mRNA-1273 vaccine-induced antibodies maintain Fc effector functions across SARS-CoV-2 variants of concern.

SARS-CoV-2 mRNA vaccines confer robust protection against COVID-19, but the emergence of variants has generated concerns regarding the protective efficacy of the currently approved vaccines, which lose neutralizing potency against some variants. Emerging data suggest that antibody functions beyond neutralization may contribute to protection from the disease, but little is known about SARS-CoV-2 antibody effector functions. Here, we profiled the binding and functional capacity of convalescent antibodies and Moderna mRNA-1273 COVID-19 vaccine-induced antibodies across SARS-CoV-2 variants of concern (VOCs). Although the neutralizing responses to VOCs decreased in both groups, the Fc-mediated responses were distinct. In convalescent individuals, although antibodies exhibited robust binding to VOCs, they showed compromised interactions with Fc-receptors. Conversely, vaccine-induced antibodies also bound robustly to VOCs but continued to interact with Fc-receptors and mediate antibody effector functions. These data point to a resilience in the mRNA-vaccine-induced humoral immune response that may continue to offer protection from SARS-CoV-2 VOCs independent of neutralization.

SARS-CoV-2 antibodies protect against reinfection for at least 6 months in a multicentre seroepidemiological workplace cohort.

Identifying the potential for SARS-CoV-2 reinfection is crucial for understanding possible long-term epidemic dynamics. We analysed longitudinal PCR and serological testing data from a prospective cohort of 4,411 United States employees in 4 states between April 2020 and February 2021. We conducted a multivariable logistic regression investigating the association between baseline serological status and subsequent PCR test result in order to calculate an odds ratio for reinfection. We estimated an odds ratio for reinfection ranging from 0.14 (95% CI: 0.019 to 0.63) to 0.28 (95% CI: 0.05 to 1.1), implying that the presence of SARS-CoV-2 antibodies at baseline is associated with around 72% to 86% reduced odds of a subsequent PCR positive test based on our point estimates. This suggests that primary infection with SARS-CoV-2 provides protection against reinfection in the majority of individuals, at least over a 6-month time period. We also highlight 2 major sources of bias and uncertainty to be considered when estimating the relative risk of reinfection, confounders and the choice of baseline time point, and show how to account for both in reinfection analysis.

A systematic review of caries risk in children <6 years of age.

BACKGROUND: For caries risk assessment (CRA) tools for young children to be evidence-based, it is important to systematically review the literature to identify factors associated with the onset of early childhood caries (ECC). AIM: This updated systematic review aimed to identify current evidence on caries risk in young children. DESIGN: A comprehensive and systematic literature search of relevant databases was conducted to update a previous systematic review and identify risk factors associated with ECC. Potential risk factors were identified based on strength of association using odds ratios, hazard ratios, relative risk, etc. GRADE was used for rating quality evidence through consensus. RESULTS: Twenty-two studies met inclusion criteria for the search from mid-2017 to 2021. Twenty-five publications from the prior systematic review, from 1997 to mid-2017, were also included. Several socioeconomic, behavioral, and clinical variables were identified as ECC risk factors. Factors included the following: age, socioeconomic status, frequency of and supervised toothbrushing, fluoride exposure, breast- and bottle-feeding, feeding habits, absence of a dental home, past caries experience, active non-cavitated lesions, visible plaque, enamel defects, and microbiome. CONCLUSION: This study provides updated evidence of risk factors for ECC that could be included in CRA tools.

Clinical manifestation and images of a patient having cardiovascular involvement in myxoedema coma.

Myxoedema coma is an endocrine emergency characterised by diminished sensorium associated with features of severe hypothyroidism. The disease carries a high mortality of 30%-60 %. The cardiac manifestation of the disease consists of bradycardia, hypotension, pericardial effusion and certain echocardiographic changes such as heart block and features of hypothermia. Here, we report a case of myxoedema coma with characteristic cardiac manifestations. These manifestations revert promptly on starting treatment, and achieving a eumetabolic status as was demonstrated in this patient.

Thyrotoxic periodic paralysis: A retrospective, observational study from India.

