Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19.

Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.

Correlates of protection against SARS-CoV-2 in rhesus macaques.

Recent studies have reported the protective efficacy of both natural1 and vaccine-induced2-7 immunity against challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in rhesus macaques. However, the importance of humoral and cellular immunity for protection against infection with SARS-CoV-2 remains to be determined. Here we show that the adoptive transfer of purified IgG from convalescent rhesus macaques (Macaca mulatta) protects naive recipient macaques against challenge with SARS-CoV-2 in a dose-dependent fashion. Depletion of CD8+ T cells in convalescent macaques partially abrogated the protective efficacy of natural immunity against rechallenge with SARS-CoV-2, which suggests a role for cellular immunity in the context of waning or subprotective antibody titres. These data demonstrate that relatively low antibody titres are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may contribute to protection if antibody responses are suboptimal. We also show that higher antibody titres are required for treatment of SARS-CoV-2 infection in macaques. These findings have implications for the development of SARS-CoV-2 vaccines and immune-based therapeutic agents.

Adjuvanting a subunit COVID-19 vaccine to induce protective immunity.

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).

Characterization of humoral and cellular immunologic responses to an mRNA-based human cytomegalovirus vaccine from a phase 1 trial of healthy adults.

mRNA-1647 is an investigational mRNA-based vaccine against cytomegalovirus (CMV) that contains sequences encoding the CMV proteins glycoprotein B and pentamer. Humoral and cellular immune responses were evaluated in blood samples collected from healthy CMV-seropositive and CMV-seronegative adults who participated in a phase 1 trial of a three-dose series of mRNA-1647 (NCT03382405). Neutralizing antibody (nAb) titers against fibroblast and epithelial cell infection in sera from CMV-seronegative mRNA-1647 recipients were higher than those in sera from control CMV-seropositive samples and remained elevated up to 12 months after dose 3. nAb responses elicited by mRNA-1647 were comparable across 14 human CMV (HCMV) strains. Frequencies of antigen-specific memory B cells increased in CMV-seropositive and CMV-seronegative participants after each mRNA-1647 dose and remained elevated for up to 6 months after dose 3. mRNA-1647 elicited robust increases in frequencies and polyfunctionality of CD4+ T helper type 1 and effector CD8+ T cells in samples from CMV-seronegative and CMV-seropositive participants after stimulation with HCMV-specific peptides. The administration of three doses of mRNA-1647 to healthy adults elicited high nAb titers with wide-breadth, long-lasting memory B cells, and strong polyfunctional T-cell responses. These findings support further clinical development of the mRNA-1647 vaccine against CMV.IMPORTANCECytomegalovirus (CMV), a common virus that can infect people of all ages, may lead to serious health problems in unborn babies and those with a weakened immune system. Currently, there is no approved vaccine available to prevent CMV infection; however, the investigational messenger RNA (mRNA)-based CMV vaccine, mRNA-1647, is undergoing evaluation in clinical trials. The current analysis examined samples from a phase 1 trial of mRNA-1647 in healthy adults to better understand how the immune system reacts to vaccination. Three doses of mRNA-1647 produced a long-lasting immune response, thus supporting further investigation of the vaccine in the prevention of CMV infection.CLINICAL TRIALSRegistered at ClinicalTrials.gov (NCT03382405).

What Is a Normal Testosterone Level for Young Men? Rethinking the 300 ng/dL Cutoff for Testosterone Deficiency in Men 20-44 Years Old.

