Putative pseudolysogeny-dependent phage gene implicated in the superinfection resistance of Cutibacterium acnes.

Objectives: Cutibacterium acnes, formerly Propionibacterium acnes, is a bacterial species characterized by tenacious acne-contributing pathogenic strains. Therefore, bacteriophage therapy has become an attractive treatment route to circumvent issues such as evolved bacterial antibiotic resistance. However, medical and commercial use of phage therapy for C. acnes has been elusive, necessitating ongoing exploration of phage characteristics that confer bactericidal capacity. Methods: A novel phage (Aquarius) was isolated and analyzed. Testing included genomic sequencing and annotation, electron microscopy, patch testing, reinfection assays, and qPCR to confirm pseudolysogeny and putative superinfection exclusion (SIE) protein expression. Results: Given a superinfection-resistant phenotype was observed, reinfection assays and patch tests were performed, which confirmed the re-cultured bacteria were resistant to superinfection. Subsequent qPCR indicated pseudolysogeny was a concomitantly present phenomenon. Phage genomic analysis identified the presence of a conserved gene (gp41) with a product containing Ltp family-like protein signatures which may contribute to phage-mediated bacterial superinfection resistance (SIR) in a pseudolysogeny-dependent manner. qPCR was performed to analyze and roughly quantify gp41 activity, and mRNA expression was high during infection, implicating a role for the protein during the phage life cycle. Conclusions: This study confirms that C. acnes bacteria are capable of harboring phage pseudolysogens and suggests that this phenomenon plays a role in bacterial SIR. This mechanism may be conferred by the expression of phage proteins while the phage persists within the host in the pseudolysogenic state. This parameter must be considered in future endeavors for efficacious application of C. acnes phage-based therapeutics.

Predictors of Human Papillomavirus Vaccination in the Postpartum Period for Individuals Aged 18-26.

Background: Human papillomavirus (HPV) vaccination during the postpartum period is an opportunity for vaccine eligible individuals to be vaccinated. Objective: Identify predictors of vaccine acceptance in the postpartum period among patients aged 18-26. Study Design: A retrospective chart review was conducted to evaluate the rate of HPV vaccination to eligible postpartum patients aged 18-26 who delivered between January 2021 and May 2023 at our institution. Clinical and demographic data were extracted. Comparisons were made between fully vaccinated individuals and those who were unvaccinated or incompletely vaccinated. Variables significantly associated with vaccination status or acceptance were included in a multivariable logistic regression model. Results: Of the 1,130 patients who met the study inclusion criteria, 42.1% were eligible for postpartum HPV vaccination. The average age was 23 years, the majority White (74.5%), and English speaking (93.1%). Nineteen percent of eligible patients accepted HPV vaccination, with differences between those who accepted or declined the vaccine identified in: preferred language, tobacco use, delivering provider's specialty, and receiving any vaccination during pregnancy. Spanish-speaking patients had >5× the odds of accepting the vaccine compared with English-speaking patients. Smokers, patients delivered by a family medicine provider, and those who accepted any vaccine during pregnancy had more than twice the odds of receiving the vaccine postpartum. Conclusion(s): The postpartum period remains an opportunity to provide HPV vaccination. Our study identified patients less likely to be vaccinated prior to delivery, as well as patients who are more likely to accept vaccinations postpartum.

Variability in temperature control practices amongst the Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP) trial.

