Comparative effectiveness of clozapine and non-clozapine atypical antipsychotics provided by the Brazilian National Health System in adults with schizophrenia.

Introduction: Currently, 21 million people live with the disease, mostly in low to middle-income countries. We aimed to assess the survival of patients with schizophrenia using clozapine compared with non-clozapine atypical antipsychotics provided by the Brazilian National Health System using real-world data. Materials and methods: This is an open retrospective cohort study of patients diagnosed with schizophrenia to whom atypical antipsychotics were dispensed by the Brazilian National Health System between 2000 and 2015, based on deterministic-probabilistic pairing of administrative data records. The Kaplan-Meier method was used to estimate the cumulative probability of survival and the Cox proportional hazards model was adjusted to assess the risk factors for survival via the hazard ratio (HR). Result: Participants were 375,352 adults with schizophrenia, with an overall survival rate of 76.0% (95%CI 75.0-76.0) at the end of the cohort. Multivariate analysis indicated a greater risk of death for men (HR=1.30; 95%CI 1.27-1.32), older adults (HR=17.05; 95%CI 16.52-17.60), and in the Southeast region of Brazil (HR=1.20; 95%CI 1.17-1.23). Patients who used non-clozapine atypical antipsychotics had a 21% greater risk of death when compared to those taking clozapine (HR=1.21; 95%CI 1.14-1.29). Additionally, a history of hospitalization for pneumonia (HR=2.17; 95%CI 2.11-2.23) was the main clinical variable associated with increased risk of death, followed by hospitalization for lung cancer (HR=1.82; 95%CI 1.58-2.08), cardiovascular diseases (HR=1.44; 95%CI 1.40-1.49) and any type of neoplasia (HR=1.29; 95%CI 1.19-1.40). Discussion: This is the first published Brazilian cohort study that evaluated survival in people with schizophrenia, highlighting the impact of atypical antipsychotics. In this real-world analysis, the use of clozapine had a protective effect on survival when compared to olanzapine, risperidone, quetiapine, and ziprasidone.

Effects of Multistrain Probiotic Supplementation on Sows' Emotional and Cognitive States and Progeny Welfare.

The intensification of production systems has resulted in detrimental effects on sow welfare, which can have an adverse influence on their offspring. Considering the relevance of the microbiota-gut-brain axis, probiotics can mitigate such impacts. To investigate the effects of the dietary inclusion of probiotics on the welfare of sows and piglets, 147 multiparous sows were randomly assigned to two groups: a control group or a group supplemented with a multistrain probiotic from the beginning of pregnancy to the end of lactation. The human-animal relationship (HAR), stereotypic behavior, position changes, salivary cortisol, and plasma serotonin levels were assessed in the sows. The piglets' back test behavior and organ weight were analyzed. The probiotic-supplemented sows exhibited a better HAR index (p = 0.017), which indicated reduced aversion towards humans. The frequency of stereotypies was not influenced by the treatments. However, the supplemented sows spent more time standing (p = 0.054) and less time lying down (p = 0.008). The cortisol level of the supplemented sows was 50% lower (p = 0.047) and the serotonin levels were 11% higher (p = 0.034) than control animals. The multistrain piglets were more passive and less resistant (p = 0.076) in the back test. The organ weights were not influenced by treatments. In conclusion, the sows supplemented with probiotics showed less fear and more motivation indicators, while their piglets showed less aggression behaviors.

Clinical benefits and economic cost-savings of remote electrical neuromodulation (REN) for migraine prevention.