PURPOSE: There is an age-related decline in male testosterone production. It is therefore surprising that young men are evaluated for testosterone deficiency with the same cutoff of 300 ng/dL that was developed from samples of older men. Our aim is to describe normative total testosterone levels and age-specific cutoffs for low testosterone levels in men 20 to 44 years old. MATERIALS AND METHODS: We analyzed the 2011-2016 National Health and Nutrition Examination Surveys, which survey nationally representative samples of United States residents. Men 20 to 44 years old with testosterone levels were included. Men on hormonal medications, with a history of testicular cancer or orchiectomy, and with afternoon/evening laboratory values were excluded. We separated men into 5-year intervals and evaluated the testosterone levels of each age group, and for all men 20 to 44 years old. We used the American Urological Association definition of a "normal testosterone level" (the "middle tertile") to calculate age-specific cutoffs for low testosterone levels. RESULTS: Our final analytic cohort contained 1,486 men. Age-specific middle tertile levels were 409-558 ng/dL (20-24 years old), 413-575 ng/dL (25-29 years old), 359-498 ng/dL (30-34 years old), 352-478 ng/dL (35-39 years old), and 350-473 ng/dL (40-44 years old). Age-specific cutoffs for low testosterone levels were 409, 413, 359, 352, and 350 ng/dL, respectively. CONCLUSIONS: Diagnosis of testosterone deficiency has traditionally been performed in an age-indiscriminate manner. However, young men have different testosterone reference ranges than older men. Accordingly, age-specific normative values and cutoffs should be integrated into the evaluation of young men presenting with testosterone deficiency.

The factor structure of the Edinburgh Postnatal Depression Scale among perinatal high-risk and community samples in London.

Timely and accurate detection of perinatal mental health problems is essential for the wellbeing of both mother and child. Growing evidence has suggested that the Edinburgh Postnatal Depression Scale (EPDS) is not a unidimensional measure of perinatal depression, but can be used to screen for anxiety disorders. We aimed to assess the factor structure of the EPDS in 3 different groups of women: n = 266 pregnant women at high-risk of depression ("Perinatal Stress Study"), n = 471 pregnant women from a community sample, and n = 637 early postnatal women from a community sample ("developing Human Connectome Project"). Exploratory factor analysis (40% of each sample) and confirmatory factor analysis (60% of each sample) were performed. The relationship between EPDS scores and history of mental health concerns was investigated. Results suggested that a 3-factor model (depression, anxiety, and anhedonia) is the most appropriate across groups. The anxiety subscale (EPDS-3A) emerged consistently and was related to maternal history of anxiety disorders in the prenatal sample (W = 6861, p < 0.001). EPDS total score was related to history of mental health problems in both the prenatal (W = 12,185, p < 0.001) and postnatal samples (W = 30,044, p < 0.001). In both high-risk and community samples in the perinatal period, the EPDS appears to consist of depression, anxiety, and anhedonia subscales. A better understanding of the multifactorial structure of the EPDS can inform diagnosis and management of women in the prenatal and postnatal period. Further research is required to validate the EPDS-3A as a screening tool for anxiety.

Molecular detection, not extended culture incubation, contributes to diagnosis of fungal infection.

BACKGROUND: Despite its low sensitivity, fungal culture remains one of the key methods for diagnosis and treatment of fungal infections, as it identifies the etiology at the genus and species level and affords the opportunity for susceptibility testing. The Manual of Clinical Microbiology recommends that fungal culture screening for all pathogens should routinely be held for 4 weeks to maximize the recovery of slow-growing species. Information on the optimal fungal culture time in this era of expansion of immunocompromised populations and availability of molecular diagnostics is lacking. We reviewed our experience with fungal culture to determine the optimal culture incubation time. In addition, our experience of broad-range ITS PCR for diagnosis of culture-negative fungal infections was also reviewed. METHODS: Fungal culture and ITS PCR results from January 1, 2013, to December 31, 2017, were reviewed. RESULTS: This study included 4234 non-duplicated positive cultures. Ninety-six percent (4058) of the positive cultures were detected in the first 7 days of incubation. During the second week of incubation, 111 (2.8%) positives were detected from day 8 to day 10, and 71 (1.7%) were detected from day 11 to day 14. Only 6 (0.1%) positive cultures were detected in the third week of incubation, and no positive culture was detected in the fourth week of incubation. No clinically significant fungal isolates were recovered after 14 days. Clinically significant pathogens were detected in 16 (0.2%) culture-negative samples by ITS PCR. CONCLUSION: Extending culture incubation beyond 2 weeks did not generate clinically relevant results. When culture failed to make a laboratory diagnosis, broad-range internal transcribed spacer (ITS) rRNA gene PCR followed by sequencing produced clinically significant results.

Creative social media use and political participation in young people: The moderation and mediation role of online political expression.

