Can platform use patterns be an indicator of HIV-related risk and sub-group heterogeneity among men who have sex with men in Singapore: a latent class analysis.

Introduction: Low-level HIV epidemic settings like Singapore face the challenge of reaching men at-risk who have less contact with programmes. We investigated patterns of meeting platform use by men seeking male sexual partners (MSM) as potential marker of risk to differentiate sub-groups for interventions. Methods: Latent Class Analysis (LCA) was applied to a survey sample of MSM recruited from bars/clubs, saunas and a smartphone application, using purposive sampling. The best-fit LCA model which identified homogeneous sub-groups with similar patterns of meeting platform was factored in multivariable regression to identify associations with risk behaviors on the pathway to HIV infection. Results: Overall 1,141 MSM were recruited from bars/clubs (n = 426), saunas (n = 531), and online (n = 184). Five patterns emerged, reflecting salient platform use characteristics: Sauna-centric (SC; n = 413), App-centric (AC; n = 276), Multiple-platforms (MP; n = 123), Platform-inactive (PI; n = 257), and "Do not hook up" (DNH; n = 72) classes. Men in the SC and MP classes had high probabilities of using saunas to meet partners; SC were older and less likely to have disclosed their sexual orientation. The MP class had high probabilities of connecting across all platforms in addition to saunas and more likely to have disclosed their sexual orientation, than the PI class. Men in the SC and MP classes had twice the odds of reporting multiple sex partners (aORSC = 2.1; 95%CI: 1.33.2; aORMP = 2.2; 95%CI: 1.14.6). Single/non-partnered MSM and those using alcohol/drugs during sex had 1.7 (95%CI: 1.22.5) and 3.2 (95%CI: 2.05.1) the odds respectively, of reporting multiple sex partners. The SC and MP classes had higher odds of engaging in group sex while MSM using alcohol/drugs during sex had twice the odds of reporting group sex. Alcohol/drugs and group sex were independently associated with condomless sex (as was lower education). Group sex, alcohol/drugs during sex, disclosure of sexual orientation or being Singaporean/permanent resident were associated with recent testing for HIV. Discussion: The five distinct risk profiles identified can help tailor differentiated HIV interventions-combined with field knowledge and other prevention-to expand HIV self-testing, Pre-Exposure Prophylaxis and other services (e.g., Mpox vaccination) to sub-groups at risk.

Prospective trajectories of depression predict mortality in cancer patients.

An ever-growing body of empirical evidence has demonstrated the relationship between depression and cancer. The objective of this study was to examine whether depression trajectories predict mortality risk above and beyond demographics and other general health-related factors. Participants (n = 2,345) were a part of the Health and Retirement Study. The sample consisted of patients who were assessed once before their cancer diagnosis and thrice after. Depressive symptoms and general health-related factors were based on self-reports. Mortality risk was determined based on whether the patient was alive or not at respective time points. Latent Growth Mixture Modeling was performed to map trajectories of depression, assess differences in trajectories based on demographics and general health-related factors, and predict mortality risk. Four trajectories of depression symptoms emerged: resilient (69.7%), emerging (13.5%), recovery (9.5%), and chronic (7.2%). Overall, females, fewer years of education, higher functional impairment at baseline, and high mortality risk characterized the emerging, recovery, and chronic trajectories. In comparison to the resilient trajectory, mortality risk was highest for the emerging trajectory and accounted for more than half of the deaths recorded for the participants in emerging trajectory. Mortality risk was also significantly elevated, although to a lesser degree, for the recovery and chronic trajectories. The data highlights clinically relevant information about the depression-cancer association that can have useful implications towards cancer treatment, recovery, and public health.

The International Olympic Committee framework on fairness, inclusion and nondiscrimination on the basis of gender identity and sex variations does not protect fairness for female athletes.

The International Olympic Committee (IOC) recently published a framework on fairness, inclusion, and nondiscrimination on the basis of gender identity and sex variations. Although we appreciate the IOC's recognition of the role of sports science and medicine in policy development, we disagree with the assertion that the IOC framework is consistent with existing scientific and medical evidence and question its recommendations for implementation. Testosterone exposure during male development results in physical differences between male and female bodies; this process underpins male athletic advantage in muscle mass, strength and power, and endurance and aerobic capacity. The IOC's "no presumption of advantage" principle disregards this reality. Studies show that transgender women (male-born individuals who identify as women) with suppressed testosterone retain muscle mass, strength, and other physical advantages compared to females; male performance advantage cannot be eliminated with testosterone suppression. The IOC's concept of "meaningful competition" is flawed because fairness of category does not hinge on closely matched performances. The female category ensures fair competition for female athletes by excluding male advantages. Case-by-case testing for transgender women may lead to stigmatization and cannot be robustly managed in practice. We argue that eligibility criteria for female competition must consider male development rather than relying on current testosterone levels. Female athletes should be recognized as the key stakeholders in the consultation and decision-making processes. We urge the IOC to reevaluate the recommendations of their Framework to include a comprehensive understanding of the biological advantages of male development to ensure fairness and safety in female sports.

DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response.

Detection of cytosolic nucleic acids by pattern recognition receptors, including STING and RIG-I, leads to the activation of multiple signalling pathways that culminate in the production of type I interferons (IFNs) which are vital for host survival during virus infection. In addition to protective immune modulatory functions, type I IFNs are also associated with autoimmune diseases. Hence, it is important to elucidate the mechanisms that govern their expression. In this study, we identified a critical regulatory function of the DUSP4 phosphatase in innate immune signalling. We found that DUSP4 regulates the activation of TBK1 and ERK1/2 in a signalling complex containing DUSP4, TBK1, ERK1/2 and IRF3 to regulate the production of type I IFNs. Mice deficient in DUSP4 were more resistant to infections by both RNA and DNA viruses but more susceptible to malaria parasites. Therefore, our study establishes DUSP4 as a regulator of nucleic acid sensor signalling and sheds light on an important facet of the type I IFN regulatory system.

Are there reciprocal interplays among Chinese adolescents', fathers', and mothers' depression at the within-family level? A family systems perspective.

Controversy surrounds the reciprocity between adolescent and parental depression. Limited studies rigorously tested the transactional model of depression from a family systems perspective considering the involvement of all family members, particularly in non-Western nations, using advanced modeling approaches that disentangle between- and within-unit (i.e., family) variances (e.g., random intercept cross-lagged panel model [RI-CLPM]). This population-based multi-informant longitudinal study applied RI-CLPM to evaluate the temporal dynamics of the interrelations among adolescent, maternal, and paternal depression in 1,733 Chinese families assessed biannually. Findings from two large independent samples (primary sample [N = 1,733]; replication sample [N = 989]) converged to suggest, in macro timescales: (a) more depressed parents-especially mothers-generally have more depressed adolescents (between-family associations); (b) a family member becoming more depressed than usual co-occurred with other members becoming more depressed than usual in the same wave (within-family cofluctuations), with the mother-adolescent dyads exhibiting greater concordance than the father-adolescent dyads; and (c) a family member becoming more depressed than usual did not prospectively predict other members becoming more depressed than usual (i.e., no within-family reciprocal effects). While patterns of cross-lagged effects were consistently null across contexts, cofluctuations were stronger in rural than urban families and stronger in families with older adolescents. Overall, findings suggest that in macro timescales, the previously identified associations between adolescent and parental depression likely occurred at the trait-like between-family level and state-like within-family cofluctuations. Future studies employing micro timescales (e.g., daily) can complement macro-timescale analysis to provide greater temporal resolution of the within-family interplays of affective symptoms between family members. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Examining resilience in Singapore in the face of COVID-19 community restrictions.

Introduction: To curb transmission of COVID-19, Singapore has experienced multiple, ongoing community restrictions. Gaining the ability to adapt and thrive under pressure will be key to addressing effects of these restrictions on mental health. To inform this, we examine the following research questions, (1) What typifies adversity related to living with on-off COVID-19 restrictions? (2) Who are the resilient? (3) How are negative effects of adversity attenuated? Methods: Participants were a part of the Strengthening Our Community's Resilience Against Threats from Emerging Infections (SOCRATES) cohort, invited to participate in this survey either via email or text message. Using the community survey data (N = 1,364), analyses including Wilcoxon rank sum test and logistic regression were conducted. Results: Adversities are identified as circumstances associated with a significant increase in Hospital Anxiety and Depression Scale (HADS) scores. These are typified by having financial worries; experiencing heightened emotions and frequent crying; having "out of body" experiences; having to move frequently or not being able to settle into accommodation; and regularly feeling mistreated by someone close to you. Being resilient in the face of adversity was determined by HADS scores for depression and anxiety (dichotomized at the median) and characterized by overall better social relationships such as having harmonious living situations and solution-driven coping strategies, especially the ability to harness the belief that difficult situations can lead to growth. Discussion: In accordance with the Loads-Levers-Lifts model, results indicate that initiatives that increase access to identified protection, while minimizing exposure to known adversities where possible, will promote resilience under COVID-19 restrictions.