AIM: Temperature control is a complex bundled intervention; the synergistic impact of each individual component is ill defined and underreported. Resultantly, the influence of parameter optimization on temperature control's overall neuroprotective effect remains poorly understood. To characterize variability in temperature control parameters and barriers to short pre-induction and induction times, we surveyed sites enrolling in an ongoing multicenter clinical trial. METHODS: This was a cross-sectional, survey study evaluating temperature control practices within the Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP) trial (NCT04217551). A 23-question web-based survey (Qualtrics) was distributed to the site principal investigators by email. Respondents were asked about site practices pertaining to the use of temperature control, including the request to upload individual institutional protocols. Open-ended responses were analyzed qualitatively by categorizing responses into identified themes. To complement survey level data, records pertaining to the quality of temperature control were extracted from the ICECAP trial database. RESULTS: The survey response rate was 75% (n = 51) including 23.5% (n = 12) survey respondents who uploaded institutional protocols. Most sites reported having institutional protocols for temperature control (n = 41; 80%), including 62.5% (n = 32) who had separate protocols for initiation of temperature control in the emergency department (ED). Fewer sites had protocols specific to sedation or neuromuscular blockade (NMB) management (n = 35, 68.6%). Use of NMB during temperature control induction was variable; 61.7% (n = 29) of sites induced paralysis less than 20% of the time. While most institutional protocols (n = 11, 83.3%) commented on the importance of early initiation of temperature control, this was incongruent with the largest reported barrier, which was clinical nihilism regarding the importance of early temperature control initiation (n = 30, 62.5%). Within the ICECAP trial database, 1 in 2 patients were treated with NMB however, use of NMB and time to initiation of temperature control device varied widely between sites. CONCLUSION: Amongst ICECAP trial sites, there was significant variability in resources, methods, and barriers for early temperature control initiation. Defining and standardizing high-quality temperature control must be prioritized, as it may impact the interpretation of past and current clinical trial findings.

A practical magnetic-resonance imaging score for outcome prediction in comatose cardiac arrest survivors.

AIM: Magnetic Resonance Imaging (MRI) is an important prognostic tool in cardiac arrest (CA) survivors given its sensitivity for detecting hypoxic-ischemic brain injury (HIBI), however, it is limited by poorly defined objective thresholds. To address this limitation, we evaluated a qualitative MRI score for predicting neurological outcome in CA survivors. METHODS: Adult comatose CA survivors who underwent MRI were retrospectively identified at a single academic medical center. Two blinded neurointensivists qualitatively scored HIBI amongst 12 MRI brain regions. Scores were summated to form four distinct score groups: cortex, deep grey nuclei (DGN), cortex-DGN combined, and total (cortex, DGN, brainstem, and cerebellum). Poor neurological outcome was defined as Cerebral Performance Category (CPC) score 3-5 at hospital discharge. Inter-rater reliability was tested using intra-class correlation (ICC) and discrimination of poor neurological outcome assessed using area under the receiver operating curve (AUC). RESULTS: Our cohort included 219 patients with median time to MRI of 96 (IQR 81-110) hours. ICC (95% CI) was good to excellent across all MRI scores: cortex 0.92 (0.89-0.94), DGN 0.88 (0.80-0.92), cortex-DGN 0.94 (0.92-0.95), and total 0.93 (0.91-0.95). AUC (95% CI) for poor outcome was good across all MRI scores: cortex 0.84 (0.78-0.90), DGN 0.83 (0.77-0.89), cortex-DGN 0.83 (0.77-0.89), and total 0.83 (0.77-0.88). CONCLUSION: A simplified, qualitative MRI score had excellent reliability and good discrimination for poor neurologic outcome. Further work is necessary to externally validate our findings in an independent, ideally prospective, cohort.

Collective action within an environment of unknown unknowns: Experiences with the port of Mars Game.

There is limited research about how groups solve collective action problems in uncertain environments, especially if groups are confronted with unknown unknowns. We aim to develop a more comprehensive view of the characteristics that allow both groups and individuals to navigate such issues more effectively. In this article, we present the results of a new online experiment where individuals make decisions of whether to contribute to the group or pursue self-interest in an environment with high uncertainty, including unknown unknowns. The behavioral game, Port of Mars is framed as a first-generation habitat on Mars where participants have to make decisions on how much to invest in the shared infrastructure to maintain system health and how much to invest in personal goals. Participants can chat during the game, and take surveys before and after the game in order to measure personality attributes and observations from the game. Initial results suggest that a higher average social value orientation and more communication are the key factors that explain why some groups are more successful than others in surviving Port of Mars. Neither other attributes of players nor the group's communication content explain the observed differences between groups.

Micronutrient deficiencies in inflammatory bowel disease: an incidence analysis.