INTRODUCTION: Educators and policymakers promote political participation in young people as a means to strengthen the legitimacy of democracy. Creative social media use has grown in popularity in the digital age; however, this creative usage still receives inadequate attention in the literature-particularly its association with political participation. METHOD: This study collected three-wave panel data from a sample of young people living in Hong Kong (56.9% male, mean age = 18.81, standard deviation = 2.70) and used cross-lagged structural equation modeling to evaluate the mediating and moderating roles of online political expression in the link between creative social media and political participation. RESULTS AND CONCLUSIONS: The results showed that creative social media use positively predicted political participation indirectly by the full mediation of enhanced online political expression. Findings did not reveal the moderation role of online political expression in the link between creative use of social media and political participation. Findings make important theoretical contributions in the field linking social media usage to political engagement.

Technique: open lumbar decompression and fusion with the Excelsius GPS robot.

The Excelsius GPS (Globus Medical, Inc.) was approved by the FDA in 2017. This novel robot allows for real-time intraoperative imaging, registration, and direct screw insertion through a rigid external arm-without the need for interspinous clamps or K-wires. The authors present one of the first operative cases utilizing the Excelsius GPS robotic system in spinal surgery. A 75-year-old man presented with severe lower back pain and left leg radiculopathy. He had previously undergone 3 decompressive surgeries from L3 to L5, with evidence of instability and loss of sagittal balance. Robotic assistance was utilized to perform a revision decompression with instrumented fusion from L3 to S1. The usage of robotic assistance in spinal surgery may be an invaluable resource in minimally invasive cases, minimizing the need for fluoroscopy, or in those with abnormal anatomical landmarks. The video can be found here: https://youtu.be/yVI-sJWf9Iw .

Spontaneous Coronary Artery Dissection: Insights From Histology and Optical Coherence Tomography.

Spontaneous coronary artery dissection (SCAD) is a well-known but infrequent cause of acute coronary syndrome (ACS), and often goes unrecognized. Although management of SCAD is, at times, controversial, when a patient presents with ACS, percutaneous coronary intervention (PCI) is frequently necessary. We present a patient with ST-segment elevation myocardial infarction (STEMI) with SCAD that illustrates two important points: use of intracoronary optical coherence tomography to guide PCI, and histologic assessment to provide a unique insight into the etiology of SCAD. Following the case, we briefly review the important aspects of the pathophysiology, epidemiology, diagnosis, and interventional management of SCAD.

An investigation of mental imagery in bipolar disorder: Exploring "the mind's eye".

OBJECTIVES: Mental imagery abnormalities occur across psychopathologies and are hypothesized to drive emotional difficulties in bipolar disorder (BD). A comprehensive assessment of mental imagery in BD is lacking. We aimed to test whether (i) mental imagery abnormalities (abnormalities in cognitive stages and subjective domains) occur in BD relative to non-clinical controls; and (ii) to determine the specificity of any abnormalities in BD relative to depression and anxiety disorders. METHODS: Participants included 54 subjects in the BD group (depressed/euthymic; n=27 in each subgroup), subjects with unipolar depression (n=26), subjects with anxiety disorders (n=25), and non-clinical controls (n=27) matched for age, gender, ethnicity, education, and premorbid IQ. Experimental tasks assessed cognitive (non-emotional) measures of mental imagery (cognitive stages). Questionnaires, experimental tasks, and a phenomenological interview assessed subjective domains including spontaneous imagery use, interpretation bias, and emotional mental imagery. RESULTS: (i) Compared to non-clinical controls, the BD combined group reported a greater impact of intrusive prospective imagery in daily life, more vivid and "real" negative images (prospective imagery task), and higher self-involvement (picture-word task). The BD combined group showed no clear abnormalities in cognitive stages of mental imagery. (ii) When depressed individuals with BD were compared to the depressed or anxious clinical control groups, no significant differences remained-across all groups, imagery differences were associated with affective lability and anxiety. CONCLUSIONS: Compared to non-clinical controls, BD is characterized by abnormalities in aspects of emotional mental imagery within the context of otherwise normal cognitive aspects. When matched for depression and anxiety, these abnormalities are not specific to BD-rather, imagery may reflect a transdiagnostic marker of emotional psychopathology.