Mental health and resilience after the covid-19 pandemic: a multi-ethnic longitudinal survey.

BACKGROUND: Longitudinal work on the impact of COVID-19 on population mental health and resilience beyond the first year of the pandemic is lacking. We aimed to understand how mental health and resilience evolved during the pandemic (2020) and two years later (2022) in a multi-ethnic Singaporean population. In addition, we assessed what characteristics were associated with mental health and resilience scores. METHODS: We surveyed and analysed two balanced panel samples up to four times between 30th April 2020 and 11th July 2022. One panel assessed psychological distress (Kessler-10) and well-being (short Warwick Edinburgh Mental Well-being scale) n = 313, and one panel assessed resilience (10-item Connor-Davidson Resilience Scale©) n = 583. A linear panel regression model with random effects assessed the temporal patterns for psychological distress, well-being, and resilience. RESULTS: Mean psychological distress scores (Kessler-10) were relatively stable over time and were not statistically significantly worse than baseline at any follow-up. Well-being scores improved over time and were significantly better than baseline by the third survey (22nd Jul-18th Aug 2020) (0.54 p = 0.007, Cohen's d 0.12). Scores had worsened by the last survey (27th June-11th July 2022) but were not significantly different from baseline 0.20 p = 0.30. Resilience scores declined over time. Scores at both follow-ups (14th Aug- 4th Sep 2020 and 27th June-11th July 2022) were statistically significantly lower than baseline: -1.69 p < 0.001 (Cohen's d 0.25) and -0.96 p = 0.006 (Cohen's d 0.14), respectively. CONCLUSIONS: Our study joins a body of work measuring the longitudinal effects of COVID-19 on population mental health and resilience. While, the magnitude of the effect related to resilience decline is small, our findings indicate that particular attention should be given to ongoing population surveillance, with the aim of maintaining good health and well-being.

Arterial spin labeling perfusion in acute Wernicke encephalopathy: a case series discussion.

Wernicke's encephalopathy (WE) is a life-threatening neurologic disorder resulting from thiamine (vitamin B1) deficiency that can be secondary to chronic alcohol abuse, gastrointestinal surgery, systemic infectious and non-infectious diseases, and chemotherapy. WE is classically characterized on MRI by reduced diffusion and T2 prolongation along the mammillothalamic tracts, periaqueductal gray and tectal plate. We present two patients with acute WE who had baseline arterial spin labeling (ASL) perfusion at the time of presentation, demonstrating increase in cerebral blood flow (CBF) within the classically involved brain regions and concurrent global cerebral cortical hypoperfusion. Both patients were successfully treated with intravenous thiamine infusion. Post-treatment MRI demonstrated improvement of reduced diffusion and normalization of CBF within the involved structures. Prior histopathological studies have documented prominent undulation and luminal dilatation of arteries and arterioles in acute WE lesions, likely explaining the increased perfusion shown by imaging. The root of this pathophysiologic process may trace back to thiamine's biochemical role in maintaining osmotic gradients and glucose metabolism, that if failed can lead to arterial hyper-perfusion. Our findings show that ASL-CBF can highlight the underlying pathophysiology in patients with acute WE by demonstrating increased CBF in involved central structures. This luxury perfusion may be a compensatory or protective mechanism by which increased metabolic demand is met in the acute setting and which, if treated timely, will show normalization of CBF on ASL imaging.

Longitudinal impacts of adverse childhood experiences on multidimensional health outcomes: Predicting trajectories in mental, physical, and behavioral health.

BACKGROUND: Adverse childhood experiences (ACEs) elevate the risk of poor health later in life. OBJECTIVE: This study aims to provide a more comprehensive investigation of the multidimensional health risks associated with ACEs, to address a gap in the understanding of their longitudinal impact on mental, physical, and behavioral health domains. PARTICIPANTS AND SETTING: This study included 6, 504 participants (51.61 % females) from the National Longitudinal Study of Adolescent to Adult Health (1994-2018). METHODS: We utilized latent class growth analysis to identify trajectories from adolescence to adulthood in three health domains: depression (Mental Health, MH), self-report physical health (SRH), and binge drinking frequency (BDF). Binary logistic regression was then used to assess the unique contributions of different types of ACEs to these longitudinal health trajectories. RESULTS: Three to four trajectories were identified for MH (consistently low, decreasing, increasing), SRH (consistently low, decreasing, increasing, consistently high), and BDF (consistently low, decreasing, moderate). Regression results showed that experience of emotional abuse and witnessed community violence elevated the risk associated with unfavorable trajectories in the mental health and behavioral health domains, respectively. CONCLUSIONS: Individual ACEs differentially predicted mental, physical, and behavioral health trajectories, potentially through various pathways. Prevention of ACEs could mitigate health risks for adolescents and young adults across these domains.