AIMS: Assess the clinical benefits and associated direct and indirect cost-savings from Remote Electrical Neuromodulation (REN) for migraine prevention. METHODS: REN, a prescribed, wearable, FDA-cleared neuromodulation-device for acute and/or preventive treatment of migraine, recently demonstrated efficacy for migraine prevention when used every-other-day, in a prospective, randomized, double-blind, placebo-controlled, multi-center study. Following baseline (4-weeks), subjects underwent treatment with REN or placebo (8-weeks), and electronically reported migraine symptoms and acute treatments daily. Therapeutic-gain was the between-groups difference (REN minus placebo) in change from baseline to the second month of intervention. Health-economics impact was derived as cost-savings associated with REN's clinical benefits. RESULTS: Out of 248 subjects randomized (128 active, 120 placebo), 179 (95:84) qualified for modified intention-to-treat (mITT) analysis. Significant therapeutic gains favoring REN vs. placebo were found (Tepper et al. 2023), including mean (±SD) reduction in number of acute medication days (3.5 ± 0.4 vs. 1.2 ± 0.5; gain = 2.2; p = .001) and presenteeism days (2.7 ± 0.3 vs. 1.1 ± 0.4; gain = 1.6, p = .001). Mean changes of provider visits (reduction of 0.09 ± 0.1 vs. increase of 0.08 ± 0.2; p = .297), and reduction of absenteeism days (0.07 ± 0.1 vs. 0.07 ± 0.2; p = .997) were not significant. Mean annual cost-saving for one patient using REN for migraine prevention estimated $10,000 (±$1,777) from reductions in these four clinical outcomes relative to baseline without REN treatment. Extrapolated to a hypothetical US commercial health-plan of one-million covered lives, assuming the national prevalence of migraine patients on preventive treatment, annual mean (±SE) cost-saving from using REN migraine prevention estimated $560.0 million (±$99.5 million) from reduction in direct (∼$330 millionm) and indirect costs (∼$230 millionm) measured. LIMITATIONS: Clinical and cost-savings benefits presented are conservative, assessed only from endpoints measured in the clinical trial. Moreover, some of the endpoints had only scarce or no occurrences during the study period. CONCLUSIONS: Coverage of the REN-device for migraine prevention may significantly reduce disease-burden and save a one-million-member payer plan at least $560 million per year.

Migraine affects more than 1 billion people worldwide, causing significant disability and substantial clinical economic burden. Remote Electrical Neuromodulation (REN) is a prescribed, wearable, non-pharmacological, non-invasive device (Nerivio), indicated for acute and/or preventive treatment of migraine with or without aura in patients 12 years and older. Efficacy of REN for migraine prevention was recently demonstrated in a randomized, blinded, placebo-controlled clinical-trial. This study further analyzes clinical benefits from endpoints measured in the clinical-trial as well as their associated direct and indirect costs. Out of 248 subjects randomized (128 active, 120 placebo), 179 (95:84) qualified for modified intention-to-treat (mITT) analysis. Significant therapeutic gains favoring REN over placebo were found, including an average reduction of 3.4 acute medication days/month, and an average reduction of 2.7 presenteeism days/month. A reduction in the number of provider visits and absenteeism days was also reported, though not significantly differed from changes in the control group. Mean annual cost-saving from reductions in these four clinical outcomes relative to baseline without REN treatment for a patient using REN for migraine prevention estimated $10,000. Extrapolated to a hypothetical US commercial health-plan of one million covered lives, annual mean cost-saving from using REN for migraine prevention is estimated to be $560.0 million, composed of $327.8 million direct costs and $232.2 million indirect costs. Thus, REN preventive treatment for migraine reduces disease burden and leads to meaningful cost-saving, both direct and indirect, proposing clinical and financial incentives for patients, health insurance systems, and employers to utilize REN for migraine prevention.

Remote Electrical Neuromodulation for the Acute Treatment of Migraine in Patients with Chronic Migraine: An Open-Label Pilot Study.

