Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.

One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.

The relationship between hematologic malignancies on male hypogonadism: a scoping review.

INTRODUCTION: The associated symptoms of hypogonadism have been reported in patients with various types of cancer. However, the prevalence and significance of hypogonadism among certain hematologic malignancies have not been completely summarized in recent literature. OBJECTIVE: In this review we aimed to examine the current literature on hypogonadism in patients with hematologic malignancies, with emphasis on leukemias, lymphomas, and multiple myeloma (MM). METHODS: This review included relevant studies published before July 2023 that were retrieved through a search of PubMed using the keywords "hematologic cancer," "hematologic malignancy," blood cancer," "leukemia," "lymphoma," "hypogonadism," "multiple myeloma," and "testosterone." RESULTS: The search yielded 214 studies, of which 21 met the inclusion criteria. Commonly reported findings were that patients who had received hematopoietic stem cell therapy for acute lymphoblastic leukemia and acute myelogenous leukemia as children had laboratory-confirmed hypogonadism as adults. However, the impact of these diseases on hypogonadal symptoms was variable in these studies.Studies reporting on lymphoma and hypogonadism had mixed results, with some studies finding that the degree of cytotoxic chemotherapy was associated with hypogonadism, while others showed no correlation. Regardless, multiple studies found that hypogonadism secondary to lymphoma treatment and symptoms of hypogonadism had no apparent association.The most comprehensive assessment of the frequency of hypogonadism in an MM cohort found that 74% of 561 MM patients were classified as hypogonadal compared to 33% of patients in a control population. Testosterone supplementation was found to lower interleukin-6 levels, which could potentially help manage some of the adverse effects of MM, including decreased bone mineral density. CONCLUSION: There is a relationship between hematologic malignancies and hypogonadism, which is likely multifactorial. In this review we established that the most plausible factors are related to the secondary effects of gonadotoxic treatments and/or systemic inflammatory responses to the diseases.

Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans.

BACKGROUND: Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, whereas supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome, and congenital anomalies. Inositol status can be influenced by diet, synthesis, transport, utilization, and catabolism. OBJECTIVES: We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites. METHODS: GC-MS was used to determine plasma MI concentration of >2000 healthy, young adults (aged 18-28 y) from the Trinity Student Study. Genotyping data were used to test association of plasma MI with single nucleotide polymorphisms (SNPs) in candidate genes, encoding inositol transporters and synthesizing enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with d-chiro-inositol (DCI), glucose, and other metabolites by Spearman rank correlation. RESULTS: Mean plasma MI showed a small but significant difference between males and females (28.5 and 26.9 µM, respectively). Candidate gene analysis revealed several nominally significant associations with plasma MI, most notably for SLC5A11 (solute carrier family 5 member 11), encoding a sodium-coupled inositol transporter, also known as SMIT2 (sodium-dependent myo-inositol transporter 2). However, these did not survive correction for multiple testing. Subsequent testing for genome-wide association with plasma MI did not identify associations of genome-wide significance (P < 5 × 10-8). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (P < 1 × 10-5), 3 of which were located within or close to genes: MTDH (metadherin), LAPTM4B (lysosomal protein transmembrane 4 ß), and ZP2 (zona pellucida 2). We found significant positive correlation of plasma MI concentration with concentration of dci and several other biochemicals including glucose, methionine, betaine, sarcosine, and tryptophan. CONCLUSIONS: Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11, which is worthy of further investigation.

Loss of the Vitamin B-12 Transport Protein Tcn2 Results in Maternally Inherited Growth and Developmental Defects in Zebrafish.