Influenza A and B Viruses in Fine Aerosols of Exhaled Breath Samples from Patients in Tropical Singapore.

Influenza is a highly contagious respiratory illness that commonly causes outbreaks among human communities. Details about the exact nature of the droplets produced by human respiratory activities such as breathing, and their potential to carry and transmit influenza A and B viruses is still not fully understood. The objective of our study was to characterize and quantify influenza viral shedding in exhaled aerosols from natural patient breath, and to determine their viral infectivity among participants in a university cohort in tropical Singapore. Using the Gesundheit-II exhaled breath sampling apparatus, samples of exhaled breath of two aerosol size fractions ("coarse" > 5 µm and "fine" ≤ 5 µm) were collected and analyzed from 31 study participants, i.e., 24 with influenza A (including H1N1 and H3N2 subtypes) and 7 with influenza B (including Victoria and Yamagata lineages). Influenza viral copy number was quantified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Infectivity of influenza virus in the fine particle fraction was determined by culturing in Madin-Darby canine kidney cells. Exhaled influenza virus RNA generation rates ranged from 9 to 1.67 × 105 and 10 to 1.24 × 104 influenza virus RNA copies per minute for the fine and coarse aerosol fractions, respectively. Compared to the coarse aerosol fractions, influenza A and B viruses were detected more frequently in the fine aerosol fractions that harbored 12-fold higher viral loads. Culturable virus was recovered from the fine aerosol fractions from 9 of the 31 subjects (29%). These findings constitute additional evidence to reiterate the important role of fine aerosols in influenza transmission and provide a baseline range of influenza virus RNA generation rates.

Severity of SARS-CoV-2 Omicron XBB subvariants in Singapore.

Several XBB subvariants such as XBB.1.5, XBB.1.9, XBB.1.16 and XBB.2.3 co-circulate in Singapore. Despite the different viral properties of XBB.1.16 as compared to other XBB subvariants, comparison on their severity is limited. In this study, we investigate the outcomes of hospitalisation and severe COVID-19 infection in individuals infected with different XBB subvariants, adjusted for potential confounders such as age and vaccination history. Overall, our preliminary analysis showed that the risk of severe outcomes when infected with XBB.1.16 is higher than that of XBB.1.5 or XBB.1.9 but there is no difference in the risk of hospitalisation across different XBB subvariants.

Potent pan huACE2-dependent sarbecovirus neutralizing monoclonal antibodies isolated from a BNT162b2-vaccinated SARS survivor.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern such as Omicron hampered efforts in controlling the ongoing coronavirus disease 2019 pandemic due to their ability to escape neutralizing antibodies induced by vaccination or prior infection, highlighting the need to develop broad-spectrum vaccines and therapeutics. Most human monoclonal antibodies (mAbs) reported to date have not demonstrated true pan-sarbecovirus neutralizing breadth especially against animal sarbecoviruses. Here, we report the isolation and characterization of highly potent mAbs targeting the receptor binding domain (RBD) of huACE2-dependent sarbecovirus from a SARS-CoV survivor vaccinated with BNT162b2. Among the six mAbs identified, one (E7) showed better huACE2-dependent sarbecovirus neutralizing potency and breadth than any other mAbs reported to date. Mutagenesis and cryo-electron microscopy studies indicate that these mAbs have a unique RBD contact footprint and that E7 binds to a quaternary structure-dependent epitope.

Early Prediction of Response of Hepatocellular Carcinoma to Yttrium-90 Radiation Segmentectomy Using a Machine Learning MR Imaging Radiomic Approach.