INTRODUCTION: Remote electrical neuromodulation (REN) is a novel acute treatment of migraine. Upper arm peripheral nerves are stimulated to induce conditioned pain modulation (CPM)-an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. The REN device (Nerivio®, Theranica Bio-Electronics LTD., Israel) is FDA-authorized for acute treatment of migraine in adults who do not have chronic migraine. The current study assessed the consistency of response over multiple migraine attacks in people with chronic migraine who are typically characterized with severe pain intensity, high disability, and less robust response to triptans. METHODS: This was an open-label, single-arm, dual-center study conducted on adults with chronic migraine. Participants underwent a 4-week treatment phase in which they treated their migraine headaches with the device for 45 min within 1 h of attack onset. Pain levels were recorded at baseline, 2 h, and 24 h post-treatment. Efficacy outcomes (pain relief and pain-free responses at 2 h, sustained pain relief and sustained pain-free responses at 24 h) focused on intra-individual consistency of response across multiple attacks, which was defined as response in at least 50% of the treatments. RESULTS: Forty-two participants were enrolled, and 38 participants were evaluable for analyses; 73.7% (28/38) achieved pain relief at 2 h, 26.3% (10/38) were pain-free at 2 h, 84.4% (27/32) had sustained pain relief response at 24 h and 45.0% (9/20) had sustained pain relief response at 24 h in at least 50% of their treated attacks. The effects of REN on associated symptoms and improvement in function were also consistent. The incidence of device-related adverse events was low (1.8%). CONCLUSIONS: REN used for a series of migraine attacks was effective and well tolerated across attacks. REN may offer a safe and effective non-pharmacological alternative for acute treatment in patients with chronic migraine. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04161807. Retrospectively registered on November 13, 2019.

Correlation between insemination dose and bovine sperm traits on the in vitro embryo production outcomes / Correlação da dose inseminante e características do sêmen bovino no sucesso da produção in vitro de embriões

In the present study we aimed to test the best insemination dose for in vitro embryo production (IVEP) and to correlate sperm traits in bovine. In vitro matured oocytes were inseminated with three different sperm concentrations of the same bull: G1 (1*106), G2 (2*106) and G3 (4*106) sperm/mL. At 18 h post-insemination (hpi), presumptive zygotes [G1 (n=114), G2 (n=139) and G3 (n=136)] were stained to evaluate the pronuclei numbers, or continued to in vitro culture [G1 (n=102), G2 (n=111) and G3 (n=106)]. Sperm kinetics were analyzed using Computer-Assisted Semen Analysis (CASA). Sperm plasma membrane, acrosome integrity and mitochondrial activity were analyzed using fluorescent probes. In vitro fertilization (IVF) and IVEP data were compared using chi-square (P<0.05) and correlated with CASA and fluorescence data using Person Correlation (P<0.05). The IVF efficiency, cleavage and total blastocyst rates did not show any significant difference (P>0.05) among the groups. In G3, the polyspermy rate was the highest (7.4%; P<0.05) without difference (P>0.05) between G1 (0%) and G2 (0%). In G1, the early blastocyst rate was the highest (7.8%; P<0.05), without significant difference (P>0.05) between G2 (1.8%) and G3 (0.9%). The IVF efficiency and total blastocyst rates were positively correlated with curvilinear velocity (VCL) (r≃+1; P<0.05). We concluded that the reduction of insemination dose may negatively affect embryo development and VCL may be used as a parameter to improve the IVEP outcomes.

