Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5.

SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged notably to become dominant in the United States and South Africa, respectively1,2. These new subvariants carrying further mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain3. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

Antibody evasion properties of SARS-CoV-2 Omicron sublineages.

The identification of the Omicron (B.1.1.529.1 or BA.1) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Botswana in November 20211 immediately caused concern owing to the number of alterations in the spike glycoprotein that could lead to antibody evasion. We2 and others3-6 recently reported results confirming such a concern. Continuing surveillance of the evolution of Omicron has since revealed the rise in prevalence of two sublineages, BA.1 with an R346K alteration (BA.1+R346K, also known as BA.1.1) and B.1.1.529.2 (BA.2), with the latter containing 8 unique spike alterations and lacking 13 spike alterations found in BA.1. Here we extended our studies to include antigenic characterization of these new sublineages. Polyclonal sera from patients infected by wild-type SARS-CoV-2 or recipients of current mRNA vaccines showed a substantial loss in neutralizing activity against both BA.1+R346K and BA.2, with drops comparable to that already reported for BA.1 (refs. 2,3,5,6). These findings indicate that these three sublineages of Omicron are antigenically equidistant from the wild-type SARS-CoV-2 and thus similarly threaten the efficacies of current vaccines. BA.2 also exhibited marked resistance to 17 of 19 neutralizing monoclonal antibodies tested, including S309 (sotrovimab)7, which had retained appreciable activity against BA.1 and BA.1+R346K (refs. 2-4,6). This finding shows that no authorized monoclonal antibody therapy could adequately cover all sublineages of the Omicron variant, except for the recently authorized LY-CoV1404 (bebtelovimab).

Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2.

The B.1.1.529/Omicron variant of SARS-CoV-2 was only recently detected in southern Africa, but its subsequent spread has been extensive, both regionally and globally1. It is expected to become dominant in the coming weeks2, probably due to enhanced transmissibility. A striking feature of this variant is the large number of spike mutations3 that pose a threat to the efficacy of current COVID-19 vaccines and antibody therapies4. This concern is amplified by the findings of our study. Here we found that B.1.1.529 is markedly resistant to neutralization by serum not only from patients who recovered from COVID-19, but also from individuals who were vaccinated with one of the four widely used COVID-19 vaccines. Even serum from individuals who were vaccinated and received a booster dose of mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies against all known epitope clusters on the spike protein, we noted that the activity of 17 out of the 19 antibodies tested were either abolished or impaired, including ones that are currently authorized or approved for use in patients. Moreover, we also identified four new spike mutations (S371L, N440K, G446S and Q493R) that confer greater antibody resistance on B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.

Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.

The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization1-3, and more treatments are under development4-7. Furthermore, multiple vaccine constructs have shown promise8, including two that have an approximately 95% protective efficacy against COVID-199,10. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants13,14 with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.

Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic continues, with devasting consequences for human lives and the global economy1,2. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this coronavirus. Here we report the isolation of sixty-one SARS-CoV-2-neutralizing monoclonal antibodies from five patients infected with SARS-CoV-2 and admitted to hospital with severe coronavirus disease 2019 (COVID-19). Among these are nineteen antibodies that potently neutralized authentic SARS-CoV-2 in vitro, nine of which exhibited very high potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng ml-1. Epitope mapping showed that this collection of nineteen antibodies was about equally divided between those directed against the receptor-binding domain (RBD) and those directed against the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody that targets the RBD, a second that targets the NTD, and a third that bridges two separate RBDs showed that the antibodies recognize the closed, 'all RBD-down' conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.

Epigenetic Aging and Musculoskeletal Outcomes in a Cohort of Women Living With HIV.

