Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability.

Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of MDD vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, these findings reveal a convergent mechanism through which MDD vulnerability is mediated in the brain.

Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.

BACKGROUND: Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. METHODS: In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed. RESULTS: A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (83%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI], 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group. CONCLUSIONS: Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).

Spontaneous-Breathing Trials with Pressure-Support Ventilation or a T-Piece.

BACKGROUND: Spontaneous-breathing trials can be performed with the use of either pressure-support ventilation (PSV) or a T-piece. Whether PSV trials may result in a shorter time to tracheal extubation than T-piece trials, without resulting in a higher risk of reintubation, among patients who have a high risk of extubation failure is unknown. METHODS: In this multicenter, open-label trial, we randomly assigned patients who had a high risk of extubation failure (i.e., were >65 years of age or had an underlying chronic cardiac or respiratory disease) to undergo spontaneous-breathing trials performed with the use of either PSV (with a pressure-support level of 8 cm of water and no positive end-expiratory pressure) or a T-piece. The primary outcome was the total time without exposure to invasive ventilation (reported as the number of ventilator-free days) at day 28 after the initial spontaneous-breathing trial. Secondary outcomes included extubation within 24 hours and extubation within 7 days after the initial spontaneous-breathing trial, as well as reintubation within 7 days after extubation. RESULTS: A total of 969 patients (484 in the PSV group and 485 in the T-piece group) were included in the analysis. At day 28, the median number of ventilator-free days was 27 (interquartile range, 24 to 27) in the PSV group and 27 (interquartile range, 23 to 27) in the T-piece group (difference, 0 days; 95% confidence interval [CI], -0.5 to 1; P = 0.31). Extubation was performed within 24 hours in 376 patients (77.7%) in the PSV group and in 350 patients (72.2%) in the T-piece group (difference, 5.5 percentage points; 95% CI, 0.01 to 10.9), and extubation was performed within 7 days in 473 patients (97.7%) and 458 patients (94.4%), respectively (difference, 3.3 percentage points; 95% CI, 0.8 to 5.9). Reintubation was performed in 72 of 481 patients (14.9%) in the PSV group and in 65 of 477 patients (13.6%) in the T-piece group (difference, 1.3 percentage points; 95% CI, -3.1 to 5.8). Cardiac or respiratory arrest was a reason for reintubation in 9 patients (3 in the PSV group and 6 in the T-piece group). CONCLUSIONS: Among patients who had a high risk of extubation failure, spontaneous-breathing trials performed with PSV did not result in significantly more ventilator-free days at day 28 than spontaneous-breathing trials performed with a T-piece. (Supported by the French Ministry of Health; TIP-EX ClinicalTrials.gov number, NCT04227639.).

Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.

SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.

Difference in Precocious Puberty Between Pre-COVID-19 and COVID-19 Periods: A Meta-Analysis.

We conducted this systematic review and meta-analysis to clarify the trend of precocious puberty (PP) incidence after the COVID-19 outbreak and explore potential contributing factors, such as age at presentation and body mass index standard deviation score (BMI SDS). Children visiting pediatric endocrinology clinics for the first time for suspected PP were included. We searched databases until February 28, 2023 for studies reporting various indicators of PP incidence before and during the pandemic. Total numbers of events and observations were recorded. A meta-analysis was performed to compare the odds of PP, BMI SDS, and age at presentation between the two periods. The dose-response relationships between time points (by number of years away from the pandemic) and PP risk were explored. In summary, a total of 32 studies including 24,200 participants were recruited. COVID-19 pandemic was associated with the increasing odds of PP among children referred for suspicious condition (OR 1.96; 95% CI 1.56-2.47; I2 = 54%; P < 0.001). Sensitivity analysis confirmed the robustness of the findings. BMI SDS did not vary between the two periods, while age at presentation was lower following the pandemic. PP incidence increased more rapidly during the pandemic period than during the prepandemic period.

Resilience after severe critical illness: a prospective, multicentre, observational study (RESIREA).

BACKGROUND: Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience. METHODS: This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ). RESULTS: Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience (p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008-1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950-0.996; p = 0.02). CONCLUSIONS: Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes.

Role of Metastasis-Directed Therapy in Genitourinary Cancers.