BACKGROUND: In humans, vitamin B-12 (cobalamin) transport involves 3 paralogous proteins: transcobalamin, haptocorrin, and intrinsic factor. Zebrafish (Danio rerio) express 3 genes that encode proteins homologous to known B-12 carrier proteins: tcn2 (a transcobalamin ortholog) and 2 atypical ß-domain-only homologs, tcnba and tcnbb. OBJECTIVES: Given the orthologous relation between zebrafish Tcn2 and human transcobalamin, we hypothesized that zebrafish carrying null mutations of tcn2 would exhibit phenotypes consistent with vitamin B-12 deficiency. METHODS: First-generation and second-generation tcn2-/- zebrafish were characterized using phenotypic assessments, metabolic analyses, viability studies, and transcriptomics. RESULTS: Homozygous tcn2-/- fish produced from a heterozygous cross are viable and fertile but exhibit reduced growth, which persists into adulthood. When first-generation female tcn2-/- fish are bred, their offspring exhibit gross developmental and metabolic defects. These phenotypes are observed in all offspring from a tcn2-/- female regardless of the genotype of the male mating partner, suggesting a maternal effect, and can be rescued with vitamin B-12 supplementation. Transcriptome analyses indicate that offspring from a tcn2-/- female exhibit expression profiles distinct from those of offspring from a tcn2+/+ female, which demonstrate dysregulation of visual perception, fatty acid metabolism, and neurotransmitter signaling pathways. CONCLUSIONS: Our findings suggest that the deposition of vitamin B-12 in the yolk by tcn2-/- females may be insufficient to support the early development of their offspring. These data present a compelling model to study the effects of vitamin B-12 deficiency on early development, with a particular emphasis on transgenerational effects and gene-environment interactions.

Applying a One Health Approach in Global Health and Medicine: Enhancing Involvement of Medical Schools and Global Health Centers.

Background: Multidisciplinary and multisectoral approaches such as One Health and related concepts (e.g., Planetary Health, EcoHealth) offer opportunities for synergistic expertise to address complex health threats. The connections between humans, animals, and the environment necessitate collaboration among sectors to comprehensively understand and reduce risks and consequences on health and wellbeing. One Health approaches are increasingly emphasized for national and international plans and strategies related to zoonotic diseases, food safety, antimicrobial resistance, and climate change, but to date, the possible applications in clinical practice and benefits impacting human health are largely missing. Methods: In 2018 the "Application of the One Health Approach to Global Health Centers" conference held at the Albert Einstein College of Medicine convened experts involved in One Health policy and practice. The conference examined issues relevant to One Health approaches, sharing examples of challenges and successes to guide application to medical school curricula and clinical practice for human health. This paper presents a synthesis of conference proceedings, framed around objectives identified from presentations and audience feedback. Findings and Recommendations: The following objectives provide opportunities for One Health involvement and benefits for medical schools and global health centers by: 1) Improving One Health resource sharing in global health and medical education; 2) Creating pathways for information flow in clinical medicine and global health practice; 3) Developing innovative partnerships for improved health sector outcomes; and 4) Informing and empowering health through public outreach. These objectives can leverage existing resources to deliver value to additional settings and stakeholders through resource efficiency, more holistic and effective service delivery, and greater ability to manage determinants of poor health status. We encourage medical and global health educators, practitioners, and students to explore entry points where One Health can add value to their work from local to global scale.

Inorganic Nitrite Supplementation Improves Endothelial Function With Aging: Translational Evidence for Suppression of Mitochondria-Derived Oxidative Stress.

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Delayed Urological Cancer Care during the COVID-19 Pandemic: Urologists' Experience.

INTRODUCTION: The arrival of coronavirus disrupted health care systems and forced delays in cancer treatment. We explored the experience of urologists who had to delay their patients' cancer care. METHODS: Urologists who treat prostate, bladder, and renal cancers, selected through purposive sampling, responded to a survey about cancer treatment delay. They were asked about their practice setting, decision making and interactions with patients, and they were asked to reflect on their personal experience. A 0 to 10 point scale, modeled on the National Comprehensive Cancer Network' Distress Thermometer (NCCN-DT), validated for cancer patients with cancer, was used to estimate physician distress. We used descriptive statistics to analyze survey results. RESULTS: Of the 64 participating urologists, 98% delayed surgical treatment; fewer delayed cases of advanced cancers (42% for ≥T3/T4 or Gleason ≥8 prostate cancers, 58% for muscle invasive bladder cancer, 61% for ≥T2 renal cancers). They reported feeling anxious (44%) and helpless (29%), and their median distress score was 5 (range 0-10). They relied on their own risk assessments (67%) and consulted colleagues (56%) and national guidelines (53%) when making treatment deferral decisions. They identified a number of concerns as they resumed surgeries. CONCLUSIONS: Based on a comparison to the NCCN-DT clinical cutoff distress level of 4, urologists experienced moderately high levels of distress as they delayed cancer care during the COVID-19 pandemic and expressed concerns going forward. While the focus on patient care is paramount in a pandemic, it is important to recognize physician distress and develop practical and psychological strategies for distress mitigation.