Background & objectives: Thyrotoxic periodic paralysis (TPP) is an endocrine emergency presenting with acute-onset flaccid paralysis in a patient having thyrotoxicosis accompanied by hypokalaemia. This study was conducted to evaluate the clinical profile of patients with TPP presenting to three centres in India. Methods: This retrospective, observational study was conducted at three tertiary care Armed Forces medical centres, located at Lucknow, Kolkata and Delhi. The history, clinical features, treatment details and outcomes were evaluated. Results: Of the 244 patients with thyrotoxicosis, 15 were diagnosed with TPP and included in the study. These 15 patients (14 male and 1 female) had 32 episodes of TPP which were analyzed. The mean age was 30.2±6.2 yr (range: 21-39), and overt thyrotoxicosis was seen in all patients except one who had subclinical hyperthyroidism. Graves' disease was the most common cause of thyrotoxicosis (13/15) and the remaining two patients had subacute thyroiditis and gestational thyrotoxicosis. Hypokalaemia (serum potassium <3.5 mmol/l) was seen in 12 patients, and the mean serum potassium was 3.2±0.9 mmol/l (range: 2.1-4.9). All patients had flaccid weakness, predominantly involving the lower limb with no bulbar, respiratory or cranial nerve involvement. The average duration of paralysis was 10.6±5.7 h (range: 3-28 h). Interpretation & conclusions: Our study demonstrated an early age of presentation and presence of clinical and biochemical thyrotoxicosis in majority of patients with TPP. Hypokalaemia may not always be evident in patients with TPP.

Aquaporin 5 promotes corneal wound healing.

Aquaporins (AQPs), ordinarily regarded as water channels, have recently been shown to participate in other cellular functions such as cell-to-cell adhesion, cell migration, cell proliferation etc. The current investigation was undertaken to find out whether AQP5 water channel plays a role in corneal epithelial wound healing. Expression of AQP5 in mouse cornea and transfected Madin-Darby canine kidney (MDCK) cells was detected using immunofluorescence or EGFP tag. Cell migration and proliferation, the two major events in wound healing, were studied in vitro using cell culture scratch-wound healing model and cell proliferation assay, in vivo by conducting wound healing experiments on corneas of wild-type and AQP5 knockout mouse model and ex vivo on corneal epithelial cells isolated from wild type and AQP5 knockout mice. MDCK cells stably expressing AQP5 showed significantly higher levels of cell migration and proliferation compared to control cells. Likewise, corneal epithelial cells of wild type mouse with innate AQP5 exhibited faster wound healing than those of AQP5 knockout in vivo and under ex vivo culture conditions. In vitro, in vivo and ex vivo studies showed that presence of AQP5 improved cell migration, proliferation and wound healing. The data collected suggest that AQP5 plays a significant role in corneal epithelial wound healing.

AQP5-1364A/C polymorphism and the AQP5 expression influence sepsis survival and immune cell migration: a prospective laboratory and patient study.

BACKGROUND: The C-allele of the aquaporin (AQP5) -1364A/C polymorphism is associated with decreased AQP5 expression but increased 30-day survival in patients with severe sepsis. AQP5 expression might affect survival via an impact on cell migration. Consequently, we tested the hypothesis that (1) Aqp5 knockout (KO) compared to wild type (WT) mice show an increased survival following lipopolysaccharide (LPS) administration, and that (2) AQP5 expression and the AQP5 -1364A/C polymorphism alters immune cell migration. METHODS: We investigated Aqp5-KO and wild type mice after intraperitoneal injection of either E.coli lipopolysaccharide (LPS, serotype O127:B8, 20 mg/kg) or saline. Furthermore, neutrophils of volunteers with the AA-AQP5 or AC/CC-AQP5- genotype were incubated with 10-8 M Chemotactic peptide (fMLP) and their migration was assessed by a filter migration assay. Additionally, AQP5 expression after fMLP incubation was analyzed by RT-PCR and Western blot. Moreover, migration of AQP5 overexpressing Jurkat cells was studied after SDF-1α-stimulation. We used exact Wilcoxon-Mann-Whitney tests; exact Wilcoxon signed-rank tests and the Kaplan-Meier estimator for statistical analysis. RESULTS: Fifty-six percent of Aqp5-KO but only 22% of WT mice survived following LPS-injection. WT mice showed increased neutrophil migration into peritoneum and lung compared to Aqp5-KO mice. Target-oriented migration of neutrophils was seen after 0.5 h in AA-genotype cells but only after 1.5 h in AC/CC-genotype cells, with a threefold lower migrating cell count. AQP5 overexpressing Jurkat cells showed a 2.4 times stronger migration compared to native Jurkat cells. CONCLUSION: The AQP5 genotype may influence survival following LPS by altering neutrophil cell migration. Trial registration DRKS00010437. Retrospectively registered 26 April 2016.

Role of Aquaporin 0 in lens biomechanics.