Stress Relaxation for Granular Materials near Jamming under Cyclic Compression.

We have explored isotropically jammed states of semi-2D granular materials through cyclic compression. In each compression cycle, systems of either identical ellipses or bidisperse disks transition between jammed and unjammed states. We determine the evolution of the average pressure P and structure through consecutive jammed states. We observe a transition point ϕ_{m} above which P persists over many cycles; below ϕ_{m}, P relaxes slowly. The relaxation time scale associated with P increases with packing fraction, while the relaxation time scale for collective particle motion remains constant. The collective motion of the ellipses is hindered compared to disks because of the rotational constraints on elliptical particles.

Bowel and bladder-control anxiety: a preliminary description of a viscerally-centred phobic syndrome.

BACKGROUND: People with anxiety disorders occasionally report fears about losing control of basic bodily functions in public. These anxieties often occur in the absence of physical disorder and have previously been recognized as "obsessive" anxieties reflecting a preoccupation with loss of bowel/bladder control. Motivated by our observations of the non-trivial occurrence of such anxieties in our clinical practice we sought to fill a gap in the current understanding of "bowel/bladder-control anxieties". METHOD: Eligible participants completed an internet survey. RESULTS: Bowel/bladder-control anxieties (n = 140) tended to emerge in the mid to late 20s and were associated with high levels of avoidance and functional impairment. There was a high prevalence of panic attacks (78%); these were especially prevalent among those with bowel-control anxiety. Of those with panic attacks, 62% indicated that their main concern was being incontinent during a panic attack. Significantly, a proportion of respondents (~16%) reported actually being incontinent during a panic attack. Seventy percent of participants reported intrusive imagery related to loss of bowel/bladder control. Intrusion-related distress was correlated with agoraphobic avoidance and general role impairment. Some differences were noted between those with predominantly bowel-, predominantly bladder- and those with both bowel and bladder-control anxieties. CONCLUSION: This preliminary characterization indicates that even in a non-treatment seeking community sample, bowel/bladder-control anxieties are associated with high levels of distress and impairment. Further careful characterization of these anxieties will clarify their phenomenology and help us develop or modify treatment protocols in a way that takes account of any special characteristics of such viscerally-centred phobic syndromes.

Social and psychological barriers to private retirement savings in Hong Kong.

Using a phone survey conducted among Hong Kong workers, we examined the association of institutional, social, and psychological factors with engagement in both private retirement savings and the total amount of savings. Alarmingly, this study demonstrates that approximately 42% of Hong Kong workers do not save privately for their retirement. We found that age, education, number of children, support from spouse and friends, social regulation, perceived financial knowledge, and financial management capacity are associated with engagement in private retirement savings. Among those who saved, age, education, perceived financial knowledge, and financial management capacity are related to the amount of savings. Measures that could increase the social support for retirement savings as well as enhance their financial knowledge and management ability should be developed and implemented so that more workers engage in private retirement savings. A promising policy option for the Hong Kong government is to offer a tax incentive to promote additional savings for old-age income protection.

Everything or Nothing: Supervised High-intensity Exercise is the Only Way to Achieve Meaningful Results.

Prehabilitation exercise should be performed via supervised, high-intensity exercise training regimens. This type of training is preferred by patients, increases exercise accountability, leads to emotional and social benefits, and ensures that exercises are performed in a safe and efficient manner.

Health Outcomes of Social Pension Expansion: A Quasi-Experiment Among Older Adults in Hong Kong.

A social pension, regarded as a reliable source of income, has the potential to significantly influence the overall wellbeing of vulnerable older adults. This study aimed to extend the understanding of the effects of social pension expansion beyond its economic impacts to encompass recipients' health status. Using three-wave data from a representative sample of older adults, we employed a quasi-experimental assessment model to evaluate the impact of a recent social pension expansion in Hong Kong on health-related consumption and health outcomes among older adults. The results of the triple difference estimations revealed that an increased social pension significantly enhanced older people's engagement in entertainment activities, utilization of healthcare services, and expenditures on preventive health products. Furthermore, the increased social pension was found to have a significant positive effect on mitigating poor self-rated health and poor sleep quality. However, it did not have a significant impact on the prevalence of depression. These findings suggest that social pension expansion should be coordinated with other policy initiatives to comprehensively improve the physical and mental health of older adults.