Performance of the Person Centered Primary Care Measure in Pediatric Continuity Clinic.

OBJECTIVE: Improvement efforts in pediatric primary care would benefit from measures that capture families' holistic experience of the practice. We sought to assess the reliability and validity of the new Person-Centered Primary Care Measure (PCPCM) in a pediatric resident continuity clinic serving low-income families. METHODS: We incorporated the 11-item PCPCM, stems adapted to reflect a parent responding about their child's visit, into a telephone survey of 194 parents presenting for care in October 2019 at a pediatric resident continuity clinic in Cleveland Ohio (64% response rate). We evaluated PCPCM items using factor analysis and Rasch modeling, and assessed associations of the PCPCM with parents' demographics and perceptions of specific elements of their child's care. RESULTS: In this sample of low-income families, the PCPCM had good reliability (Cronbach's alpha 0.85). All items loaded onto a single factor in principal axes factor analysis. Of the 11 aspects of primary care represented in the scale, "shared experience" was most difficult for parents to endorse in Rasch modeling. All 11 items contributed significantly to the total scale score with corrected item-total correlations >0.4. The PCPCM score was independent of socio demographics and was associated with parent's report that their child's clinician spends enough time with them. CONCLUSIONS: The PCPCM performs well in a pediatric continuity clinic setting, warranting consideration for its use as a parsimonious parent-reported measure of what patients and clinicians say matters most in pediatric primary care.

Assessing Time-Resolved fNIRS for Brain-Computer Interface Applications of Mental Communication.

Brain-computer interfaces (BCIs) are becoming increasingly popular as a tool to improve the quality of life of patients with disabilities. Recently, time-resolved functional near-infrared spectroscopy (TR-fNIRS) based BCIs are gaining traction because of their enhanced depth sensitivity leading to lower signal contamination from the extracerebral layers. This study presents the first account of TR-fNIRS based BCI for "mental communication" on healthy participants. Twenty-one (21) participants were recruited and were repeatedly asked a series of questions where they were instructed to imagine playing tennis for "yes" and to stay relaxed for "no." The change in the mean time-of-flight of photons was used to calculate the change in concentrations of oxy- and deoxyhemoglobin since it provides a good compromise between depth sensitivity and signal-to-noise ratio. Features were extracted from the average oxyhemoglobin signals to classify them as "yes" or "no" responses. Linear-discriminant analysis (LDA) and support vector machine (SVM) classifiers were used to classify the responses using the leave-one-out cross-validation method. The overall accuracies achieved for all participants were 75% and 76%, using LDA and SVM, respectively. The results also reveal that there is no significant difference in accuracy between questions. In addition, physiological parameters [heart rate (HR) and mean arterial pressure (MAP)] were recorded on seven of the 21 participants during motor imagery (MI) and rest to investigate changes in these parameters between conditions. No significant difference in these parameters was found between conditions. These findings suggest that TR-fNIRS could be suitable as a BCI for patients with brain injuries.

An Evaluation of a Clinical Care Pathway for the Management of Men With Nonorganic Erectile Dysfunction.

