Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months.

BACKGROUND: BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, conditionally approved, or authorized for emergency use worldwide. At the time of initial authorization, data beyond 2 months after vaccination were unavailable. METHODS: In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 participants 12 to 15 years of age to receive two 30-µg doses, at 21 days apart, of BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory-confirmed Covid-19 and safety, which were both evaluated through 6 months after vaccination. RESULTS: BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few participants had adverse events leading to withdrawal from the trial. Vaccine efficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2) through 6 months of follow-up among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in populations with diverse ages, sexes, race or ethnic groups, and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was predominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed. CONCLUSIONS: Through 6 months of follow-up and despite a gradual decline in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. METHODS: In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 µg per dose). BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. RESULTS: A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. CONCLUSIONS: A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).

Guideline: Vulvovaginal candidosis (AWMF 015/072, level S2k).

Approximately 70-75% of women will have vulvovaginal candidosis (VVC) at least once in their lifetime. In premenopausal, pregnant, asymptomatic and healthy women and women with acute VVC, Candida albicans is the predominant species. The diagnosis of VVC should be based on clinical symptoms and microscopic detection of pseudohyphae. Symptoms alone do not allow reliable differentiation of the causes of vaginitis. In recurrent or complicated cases, diagnostics should involve fungal culture with species identification. Serological determination of antibody titres has no role in VVC. Before the induction of therapy, VVC should always be medically confirmed. Acute VVC can be treated with local imidazoles, polyenes or ciclopirox olamine, using vaginal tablets, ovules or creams. Triazoles can also be prescribed orally, together with antifungal creams, for the treatment of the vulva. Commonly available antimycotics are generally well tolerated, and the different regimens show similarly good results. Antiseptics are potentially effective but act against the physiological vaginal flora. Neither a woman with asymptomatic colonisation nor an asymptomatic sexual partner should be treated. Women with chronic recurrent Candida albicans vulvovaginitis should undergo dose-reducing maintenance therapy with oral triazoles. Unnecessary antimycotic therapies should always be avoided, and non-albicans vaginitis should be treated with alternative antifungal agents. In the last 6 weeks of pregnancy, women should receive antifungal treatment to reduce the risk of vertical transmission, oral thrush and diaper dermatitis of the newborn. Local treatment is preferred during pregnancy.

Upper cervical two-point discrimination thresholds in migraine patients and headache-free controls.

BACKGROUND: Chronic pain including migraine is associated with structural and functional changes in the somatosensory cortex. Previous reports proposed two-point discrimination (TPD) as a measurement for cortical alterations. Limited evidence exists for tactile acuity in the neck and no data is available for migraine. METHODS: To introduce a standardized protocol for the measurement of TPD in the upper cervical spine, 51 healthy participants were investigated with a newly developed paradigm which was evaluated for intra-rater reliability. The same protocol was applied by two further examiners to 28 migraine patients and 21 age-, and gender-matched healthy controls to investigate inter-rater reliability and between group differences. RESULTS: Results indicated excellent intra-rater (right ICC(2,4) = 0.82, left ICC(2,4) = 0.83) and good inter-rater reliability (right ICC(2,4) = 0.70, left ICC(2,4) = 0.75). Migraine patients had larger TPD thresholds (26.86 ± 7.21) than healthy controls (23.30 ± 6.17) but these became only statistically significant for the right side of the neck (p = 0.02). There was a significant, moderate association with age for the right side (r = 0.42 p = 0.002, n = 51), and less strong association for the left side (r = 0.34, p = 0.14) in healthy individuals. TPD did not correlate with headache days per month or the dominant headache side in migraine patients. CONCLUSIONS: Surprisingly, migraine patients showed increased TPD thresholds in the upper cervical spine interictally. Although a body of evidence supports that hypersensitivity is part of the migraine attack, the current report indicates that interictally, migraine patients showed worse tactile acuity similar to other chronic pain populations. This has been hypothesized to indicate structural and functional re-organisation of the somatosensory cortex.

Prospective evaluation to characterize the real-world performance of the EMBOVAC aspiration catheter for neurothrombectomy: a post-market clinical follow-up trial.

BACKGROUND: A direct aspiration first pass technique (ADAPT) is an effective alternative to stent retriever thrombectomy for patients with large vessel occlusion (LVO). The PERFECT study evaluated direct aspiration with the EMBOVAC large bore aspiration catheter in patients with LVO strokes. METHODS: PERFECT was a prospective, post-market, single-arm, multicenter, observational study of patients enrolled across 11 European centers between October 2020 and July 2022. Three direct aspiration passes with EMBOVAC were mandated before switching strategy. The primary endpoint was core-lab assessed successful reperfusion (modified Thrombolysis In Cerebral Infarction (mTICI) ≥2b) post-procedure. Other outcomes included first pass mTICI ≥2c, independent 90-day modified Rankin Scale (mRS) evaluation, and symptomatic intracerebral hemorrhage (sICH) at 24 hours by a clinical events committee. RESULTS: EMBOVAC was used in 100 patients (mean age 70.4±14.0 years, 59.0% (59/100) female). Final mTICI ≥2b was achieved in 98.0% (97/99), final mTICI ≥2b with no change in frontline therapy or thrombolytics use during the procedure was achieved in 87.9% (87/99), final mTICI ≥2c in 86.9% (86/99), and first pass mTICI ≥2c in 53.5% (53/99). sICH at 24 hours was 0%. The 90-day mRS ≤2 rate was 56.6% (56/99) and all-cause mortality was 12.9%. One device-related serious adverse event occurred within 90 days (1.0%). CONCLUSIONS: PERFECT demonstrates that EMBOVAC achieves successful reperfusion rates and favorable clinical outcomes when used in the endovascular treatment of acute ischemic stroke (AIS) using a direct aspiration technique as first line therapy in a real-world setting in patients with AIS secondary to large vessel occlusion. TRIAL REGISTRATION: www. CLINICALTRIALS: gov Unique identifier: NCT04531904.