BACKGROUND: Micronutrient deficiencies associated with malnutrition in patients with inflammatory bowel disease (IBD) can lead to complications including anemia, coagulopathy, poor wound healing, and colorectal cancer. This study aimed to investigate micronutrient deficiencies (copper, vitamins A, B 9 , E, and K) in IBD patients and highlight associated symptoms to aid in the recognition of micronutrient deficiencies. METHODS: A retrospective electronic chart review was performed on adults diagnosed with Crohn's disease or ulcerative colitis hospitalized at a tertiary care center for IBD flare between January 2013 and June 2017. Patients with serum or whole blood micronutrient levels were included. Pregnant and incarcerated patients were excluded. RESULTS: A total of 611 IBD patients (440 Crohn's disease, 171 ulcerative colitis) met the inclusion criteria. Micronutrients were assessed in a subset of IBD patients (copper: 12.3%, A: 10.1%, B 9  : 95.9%, E: 10.3%, and K: 4.6%). Overall, 10.1% of patients had micronutrient deficiencies. The proportion of patients with copper, A, B 9 , E, and K deficiencies were 25.4, 53.3, 1.9, 23.7, and 29.4% for Crohn's disease and 50, 52.9, 1.2, 43.8, and 18.2% for ulcerative colitis, respectively. The most common symptoms or historical features associated with micronutrient deficiency were anemia (copper, B 9 ), muscle weakness (copper, E) thrombocytopenia, fatigue (copper, B 9 ), diarrhea (B 9 ), dry skin, hyperkeratosis, pruritus, significant weight loss, elevated C-reactive protein (A), bleeding, and osteoporosis (K). CONCLUSION: Micronutrient deficiencies are common in IBD patients, yet they are not routinely assessed. Copper, vitamins A, E, and K deficiencies are particularly underrecognized. Associated historical features should raise suspicion and prompt assessment and treatment.

HLA-DR-Expressing Fibroblast-Like Synoviocytes Are Inducible Antigen Presenting Cells That Present Autoantigens in Lyme Arthritis.

OBJECTIVE: HLA-DR-expressing fibroblast-like synoviocytes (FLS) are a prominent cell type in synovial tissue in chronic inflammatory forms of arthritis. FLS-derived extracellular matrix (ECM) proteins, including fibronectin-1 (FN1), contain immunogenic CD4+ T cell epitopes in patients with postinfectious Lyme arthritis (LA). However, the role of FLS in presentation of these T cell epitopes remains uncertain. METHODS: Primary LA FLS and primary murine FLS stimulated with interferon gamma (IFNγ), Borrelia burgdorferi, and/or B burgdorferi peptidoglycan (PG) were assessed for properties associated with antigen presentation. HLA-DR-presented peptides from stimulated LA FLS were identified by immunopeptidomics analysis. OT-II T cells were co-cultured with stimulated murine FLS in the presence of cognate ovalbumin antigen to determine the potential of FLS to act as inducible antigen presenting cells (APCs). RESULTS: FLS expressed HLA-DR molecules within inflamed synovial tissue and tendons from patients with postinfectious LA in situ. Major histocompatibility complex (MHC) class II and co-stimulatory molecules were expressed by FLS following in vitro stimulation with IFNγ and B burgdorferi and presented both foreign and self-MHC-II peptides, including an immunogenic T cell epitope derived from Lyme autoantigen FN1. Stimulated FLS induced proliferation of naive OT-II CD4+ T cells that were dependent on OT-II antigen and CD40. Stimulation with B burgdorferi PG enhanced FLS-mediated T cell activation. CONCLUSION: MHC-II+ FLS are inducible APCs that can induce CD4+ T cell activation in an antigen- and CD40-dependent manner. Activated FLS can also present ECM-derived Lyme autoantigens, implicating FLS in amplifying tissue-localized autoimmunity in LA.

Temperature Control Parameters Are Important: Earlier Preinduction Is Associated With Improved Outcomes Following Out-of-Hospital Cardiac Arrest.