INTRODUCTION: There exists little literature on the outcomes of the medical management of men with erectile dysfunction (ED) with no overt organic etiology. AIM: This study was conducted to assess the outcomes of men with nonorganic ED treated medically. METHODS: All patients had normal hormone profiles and vascular assessment. All were given a trial of a phosphodiesterase type 5 inhibitor (PDE5i). If no improvement was experienced, intracavernosal injection (ICI) therapy was administered. All patients were encouraged to seek a consultation with a mental health professional. MAIN OUTCOME MEASURE: Patient demographics, medical comorbidities, hormone and hemodynamics assessments, and change in International Index of Erectile Function scores of patients were recorded. RESULTS: 116 men with a mean age or 38 ± 19 (range 16-57) years were studied. 21% had mild ED, 47% had moderate ED, and 32% had severe ED. 21% had seen a psychiatrist. 81% of patients responded to PDE5i with a penetration hardness erection on follow-up (mean duration of 7 ± 3 months postcommencement of PDE5i). However, only 68% of these were capable of a consistently good response. The mean Erectile Function domain score on PDE5i for the entire group improved from 18 ± 11 to 22 ± 6 (P = .01), and for PDE5i responders it was 27 ± 4 (P < .001). 28% of men (22 PDE5i failures and 10 with a mixed response to PDE5i) attempted ICI, all obtaining consistently functional erections. At a mean time point of 11 ± 5 months, 83% of those responding to PDE5i had ceased using PDE5i due to a lack of need. 11% of those using ICI continued to use them 6 months after starting ICI; the remainder had been transitioned back to PDE5i. Of the 29 patients in the latter subgroup, 66% were no longer using PDE5i consistently due to a lack of need. CLINICAL IMPLICATIONS: Not all men with nonorganic ED respond to PDE5i initially and many of those who respond do so only intermittently; such patients are potentially curable, using erectogenic pharmacotherapy for erectile confidence restoration, most men are capable of being weaned from drug therapy. STRENGTHS & LIMITATIONS: The strengths of the study are the large number of patients and the use of serial validated instruments to assess erectile function outcomes. As a weakness, despite normal hormone and vascular assessments, the diagnosis of nonorganic ED is still a presumptive one. CONCLUSION: Medical management of nonorganic ED utilizing the process of care model results in cure in a large proportion of such patients. The transient use of ICI in some patients permits successful PDE5i rechallenge. Jenkins LC, Hall M, Deveci S, et al. An Evaluation of a Clinical Care Pathway for the Management of Men With Nonorganic Erectile Dysfunction. J Sex Med 2019;16:1541-1546.

Integrating clinical medicine and population health: where to from here?

Efforts to contain healthcare costs have led a renewed clinician interest in addressing population-level outcomes, with some proposing that the integration of population health into clinical practice represents a novel concept entitled "clinical population medicine" (CPM). This commentary offers an examination of the function and utility of CPM. In reviewing relevant literature, we note several inconsistencies in CPM's purported mandate, which ranges from simply incorporating the social determinants of health into clinical practice to broad involvement in community health planning. The latter of these seems to overlap, and potentially conflict, with the work of public health practitioners, and cited examples of activities used to define "CPM" seem to apply a label to established clinician activities around the determinants of health that would be captured more simply as research, evaluation, or advocacy undertaken by clinicians in other areas of practice. Our analysis suggests that CPM may have value in encouraging clinicians to incorporate community determinants and contextual considerations into their practices, but must take care to remain complementary and distinct from public health practice.

ComPaSS-GWAS: A method to reduce type I error in genome-wide association studies when replication data are not available.

Results from association studies are traditionally corroborated by replicating the findings in an independent data set. Although replication studies may be comparable for the main trait or phenotype of interest, it is unlikely that secondary phenotypes will be comparable across studies, making replication problematic. Alternatively, there may simply not be a replication sample available because of the nature or frequency of the phenotype. In these situations, an approach based on complementary pairs stability selection for genome-wide association study (ComPaSS-GWAS), is proposed as an ad-hoc alternative to replication. In this method, the sample is randomly split into two conditionally independent halves multiple times (resamples) and a GWAS is performed on each half in each resample. Similar in spirit to testing for association with independent discovery and replication samples, a marker is corroborated if its p-value is significant in both halves of the resample. Simulation experiments were performed for both nongenetic and genetic models. The type I error rate and power of ComPaSS-GWAS were determined and compared to the statistical properties of a traditional GWAS. Simulation results show that the type I error rate decreased as the number of resamples increased with only a small reduction in power and that these results were comparable with those from a traditional GWAS. Blood levels of vitamin pyridoxal 5'-phosphate from the Trinity Student Study (TSS) were used to validate this approach. The results from the validation study were compared to, and were consistent with, those obtained from previously published independent replication data and functional studies.

Development of Collagenase Treatment for Dupuytren Disease.

Proof-of-principle, basic-science studies, using a rat-tail tendon model and surgically removed Dupuytren cords, began collagenase Clostridium histolyticum (CCH) development. Clinical studies in humans were then conducted, where the primary endpoint was reduction in contracture to within 0° to 5° of extension. Phase 2 studies, which confirmed the optimal dose of collagenase as 0.58 mg, showed injectable CCH reduced contractures in MP and PIP joints to within 0° to 5° in many joints and was well tolerated. Clinical results from phase 3 studies confirmed the efficacy and safety of injectable CCH as a viable nonsurgical intervention.

