferior with respect to the risk of preterm live birth in the trial in India but not in the trial in Tanzania. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03350516; Clinical Trials Registry-India number, CTRI/2018/02/012119; and Tanzania Medicines and Medical Devices Authority Trials Registry number, TFDA0018/CTR/0010/5).

Community-engaged basic science in an NCI-designated comprehensive cancer center: antioxidants and chemotherapeutic efficacy.

PURPOSE: While community engagement has been a longstanding aspect of cancer-relevant research in social and behavioral sciences, it is far less common in basic/translational/clinical research. With the National Cancer Institute's incorporation of Community Outreach and Engagement into the Cancer Center Support Grant guidelines, successful models are desirable. We report on a pilot study supported by the University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC), that used a community-engaged, data-driven process to inform a pre-clinical study of the impact of antioxidants on the efficacy of platinum-based chemotherapeutics. METHODS: We conducted a survey of UMGCCC catchment area residents (n = 120) to identify commonly used antioxidants. We then evaluated the effect of individually combining commonly used antioxidants from the survey (vitamin C, green tea, and melatonin) with platinum agents in models of non-small cell lung cancer (A549), colon adenocarcinoma (SW620) and head and neck squamous cell carcinoma (FaDu). RESULTS: In vitro, the anti-neoplastic activity of each chemotherapy was not potentiated by any of the antioxidants. Instead, when combined at fixed ratios, most antioxidant-chemotherapy combinations were antagonistic. In vivo, addition of antioxidants did not improve chemotherapeutic efficacy and in a FaDu-tumor bearing model, cisplatin-mediated tumor growth inhibition was significantly impeded by the addition of epigallocatechin gallate, the main antioxidant in green tea. CONCLUSION: These initial findings do not support addition of antioxidant supplementation to improve platinum-based chemotherapeutic efficacy. This study's approach can serve as a model of how to bring together the two seemingly discordant areas of basic research and community engagement.

Effects of Zinc Supplementation on Metabolomic Profiles in Tanzanian Infants: A Randomized Trial.

BACKGROUND: Provision of zinc supplementation to young children has been associated with reduced infectious morbidity and better growth outcomes. However, the metabolic pathways underlying these outcomes are unclear, and metabolomic data from humans undergoing zinc supplementation, particularly infants, are generally lacking. OBJECTIVES: This study aimed to examine the effect of zinc supplementation on metabolic profiles in Tanzanian infants aged 6 wk and 6 mo. METHODS: Blood samples were collected at age 6 wk and 6 mo from 50 Tanzanian infants who were enrolled in a randomized placebo-controlled trial of zinc supplementation (5 mg oral daily). Metabolomic analysis using an ultrahigh-performance liquid chromatography/tandem mass spectroscopy platform was performed to identify potential metabolomic profiles and biomarkers associated with zinc supplementation. Principal component analysis (PCA) was used to summarize metabolomic data from all samples. Two-way repeated measures analysis of variance with compound symmetry covariance structures were used to compare metabolome levels over time between infants in the 2 treatment arms. RESULTS: In PCA, the samples tended to be more separated by child age (6 wk compared with 6 mo) than by zinc supplementation status. We found that zinc supplementation affected a variety of metabolites associated with amino acid, lipid, nucleotide, and xenobiotic metabolism, including indoleacetate in the tryptophan metabolism pathway; 3-methoxytrosine and 4-hydrxoyphenylphruvate in the tyrosine pathway; eicosanedioate, 2-aminooctanoate, and N-acetyl-2-aminooctanoate in the fatty acid pathway; and N6-succinyladenosine in the purine metabolism pathway. Compared to the relatively small number of metabolites associated with zinc supplements, many infant metabolites changed significantly from age 6 wk to 6 mo. CONCLUSIONS: Zinc supplementation, despite having overall clinical benefits, appears to induce limited metabolomic changes in blood metabolites in young infants. Future larger studies may be warranted to further examine metabolic pathways associated with zinc supplementation. The parent trial was registered at clinicaltrials.gov as NCT00421668.

The Safety and Comparative Effectiveness of Non-Psychoactive Cannabinoid Formulations for the Improvement of Sleep: A Double-Blinded, Randomized Controlled Trial.

BACKGROUND: Clinical evidence on the use of cannabidiol (CBD) for sleep remains limited. Even fewer studies have tested the comparative effectiveness of cannabinoid formulations found within CBD products used for sleep or how they compare to other complementary therapies such as melatonin. METHODS: Participants (N = 1,793 adults experiencing symptoms of sleep disturbance) were randomly assigned to receive a 4-week supply of 1 of 6 products (all capsules) containing either 15 mg CBD or 5 mg melatonin, alone or in combination with minor cannabinoids. Sleep disturbance was assessed over a period of 5 weeks (baseline week and 4 weeks of product use) using Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A, administered via weekly online surveys. A linear mixed-effects regression model was used to assess the differences in the change in sleep disturbance through time between each active product arm and CBD isolate. RESULTS: All formulations exhibited a favorable safety profile (12% of participants reported a side effect and none were severe) and led to significant improvements in sleep disturbance (p < 0.001 in within-group comparisons). Most participants (56% to 75%) across all formulations experienced a clinically important improvement in their sleep quality. There were no significant differences in effect, however, between 15 mg CBD isolate and formulations containing 15 mg CBD and 15 mg cannabinol (CBN), alone or in combination with 5 mg cannabichromene (CBC). There were also no significant differences in effect between 15 mg CBD isolate and formulations containing 5 mg melatonin, alone or in combination with 15 mg CBD and 15 mg CBN. CONCLUSIONS: Our findings suggest that chronic use of a low dose of CBD is safe and could improve sleep quality, though these effects do not exceed that of 5 mg melatonin. Moreover, the addition of low doses of CBN and CBC may not improve the effect of formulations containing CBD or melatonin isolate.