STUDY OBJECTIVE: Temperature control trials in cardiac arrest patients have not reliably conferred neuroprotective benefit but have been limited by inconsistent treatment parameters. To evaluate the presence of a time dependent treatment effect, we assessed the association between preinduction time and clinical outcomes. METHODS: In this retrospective, single academic center study between 2014 and 2022, consecutive out-of-hospital cardiac arrest (OHCA) patients treated with temperature control were identified. Preinduction was defined as the time from hospital arrival to initiation of a closed-loop temperature feedback device [door to temperature control initiation time], and early door to temperature control device time was defined a priori as <3 hours. We assessed the association between good neurologic outcome (cerebral performance category 1 to 2) and door to temperature control device time using logistic regression. The proportion of patients who survived to hospital discharge was evaluated as a secondary outcome. A sensitivity analysis using inverse probability treatment weighting, created using a propensity score, was performed to minimize measurable confounding. RESULTS: Three hundred and forty-seven OHCA patients were included; the early door to temperature control device cohort included 75 (21.6%) patients with a median (interquartile range) door to temperature control device time of 2.50 (2.03 to 2.75) hours, whereas the late door to temperature control device cohort included 272 (78.4%) patients with a median (interquartile range) door to temperature control device time of 5.18 (4.19 to 6.41) hours. In the multivariable logistic regression model, early door to temperature control device time was associated with improved good neurologic outcome and survival before [adjusted odds ratio (OR) (95% confidence interval) 2.36 (1.16 to 4.81) and 3.02 (1.54 to 6.02)] and after [adjusted OR (95% confidence interval) 1.95 (1.19 to 3.79) and 2.14 (1.33 to 3.36)] inverse probability of treatment weighting, respectively. CONCLUSION: In our study of OHCA patients, a shorter preinduction time for temperature control was associated with improved good neurologic outcome and survival. This finding may indicate that early initiation in the emergency department will confer benefit. Our findings are hypothesis generating and need to be validated in future prospective trials.

Retinal hyperspectral imaging in mouse models of Parkinson's disease and healthy aging.

Retinal hyperspectral imaging (HSI) is a non-invasive in vivo approach that has shown promise in Alzheimer's disease. Parkinson's disease is another neurodegenerative disease where brain pathobiology such as alpha-synuclein and iron overaccumulation have been implicated in the retina. However, it remains unknown whether HSI is altered in in vivo models of Parkinson's disease, whether it differs from healthy aging, and the mechanisms which drive these changes. To address this, we conducted HSI in two mouse models of Parkinson's disease across different ages; an alpha-synuclein overaccumulation model (hA53T transgenic line M83, A53T) and an iron deposition model (Tau knock out, TauKO). In comparison to wild-type littermates the A53T and TauKO mice both demonstrated increased reflectivity at short wavelengths ~ 450 to 600 nm. In contrast, healthy aging in three background strains exhibited the opposite effect, a decreased reflectance in the short wavelength spectrum. We also demonstrate that the Parkinson's hyperspectral signature is similar to that from an Alzheimer's disease model, 5xFAD mice. Multivariate analyses of HSI were significant when plotted against age. Moreover, when alpha-synuclein, iron or retinal nerve fibre layer thickness were added as a cofactor this improved the R2 values of the correlations in certain groups. This study demonstrates an in vivo hyperspectral signature in Parkinson's disease that is consistent in two mouse models and is distinct from healthy aging. There is also a suggestion that factors including retinal deposition of alpha-synuclein and iron may play a role in driving the Parkinson's disease hyperspectral profile and retinal nerve fibre layer thickness in advanced aging. These findings suggest that HSI may be a promising translation tool in Parkinson's disease.

Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection.

Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Studies have demonstrated that the retina in patients with Parkinson's disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells-a sensitive neuron in the retina-at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson's disease and retinal ganglion cell injury.

A Case Report of Renal Infarcts Secondary to Segmental Arterial Mediolysis.

