Critical Behaviour of the Number of Minima of a Random Landscape at the Glass Transition Point and the Tracy-Widom distribution

We exploit a relation between the mean number $N_{m}$ of minima of random Gaussian surfaces and extreme eigenvalues of random matrices to understand the critical behaviour of $N_{m}$ in the simplest glass-like transition occuring in a toy model of a single particle in $N$-dimensional random environment, with $N\gg 1$. Varying the control parameter $\mu$ through the critical value $\mu_c$ we analyse in detail how $N_{m}(\mu)$ drops from being exponentially large in the glassy phase to $N_{m}(\mu)\sim 1$ on the other side of the transition. We also extract a subleading behaviour of $N_{m}(\mu)$ in both glassy and simple phases. The width $\delta{\mu}/\mu_c$ of the critical region is found to scale as $N^{-1/3}$ and inside that region $N_{m}(\mu)$ converges to a limiting shape expressed in terms of the Tracy-Widom distribution

Uncovering cryptic asexuality in Daphnia magna by RAD sequencing

The breeding systems of many organisms are cryptic and difficult to investigate with observational data, yet they have profound effects on a species’ ecology, evolution, and genome organization. Genomic approaches offer a novel, indirect way to investigate breeding systems, specifically by studying the transmission of genetic information from parents to offspring. Here we exemplify this method through an assessment of self-fertilization vs. automictic parthenogenesis in Daphnia magna. Self-fertilization reduces heterozygosity by 50% compared to the parents, but under automixis, whereby two haploid products from a single meiosis fuse, the expected heterozygosity reduction depends on whether the two meiotic products are separated during meiosis I or II (i.e., central vs. terminal fusion). Reviewing the existing literature and incorporating recombination interference, we derive an interchromosomal and an intrachromosomal prediction of how to distinguish various forms of automixis from self-fertilization using offspring heterozygosity data. We then test these predictions using RAD-sequencing data on presumed automictic diapause offspring of so-called nonmale producing strains and compare them with “self-fertilized” offspring produced by within-clone mating. The results unequivocally show that these offspring were produced by automixis, mostly, but not exclusively, through terminal fusion. However, the results also show that this conclusion was only possible owing to genome-wide heterozygosity data, with phenotypic data as well as data from microsatellite markers yielding inconclusive or even misleading results. Our study thus demonstrates how to use the power of genomic approaches for elucidating breeding systems, and it provides the first demonstration of automictic parthenogenesis in Daphnia

D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease

This is the published version. Copyright 2003 : American Society for Clinical Investigation.Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of the nigrostriatal dopaminergic neurons accompanied by a deficit in mitochondrial respiration. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes dopaminergic neurodegeneration and a mitochondrial deficit reminiscent of PD. Here we show that the infusion of the ketone body D-β-hydroxybutyrate (DβHB) in mice confers partial protection against dopaminergic neurodegeneration and motor deficits induced by MPTP. These effects appear to be mediated by a complex II–dependent mechanism that leads to improved mitochondrial respiration and ATP production. Because of the safety record of ketone bodies in the treatment of epilepsy and their ability to penetrate the blood-brain barrier, DβHB may be a novel neuroprotective therapy for PD

Association of Long-Acting Injectable Antipsychotics and Oral Antipsychotics With Disease Relapse, Health Care Use, and Adverse Events Among People With Schizophrenia