The Efficacy of the Manual Circumlaryngeal Therapy for Muscle Tension Dysphonia: A Systematic Review and Meta-analysis.

OBJECTIVE: Muscle tension dysphonia (MTD) is the most common functional voice disorder. Behavioral voice therapy is the front-line treatment for MTD, and laryngeal manual therapy may be a part of this treatment. The objective of this study was to investigate the effect of manual circumlaryngeal therapy (MCT) on acoustic markers of voice quality (jitter, shimmer, and harmonics-to-noise ratio) and vocal function (fundamental frequency) through a systematic review with meta-analysis. DATA SOURCES: Four databases were searched from inception to December 2022, and a manual search was performed. REVIEW METHODS: The PRISMA extension statement for reporting systematic reviews incorporating a meta-analysis of health care interventions was applied, and a random effects model was used for the meta-analyses. RESULTS: We identified 6 eligible studies from 30 studies (without duplicates). The MCT approach was highly effective on acoustics with large effect sizes (Cohen's d > 0.8). Significant improvements were obtained in jitter in percent (mean difference of -.58; 95% CI -1.00 to 0.16), shimmer in percent (mean difference of -5.66; 95% CI -8.16 to 3.17), and harmonics-to-noise ratio in dB (mean difference of 4.65; 95% CI 1.90-7.41), with the latter two measurements continuing to be significantly improved by MCT when measurement variability is considered. CONCLUSION: The efficacy of MCT for MTD was confirmed in most clinical studies by assessing jitter, shimmer, and harmonics-to-noise ratio related to voice quality. The effects of MCT on the fundamental frequency changes could not be verified. Further contributions of high-quality randomized control trials are needed to support evidence-based practice in laryngology. Laryngoscope, 134:18-26, 2024.

Photobiomodulation and Vascularization in Conduit-Based Peripheral Nerve Repair: A Narrative Review.

Background: Peripheral nerve injuries pose a significant clinical issue for patients, especially in the most severe cases wherein complete transection (neurotmesis) results in total loss of sensory/motor function. Nerve guidance conduits (NGCs) are a common treatment option that protects and guides regenerating axons during recovery. However, treatment outcomes remain limited and often fail to achieve full reinnervation, especially in critically sized defects (>3 cm) where a lack of vascularization leads to neural necrosis. Conclusions: A multitreatment approach is, therefore, necessary to improve the efficacy of NGCs. Stimulating angiogenesis within NGCs can help alleviate oxygen deficiency through rapid inosculation with the host vasculature, whereas photobiomodulation therapy (PBMT) has demonstrated beneficial therapeutic effects on regenerating nerve cells and neovascularization. In this review, we discuss the current trends of NGCs, vascularization, and PBMT as treatments for peripheral nerve neurotmesis and highlight the need for a combinatorial approach to improve functional and clinical outcomes.

Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study.

Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract.Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test.All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases.CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery.ClinicalTrials.gov identifier: NCT02881151 .

Effects of S-Allylcysteine-Rich Garlic Extract and Dietary Inorganic Nitrate Formula on Blood Pressure and Salivary Nitric Oxide: An Open-Label Clinical Trial Among Hypertensive Subjects.

INTRODUCTION:  The conversion of dietary inorganic nitrate (NO3-) to nitric oxide (NO) is a non-canonical pathway that plays an important role in NO biology, especially under pathological conditions. Inorganic NO3- supplementation is a proven method for controlling mild hypertension. Recent reports have suggested that another gaseous transmitter, hydrogen sulfide (H2S), influences NO biosynthesis and metabolism. Here, data are presented from an open-label clinical trial examining the effect of an encapsulated formulation (Vascanox® HP) that combines dietary sources of inorganic NO3- and S-allylcysteine (SAC), a source of H2S from garlic, on NO bioavailability and blood pressure in subjects experiencing elevated blood pressure or mild hypertension. METHODS:  An open-label clinical trial was conducted among patients with hypertension. Participants took Vascanox® for four weeks. Blood pressure was measured at baseline, two weeks, and four weeks. Salivary nitrite (NO2-), a surrogate of NO bioavailability, and NO3- were assessed prior to and two, six, and 24 hours after dosing on the first day of the study and prior to and two hours after dosing at subsequent study visits using saliva NO test strips. Changes in study outcomes over time were evaluated via analysis of variance (ANOVA) and paired t-tests. RESULTS:  Twelve participants completed the clinical trial. Vascanox® HP decreased systolic blood pressure by ~11 mmHg (p < 0.001) at two weeks and persisted beyond four weeks with daily supplementation. It also decreased the diastolic blood pressure of hypertensive subjects but not normotensive ones. The magnitude of the decrease was 11 mmHg (p < 0.01) at four weeks of study. Measurements of salivary concentrations of NO2- revealed high peak levels (743 uM) at two hours post-administration and a slow decay to elevated levels (348 uM) at 24 hours. NO2- salivary concentrations, a surrogate biomarker of NO bioavailability, remained above baseline for the duration of the study. CONCLUSIONS:  Vascanox® HP was shown to be a safe, effective, quick-acting, and long-lasting dietary supplement for controlling mild hypertension.