BACKGROUND: The relationship between accelerated epigenetic aging and musculoskeletal outcomes in women with HIV (WWH) has not been studied. METHODS: We measured DNA methylation age using the Infinium MethylationEPIC BeadChip in a cohort from the Women's Interagency HIV Study (n = 190) with measures of bone mineral density (BMD) and physical function. We estimated 6 biomarkers of epigenetic aging-epigenetic age acceleration (EAA), extrinsic EAA, intrinsic EAA, GrimAge, PhenoAge, and DNA methylation-estimated telomere length-and evaluated associations of epigenetic aging measures with BMD and physical function. We also performed epigenome-wide association studies to examine associations of DNA methylation signatures with BMD and physical function. RESULTS: This study included 118 WWH (mean age, 49.7 years; 69% Black) and 72 without HIV (mean age, 48.9 years; 69% Black). WWH had higher EAA (mean ± SD, 1.44 ± 5.36 vs -1.88 ± 5.07; P < .001) and lower DNA methylation-estimated telomere length (7.13 ± 0.31 vs 7.34 ± 0.23, P < .001) than women without HIV. There were no significant associations between accelerated epigenetic aging and BMD. Rather, measures of accelerated epigenetic aging were associated with lower physical function. CONCLUSIONS: Accelerated epigenetic aging was observed in WWH as compared with women without HIV and was associated with lower physical function in both groups.

Menopause-Associated Changes in Mandibular Bone Microarchitecture Are Site-Specific.

BACKGROUND: There are conflicting reports on the effects of decreased estrogen levels on mandibular bone microarchitecture. Whether these effects are consistent throughout the mandible is unclear and may have important implications for treatment planning. PURPOSE: The goal of this study was to evaluate trabecular and cortical bone microstructure in the mandibular condyle and the mandibular basal bone and compare these sites between premenopausal and postmenopausal women. STUDY DESIGN, SETTING, SAMPLE: Participants were recruited for a cross-sectional cohort study at Columbia University Irving Medical Center. Each participant had cone-beam computed tomography taken of their mandibular condyles and the basal bone. Exclusion criteria for the population included a) current chemotherapy or immunotherapy; b) history of bisphosphonate or other osteoporosis therapy; and c) currently pregnant, nursing, or on hormonal birth control. INDEPENDENT VARIABLE: The predictor variables are menopausal status (before or after menopause) and mandibular region of interest (condyle/basal bone). MAIN OUTCOME VARIABLE: Parameters of interest included the following indicators of bone quality: trabecular bone volume fraction, trabecular thickness, trabecular number, trabecular separation, cortical bone volume fraction, cortical thickness, and cortical porosity. COVARIATES: Covariates included demographic variables such as age, estrogen levels, and ethnicity. ANALYSES: Quantitative microstructure analyses were conducted on cone-beam computed tomography images, and differences between groups for continuous measures (including age) were assessed with an unpaired t-test, and demographic variables were assessed by χ2. Statistical significance was recorded at P < .05. RESULTS: The premenopausal and postmenopausal groups each had 31 participants, with the following average age: premenopausal = 43.9 ± 6.9 versus postmenopausal = 57.5 ± 7.6 years old; P < .001, and estrogen levels: premenopausal = 91.77 ± 80.13 pg/ml versus postmenopausal = 41.44 ± 61.62 pg/ml; P < .01). Postmenopausal women had significantly greater condylar trabecular separation (0.61 ± 0.18 vs 0.47 ± 0.11 mm; P < .001) and lower trabecular number (1.03 ± 0.18 vs 1.21 ± 0.19 mm-1; P < .001) compared to premenopausal women. There were no significant differences in the basal bone microarchitectural parameters between the menopausal groups. CONCLUSION AND RELEVANCE: Menopause is associated with mandibular condylar trabecular bone loss but has minimal effects on the mandibular basal bone. This may have important ramifications for treatment planning in advanced-age individuals.

Postmenopausal women with HIV have increased tooth loss.