The respiratory syncytial virus prefusion F protein vaccine attenuates the severity of respiratory syncytial virus-associated disease in breakthrough infections in adults ≥60 years of age.

Background: Respiratory syncytial virus (RSV) is a contagious pathogen causing acute respiratory infections (ARIs). Symptoms range from mild upper respiratory tract infections to potentially life-threatening lower respiratory tract disease (LRTD). In adults ≥60 years old, vaccine efficacy of a candidate vaccine for older adults (RSVPreF3 OA) was 71.7% against RSV-ARI and 82.6% against RSV-LRTD (AReSVi-006/NCT04886596). We present the patient-reported outcomes (PROs) from the same trial at the end of the first RSV season in the northern hemisphere (April 2022). Methods: In this phase 3 trial, adults aged ≥60 years were randomized (1:1) to receive one dose of RSVPreF3 OA vaccine or placebo. PROs were assessed using InFLUenza Patient-Reported Outcome (FLU-PRO), Short Form-12 (SF-12), and EuroQol-5 Dimension (EQ-5D) questionnaires. Peak FLU-PRO Chest/Respiratory scores during the first 7 days from ARI episode onset were compared using a Wilcoxon test. Least squares mean (LSMean) of SF-12 physical functioning (PF) and EQ-5D health utility scores were estimated using mixed effects models. Results: In the RSVPreF3 OA group (N = 12,466), 27 first RSV-ARI episodes were observed versus 95 in the Placebo group (N = 12,494). Median peak FLU-PRO Chest/Respiratory scores were lower in RSVPreF3 OA (1.07) versus Placebo group (1.86); p = 0.0258. LSMean group differences for the PF and EQ-5D health utility score were 7.00 (95% confidence interval [CI]: -9.86, 23.85; p = 0.4125) and 0.0786 (95% CI: -0.0340, 0.1913; p = 0.1695). Conclusions: The RSVPreF3 OA vaccine, in addition to preventing infection, attenuated the severity of RSV-associated symptoms in breakthrough infections, with trends of reduced impact on PF and health utility.

Efficacy and safety of diclofenac diethylamine 1.16% gel in acute neck pain: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Neck pain (NP) is a common musculoskeletal disorder in primary care that frequently causes discomfort. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to reduce neck pain and associated inflammation and facilitate earlier recovery. Topical diclofenac diethylamine (DDEA) 1.16% gel is clinically proven to be effective and well tolerated in acute and chronic musculoskeletal conditions, but until now no clinical data existed for its use in acute NP. The aim of this study was to assess the efficacy and safety of DDEA 1.16% gel compared with placebo gel in acute NP. METHODS: In a randomized, double-blind, placebo-controlled study, patients with acute NP (n = 72) were treated with DDEA 1.16% gel (2 g, 4x/day, for 5 days) or placebo. Efficacy assessments included pain-on-movement (POM), pain-at-rest (PAR), functional neck disability index (NDI) and response to treatment (decrease in POM by 50% after 48 h). Adverse events (AEs) were recorded throughout the study. RESULTS: The primary outcome, POM at 48 h, was statistically significantly lower with DDEA gel (19.5 mm) vs. placebo (56.9 mm) (p < 0.0001), representing a clinically relevant decrease from baseline (75% vs. 23%, respectively). All POM scores were significantly lower with DDEA gel vs. placebo from 1 h, as were PAR and NDI scores from first assessment (24 h) onwards (all p < 0.0001). Response to treatment was significantly higher with DDEA gel (94.4%) vs. placebo (8.3%) (p < 0.0001). There were no AEs with DDEA gel. CONCLUSIONS: DDEA 1.16% gel, which is available over-the-counter, was effective and well tolerated in the treatment of acute neck pain. The tools used to assess efficacy suggest that it quickly reduced neck pain and improved neck function. However, questions remain regarding the comparability and validity of such tools. Further studies will help ascertain whether DDEA 1.16% gel offers an alternative treatment option in this common, often debilitating condition. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01335724.

Combination of comfrey root extract plus methyl nicotinate in patients with conditions of acute upper or low back pain: a multicentre randomised controlled trial.