Flank pain is an exceptionally common presenting symptom in the emergency and primary care setting; however, most clinicians may not include a differential diagnosis of renal infarct (RI) due to the reported low incidence of this condition. Delayed diagnosis or treatment intervention for RI can have dire consequences for the patient including hypertension and longstanding renal impairment. In this report, we review a case of a previously healthy 39-year-old male presenting with flank pain, which after extensive workup, was revealed to be caused by renal infarction from a renal artery dissection secondary to segmental arterial mediolysis (SAM).

Rare Lung Malignancy Mimic: A Case of Daptomycin-Induced Acute Eosinophilic Pneumonia.

Daptomycin is an antibiotic used for resistant Gram-positive organisms and has the rare side effect of inducing acute eosinophilic pneumonia (AEP). This condition can be fatal due to respiratory failure if not treated, as eosinophils migrate to the lungs and inflammatory cascades cause epithelial injury. Daptomycin-induced AEP can be misdiagnosed as bacterial pneumonia or malignancy, which may lead to unnecessary testing or treatments. Diagnostic criteria include dyspnea, fever, recent daptomycin exposure, infiltrates on imaging, eosinophils on bronchoalveolar lavage or peripheral eosinophilia, and clinical improvement with medication discontinuation. We present a unique case of daptomycin-induced eosinophilic pneumonia in a 72-year-old male with the chief complaint of dyspnea and initial concerns for lung cancer after a spiculated nodule was seen on imaging. Prior to undergoing a lung biopsy, repeat imaging showed a decrease in the suspicious nodule, reducing the likelihood of malignancy and prompting a re-evaluation of the history of the present illness and medication list. Daptomycin was stopped, and the patient's symptoms and imaging improved. This case illustrates the importance of early recognition and appropriate treatment of AEP, which allows for complete clinical recovery.

Bhlhe40 Promotes CD4+ T Helper 1 Cell and Suppresses T Follicular Helper Cell Differentiation during Viral Infection.

In response to acute infection, naive CD4+ T cells primarily differentiate into T helper 1 (Th1) or T follicular helper (Tfh) cells that play critical roles in orchestrating cellular or humoral arms of immunity, respectively. However, despite the well established role of T-bet and BCL-6 in driving Th1 and Tfh cell lineage commitment, respectively, whether additional transcriptional circuits also underlie the fate bifurcation of Th1 and Tfh cell subsets is not fully understood. In this article, we study how the transcriptional regulator Bhlhe40 dictates the Th1/Tfh differentiation axis in mice. CD4+ T cell-specific deletion of Bhlhe40 abrogates Th1 but augments Tfh differentiation. We also assessed an increase in germinal center B cells and Ab production, suggesting that deletion of Bhlhe40 in CD4+ T cells not only alters Tfh differentiation but also their capacity to provide help to B cells. To identify molecular mechanisms by which Bhlhe40 regulates Th1 versus Tfh lineage choice, we first performed epigenetic profiling in the virus specific Th1 and Tfh cells following LCMV infection, which revealed distinct promoter and enhancer activities between the two helper cell lineages. Furthermore, we identified that Bhlhe40 directly binds to cis-regulatory elements of Th1-related genes such as Tbx21 and Cxcr6 to activate their expression while simultaneously binding to regions of Tfh-related genes such as Bcl6 and Cxcr5 to repress their expression. Collectively, our data suggest that Bhlhe40 functions as a transcription activator to promote Th1 cell differentiation and a transcription repressor to suppress Tfh cell differentiation.

Effects of sensory overstimulation in postpartum rats.