PURPOSE: To assess the accuracy of a machine learning (ML) approach based on magnetic resonance (MR) imaging radiomic quantification obtained before treatment and early after treatment for prediction of early hepatocellular carcinoma (HCC) response to yttrium-90 transarterial radioembolization (TARE). MATERIALS AND METHODS: In this retrospective single-center study of 76 patients with HCC, baseline and early (1-2 months) post-TARE MR images were collected. Semiautomated tumor segmentation facilitated extraction of shape, first-order histogram, and custom signal intensity-based radiomic features, which were then trained (n = 46) using a ML XGBoost model and validated on a separate cohort (n = 30) not used in training to predict treatment response assessed at 4-6 months (based on modified Response and Evaluation Criteria in Solid Tumors criteria). Performance of this ML radiomic model was compared with those of models comprising clinical parameters and standard imaging characteristics using area under the receiver operating curve (AUROC) analysis for prediction of complete response (CR). RESULTS: Seventy-six tumors with a mean (±SD) diameter of 2.6 cm ± 1.6 were included. Sixty, 12, 1, and 3 patients were classified as having CR, partial response, stable disease, and progressive disease, respectively, at 4-6 months posttreatment on the basis of MR images. In the validation cohort, the radiomic model showed good performance (AUROC, 0.89) for prediction of CR, compared with models comprising clinical and standard imaging criteria (AUROC, 0.58 and 0.59, respectively). Baseline imaging features appeared to be more heavily weighted in the radiomic model. CONCLUSIONS: The use of ML modeling of radiomic data combining baseline and early follow-up MR imaging could predict HCC response to TARE. These models need to be investigated further in an independent cohort.

Mitophagy restricts BAX/BAK-independent, Parkin-mediated apoptosis.

Degradation of defective mitochondria is an essential process to maintain cellular homeostasis and it is strictly regulated by the ubiquitin-proteasome system (UPS) and lysosomal activities. Here, using genome-wide CRISPR and small interference RNA screens, we identified a critical contribution of the lysosomal system in controlling aberrant induction of apoptosis following mitochondrial damage. After treatment with mitochondrial toxins, activation of the PINK1-Parkin axis triggered a BAX- and BAK-independent process of cytochrome c release from mitochondria followed by APAF1 and caspase 9-dependent apoptosis. This phenomenon was mediated by UPS-dependent outer mitochondrial membrane (OMM) degradation and was reversed using proteasome inhibitors. We found that the subsequent recruitment of the autophagy machinery to the OMM protected cells from apoptosis, mediating the lysosomal degradation of dysfunctional mitochondria. Our results underscore a major role of the autophagy machinery in counteracting aberrant noncanonical apoptosis and identified autophagy receptors as key elements in the regulation of this process.

Erratum to "Impact of delta variant and vaccination on SARS-CoV-2 secondary attack rate among household close contacts" [The Lancet Regional Health - Western Pacific 17 (2021) 100299].

[This corrects the article DOI: 10.1016/j.lanwpc.2021.100299.].

The Importance of Segment 4 Anatomy on Outcomes Following Living Donor Left Lateral Segmentectomy.

BACKGROUND: During left lateral section (LLS) resection for live liver donation, the vascular inflow and the bile drainage of segment 4 (S4) are compromised. We investigated the long-term changes of S4 after donation and their potential prognostic impact on living liver donors. MATERIALS AND METHODS: This was a retrospective analysis of 42 consecutive left lateral (LLS, S2/3) liver resections for living donation. RESULTS: There were 25 female and 17 male donors. Median age was 33 y and median body mass index was 26. Median LLS, S2/3, volume was 262 cc, and median sS4 volume was 160 cc. Complications were encountered in three donors (7%). An independent extrahepatic S4 artery (S4A) (with a proximal left heptic artery or a right hepatic artery origin) was identified in 41% of the donors. Ligation of the independent S4A was not associated with the rate of post resection liver dysfunction, complications, or the degree of S4 atrophy. Having a dominant S4 portal triad pedicle feeding the right anterior sectors, segment 5/8, of the liver was associated with increased parenchymal damage as evidenced by a higher peak of alanine aminotransferase but was not associated with postoperative complications. The median degree of atrophy of S4 at 1 y post donation as noted on imaging was 66%. The presence of a dominant S4 portal triad pedicle and the peak alanine aminotransferase early postoperatively were both predictors of the degree of S4 atrophy post donation. CONCLUSIONS: The presence of an independent S4A or dominant S4 portal triad pedicle feeding the liver right anterior sectors, segment 5/8, should not be a contraindication for left lateral segment living donation.

Healthcare worker safety program in a coronavirus disease 2019 (COVID-19) alternate care site: The Javits New York Medical Station experience.