This randomised, multicentre, double-blind, three-arm, placebo-controlled trial compared a topical combination of 35% comfrey root extract plus 1.2% methyl nicotinate versus a single preparation of methyl nicotinate or placebo cream for relief of acute upper or low back pain. 379 patients were randomly assigned to three groups (combination, n = 163; methyl nicotinate, n = 164; placebo, n = 52). They applied a 12 cm layer of cream three times daily for 5 days. The primary efficacy variable was the area under the curve (AUC) of the visual analogue scale (VAS) on active standardised movement values at visits 1 to 4. Secondary measures included back pain at rest, pressure algometry, consumption of analgesic medication, functional impairment measured with Oswestry Disability Index, and global assessment of response. The AUC of the VAS on active standardised movement was markedly smaller in the combination treatment group than in the methyl nicotinate and in the placebo group (ANOVA: p < 0.0001). The combination demonstrated superiority to the two other treatment arms, while methyl nicotinate displayed a considerable effect as well.

Diagnosing different binge-eating disorders based on reward-related brain activation patterns.

This study addresses how visual food cues are encoded in reward related brain areas and whether this encoding might provide information to differentiate between patients suffering from eating disorders [binge-eating disorder (BED) and bulimia nervosa (BN)], overweight controls (C-OW), and normal-weight controls (C-NW). Participants passively viewed pictures of food stimuli and neutral stimuli in a cue reactivity design. Two classification analyses were conducted. First, we used multivariate pattern recognition techniques to decode the category of a currently viewed picture from local brain activity patterns. In the second analysis, we applied an ensemble classifier to predict the clinical status of subjects (BED, BN, C-OW, and C-NW) based on food-related brain response patterns. The left insular cortex separated between food and neutral contents in all four groups. Patterns in the right insular cortex provided a maximum diagnostic accuracy for the separation of BED patients and C-NW (86% accuracy, P < 10(-5) , 82% sensitivity, and 90% specificity) as well as BN patients and C-NW (78% accuracy, P = 0.001, 86% sensitivity, and 70% specificity). The right ventral striatum separated maximally between BED patients and C-OW (71% accuracy, P = 0.013, 59% sensitivity, and 82% specificity). The right lateral orbitofrontal cortex separated maximally between BN patients and C-OW (86% accuracy, P < 10(-4) , 79% sensitivity, and 94% specificity). The best differential diagnostic separation between BED and BN patients was obtained in the left ventral striatum (84% accuracy, P < 10(-3) , 82% sensitivity, and 86% specificity). Our results indicate that pattern recognition techniques are able to contribute to a reliable differential diagnosis of BN and BED.

Efficacy of two dosing schemes of a liquid containing ivy leaves dry extract EA 575 versus placebo in the treatment of acute bronchitis in adults.

INTRODUCTION: The results of a clinical trial published in 2016 showed the efficacy of ivy leaves dry extract EA 575 versus placebo in the treatment of patients suffering from acute cough. A clinical trial with a very similar design was conducted to not only show the reproducibility of former results but also to investigate an alternative dosing scheme. METHODS: This randomised, placebo-controlled, multicentre, double-blind clinical trial was conducted to assess the efficacy and safety of a liquid containing EA 575 in the treatment of acute bronchitis. A total of 209 patients were treated with a liquid containing EA 575 as an active investigational medicinal product (verum) either two (7.5 mL) or three (5 mL) times a day or placebo in the respective dosing scheme for 1 week, with a total observational period of 2 weeks. The primary efficacy outcome was a change in Bronchitis Severity Score (BSS) of the pooled placebo and pooled verum groups between visits 1 and 5. Additional secondary parameters were assessed, including, for example, change in cough severity as assessed by a visual analogue scale (VAS) and the Verbal Category Descriptive (VCD) score. RESULTS: Superiority of verum over placebo was during and at the end of treatment, as measured by BSS. No significant differences between the dosing schemes were observed. VCD scores and VAS measurements also showed the superiority of verum over placebo. CONCLUSION: The existing data on the clinical efficacy of EA 575 were confirmed. Furthermore, a new dosing scheme was shown to be noninferior to the currently used scheme while maintaining the safety and tolerability of the well-established cough liquid containing EA 575.

From Maps to Multi-dimensional Network Mechanisms of Mental Disorders.

The development of advanced neuroimaging techniques and their deployment in large cohorts has enabled an assessment of functional and structural brain network architecture at an unprecedented level of detail. Across many temporal and spatial scales, network neuroscience has emerged as a central focus of intellectual efforts, seeking meaningful descriptions of brain networks and explanatory sets of network features that underlie circuit function in health and dysfunction in disease. However, the tools of network science commonly deployed provide insight into brain function at a fundamentally descriptive level, often failing to identify (patho-)physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Here we describe recently developed techniques stemming from advances in complex systems and network science that have the potential to overcome this limitation, thereby contributing mechanistic insights into neuroanatomy, functional dynamics, and pathology. Finally, we build on the Research Domain Criteria framework, highlighting the notion that mental illnesses can be conceptualized as dysfunctions of neural circuitry present across conventional diagnostic boundaries, to sketch how network-based methods can be combined with pharmacological, intermediate phenotype, genetic, and magnetic stimulation studies to probe mechanisms of psychopathology.