Research in rodents has shown that exposure to excessive early life audiovisual stimulation leads to altered anxiety-like behaviors and cognitive deficits. Since this period of stimulation typically begins prior to weaning, newborn rodents receive sensory overstimulation (SOS) as a litter within their home cage while the dam is present. However, the effects of SOS during the postpartum period remain unexplored. To this end, we adapted an SOS paradigm for use in rats and exposed rat dams and their litters from postpartum days (PD) 10-23. Maternal observations were conducted to determine whether SOS produced changes in positive and/or negative maternal behaviors. Next, we assessed changes in anxiety-like behavior and cognition by testing dams in the elevated zero maze, open field, and novel object recognition tests. To assess potential effects on HPA-axis function, levels of the stress hormone corticosterone (CORT) were measured approximately 1-week after the cessation of SOS exposure. Our results indicate increased nursing and licking in SOS dams compared to controls, although SOS dams also exhibited significant increases in pup dragging. Moreover, SOS dams exhibited reduced self-care behaviors and nest-building compared to control dams. No differences were found for anxiety-like behaviors, object recognition memory, or CORT levels. This study is the first to assess the impact of postpartum SOS exposure in rat dams. Our findings suggest an SOS-induced enhancement in positive caregiving, but limited impact in all other measures.

The effects of prenatal and postnatal high-dose vitamin B-12 supplementation on human milk vitamin B-12: a randomized, double-blind, placebo-controlled trial in Tanzania.

BACKGROUND: Vitamin B-12 status in human milk (HM) has critical implications for infant growth and development. Few studies have separately evaluated the effects of prenatal and postnatal maternal high-dose vitamin B-12 supplementation on HM vitamin B-12 concentration. OBJECTIVES: This randomized controlled trial aimed to assess the effects of prenatal and postnatal vitamin B-12 supplementation on HM vitamin B-12 at 6 wk and 7 mo postpartum. METHODS: Pregnant women were enrolled in Dar es Salaam, Tanzania, between 2001 and 2004. From recruitment (12-27 weeks of gestation) through 6 wk postpartum, participants were randomly assigned to daily oral multiple micronutrient supplementation or placebo. From 6 wk to 18 mo postpartum, a subset of participants was randomly assigned to a postnatal supplement or placebo. The supplement included 50 µg/d of vitamin B-12 and various other vitamins. HM vitamin B-12 concentrations were analyzed at 6 wk and 7 mo postpartum for 412 participants. RESULTS: The prevalence of HM vitamin B-12 of <310 pmol/L was 73.3% and 68.4% at 6 wk and 7 mo postpartum, respectively. Prenatal supplementation increased HM vitamin B-12 concentration (percent difference: 34.4; 95% CI: 17.0, 54.5; P < 0.001) at 6 wk; this effect was not present at 7 mo. Postnatal supplementation increased HM vitamin B-12 concentration (percent difference: 15.9; 95% CI: 1.91, 31.9; P = 0.025) at 7 mo. Effect modification between prenatal and postnatal supplementation on HM vitamin B-12 status at 7 mo was found, with the effects of prenatal and postnatal supplements more pronounced among those receiving control during the other period; the prenatal supplement had a greater effect with postnatal control, and the postnatal supplement had a greater effect with prenatal control. CONCLUSIONS: Prenatal maternal vitamin B-12 supplementation has benefits on short-term HM status, and postnatal maternal vitamin B-12 supplementation has benefits on long-term HM status. This trial was registered at clinicaltrials.gov as NCT00197548. https://clinicaltrials.gov/ct2/show/NCT00197548.

Sports and Weight Control in Children.

Pediatric obesity is a global concern with distressing comorbid conditions, including mood disturbance, cardiovascular changes, endocrine imbalance, liver disease, sleep apnea, and orthopedic conditions. The primary treatment of this condition includes physical activity. Participating in organized sports has been shown to reduce weight and the complications of pediatric obesity more effectively than individual exercise.

Factors associated with longer survival among older medicare patients after diagnosis of supratentorial primary brain malignancies: a retrospective cohort study.