OPINION STATEMENT: The treatment of oligometastatic genitourinary cancers is a rapidly advancing field with ablative radiotherapy as one of the critical treatment components. The oligometastatic disease state, which can be defined as 1-5 metastatic sites with a controlled primary, represents a distinct clinical state where comprehensive ablative local therapies may provide improved outcomes. Enhanced imaging has increased the number of patients identified with oligometastatic disease. Evidence for improved outcomes with metastasis-directed therapy (MDT) in oligometastatic genitourinary cancers is increasing, and previously published outcome data continues to mature with an increasing body of prospective data to inform the role of MDT in histology-specific settings or in the context of systemic therapy. In select patients, MDT can offer benefits beyond improved local control and allow for time off of systemic therapy, prolonged time until next therapy, or even the hope of cure. However, treatment decisions for locally ablative therapy must be balanced with consideration towards safety. There are exciting advances in technologies to target and adapt treatment in real-time which have expanded options for safer delivery and dose escalation to metastatic targets near critical organs at risk. The role of systemic therapies in conjunction with MDT and incorporation of tumor genetic information to further refine prognostication and treatment decision-making in the oligometastatic setting is actively being investigated. These developments highlight the evolving field of treatment of oligometastatic disease. Future prospective studies combining MDT with enhanced imaging and integrating MDT with evolving systemic therapies will enable the optimal selection of patients most likely to benefit from this "all-or-none" approach and reveal settings in which a combination of therapies could result in synergistic outcomes.

Suaedamas A-D: Four New Compounds from the Aerial Parts of Suaeda maritima with Inhibition of NO Production Activity.

Four new compounds, suaedamas A-D (1-4), and seven known ones (5-11) were isolated from the aerial parts of Suaeda maritima. Their chemical structures were evaluated by the IR, HR-ESI-MS, 1D-, and 2D-NMR, experimental and calculated ECD spectra. Compounds 1-6 inhibited nitric oxide production in LPS activated RAW 264.7 cells with IC50 values ranging from 29.3 to 85.5 µM, compared to that of the positive control compound, dexamethasone, which showed IC50 value of 13.4 µM.

Place of high-flow nasal oxygen in nonoperating room anesthesia.

PURPOSE OF REVIEW: This article aims to assess the utility of high-flow nasal oxygen (HFNO) therapy in nonoperating room anesthesia (NORA) settings. RECENT FINDINGS: The number of procedural interventions under deep sedation in NORA is still increasing. Administration of oxygen is recommended to prevent hypoxemia and is usually delivered with standard oxygen through nasal cannula or a face mask. HFNO is a simple alternative with a high warmed humidified flow (ranging from 30 to 70 l/min) with a precise fraction inspired of oxygen (ranging from 21 to 100%). Compared to standard oxygen, HFNO has demonstrated efficacy in reducing the incidence of hypoxemia and the need for airway maneuvers. Research on HFNO has primarily focused on its application in gastrointestinal endoscopy procedures. Yet, it has also shown promising results in various other procedural interventions including bronchoscopy, cardiology, and endovascular procedures. However, the adoption of HFNO prompted considerations regarding cost-effectiveness and environmental impact. SUMMARY: HFNO emerges as a compelling alternative to conventional oxygen delivery methods for preventing hypoxemia during procedural interventions in NORA. However, its utilization should be reserved for patients at moderate-to-high risk to mitigate the impact of cost and environmental factors.

Trapping of a Polyketide Synthase Module after C-C Bond Formation Reveals Transient Acyl Carrier Domain Interactions.

Modular polyketide synthases (PKSs) are giant assembly lines that produce an impressive range of biologically active compounds. However, our understanding of the structural dynamics of these megasynthases, specifically the delivery of acyl carrier protein (ACP)-bound building blocks to the catalytic site of the ketosynthase (KS) domain, remains severely limited. Using a multipronged structural approach, we report details of the inter-domain interactions after C-C bond formation in a chain-branching module of the rhizoxin PKS. Mechanism-based crosslinking of an engineered module was achieved using a synthetic substrate surrogate that serves as a Michael acceptor. The crosslinked protein allowed us to identify an asymmetric state of the dimeric protein complex upon C-C bond formation by cryo-electron microscopy (cryo-EM). The possible existence of two ACP binding sites, one of them a potential "parking position" for substrate loading, was also indicated by AlphaFold2 predictions. NMR spectroscopy showed that a transient complex is formed in solution, independent of the linker domains, and photochemical crosslinking/mass spectrometry of the standalone domains allowed us to pinpoint the interdomain interaction sites. The structural insights into a branching PKS module arrested after C-C bond formation allows a better understanding of domain dynamics and provides valuable information for the rational design of modular assembly lines.