Synergistic antifungal effect of chitosan-stabilized selenium nanoparticles synthesized by pulsed laser ablation in liquids against Candida albicans biofilms.

BACKGROUND: Candida albicans is a major opportunistic fungal pathogen. One of the most important virulence factors that contribute to the pathogenesis of candidiasis is its ability to form biofilms. A key characteristic of Candida biofilms is their resistance to antifungal agents. Due to significant morbidity and mortality rates related to biofilm-associated drug resistance, there is an urgency to develop novel nanotechnology-based approaches preventing biofilm-related infections. METHODS: In this study, we report, for the first time, the synthesis of selenium nanoparticles by irradiating selenium pellets by nanosecond pulsed laser ablation in liquid chitosan as a capping agent. Synergy of the fungicidal effect of selenium nanoparticles and chitosan was quantified by the combination index theorem of Chou-Talalay. RESULTS: This drug combination resulted in a potent fungicidal effect against a preformed C. albicans biofilm in a dose-response manner. By advanced electron microscopy techniques, we documented the adhesive and permeabilizing properties of chitosan, therefore allowing selenium nanoparticles to enter as the cell wall of the yeast became disrupted and distorted. Most importantly, we demonstrated a potent quantitative synergistic effect when compounds such as selenium and chitosan are combined. CONCLUSION: These chitosan-stabilized selenium nanoparticles could be used for ex vivo applications such as sterilizers for surfaces and biomedical devices.

Emerging Strategies on Adjuvant Therapies for Nerve Recovery.

Current strategies for promoting faster and more effective peripheral nerve healing have utilized a wide variety of techniques and approaches. Nerve grafts, conduits, and stem cell therapy all have their respective advantages. However, there are still some difficulties in attaining complete functional recovery with a single treatment modality. The utilization of adjuvant treatments, in combination with current standard-of-care methods, offers the potential to improve patient outcomes. This paper highlights the current landscape of adjuvant treatments for enhancing peripheral nerve repair and regeneration.

Case Reports of Acne and Homeopathy.

BACKGROUND: Acne vulgaris is a self-limiting disorder of the pilosebaceous unit. The aesthetic aspect of the disorder may provoke depression and diminish the quality of life. A number of agents are used for acne treatment, e.g., retinoids, antibiotics, benzoic acid, azelaic acid, and hormones. These agents have side-effects, sometimes severe ones. CASE REPORTS: Presented are 2 cases of severe acne treated with individualized homeopathic medicines. Both patients were treated using the classical method of homeopathy, i.e., a single medicine based on the patient's individual characteristics was prescribed. The cases were documented photographically at onset and during the course of treatment. Both patients went into remission following treatment, and long-term follow-up suggested that the therapy remained efficacious long after cessation of treatment. No significant side effects were noted. CONCLUSIONS: Homeopathic medicines may be useful as stand-alone treatment of patients with severe acne vulgaris. A case series suggested a remission rate of more than 80% using individualized homeopathic treatment. The treatment remained efficacious long after cessation and is not accompanied by significant side-effects. It is to be hoped that this presentation will stimulate research interest into homeopathic medicines as stand-alone or adjunct treatments of acne.

Lifestyle, metabolite, and genetic determinants of formate concentrations in a cross-sectional study in young, healthy adults.

Background: Formate is an important metabolite that serves as a donor of one-carbon groups to the intracellular tetrahydrofolate pool. However, little is known of its circulating concentrations or of their determinants. Objective: This study aimed to define formate concentrations and their determinants in a healthy young population. Design: Serum formate was measured in 1701 participants from the Trinity Student Study. The participants were men and women, aged 18 to 28 y, enrolled at Trinity College, Dublin. Formate concentrations were compared with other one-carbon metabolites, vitamin status, potential formate precursors, genetic polymorphisms, and lifestyle factors. Results: Serum formate concentrations ranged from 8.7 to 96.5 µM, with a mean of 25.9 µM. Formate concentrations were significantly higher in women than in men; oral contraceptive use did not further affect them. There was no effect of smoking or of alcohol ingestion, but the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) polymorphism was associated with a significantly decreased formate concentration. Formate was positively associated with potential metabolic precursors (serine, methionine, tryptophan, choline) but not with glycine. Formate concentrations were positively related to serum folate and negatively related to serum vitamin B-12. Conclusions: Formate concentrations were sensitive to the concentrations of metabolic precursors. In view of the increased susceptibility of women with the TT genotype of MTHFR to give birth to infants with neural tube defects as well as the effectiveness of formate supplementation in decreasing the incidence of folate-resistant neural tube defects in susceptible mice, it will be important to understand how this genotype decreases the serum formate concentration. This trial was registered at www.clinicaltrials.gov as NCT03305900.