Short-Term Changes in Vasectomy Consults and Procedures Following Dobbs v Jackson Women's Health Organization.

INTRODUCTION: On June 24, 2022, the US Supreme Court issued its decision on Dobbs v Jackson Women's Health Organization (Dobbs). This decision had major implications on female reproductive choices, but also had potential implications on their male counterparts. We sought to determine the association of Dobbs with the number and characteristics of men seeking vasectomy. METHODS: A retrospective review was performed to determine the number of vasectomy consults and procedures completed at a single Michigan health system in the 6 months following Dobbs (June 24, 2022-December 24, 2022) vs the same 6-month time frame between 2019 and 2021. Another retrospective review was conducted in the 3 months following Dobbs (June 24, 2022-September 24, 2022) vs the same days in 2021 to determine the number of vasectomy consults completed and to evaluate for differences in the characteristics of these men. RESULTS: In the 6 months after Dobbs, there was a 150% and 160% increase in vasectomy consults and procedures completed, respectively, compared to a similar time frame in 2019 to 2021. In the 3 months after Dobbs, there was a 225% increase in new vasectomy consults compared to a similar time frame in 2021. There were no differences in the age, race, religion, median household income, or insurance type of men seeking vasectomy consult pre- vs post-Dobbs. Partnerless men (odds ratio 3.66) and those without children (odds ratio 2.85) were more likely than married men and those with 3 or more children, respectively, to seek vasectomy consult post-Dobbs. CONCLUSIONS: Dobbs was associated with a marked increase in vasectomy consultations and procedures at our institution in the state of Michigan. Future studies are needed to determine the long-term implications of Dobbs on vasectomy practices and determine if vasectomy practices differ by states and their respective abortion laws.

The Effects of Multidimensional Poverty on Life Satisfaction Among Older Adults in Hong Kong.

Poverty indicators such as income-based poverty, material deprivation, asset-based poverty, and expenditure-based poverty each carries an aspect of economic deprivation. This current study examined and compared the unique effects of each poverty dimension on life satisfaction during old age. We measured four poverty indicators-life satisfaction, social resources, physical health, and mental well-being-in a three-wave sample of older Hong Kong adults (N = 563). Panel data were fitted to a structural model that involved the constraints of the path coefficients (e.g., effects of poverty indicators on life satisfaction). The model results indicate that while material deprivation and asset-based poverty reduce life satisfaction, income-based poverty and expenditure-based poverty do not significantly shape life satisfaction. Based on these findings, we suggest implementing future-oriented interventions into policy agendas to promote current working adults' financial preparation for retirement to reduce their risk of falling into asset-based poverty and thus material deprivation after retirement.

Ensemble-Learning and Feature Selection Techniques for Enhanced Antisense Oligonucleotide Efficacy Prediction in Exon Skipping.

Antisense oligonucleotide (ASO)-mediated exon skipping has become a valuable tool for investigating gene function and developing gene therapy. Machine-learning-based computational methods, such as eSkip-Finder, have been developed to predict the efficacy of ASOs via exon skipping. However, these methods are computationally demanding, and the accuracy of predictions remains suboptimal. In this study, we propose a new approach to reduce the computational burden and improve the prediction performance by using feature selection within machine-learning algorithms and ensemble-learning techniques. We evaluated our approach using a dataset of experimentally validated exon-skipping events, dividing it into training and testing sets. Our results demonstrate that using a three-way-voting approach with random forest, gradient boosting, and XGBoost can significantly reduce the computation time to under ten seconds while improving prediction performance, as measured by R2 for both 2'-O-methyl nucleotides (2OMe) and phosphorodiamidate morpholino oligomers (PMOs). Additionally, the feature importance ranking derived from our approach is in good agreement with previously published results. Our findings suggest that our approach has the potential to enhance the accuracy and efficiency of predicting ASO efficacy via exon skipping. It could also facilitate the development of novel therapeutic strategies. This study could contribute to the ongoing efforts to improve ASO design and optimize gene therapy approaches.