Noninvasive Monitoring of Arterial Pressure: Finger or Lower Leg As Alternatives to the Upper Arm: A Prospective Study in Three ICUs.

OBJECTIVES: When the upper arm is inaccessible for measurements of arterial pressure (AP), the best alternative site is unknown. We performed a between-site comparison of the agreement between invasive and noninvasive readings of AP taken at the lower leg, the finger, and the upper arm. The risk associated with measurement errors and the trending ability were also assessed. DESIGN: Prospective observational study. SETTING: Three ICUs. PATIENTS: Patients having an arterial catheter and an arm circumference less than 42 cm. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three triplicates of AP measurements were collected via an arterial catheter (reference AP), a finger cuff system (ClearSight; Edward Lifesciences, Irvine, CA), and an oscillometric cuff (at the lower leg then the upper arm). Trending ability was assessed through an additional set of measurements after a cardiovascular intervention. The default bed backrest angle was respected. Failure to measure and display AP occurred in 19 patients (13%) at the finger, never at other sites. In 130 patients analyzed, the agreement between noninvasive and invasive readings was worse at the lower leg than that observed at the upper arm or the finger (for mean AP, bias ± sd of 6.0 ± 15.8 vs 3.6 ± 7.1 and 0.1 ± 7.4 mm Hg, respectively; p < 0.05), yielding a higher frequency of error-associated clinical risk (no risk for 64% vs 84% and 86% of measurements, respectively, p < 0.0001). According to the International Organization for Standardization (ISO) 81060-2:2018 standard, mean AP measurements were reliable at the upper arm and the finger, not the lower leg. In 33 patients reassessed after a cardiovascular intervention, both the concordance rate for change in mean AP and the ability to detect a therapy-induced significant change were good and similar at the three sites. CONCLUSIONS: As compared with lower leg measurements of AP, finger measurements were, when possible, a preferable alternative to upper arm ones.

Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs.

St. John's wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.

Insect repellents: An updated review for the clinician.

Malaria, Zika virus, West Nile virus, Dengue fever, and Lyme disease are common causes of morbidity and mortality around the world. While arthropod bites may cause local inflammation and discomfort, a greater concern is the potential to develop deadly systemic infection. The use of insect repellents (IRs) to prevent systemic infections constitutes a fundamental public health effort. Cost effectiveness, availability, and high efficacy against arthropod vectors are key characteristics of an ideal IR. Currently, numerous IRs are available on the market, with N,N-diethyl-3-methylbenzamide (DEET) being the most widely used. DEET has an excellent safety profile and remarkable protection against mosquitoes and various other arthropods. Other Environmental Protection Agency-registered IR ingredients (eg, permethrin, picaridin, IR3535, oil of lemon eucalyptus, oil of citronella, catnip oil, and 2-undecanone) are alternative IRs of great interest because some of these ingredients have efficacies comparable to that of DEET. These alternative IRs possess low toxicity and favorable customer experiences in use (eg, cosmetically pleasant, naturally occurring). This review summarizes the currently available Environmental Protection Agency-registered IRs, including their origins, mechanisms of action, side effect profiles, and available formulations. This review will enable the clinician to select the best IR option to meet a patient's needs and provide the greatest protection from arthropod bites and their sequelae.

Prone position versus usual care in hypoxemic COVID-19 patients in medical wards: a randomised controlled trial.