O objetivo deste estudo foi testar a melhor dose inseminante para a produção de embriões in vitro (IVEP) e sua correlação com as características espermáticas na espécie bovina. Oócitos maturados in vitro foram inseminados com três concentrações diferentes de espermatozoides de único touro: G1 (1*106), G2 (2*106) e G3 (4*106) espermatozoides/mL. Às 18h pós-inseminação (hpi), os presumíveis zigotos [G1 (114), G2 (139) e G3 (136)] foram corados para avaliar o número de pronúcleos, ou continuaram para o cultivo in vitro [G1 (102), G2 (111) e G3 (106)]. Os parâmetros da cinética espermática foram analisados usando o Computer-Assisted Semen Analysis (CASA). A integridade de membrana plasmática espermática, acrossomal e a atividade mitocondrial foram analisadas usando sondas fluorescentes. Os dados da fertilização in vitro (FIV) e IVEP foram comparadas com qui-quadrado (P=0,05) e correlacionados com dados de CASA e Fluorescência usando Correlação de Pearson (r=±1; P<0,05). A eficiência da FIV, taxas de clivagem e blastocisto total não mostraram diferença significativa (P>0,05) entre os grupos. Em G3, a taxa de polispermia foi a maior (7,4%; P<0,05), sem diferença (P>0,05) entre G1 (0%) e G2 (0%). Em G1, a taxa de blastocisto inicial foi a maior (7,8%; P<0,05), sem apresentar diferença significativa (P>0,05) com G2 (1,8%) e G3 (0,9%). A eficiência de FIV e a taxa de blastocisto total foram positivamente correlacionadas com velocidade curvilinear (VCL) (P<0,05). Concluímos que a dose inseminante reduzida pode negativamente afetar o desenvolvimento embrionário e VCL pode ser usada como parâmetro para melhorar os resultados da PEIV.

Association Between Obesity and Migraine in Women.

PURPOSE OF REVIEW: Migraine is a common and highly disabling condition that is particularly prevalent among women and especially women of reproductive age. The tremendous rise in adiposity in the Western world has led to an epidemic of obesity in women. The particular effects of obesity on women with migraine of various ages are the focus of this review. RECENT FINDINGS: Conflicting findings from various studies with different approaches and populations have made challenging definitive conclusions about associations between migraine and obesity. While the association between obesity and migraine frequency has been consistently demonstrated and obesity is considered a risk factor for progression from episodic to chronic migraine, the association between obesity and migraine prevalence is still somewhat debated and appears to be dependent on gender and age, with the most consistent effects observed in women younger than 55 years of age. Association between migraine and obesity is most commonly observed in women of reproductive age. The multimodal changes associated with age and hormonal change in women likely play a role in this relationship, as obesity does not appear to be related to migraine in women over 55 years of age. Future studies focusing on the migraine-obesity relationship in women should examine the effects of age, endogenous hormonal state, and exogenous hormones on migraine and obesity.

Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study.

BACKGROUND AND PURPOSE: Diabetes increases stroke risk, but whether diabetes status immediately before stroke improves prediction and whether duration is important are less clear. We hypothesized that diabetes duration independently predicts ischemic stroke. METHODS: Among 3298 stroke-free participants in the Northern Manhattan Study, baseline diabetes and age at diagnosis were determined. Incident diabetes was assessed annually (median, 9 years). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CI for incident ischemic stroke using baseline diabetes, diabetes as a time-dependent covariate, and duration of diabetes as a time-varying covariate; models were adjusted for demographic and cardiovascular risk factors. RESULTS: Mean age was 69 ± 10 years (52% Hispanic, 21% white, and 24% black); 22% had diabetes at baseline and 10% had development of diabetes. There were 244 ischemic strokes, and both baseline diabetes (HR, 2.5; 95% CI, 1.9-3.3) and diabetes considered as a time-dependent covariate (HR, 2.4; 95% CI, 1.8-3.2) were similarly associated with stroke risk. Duration of diabetes was associated with ischemic stroke (adjusted HR, 1.03 per year with diabetes; 95% CI, 1.02-1.04). Compared to nondiabetic participants, those with diabetes for 0 to 5 years (adjusted HR, 1.7; 95% CI, 1.1-2.7), 5 to 10 years (adjusted HR, 1.8; 95% CI, 1.1-3.0), and ≥ 10 years (adjusted HR, 3.2; 95% CI, 2.4-4.5) were at increased risk. CONCLUSIONS: Duration of diabetes is independently associated with ischemic stroke risk adjusting for risk factors. The risk increases 3% each year, and triples with diabetes ≥ 10 years.