OBJECTIVE: In March 2020, New York City became the epicenter of the coronavirus disease 2019 (COVID-19) pandemic in the United States. Because healthcare facilities were overwhelmed with patients, the Jacob K. Javits Convention Center was transformed into the nation's largest alternate care site: Javits New York Medical Station (hereafter termed Javits). Protecting healthcare workers (HCWs) during a global shortage of personal protective equipment (PPE) in a nontraditional healthcare setting posed unique challenges. We describe components of the HCW safety program implemented at Javits. SETTING: Javits, a large convention center transformed into a field hospital, with clinical staff from the US Public Health Service Commissioned Corps and the US Department of Defense. METHODS: Key strategies to ensure HCW safety included ensuring 1-way flow of traffic on and off the patient floor, developing a matrix detailing PPE required for each work activity and location, PPE extended use and reuse protocols, personnel training, and monitoring adherence to PPE donning/doffing protocols when entering or exiting the patient floor. Javits staff who reported COVID-19 symptoms were immediately isolated, monitored, and offered a severe acute respiratory coronavirus virus 2 (SARS-CoV-2) reverse-transcriptase polymerase chain reaction (RT-PCR) test. CONCLUSIONS: A well-designed and implemented HCW safety plan can minimize the risk of SARS-CoV-2 infection for HCWs. The lessons learned from operating the nation's largest COVID-19 alternate care site can be adapted to other environments during public health emergencies.

Evaluating the Downstream Revenues of a Self-Pay Bi-Parametric Prostate MRI Program.

OBJECTIVE: To quantify downstream healthcare utilization and revenue associated with a self-pay bi-parametric prostate MRI (bpMRI) program. METHODS: Medical records of 592 patients who underwent bpMRI between August 2017 and March 2020 were examined for follow-up clinical activities. These include prostate biopsy, radical prostatectomy, external beam radiation therapy, brachytherapy, androgen deprivation therapy, CT Chest, Abdomen and Pelvis, PET/CT, MRI Pelvis, and Nuclear Medicine Bone Scans. The charges for each clinical activity were derived from the Medicare Physician Fee Schedule to conservatively estimate revenues. This patient population was further divided into four groups: Group A, patients who demonstrated an MRI lesion and underwent prostatectomy; Group B, patients who did not demonstrate lesion but underwent prostatectomy; Group C, patients who demonstrated lesion but did not undergo prostatectomy; and Group D, patients who neither demonstrated lesion nor underwent prostatectomy. Revenues for each group were categorized by Urology, Radiation Oncology and Radiology subspecialties. RESULTS: Conservative estimates yielded $520 of downstream revenue per patient who underwent bpMRI. Group A patients yielded 47% of total revenue ($1974 per patient). Group B patients, the smallest group, yielded $1828 per patient. Group C patients made up the largest group and grossed $398 per patient. Group D demonstrated the lowest per patient revenue of $179. Groups A and B yielded most relative revenue for Urology. Group C yielded most relative revenue for Radiation Oncology, and Group D yielded most relative revenue for Radiology. CONCLUSION: A self-pay bpMRI program has the potential to improve patient access to prostate cancer screening while remaining financial sustainable.

Conserved longitudinal alterations of anti-S-protein IgG subclasses in disease progression in initial ancestral Wuhan and vaccine breakthrough Delta infections.

Introduction: COVID-19 has a wide disease spectrum ranging from asymptomatic to severe. While humoral immune responses are critical in preventing infection, the immune mechanisms leading to severe disease, and the identification of biomarkers of disease progression and/or resolution of the infection remains to be determined. Methods: Plasma samples were obtained from infections during the initial wave of ancestral wildtype SARS-CoV-2 and from vaccine breakthrough infections during the wave of Delta variant, up to six months post infection. The spike-specific antibody profiles were compared across different severity groups and timepoints. Results: We found an association between spike-specific IgM, IgA and IgG and disease severity in unvaccinated infected individuals. In addition to strong IgG1 and IgG3 response, patients with severe disease develop a robust IgG2 and IgG4 response. A comparison of the ratio of IgG1 and IgG3 to IgG2 and IgG4 showed that disease progression is associated with a smaller ratio in both the initial wave of WT and the vaccine breakthrough Delta infections. Time-course analysis revealed that smaller (IgG1 and IgG3)/(IgG2 and IgG4) ratio is associated with disease progression, while the reverse associates with clinical recovery. Discussion: While each IgG subclass is associated with disease severity, the balance within the four IgG subclasses may affect disease outcome. Acute disease progression or infection resolution is associated with a specific immunological phenotype that is conserved in both the initial wave of WT and the vaccine breakthrough Delta infections.