BACKGROUND: Benefit of early awake prone positioning for COVID-19 patients hospitalised in medical wards and who need oxygen therapy remains to be demonstrated. The question was considered at the time of COVID-19 pandemic to avoid overloading the intensive care units. We aimed to determine whether prone position plus usual care could reduce the rate of non-invasive ventilation (NIV) or intubation or death as compared to usual care alone. METHODS: In this multicentre randomised clinical trial, 268 patients were randomly assigned to awake prone position plus usual care (N = 135) or usual care alone (N = 132). The primary outcome was the proportion of patients who underwent NIV or intubation or died within 28 days. Main secondary outcomes included the rates of NIV, of intubation or death, within 28 days. RESULTS: Median time spent each day in the prone position within 72 h of randomisation was 90 min (IQR 30-133). The proportion of NIV or intubation or death within 28 days was 14.1% (19/135) in the prone position group and 12.9% (17/132) in the usual care group [odds ratio adjusted for stratification (aOR) 0.43; 95% confidence interval (CI) 0.14-1.35]. The probability of intubation, or intubation or death (secondary outcomes) was lower in the prone position group than in the usual care group (aOR 0.11; 95% CI 0.01-0.89 and aOR 0.09; 95% CI 0.01-0.76, respectively) in the whole study population and in the prespecified subgroup of patients with SpO2 ≥ 95% on inclusion (aOR 0.11; 95% CI 0.01-0.90, and aOR 0.09; 95% CI 0.03-0.27, respectively). CONCLUSIONS: Awake prone position plus usual care in COVID-19 patients in medical wards did not decrease the composite outcome of need for NIV or intubation or death. Trial registration ClinicalTrials.gov Identifier: NCT04363463 . Registered 27 April 2020.

Beneficial Effects of Noninvasive Ventilation after Extubation in Obese or Overweight Patients: A Post Hoc Analysis of a Randomized Clinical Trial.

Rationale: Although noninvasive ventilation (NIV) may prevent reintubation in patients at high risk of extubation failure in ICUs, this oxygenation strategy has not been specifically assessed in obese patients. Objectives: We hypothesized that NIV may decrease the risk of reintubation in obese patients compared with high-flow nasal oxygen. Methods:Post hoc analysis of a multicenter randomized controlled trial (not prespecified) comparing NIV alternating with high-flow nasal oxygen versus high-flow nasal oxygen alone after extubation, with the aim of assessing NIV effects according to patient body mass index (BMI). Measurements and Main Results: Among 623 patients at high risk of extubation failure, 206 (33%) were obese (BMI ⩾ 30 kg/m2), 204 (33%) were overweight (25 kg/m2 ⩽ BMI < 30 kg/m2), and 213 (34%) were normal or underweight (BMI < 25 kg/m2). Significant heterogeneity of NIV effects on the rate of reintubation was found according to BMI (Pinteraction = 0.007). Reintubation rates at Day 7 were significantly lower with NIV alternating with high-flow nasal oxygen than with high-flow nasal oxygen alone in obese or overweight patients: 7% (15/204) versus 20% (41/206) (difference, -13% [95% confidence interval, -19 to -6]; P = 0.0002), whereas it did not significantly differ in normal or underweight patients. In-ICU mortality was significantly lower with NIV than with high-flow nasal oxygen alone in obese or overweight patients (2% vs. 9%; difference, -6% [95% confidence interval, -11 to -2]; P = 0.006). Conclusions: Prophylactic NIV alternating with high-flow nasal oxygen immediately after extubation significantly decreased the risk of reintubation and death compared with high-flow nasal oxygen alone in obese or overweight patients at high risk of extubation failure. By contrast, NIV was not effective in normal or underweight patients. Clinical trial registered with www.clinicaltrials.gov (NCT03121482).

Riding high: seroprevalence of SARS-CoV-2 after 4 pandemic waves in Manitoba, Canada, April 2020-February 2022.

BACKGROUND: Canada is emerging from the largest SARS-CoV-2 Omicron wave to date, with over 3.3 million confirmed cases. Unfortunately, PCR confirmed cases illuminate only a small portion of infections in the community and underestimate true disease burden. Population based seroprevalence studies, which measure antibody levels against a virus can more accurately estimate infection rates in the community and identify geographical and epidemiological trends to inform public health responses. METHODS: The Manitoba COVID-19 Seroprevalence (MCS) study is a population-based cross-sectional study to assess the prevalence of SARS-CoV-2 antibodies across the province. Residual convenience specimens (n = 14,901) were tested for anti-SARS-CoV-2 nucleocapsid and spike IgG antibodies from April 1, 2020 to February 31, 2022. We estimated the monthly and cumulative prevalence using an exponential decay model, accounting for population demographics, sensitivity/specificity, and antibody waning. This approach generated estimates of natural infection as well as total antibody including vaccine-induced immunity within the community. FINDINGS: After four waves of the pandemic, 60.1% (95%CI-56.6-63.7) of Manitobans have generated SARS-CoV-2 antibodies due to natural exposure independent of vaccination. Geographical analysis indicates a large portion of provincial prevalence stems from increased transmission in the Northern (92.3%) and Southern (71.8%) regional health authorities. Despite the high mortality rates reported by Manitoba, infection fatality ratios (IFR) peaked at 0.67% and declined to 0.20% following the Omicron wave, indicating parity with other national and international jurisdictions. Manitoba has achieved 93.4% (95%CI- 91.5-95.1) total antibody when including vaccination. INTERPRETATION: Our data shows that more than 3 in 5 Manitobans have been infected by SARS-CoV-2 after four waves of the pandemic. This study also identifies key geographical and age specific prevalence rates that have contributed greatly to the overall severity of the pandemic in Manitoba and will inform jurisdictions considering reduction of public health measures.