OBJECTIVES: Despite recent advances, the prognosis for primary malignant brain tumors (PMBTs) remains poor. Some commonly prescribed medications may exhibit anti-tumor properties in various cancers, and neurodegenerative diseases may activate pathways that counteract gliomagenesis. Our study is focused on determining if there is a correlation between the use of metformin, beta-blockers, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs), or the presence of Parkinson's disease (PD), and the survival rates following a diagnosis of a PMBT. METHODS: This analysis of the 100% Texas Medicare Database identified patients aged 66+ years diagnosed with a supratentorial PMBT from 2014-2017. Cox proportional hazards regression was employed to analyze survival following diagnosis and associations of survival with surgical intervention, radiation, PD diagnosis, and prescription of metformin, beta-blockers, ACEIs, or ARBs. RESULTS: There were 1,943 patients who met study criteria, and the median age was 74 years. When medication utilization was stratified by none, pre-diagnosis only, post-diagnosis only, or both pre- and post-diagnosis (continuous), continuous utilization of metformin, beta-blockers, ACEIs, or ARBs was associated with prolonged survival compared to no utilization (hazard ratio [HR]:0.45, 95% CI:0.33-0.62; HR:0.71. 95% CI:0.59-0.86; HR:0.59, 95% CI:0.48-0.72; and HR:0.45, 95% CI:0.35-0.58 respectively). PD was also associated with longer survival (HR:0.59-0.63 across the four models). DISCUSSION: Our study suggests that metformin, beta-blockers, ACEIs, ARBs, and comorbid PD are associated with a survival benefit among geriatric Medicare patients with supratentorial PMBTs.

Electron microscopic analysis of the influence of iPSC-derived motor neurons on bioengineered human skeletal muscle tissues.

3D bioengineered skeletal muscle macrotissues are increasingly important for studies of cell biology and development of therapeutics. Tissues derived from immortalized cells obtained from patient samples, or from pluripotent stem cells, can be co-cultured with motor-neurons to create models of human neuromuscular junctions in culture. In this study, we present foundational work on 3D cultured muscle ultrastructure, with and without motor neurons, which is enabled by the development of a new co-culture platform. Our results show that tissues from Duchenne muscular dystrophy patients are poorly organized compared to tissues grown from healthy donor and that the presence of motor neurons invariably improves sarcomere organization. Electron micrographs show that in the presence of motor neurons, filament directionality, banding patterns, z-disc continuity, and the appearance of presumptive SSR and T-tubule profiles all improve in healthy, DMD-, and iPSC-derived muscle tissue. Further work to identify the underlying defects of DMD tissue disorganization and the mechanisms by which motor neurons support muscle are likely to yield potential new therapeutic approaches for treating patients suffering from Duchenne muscular dystrophy.

Altered Outer Retinal Structure, Electrophysiology and Visual Perception in Parkinson's Disease.

BACKGROUND: Visual biomarkers of Parkinson's disease (PD) are attractive as the retina is an outpouching of the brain. Although inner retinal neurodegeneration in PD is well-established this has overlap with other neurodegenerative diseases and thus outer retinal (photoreceptor) measures warrant further investigation. OBJECTIVE: To examine in a cross-sectional study whether clinically implementable measures targeting outer retinal function and structure can differentiate PD from healthy ageing and whether these are sensitive to intraday levodopa (L-DOPA) dosing. METHODS: Centre-surround perceptual contrast suppression, macular visual field sensitivity, colour discrimination, light-adapted electroretinography and optical coherence tomography (OCT) were tested in PD participants (n = 16) and controls (n = 21). Electroretinography and OCT were conducted before and after midday L-DOPA in PD participants, or repeated after ∼2 hours in controls. RESULTS: PD participants had decreased center-surround contrast suppression (p < 0.01), reduced macular visual field sensitivity (p < 0.05), color vision impairment (p < 0.01) photoreceptor dysfunction (a-wave, p < 0.01) and photoreceptor neurodegeneration (outer nuclear layer thinning, p < 0.05), relative to controls. Effect size comparison between inner and outer retinal parameters showed that photoreceptor metrics were similarly robust in differentiating the PD group from age-matched controls as inner retinal changes. Electroretinography and OCT were unaffected by L-DOPA treatment or time. CONCLUSIONS: We show that outer retinal outcomes of photoreceptoral dysfunction (decreased cone function and impaired color vision) and degeneration (i.e., outer nuclear layer thinning) were equivalent to inner retinal metrics at differentiating PD from healthy age-matched adults. These findings suggest outer retinal metrics may serve as useful biomarkers for PD.