Maintenance of proper biomechanics of the eye lens is important for its structural integrity and for the process of accommodation to focus near and far objects. Several studies have shown that specialized cytoskeletal systems such as the beaded filament (BF) and spectrin-actin networks contribute to mammalian lens biomechanics; mutations or deletion in these proteins alters lens biomechanics. Aquaporin 0 (AQP0), which constitutes ∼45% of the total membrane proteins of lens fiber cells, has been shown to function as a water channel and a structural cell-to-cell adhesion (CTCA) protein. Our recent ex vivo study on AQP0 knockout (AQP0 KO) mouse lenses showed the CTCA function of AQP0 could be crucial for establishing the refractive index gradient. However, biomechanical studies on the role of AQP0 are lacking. The present investigation used wild type (WT), AQP5 KO (AQP5(-/-)), AQP0 KO (heterozygous KO: AQP0(+/-); homozygous KO: AQP0(-/-); all in C57BL/6J) and WT-FVB/N mouse lenses to learn more about the role of fiber cell AQPs in lens biomechanics. Electron microscopic images exhibited decreases in lens fiber cell compaction and increases in extracellular space due to deletion of even one allele of AQP0. Biomechanical assay revealed that loss of one or both alleles of AQP0 caused a significant reduction in the compressive load-bearing capacity of the lenses compared to WT lenses. Conversely, loss of AQP5 did not alter the lens load-bearing ability. Compressive load-bearing at the suture area of AQP0(+/-) lenses showed easy separation while WT lens suture remained intact. These data from KO mouse lenses in conjunction with previous studies on lens-specific BF proteins (CP49 and filensin) suggest that AQP0 and BF proteins could act co-operatively in establishing normal lens biomechanics. We hypothesize that AQP0, with its prolific expression at the fiber cell membrane, could provide anchorage for cytoskeletal structures like BFs and together they help to confer fiber cell shape, architecture and integrity. To our knowledge, this is the first report identifying the involvement of an aquaporin in lens biomechanics. Since accommodation is required in human lenses for proper focusing, alteration in the adhesion and/or water channel functions of AQP0 could contribute to presbyopia.

A prospective cohort study of acute kidney injury in multi-stage ultramarathon runners: the Biochemistry in Endurance Runner Study (BIERS).

The purpose of the study was to evaluate the prevalence of acute kidney injury (AKI) during a multi-stage ultramarathon foot race. A prospective observational study was taken during the Gobi 2008; Sahara 2008; and Namibia 2009 RacingThePlanet 7-day, 6-stage, 150-mile foot ultramarathons. Blood was analyzed before, and immediately after stage 1 (25 miles), 3 (75 miles), and 5 (140 miles). Creatinine (Cr), glomerular filtration rate (GFR), and incidence of AKI were calculated and defined by RIFLE criteria. Thirty participants (76% male, mean age 40 + 11 years) were enrolled. There were significant declines in GFR after each stage compared with the pre-race baseline (p < 0.001), with the majority of participants (55-80%) incurring AKI. The majority of study participants encountered significant renal impairment; however, no apparent cumulative effect was observed, with resolution of renal function to near baseline levels between stages.

Can endorsement by religious leaders move the needle on vaccine hesitancy?

Existing research, including work specific to COVID-19, suggests that endorsement by medical practitioners increases vaccine uptake. Yet, vaccine hesitancy persists despite health professionals continuing to widely endorse multiple vaccines to combat COVID-19 since late 2020. Could endorsement by other trusted leaders reduce vaccine hesitancy? Although some studies suggest that trust in religious leaders can influence individuals' health attitudes and behaviors, the evidence is mixed. Our study explores the potential added value of messaging by religious leaders across religious traditions - specifically, it asks whether their endorsement of the COVID-19 vaccine might increase vaccine uptake in an environment where health professionals are already endorsing vaccines. To investigate this question, we conducted an online survey experiment with 6,000 respondents across five countries with different dominant religions (Buddhism, Christianity, and Islam). Respondents were randomly assigned to either a control group that only included endorsement by medical practitioners or a treatment group that added either endorsement by religious leaders or, for comparative purposes, endorsement by political leaders. We found that endorsement by religious leaders reduced vaccine hesitancy only in one country. These findings corroborate existing research that medical practitioners are the best line of defense to combat vaccine hesitancy. They also suggest the limitations of endorsement by non-experts.

Immunovirological discordance among people living with human immunodeficiency virus at a center in Western India: A retrospective study.