BACKGROUND: With effective antiretroviral therapy, people with HIV (PWH) are living longer and aging; the majority of PWH in the United States are now over the age of 50 and in women have gone through the menopause transition. Menopause potentiates skeletal bone loss at the spine, hip, and radius in PWH. The alveolar bone which surronds the teeth is different than long bones because it is derived from the neural crest. However, few studies have assessed the oral health and alveolar bone in middle aged and older women with HIV. Therefore, the objective of this study was to evaluate periodontal disease and alveolar bone microarchitecture in postmenopausal women with HIV. METHODS: 135 self-reported postmenopausal women were recruited (59 HIV-, 76 HIV + on combination antiretroviral therapy with virological suppression) from a single academic center. The following parameters were measured: cytokine levels (IFN-γ, TNF-α, IL-1ß, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17 A, OPG, and RANKL) in gingival crevicular fluid, bleeding on probing, probing depth, clinical attachment loss, number of teeth present, alveolar crestal height, and alveolar bone microarchitecture. RESULTS: The mean age of participants was 57.04+/-6.25 years and a greater proportion of women with HIV were black/African American (HIV + 68.42%, HIV- 23.73%; p < 0.001). There was no significant difference in bleeding on probing (p = 0.17) and attachment loss (p = 0.39) between women who were HIV infected vs. HIV uninfected. Women with HIV had significantly higher RANKL expression in Gingival Crevicular Fluid (HIV + 3.80+/-3.19 pg/ul, HIV- 1.29+/-2.14 pg/ul ; p < 0.001), fewer teeth present (HIV + 17.75+/-7.62, HIV- 22.79+/-5.70; p < 0.001), ), lower trabecular number (HIV + 0.08+/-0.01, HIV- 0.09+/-0.02; p = 0.004) and greater trabecular separation (HIV + 9.23+/-3.11, HIV- 7.99+/-3.23; p = 0.04) compared to women without HIV that remained significant in multivariate logistic regression analysis in a sub-cohort after adjusting for age, race/ethnicity, smoking status, and diabetes. CONCLUSION: Postmenopausal women with HIV have deterioration of the alveolar trabecular bone microarchitecture that may contribute to greater tooth loss.

Significance of radiographic temporomandibular degenerative joint disease findings.

The field of orthodontics has seen a recent increase in the number of patients over the age of 50 seeking treatment and also an increase in the use of cone beam technology. Similar to other joints in the body, the temporomandibular joint (TMJ) is associated with age-related degeneration. However, unlike other joints, degeneration of the TMJ is rarely symptomatic and when there is pain, it is usually self-limiting. In this article, we will review: a) the incidence and prevalence of TMJ degenerative diseases, b) similarities and differences of TMJ vs knee degenerative diseases, and c) current treatment recommendations for TMJ degenerative diseases. In the vast majority of people, radiographic evidence of TMJ degeneration is an incidental finding. Future longitudinal research is needed to follow the natural course of TMJ degenerative patients.

Menopausal Hormone Therapy and Subclinical Cardiovascular Disease in Women With and Without Human Immunodeficiency Virus.

BACKGROUND: Estrogen-based hormone therapy (HT) may have beneficial cardiovascular effects when initiated in early menopause. This has not been examined in women with human immunodeficiency virus (HIV), who have heightened immune activation and cardiovascular risks. METHODS: Among 609 postmenopausal women (1234 person-visits) in the Women's Interagency HIV Study, we examined the relationship of ever HT use (oral, patch, or vaginal) with subclinical atherosclerosis: carotid artery intima-media thickness (CIMT), distensibility, and plaque assessed via repeated B-mode ultrasound imaging (2004-2013). We also examined associations of HT with cross-sectional biomarkers of immune activation and D-dimer. Statistical models were adjusted for sociodemographic, behavioral, and cardiometabolic factors. RESULTS: Women (mean age, 51 years; 80% HIV positive) who ever used HT at baseline were older, and more likely to be non-Hispanic White and report higher income, than never-users. Women who ever used HT had 43% lower prevalence of plaque (prevalence ratio, 0.57 [95% confidence interval {CI}, .40-.80]; P < .01), 2.51 µm less progression of CIMT per year (95% CI, -4.60, to -.41; P = .02), and marginally lower incidence of plaque over approximately 7 years (risk ratio, 0.38 [95% CI, .14-1.03; P = .06), compared with never-users, adjusting for covariates; ever HT use was not associated with distensibility. These findings were similar for women with and without HIV. Ever HT use was associated with lower serum D-dimer, but not with biomarkers of immune activation after covariate adjustment. CONCLUSIONS: HT may confer a subclinical cardiovascular benefit in women with HIV. These results begin to fill a knowledge gap in menopausal care for women with HIV, in whom uptake of HT is very low.

Systemic exposure to hydroxychloroquine and its relationship with outcome in severely ill COVID-19 patients in New York City.