IMPORTANCE: Evidence for improved clinical outcomes with long-acting injectable antipsychotics (LAIAs) vs oral antipsychotics (OAs) is limited in Asian populations and special patient groups, including older people (>65 years), people with substance use, and early initiators of LAIAs. OBJECTIVE: To compare the risk of disease relapse, health care use, and adverse events associated with the use of LAIAs vs OAs among people in Hong Kong with schizophrenia. DESIGN, SETTINGS, AND PARTICIPANTS: In this self-controlled case series study, individuals with a diagnosis of schizophrenia who were prescribed LAIAs and OAs between January 1, 2004, and December 31, 2019, were identified from the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority. Data analysis was conducted from May to August in 2021. EXPOSURES: Use of LAIAs vs OAs. MAIN OUTCOMES AND MEASURES: Risk of disease relapse (hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, and suicide attempts), health care use (all-cause emergency department visits and hospitalizations), and adverse events (hospitalizations for somatic disorders, hospitalizations for cardiovascular diseases, and extrapyramidal symptoms) between the period in which patients were treated with LAIAs and the period in which patients were treated with OAs were compared using Poisson regression. RESULTS: Of the 70 396 individuals with schizophrenia (37 200 women [52.8%]; mean [SD] age, 44.2 [15.8] years), 23 719 (33.7%) were prescribed both LAIAs and OAs. Compared with OAs, LAIAs were associated with a lower risk of hospitalizations for any cause (n = 20 973; incidence rate ratio [IRR], 0.63 [95% CI, 0.61-0.65]), hospitalizations for psychiatric disorders (n = 19 283; IRR, 0.52 [95% CI, 0.50-0.53]), hospitalizations for schizophrenia (n = 18 385; IRR, 0.53 [95% CI, 0.51-0.55]), and incident suicide attempts (n = 1453; IRR, 0.56 [95% CI, 0.44-0.71]). During full treatment with LAIAs, there was a reduction in hospitalizations for somatic disorders (n = 15 396; IRR, 0.88 [95% CI, 0.85-0.91]), hospitalizations for cardiovascular diseases (n = 3710; IRR, 0.88 [95% CI, 0.81-0.96]), and extrapyramidal symptoms (n = 22 182; IRR, 0.86 [95% CI, 0.82-0.91]) compared with full treatment with OAs. No significant difference was found for emergency department visits. Similar associations were observed during the subsequent treatment periods (beyond 90 days) and among older people and those with substance use, except for an increased risk of extrapyramidal symptoms among older people when initiating LAIAs (first 90 days). Compared with late initiators, early LAIA initiators had a greater reduction in these outcome events. CONCLUSIONS AND RELEVANCE: This self-controlled case series study of people in Hong Kong with schizophrenia suggests that LAIAs were associated with a lower risk of disease relapse and hospitalization than OAs, without an increased risk of adverse events. Clinicians should more broadly consider the long-term use of LAIAs for Chinese people with schizophrenia, especially early in the course of illness

The Safety and Immunogenicity of GTU®MultiHIV DNA Vaccine Delivered by Transcutaneous and Intramuscular Injection With or Without Electroporation in HIV-1 Positive Subjects on Suppressive ART

International audiencePrevious studies have shown targeting different tissues via the transcutaneous (TC) and intramuscular injection (IM) with or without electroporation (EP) has the potential to trigger immune responses to DNA vaccination. The CUTHIVTHER 001 Phase I/II randomized controlled clinical trial was designed to determine whether the mode of DNA vaccination delivery (TC+IM or EP+IM) could influence the quality and function of induced cellular immune responses compared to placebo, in an HIV positive clade B cohort on antiretroviral therapy (ART). The GTU®MultiHIV B DNA vaccine DNA vaccine encoded a MultiHIV B clade fusion protein to target the cellular response. Overall the vaccine and regimens were safe and well-tolerated. There were robust pre-vaccination IFN-γ responses with no measurable change following vaccination compared to placebo. However, modest intracellular cytokine staining (ICS) responses were seen in the TC+IM group. A high proportion of individuals demonstrated potent viral inhibition at baseline that was not improved by vaccination. These results show that HIV positive subjects with nadir CD4+ counts ≥250 on suppressive ART display potent levels of cellular immunity and viral inhibition, and that DNA vaccination alone is insufficient to improve such responses. These data suggest that more potent prime-boost vaccination strategies are likely needed to improve pre-existing responses in similar HIV-1 cohorts (This study has been registered at http://ClinicalTrials.gov under registration no. NCT02457689)

Safety of two-dose COVID-19 vaccination (BNT162b2 and CoronaVac) in adults with cancer: a territory-wide cohort study

BACKGROUND: The World Health Organization has defined a list of adverse events of special interest (AESI) for safety surveillance of vaccines. AESI have not been adequately assessed following COVID-19 vaccination in patients with cancer contributing to vaccine hesitancy in this population. We aimed to evaluate the association between BNT162b2 and CoronaVac vaccines and the risk of AESI in adults with active cancer or a history of cancer. PATIENTS AND METHODS: We conducted a territory-wide cohort study using electronic health records managed by the Hong Kong Hospital Authority and vaccination records provided by the Department of Health. Patients with a cancer diagnosis between January 1, 2018, and September 30, 2021, were included and stratified into two cohorts: active cancer and history of cancer. Within each cohort, patients who received two doses of BNT162b2 or CoronaVac were 1:1 matched to unvaccinated patients using the propensity score. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for AESI 28 days after the second vaccine dose. RESULTS: A total of 74,878 patients with cancer were included (vaccinated: 25,789 [34%]; unvaccinated: 49,089 [66%]). Among patients with active cancer, the incidence of AESI was 0.31 and 1.02 per 10,000 person-days with BNT162b2 versus unvaccinated patients and 0.13 and 0.88 per 10,000 person-days with CoronaVac versus unvaccinated patients. Among patients with history of cancer, the incidence was 0.55 and 0.89 per 10,000 person-days with BNT162b2 versus unvaccinated patients and 0.42 and 0.93 per 10,000 person-days with CoronaVac versus unvaccinated patients. Neither vaccine was associated with a higher risk of AESI for patients with active cancer (BNT162b2: HR 0.30, 95% CI 0.08-1.09; CoronaVac: 0.14, 95% CI 0.02-1.18) or patients with history of cancer (BNT162b2: 0.62, 95% CI 0.30-1.28; CoronaVac: 0.45, 95% CI 0.21-1.00). CONCLUSIONS: In this territory-wide cohort study of patients with cancer, the incidence of AESI following vaccination with two doses of either BNT162b2 or CoronaVac vaccines was low. The findings of this study can reassure clinicians and patients with cancer about the overall safety of BNT162b2 and CoronaVac in patients with cancer, which could increase the COVID-19 vaccination rate in this vulnerable group of patients