Change in Pneumococcus Serotypes but not Mortality or Morbidity in Pre- and Post-13-Valent Polysaccharide Conjugate Vaccine Era: Epidemiology in a Pediatric Intensive Care Unit over 10 Years.

Aim: Pneumococcus is a common commensal and an important pathogen among children for which immunization is available. Some serotypes occasionally cause severe pneumococcal disease with high mortality and morbidity. We reviewed all pneumococcal serotypes and mortality/morbidity in a pediatric intensive care unit (PICU) following universal pneumococcal conjugate vaccine (PCV) immunization. Methods: A 13-valent PCV was introduced in the universal immunization program in late 2011 in Hong Kong. We retrospectively reviewed all pneumococcal serotypes in the pre-(2007-11) and post-(2012-16) 13-valent PCV era. Results: There were 29 (1.9%) PICU patients with pneumococcal isolation, of which 6 died (20% motality). Serogroups 6 and 19 predominated before and Serogroup 3 after 2012. In the post-13-valent PCV era, the prevalence of pneumococcus isolation in PICU was increased from 1 to 2% (p = 0.04); Serogroup 3 was the major serotype of morbidity, despite supposedly under vaccine coverage. The majority of pneumococcus were penicillin-sensitive (94%) in the post 13-valent PCV era. All pneumococcus specimens were sensitive to cefotaxime and vancomycin. Binary logistic regression showed that there were reductions in Serogroup 6 (odds ratio [OR], 0.050; 95% confidence interval [CI], 0.004-0.574; p = 0.016) and Serogroup 19 (odds ratio [OR], 0.105; 95% confidence interval [CI], 0.014-0.786; p = 0.028) but not mortality or morbidity for patients admitted after 2012. Conclusions: SPD is associated with significant morbidity and mortality, despite treatment with systemic antibiotics and ICU support. The expanded coverage of 13-valent PCV results in the reduction of Serotypes 6 and 19 but not mortality/morbidity associated with SPD in the setting of a PICU.

Development of a stretch-induced neurotrauma model for medium-throughput screening in vitro: identification of rifampicin as a neuroprotectant.

BACKGROUND AND PURPOSE: We hypothesized that an in vitro, stretch-based model of neural injury may be useful to identify compounds that decrease the cellular damage in neurotrauma. EXPERIMENTAL APPROACH: We screened three neural cell lines (B35, RN33B and SH-SY5Y) subjected to two differentiation methods and selected all-trans-retinoic acid-differentiated B35 rat neuroblastoma cells subjected to rapid stretch injury, coupled with a subthreshold concentration of H2 O2 , for the screen. The model induced marked alterations in gene expression and proteomic signature of the cells and culminated in delayed cell death (LDH release) and mitochondrial dysfunction [reduced 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) conversion]. Follow-up studies utilized human stem cell-derived neurons subjected to rapid stretch injury. KEY RESULTS: From screening of a composite library of 3500 drugs, five drugs (when applied in a post-treatment regimen relative to stretch injury) improved both LDH and MTT responses. The effects of rifampicin were investigated in further detail. Rifampicin reduced cell necrosis and apoptosis and improved cellular bioenergetics. In a second model (stretch injury in human stem cell-derived neurons), rifampicin pretreatment attenuated LDH release, protected against the loss of neurite length and maintained neuron-specific class III ß-tubulin immunoreactivity. CONCLUSIONS AND IMPLICATIONS: We conclude that the current model is suitable for medium-throughput screening to identify compounds with neuroprotective potential. Rifampicin, when applied either in pre- or post-treatment, improves the viability of neurons subjected to stretch injury and protects against neurite loss. Rifampicin may be a candidate for repurposing for the therapy of traumatic brain injury. LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.