AIM: To investigate the relationship between systemic exposure to hydroxychloroquine (HCQ) and its metabolite desethylhydroxychloroquine (DHCQ) and clinical outcome in severely ill patients treated with a standard oral dose regimen of HCQ during the first wave of COVID-19 in New York City. METHODS: We correlated retrospective clinical data with drug exposure prospectively assessed from convenience samples using population pharmacokinetics and Bayesian estimation. Systemic exposure was assessed in 215 patients admitted to ICU or COVID-ward for whom an interleukin-6 level was requested and who were still alive 24 hours after the last dose of HCQ. Patients received oral HCQ 600 mg twice daily on day 1 followed by 4 days of 400 mg daily. RESULTS: Fifty-three precent of the patients were intubated at 5.4 ± 6.4 days after admission and 26.5% died at an average of 32.2 ± 19.1 days. QTc at admission was 448 ± 34 ms. Systemic exposure to HCQ and DHCQ demonstrated substantial variability. Cumulative area under the serum concentration-time curve up to infinity for HCQ was 71.4 ± 19.3 h mg/L and for DHCQ 56.5 ± 28.3 h mg/L. Variability in systemic exposure was not clearly explained by renal function, liver function or inflammatory state. In turn, systemic exposure did not correlate with intubation status, survival or QTc prolongation. CONCLUSION: This study in severely ill patients was not able to find any relationship between systemic exposure to HCQ and DHCQ and clinical outcome at a routine dose regimen and adds to the growing body of evidence that oral HCQ does not alter the course of disease in COVID-19 patients.

The Long-Acting Cabotegravir Tail as an Implementation Challenge: Planning for Safe Discontinuation.

The long-acting feature of cabotegravir, an integrase-inhibitor highly effective in preventing acquisition of HIV in adolescents and adults, is both its greatest strength and a challenge to its implementation. Cab-LA is administered at 8-week intervals (after an initial loading dose) but has a long, variable drug "tail" that may leave users vulnerable to future drug resistance if they contract HIV during this critical period. The potential for cab-LA to meaningfully contribute to ending the HIV Epidemic is hindered by, among other factors, limited resources to guide patients and providers on how to safely discontinue injections. We suggest three key strategies to overcome this specific challenge: (1) Comprehensive patient education and counseling about the drug tail; (2) Training and coaching PrEP care teams, including clinical and non-clinical staff, on communication around the tail; (3) Adherence support strategies, including monitoring of cabotegravir drug levels after discontinuation, for a personalized medicine approach to safe discontinuation.

Disclosure to South African children about their own HIV status over time.

Disclosure to children living with HIV (CLHIV) about their own status is associated with positive outcomes such as treatment adherence, but prior cross-sectional studies in sub-Saharan Africa report disclosure rates of <50%. This study aims to assess pediatric disclosure over time. 548 CLHIV were followed from 2/2013-4/2018 in Johannesburg, South Africa. Cumulative incidence of disclosure was calculated with Kaplan-Meier analysis, and disclosure characteristics assessed with a Cox model. By end of follow-up, cumulative disclosure was 70.3% (95% confidence interval: 60.0-79.9). Median age at disclosure was 9 years (range: 3-13). Baseline predictors of disclosure included older child age and the child having a history of going hungry. Prior to disclosure, 98.0% of caregivers who disclosed had conversed with their child about their illness or an HIV-related topic, or their child had asked about HIV, versus 88.6% of caregivers who never disclosed. While many children did not receive disclosure during this relatively large, longitudinal study of South African CLHIV, caregivers who had not yet disclosed may have been preparing to do so by discussing their child's health or HIV generally with their child. This highlights the need for clinicians to consistently support caregivers throughout the incremental disclosure process.

Depression and PrEP uptake, interruption, and adherence among young women in Uganda.

Depression is a common cause of morbidity globally and can impact adherence to medications, posing challenges to medication-based HIV prevention. The objectives of this work are to describe the frequency of depression symptoms in a cohort of 499 young women in Kampala, Uganda and to determine the association of depression symptoms with use of HIV pre-exposure prophylaxis (PrEP). Mild or greater depression, assessed by the patient health questionnaire (PHQ-9), was experienced by 34% of participants at enrollment. Participants with mild depression symptoms tended to uptake PrEP, request PrEP refills, and adhere to PrEP with similar frequency to women with no/minimal signs of depression. These findings highlight opportunities to leverage existing HIV prevention programs to identify women who may benefit from mental health services and may not otherwise be screened.Trial registration: ClinicalTrials.gov identifier: NCT03464266..