BNT162b2 or CoronaVac Vaccinations Are Associated With a Lower Risk of Myocardial Infarction and Stroke After SARS‐CoV‐2 Infection Among Patients With Cardiovascular Disease

Background: COVID‐19 vaccines have demonstrated effectiveness against SARS‐CoV‐2 infection, hospitalization, and mortality. The association between vaccination and risk of cardiovascular complications shortly after SARS‐CoV‐2 infection among patients with cardiovascular disease remains unknown. Methods and Results: A case–control study was conducted with cases defined as patients who had myocardial infarction or stroke within 28 days after SARS‐CoV‐2 infection between January 1, 2022 and August 15, 2022. Controls were defined as all other patients who attended any health services and were not cases. Individuals without history of cardiovascular disease were excluded. Each case was randomly matched with 10 controls according to sex, age, Charlson comorbidity index, and date of hospital admission. Adjusted odds ratio with 95% CI was estimated using conditional logistic regression. We identified 808 cases matched with 7771 controls among all patients with cardiovascular disease. Results showed that vaccination with BNT162b2 or CoronaVac was associated with a lower risk of myocardial infarction or stroke after SARS‐CoV‐2 infection with a dose–response relationship. For BNT162b2, risk decreased from 0.49 (95% CI, 0.29–0.84) to 0.30 (95% CI, 0.20–0.44) and 0.17 (95% CI, 0.08–0.34) from 1 to 3 doses, respectively. Similar trends were observed for CoronaVac, with risk decreased from 0.69 (95% CI, 0.57–0.85) to 0.42 (95% CI, 0.34–0.52) and 0.32 (95% CI, 0.21–0.49) from 1 to 3 doses, respectively. Conclusions: Vaccination with BNT162b2 or CoronaVac is associated with a lower risk of myocardial infarction or stroke after SARS‐CoV‐2 infection among patients with cardiovascular disease

Safety of BNT162b2 or CoronaVac COVID-19 vaccines in patients with heart failure: A self-controlled case series study

BACKGROUND: COVID-19 vaccines are important for patients with heart failure (HF) to prevent severe outcomes but the safety concerns could lead to vaccine hesitancy. This study aimed to investigate the safety of two COVID-19 vaccines, BNT162b2 and CoronaVac, in patients with HF. METHODS: We conducted a self-controlled case series analysis using the data from the Hong Kong Hospital Authority and the Department of Health. The primary outcome was hospitalization for HF and the secondary outcomes were major adverse cardiovascular events (MACE) and all hospitalization. We identified patients with a history of HF before February 23, 2021 and developed the outcome event between February 23, 2021 and March 31, 2022 in Hong Kong. Incidence rate ratios (IRR) were estimated using conditional Poisson regression to evaluate the risks following the first three doses of BNT162b2 or CoronaVac. FINDINGS: We identified 32,490 patients with HF, of which 3035 were vaccinated and had a hospitalization for HF during the observation period (BNT162b2 = 755; CoronaVac = 2280). There were no increased risks during the 0–13 days (IRR 0.64 [95% confidence interval 0.33–1.26]; 0.94 [0.50–1.78]; 0.82 [0.17–3.98]) and 14–27 days (0.73 [0.35–1.52]; 0.95 [0.49–1.84]; 0.60 [0.06–5.76]) after the first, second and third doses of BNT162b2. No increased risks were observed for CoronaVac during the 0–13 days (IRR 0.60 [0.41–0.88]; 0.71 [0.45–1.12]; 1.64 [0.40–6.77]) and 14–27 days (0.91 [0.63–1.32]; 0.79 [0.46–1.35]; 1.71 [0.44–6.62]) after the first, second and third doses. We also found no increased risk of MACE or all hospitalization after vaccination. INTERPRETATION: Our results showed no increased risk of hospitalization for HF, MACE or all hospitalization after receiving BNT162b2 or CoronaVac vaccines in patients with HF. FUNDING: The project was funded by a Research Grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (Ref. No. COVID19F01). F.T.T.L. (Francisco T.T. Lai) and I.C.K.W. (Ian C.K. Wong)'s posts were partly funded by the D24H; hence this work was partly supported by AIR@InnoHK administered by Innovation and Technology Commission