Too good to treat? Outcomes in patients not receiving thrombolysis due to mild deficits or rapidly improving symptoms.

INTRODUCTION: Among ischemic stroke patients arriving within the treatment window, rapidly improving symptoms or having a mild deficit (i.e. too good to treat) is a common reason for exclusion. Several studies have reported poor outcomes in this group. We addressed the question of early neurological deterioration in too good to treat patients in a larger prospective cohort study. METHODS: Admission and discharge information were collected prospectively in acute stroke patients who presented to the emergency room within three-hours from onset. The primary outcome measure was change in the National Institutes of Health Stroke Scale from baseline to discharge. Secondary outcomes were discharge National Institutes of Health Stroke Scale >4, not being discharged home, and discharge modified Rankin scale. RESULTS: Of 355 patients who presented within three-hours, 127 (35·8%) had too good to treat listed as the only reason for not receiving thrombolysis, with median admission National Institutes of Health Stroke Scale = 1 (range = 0 to 19). At discharge, seven (5·5%) showed a worsening of National Institutes of Health Stroke Scale ≥1, and nine (7·1%) had a National Institutes of Health Stroke Scale >4. When excluding prior stroke (remaining n = 97), discharge status was even more benign: only five (5·2%) had a discharge National Institutes of Health Stroke Scale >4, and two (2·1%) patients were not discharged home. CONCLUSION: We found that a small proportion of patients deemed too good to treat will have early neurological deterioration, in contrast to other studies. Decisions about whether to treat mild stroke patients depend on the outcome measure chosen, particularly when considering discharge disposition among patients who have had prior stroke. The decision to thrombolyze may ultimately rest on the nature of the presentation and deficit.

The metabolic syndrome and cognitive performance: the Northern Manhattan Study.

BACKGROUND: The metabolic syndrome (MetS) is a risk factor for diabetes, stroke, myocardial infarction, and increased mortality, and has been associated with cognition in some populations. We hypothesized that MetS would be associated with lower Mini-Mental State Examination (MMSE) scores in a multi-ethnic population, and that MetS is a better predictor of cognition than its individual components or diabetes. METHODS: We conducted a cross-sectional analysis among 3,150 stroke-free participants. MetS was defined by the modified National Cholesterol Education Program guidelines-Adult Treatment Panel III (NCEP-ATPIII) criteria. Linear regression and polytomous logistic regression estimated the association between MMSE score and MetS, its individual components, diabetes, and inflammatory biomarkers. RESULTS: MetS was inversely associated with MMSE score (unadjusted ß = -0.67; 95% CI -0.92, -0.41). Adjusting for potential confounders, MetS was associated with lower MMSE score (adjusted ß = -0.24; 95% CI -0.47, -0.01), but its individual components and diabetes were not. Those with MetS were more likely to have an MMSE score of <18 than a score of ≥ 24 (adjusted OR = 1.94; 95% CI 1.26, 3.01). There was an interaction between MetS and race-ethnicity, such that MetS was associated with lower MMSE score among non-Hispanic whites and Hispanics but not non-Hispanic blacks. CONCLUSIONS: MetS was associated with lower cognition in a multi-ethnic population. Further studies of the effect of MetS on cognition are warranted, and should account for demographic differences.

Symptomatic intracerebral hemorrhage among eligible warfarin-treated patients receiving intravenous tissue plasminogen activator for acute ischemic stroke.