Evaluation of the mandibular condylar bone microarchitecture in people living with HIV.

OBJECTIVES: People living with HIV (PLWH) have been shown to have lower bone density at the spine, hip, and radius. However, whether a similar bone phenotype is seen in craniofacial bones is not known. The goal of this study was to evaluate the bone microarchitecture of the mandibular condyle in PLWH. METHODS: We recruited 212 participants, which included 88 HIV-negative participants and 124 PLWH on combination antiretroviral therapy with virological suppression from a single academic center. Each participant filled out a validated temporomandibular disorder (TMD) pain screening questionnaire and had cone beam computed tomography (CBCT) of their mandibular condyles. Qualitative radiographic evidence of temporomandibular joint disorders-osteoarthritis (TMJD-OA) assessment and quantitative microarchitecture analysis of their mandibular condylar bones were conducted. RESULTS: There was no statistically significant difference in either self-reported TMD or in radiographic evidence of TMJD-OA in PLWH compared with HIV-negative controls. Linear regression analysis revealed that positive HIV status remained significantly associated with increased trabecular thickness, decreased cortical porosity, and increased cortical bone volume fraction after adjusting for race, diabetes, sex, and age. CONCLUSION: PLWH have increased mandibular condylar trabecular bone thickness and cortical bone volume fraction compared with HIV-negative controls.

Veno-arterial extracorporeal membrane oxygenation with concomitant Impella versus concomitant intra-aortic-balloon-pump for cardiogenic shock.

INTRODUCTION: The intra-aortic balloon pump (IABP) and Impella are left ventricular unloading devices with peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) in place and later serve as bridging therapy when VA-ECMO is terminated. We aimed to determine the potential differences in clinical outcomes and rate of complications between the two combinations of mechanical circulatory support. METHODS: This was a retrospective, single institutional cohort study conducted in the intensive care unit (ICU) of Queen Elizabeth Hospital, Hong Kong. Inclusion criteria included all patients aged ⩾18 years, who had VA-ECMO support, and who had left ventricular unloading by either IABP or Impella between January 1, 2018 and October 31, 2020. Patients <18 years old, with central VA-ECMO, who did not require left ventricular unloading, or who underwent surgical venting procedures were excluded. The primary outcome was ECMO duration. Secondary outcomes included length of stay (LOS) in the ICU, hospital LOS, mortality, and complication rate. RESULTS: Fifty-two patients with ECMO + IABP and 14 patients with ECMO + Impella were recruited. No statistically significant difference was observed in terms of ECMO duration (2.5 vs 4.6 days, p = 0.147), ICU LOS (7.7 vs 10.8 days, p = 0.367), and hospital LOS (14.8 vs 16.5 days, p = 0.556) between the two groups. No statistically significant difference was observed in the ECMO, ICU, and hospital mortalities between the two groups. Specific complications related to the ECMO and Impella combination were also noted. CONCLUSIONS: Impella was not shown to offer a statistically significant clinical benefit compared with IABP in conjunction with ECMO. Clinicians should be aware of the specific complications of using Impella.

Human Immunodeficiency Virus (HIV) and Menopause Are Independently Associated With Lower Bone Mineral Density: Results From the Women's Interagency HIV Study.

BACKGROUND: We previously reported lower bone mineral density (BMD) among premenopausal women with HIV (WWH) compared to women without HIV (HIV-). Rate of bone loss may be even greater for WWH during the menopausal transition. METHODS: Pre-, peri- and postmenopausal women in the Women\'s Interagency HIV Study (WIHS) underwent whole body DXA and central quantitative computed tomography to measure areal BMD (aBMD) and volumetric BMD (vBMD), respectively. Multivariable regression models with covariates associated with low aBMD (T score < -1.0) in univariate analyses (P≤.05) and known risk factors for low BMD assessed contributions of HIV and menopausal stage to the prediction of aBMD. RESULTS: Compared to HIV- women, in unadjusted analyses, WWH had 5-9% lower aBMD at the lumbar spine (P=.001), femoral neck (P=.04), total hip (P=.003) and the ultradistal radius (P=.004), and higher osteoporosis prevalence (T score<-2.5) at the ultradistal radius only (13.5% vs 0%, P=.0003). WWH also had lower vBMD at the spine and hip. In fully adjusted models, HIV independently predicted reduced aBMD at the lumbar spine, total hip, femoral neck, and ultradistal radius; menopausal stage remained a significant predictor of lumbar spine and ultradistal radius aBMD. CONCLUSIONS: HIV infection and menopausal stage were independent predictors of lower BMD, and had an additive effect on lumbar spine and total hip BMD. Additional research is needed to better understand underlying mechanisms by which HIV impacts BMD as women age and transition through menopause, and develop strategies to mitigate osteoporosis and fracture risk in this growing population.