Effectiveness of BNT162b2 and CoronaVac vaccinations against SARS-CoV-2 omicron infection in people aged 60 years or above: a case–control study

BACKGROUND: In view of limited evidence that specifically addresses vaccine effectiveness (VE) in the older population, this study aims to evaluate the real-world effectiveness of BNT162b2 and CoronaVac in older adults during the Omicron BA.2 outbreak. METHODS: This case-control study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Each case was matched with up to 10 controls by age, sex, index date and Charlson Comorbidity Index for the four outcomes (COVID-19 infection, COVID-19-related hospitalization, severe complications, and all-cause mortality) independently. Conditional logistic regression was conducted to evaluate VE of BNT162b2 and CoronaVac against COVID-19-related outcomes within 28 days after COVID-19 infection among participants stratified by age groups (60-79, ≥80 years old). RESULTS: A dose-response relationship between the number of vaccine doses received and protection against severe or fatal disease was observed. Highest VE (95% CI) against COVID-19 infection was observed in individuals aged ≥80 who received three doses of BNT162b2 [75.5% (73.1-77.7%)] or three doses of CoronaVac [53.9% (51.0-56.5%)] compared to those in the younger age group who received three doses of BNT162b2 [51.1% (49.9-52.4%)] or three doses of CoronaVac [2.0% (-0.1-4.1%)]. VE (95% CI) was higher for other outcomes, reaching 91.9% (89.4-93.8%) and 86.7% (84.3-88.8%) against COVID-19-related hospitalization; 85.8% (61.2-94.8%) and 89.8% (72.4-96.3%) against COVID-19-related severe complications; and 96.4% (92.9-98.2%) and 95.0% (92.1-96.8%) against COVID-19-related mortality after three doses of BNT162b2 and CoronaVac in older vaccine recipients, respectively. A similar dose-response relationship was established in younger vaccine recipients and after stratification by sex and Charlson Comorbidity Index. CONCLUSION: Both BNT162b2 and CoronaVac vaccination were effective in protecting older adults against COVID-19 infection and COVID-19-related severe outcomes amidst the Omicron BA.2 pandemic, and VE increased further with the third dose

Association between the risk of seizure and COVID-19 vaccinations: A self-controlled case-series study

OBJECTIVE: The risk of seizure following BNT162b2 and CoronaVac vaccinations has been sparsely investigated. This study aimed to evaluate this association. METHOD: Patients who had their first seizure-related hospitalization between February 23, 2021 and January 31, 2022 were identified in Hong Kong. All seizure episodes happening on the day of vaccination (day 0) were excluded since clinicians validated that most of the cases on day 0 were syncopal episodes. Within-individual comparison using a modified self-controlled case series analysis was applied to estimate the incidence rate ratio (IRR) with 95% confidence intervals (CI) of seizure using conditional Poisson regression. RESULTS: We identified 1656 individuals who had their first seizure-related hospitalization (BNT162b2: 426; CoronaVac: 263; unvaccinated: 967) within the observation period. The incidence of seizure was 1.04 (95% CI: 0.80-1.33) and 1.11 (95% CI: 0.80-1.50) per 100,000 doses of BNT162b2 and CoronaVac administered respectively. 16 and 17 individuals received second dose after having first seizure within 28 days after first dose of BNT162b2 and CoronaVac vaccinations, respectively. None had recurrent seizures after the second dose. There was no increased risk during day 1-6 after the first (BNT162b2: IRR=1.39, 95% CI=0.75-2.58; CoronaVac: IRR=1.19, 95% CI=0.50-2.83) and second doses (BNT162b2: IRR=1.36, 95% CI 0.72-2.57; CoronaVac: IRR=0.71, 95% CI=0.22-2.30) of vaccinations. During 7-13, 14-20- and 21-27-days post-vaccination, no association was observed for both vaccines. SIGNIFICANCE: The findings demonstrated no increased risk of seizure following BNT162b2 and CoronaVac vaccinations. Future studies will be warranted to evaluate the risk of seizure following COVID-19 vaccinations in different populations with subsequent doses to ensure the generalizability