OBJECTIVE: To determine whether warfarin-treated patients with an international normalized ratio less than 1.7 who receive intravenous tissue plasminogen activator for acute ischemic stroke are at increased risk for symptomatic intracerebral hemorrhage. DESIGN: Retrospective study. SETTING: Academic hospital. PATIENTS: Consecutive patients with acute ischemic stroke who are treated with intravenous tissue plasminogen activator. MAIN OUTCOME MEASURE: Symptomatic intracerebral hemorrhage. RESULTS: One hundred seven patients were included (mean age, 69.2 years; 43.9% men; median National Institutes of Health Stroke Scale score, 14; median onset-to-treatment time, 140 minutes; baseline warfarin use, 12.1%). The median international normalized ratio was 1.04 (range, 0.82-1.61). The overall rate of symptomatic intracerebral hemorrhage was 6.5%, but it was nearly 10-fold higher among patients taking warfarin compared with those not taking warfarin at baseline (30.8% vs 3.2%, respectively; P = .004). Baseline warfarin use remained strongly associated with symptomatic intracerebral hemorrhage (P = .004) after adjusting for relevant covariates, including age, atrial fibrillation, National Institutes of Health Stroke Scale score, and international normalized ratio. CONCLUSIONS: Despite an international normalized ratio less than 1.7, warfarin-treated patients are more likely than those not taking warfarin to experience symptomatic intracerebral hemorrhage following treatment with intravenous tissue plasminogen activator. Larger studies in this subgroup are warranted.

Toxoplasma gondii: the role of IFN-gamma, TNFRp55 and iNOS in inflammatory changes during infection.

In order to examine the role of IFN-gamma, TNFRp55 and iNOS in inflammatory reaction during toxoplasmosis, IFN-gamma(-/-), TNFRp55(-/-) and iNOS(-/-) mice were experimentally infected with Toxoplasma gondii ME-49 strain. The organs of the mice were evaluated for histology and immunohistochemistry in detection of tissue parasitism and iNOS positive cells. IFN-gamma(-/-) mice presented mild inflammation in peripheral organs associated with a high parasitism and mortality in the acute phase of infection. In contrast, the peripheral organs of WT, TNFRp55(-/-) and iNOS(-/-) mice, presented a significant inflammatory reaction and low tissue parasitism in the same period of infection. The inflammatory lesions and tissue parasitism were increased and more severe in the Central Nervous System (CNS) of TNFRp55(-/-) and iNOS(-/-) with a progression of infection, when compared to WT mice. In these knockout animals, the inflammatory changes were associated with low levels or no expression of iNOS in TNFRp55(-/-) and iNOS(-/-) mice, respectively.

Laringe: falsas cordas vocais e as cordas verdadeiras / Larynx: false vocal cords and true vocal cords

O presente estudo tem a finalidade de ser uma revisão mais judiciosa da correlação anatomofisiológica entre as falsas cordas vocais e as cordas vocais verdadeiras. Também foram incluídos elementos fundamentais no funcionamento da laringe, tais como pressão torácica, tosse, espirro, pressão abdominal, trabalho de parto e bacia escápulo-umeral...

E o espirro, sai ou nao sai? / And the sneeze, does it get out or not?

O espirro podera ser definido como uma expiracao espasmodica que foi precedida por uma ou mais inspiracoes espasmodicas. A expiracao e temporariamente impedida pelo fechamento da nasofaringe e maior ou menor oclusao da boca. Quando se inicia a expiracao, ha uma rapida elevacao da pressao intrapulmonar, a qual, atingindo um certo valor, forca abrir bruscamente o componente nasofaringeo. Em vista disto, uma rajada de ar e levada atraves das fossas nasais, ao mesmo tempo em que a boca e parcialmente aberta, permitindo que certa porcao de ar passe por ela. O objetivo do espasmo esternutatorio e o deslocamento de muco, ou uma outra ordem de fluido, presente na superficie da mucosa nasal. O ato deste fenomeno e, em conjunto, totalmente complexo, podendo ser dividido, para fins didaticos, em duas fases: uma respiratoria e outra nasal, propriamente dita. Ambas as fases sao reflexas e envolvem dois mecanismos reflexos diferentes: um nasal e outro respiratorio. Ora, cada mecanismo consiste em nervos aferentes, mecanismo central, nervos eferentes e os orgaos correspondentes a eles.