Assessing the accuracy of the International Academy of Cytology Yokohama System for reporting breast fine needle aspiration biopsy cytology at a Vietnamese oncology centre.

BACKGROUND: Fine needle aspiration biopsy (FNAB), accompanied by classification systems for cytology, can offer a cheap and convenient option for the diagnosis of breast cancer in women with suspicious breast lumps. In this study, we aimed to assess the accuracy of the International Academy of Cytology (IAC) Yokohama system in a Vietnamese oncology centre. METHODS: A retrospective cross-sectional study was conducted from November 2021 to April 2022 at Vietnam National Cancer Hospital. We included patients with full hospital records regarding breast lesions for which FNAB was indicated. A total of 803 patients' FNAB specimens were assessed according to the IAC Yokohama system. The basic characteristics were summarised using the appropriate summary measurements. The risk of malignancy (ROM) was calculated for each classification category. RESULTS: The median age was 42.7 years (range: 14-85). The mean size of the lesions was 17.9 mm (range: 4-123 mm). We had 215 histopathological reports. The most common benign and malignant diagnoses were fibroadenoma and invasive carcinoma, respectively. The ROM for categories II, III, IV, and V was calculated as 3.4%, 37.5%, 95%, and 99.2% respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 96.4%, 97.2%, 98.5%, and 93.2%, respectively. CONCLUSION: The IAC Yokohama system offers a good option with which to predict underlying breast pathology using a simple and cheap procedure. However, pathologists require continuous training to ensure accurate interpretation of the slides.

Four New Flavonoid C-Glycosides Isolated from Achyranthes aspera and Their Nitric Oxide Production Inhibitory Activities.

A chemical study of the methanol extract of the aerial parts of Achyranthes aspera led to the isolation of four new flavonoid C-glycosides (1-4) along with eight known analogs (5-12). Their structures were elucidated by a combination of spectroscopic data analysis, HR-ESI-MS, 1D and 2D NMR spectra. All the isolates were evaluated their NO production inhibitory activity in LPS-activated RAW264.7 cells. Compounds 2, 4, and 8-11 showed significant inhibition with IC50 values ranging from 25.06 to 45.25 µM, compared to that of the positive control compound, L-NMMA, IC50 value of 32.24 µM, whereas the remaining compounds were weak inhibitory activity with IC50 values over 100 µM. This is the first report of 7 from Amaranthaceae family, and 11 from the genus Achyranthes.

Antimicrobial Activity of Depsidones and Macrocyclic Peptides Isolated from Marine Sponge-Derived Fungus Aspergillus nidulans M256.

Chemical study on marine sponge-derivated fungus Aspergillus nidulans resulted in the isolation of seven depsidones (1-7) and two macrocyclic peptides (8 and 9). Their chemical structures were elucidated by extensive analyses of HRESIMS and NMR spectral data, as well as comparison with the literature. Compound 1 was an undescribed depsidone. All compounds exhibited significant antimicrobial activity (MICs: 2-128 µg/mL) towards at least one of seven microbial strains, including Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, and Candida albicans. Of these, chlorinated depsidones (1-3, and 5) displayed potential antimicrobial activity. Nidulin (2) possessed good activity against tested strains except for S. enterica with MIC values in range of 2-16 µg/mL. Interestingly, undescribed depsidone 1 was selectively bioactive on the Gram-positive bacteria (MICs: 2-4 µg/mL) and yeast (MIC: 8 µg/mL) but inactivity on the Gram-negative bacteria (MICs: >256 µg/mL). Macrocyclic peptides, 8 and 9, displayed modest activity against E. faecalis strain with MIC values of 32 and 128 µg/mL, respectively.