SARS-CoV-2 RNA Shedding in Semen and Oligozoospermia of Patient with Severe Coronavirus Disease 11 Weeks after Infection.

We report severe acute respiratory syndrome coronavirus 2 in semen by using quantitative reverse transcription PCR during the late convalescent phase. Virus was associated with adequate humoral and cell-mediated responses, suggesting possible seeding of the immune-privileged testes. We provide longitudinal semen quality data for 6 other men, including 3 who had oligozoospermia.

Prolonged severe acute respiratory syndrome coronavirus 2 persistence, attenuated immunologic response, and viral evolution in a solid organ transplant patient.

Unlike immunocompetent hosts, the duration of viral persistence after infection with severe acute respiratory syndrome coronavirus 2 can be prolonged in immunosuppressed patients. Here, we present a case of viral persistence for over 19 weeks in a patient with a history of solid organ transplant and explore the clinical, virologic, and immunologic course. Our patient still demonstrated viral persistence at 138 days with low polymerase chain reaction cycle threshold values and evidence of continuing viral sequence evolution indicative of ongoing virus replication. These findings have important implications for infection prevention and control recommendations in immunosuppressed patients. Immune response, including neutralizing antibody titers, T cell activity, and cytokine levels, peaked around days 44-72 after diagnosis. Anti-S trimer antibodies were low at all time points, and T cell response was attenuated by day 119. As immune response waned and viral load increased, increased genetic diversity emerged, suggesting a mechanism for the development of viral variants.

Antibiotic-Specific Risk for Community-Acquired Clostridioides difficile Infection in the United States from 2008 to 2020.

Antibiotic exposure is a crucial risk factor for community-acquired Clostridioides difficile infection (CA-CDI). However, the relative risks associated with specific antibiotics may vary over time, and the absolute risks have not been clearly established. This is a retrospective cohort study. Adults were included if they received an outpatient antibiotic prescription within the IBM MarketScan databases between 2008 and 2020. The primary exposure was an outpatient antibiotic prescription, and the receipt of doxycycline was used as the reference comparison. The primary outcome was CA-CDI, defined as the presence of an International Classification of Diseases (ICD) diagnosis code for CDI within 90 days of receiving an outpatient antibiotic prescription, and subsequent treatment for CDI. There were 36,626,794 unique patients who received outpatient antibiotics, including 11,607 (0.03%) who developed CA-CDI. Relative to doxycycline, the antibiotics conferring the highest risks for CA-CDI were clindamycin (adjusted odds ratio [aOR], 8.81; 95% confidence interval [CI], 7.76 to 10.00), cefdinir (aOR, 5.86; 95% CI, 5.03 to 6.83), cefuroxime (aOR, 4.57; 95% CI, 3.87 to 5.39), and fluoroquinolones (aOR, 4.05; 95% CI, 3.58 to 4.59). Among older patients with CA-CDI risk factors, nitrofurantoin was also associated with CA-CDI (aOR, 3.05; 95% CI, 1.92 to 4.84), with a smaller number needed to harm, compared to the fluoroquinolones. While clindamycin, cefuroxime, and fluoroquinolone use declined from 2008 to 2020, nitrofurantoin use increased by 40%. Clindamycin was associated with the greatest CA-CDI risk, overall. Among older patients with an elevated baseline risk for CA-CDI, multiple antibiotics, including nitrofurantoin, had strong associations with CA-CDI. These results may guide antibiotic selection and future stewardship efforts.