Background and Objectives: Treatment of people living with human immunodeficiency virus (HIV) (PLHIV) is monitored using plasma HIV viral load levels and CD4 counts. Patients with either immunological nonresponse (virological suppression achieved) or virological nonresponse (immune reconstitution achieved) are termed as having a discordant response. These patients are at higher risk for acquired immunodeficiency syndrome (AIDS)-related infections/diseases/neoplasms, non-AIDS-related illnesses (cardiovascular, neurological, renal, hepatic diseases), and all-cause death. This study was conducted to assess the prevalence of immunovirological discordance among PLHIV after completion of at least 1 year of combination antiretroviral therapy (cART) at an antiretroviral therapy (ART) plus center in India and analyze contributory factors. Methods: The study was a retrospective study of PLHIV receiving cART at the ART plus clinic in Western India from January 18 to December 21. Four hundred and ninety-six patients were studied based on sample size calculated and assessed for CD4 and viral load response at 0, 6, and 12 months of ART. Results: Of the 496 patients, 48 patients (9.7%) had immunovirological discordance. Out of them, 36 patients (75%) had a virological response (immunological nonresponse) and 12 (25%) patients had an immunological response (virological nonresponse). The factors contributing to immunological nonresponse were as follows - low baseline CD4 levels (<100 cells) (36.1%), adherence <95% (33.3%), presence of opportunistic infections (16.6%), and failure on first-line therapy (11.1%). Other factors noted included higher baseline viral load (2.7%), chronic kidney disease (5.5%), and chronic hepatitis B virus co-infection (5.5%). Virological nonresponse was associated with poor adherence to therapy <95% (33%) and failure of first-line regimen (33%). Opportunistic infections were noted among 33% of patients and 8.3% of patients were found to have higher baseline viral load. Interpretation and Conclusion: Immunovirological discordance is an important factor influencing response to cART and is associated with many complications such as AIDS and non-AIDS-related events and even death. Improved adherence and timely identification and management of opportunistic infections are measures that are beneficial in reducing the incidence of immunovirological discordance.

Coexistence of human immunodeficiency virus infection and autoimmune hepatitis: A double trouble.

A wide spectrum of hepatobiliary manifestations occur in Human Immunodeficiency Virus (HIV)-infected patients. Among the common causes are the infectious hepatitis, drug-related hepatitis, opportunistic infections, non-alcoholic steatohepatitis, HIV cholangiopathy and neoplasm. Auto-immune hepatitis (AIH) is rarely reported in this setting. We present two different presentations of auto immune hepatitis in HIV positive patients. One developed jaundice and ascites as a consequence of liver decompensation and other exhibited cholestatic pattern. Their serology and liver biopsy confirmed autoimmune hepatitis as underlying aetiology. We would like to share the clinical improvement with simultaneous immunosuppressive therapy and combination Anti Retroviral Therapy (cART). There are no documented cases on this issue from the Indian subcontinent that we are aware of.

Layperson Physiological Tolerance and Operational Performance in Centrifuge-Simulated Spaceflight.

INTRODUCTION: Prior study has indicated that individuals of varied age, medical history, and limited-to-no experience tolerate spaceflight conditions. We sought to expand upon the understanding of layperson response to hypergravity conditions expected in commercial spaceflight by exposing subjects, following minimal training, to centrifuge-simulated, high-fidelity commercial spaceflight profiles. We further explored how these individuals perform in simulated operational activities during and following hypergravity.METHODS: Volunteer subjects participated in up to five centrifuge runs (maximum +4.0 Gz, +4.5 Gx, 6.1 G resultant; onset rate <0.5 Gz · s-1, ≤1 Gx · s-1). Profiles included two winged spacecraft simulations with sequential and combined +Gx/+Gz and two capsule simulations representing nominal +Gx launch and reentry. The final profile simulated a capsule launch abort, with a more dynamic cycling of +Gx exposures and oscillatory multi-axis exposures simulating parachutes and water motion. Touchscreen tablets were used to administer pattern-replication tasks during and after profiles.RESULTS: A total of 46 subjects participated, including 4 diabetics and 9 with cardiac disease. There was increased frequency of motion sickness, subjectively associated with capsule-type profiles, and increased termination of participation compared to prior studies. There was no association between medical history, age, sex, or motion sickness history and tolerance or noncompletion. Tablet test errors were common; accuracy and time to completion were associated with age. There was no association between any time metric or accuracy and sex.DISCUSSION: This study improves understanding of layperson tolerance in commercial spaceflight analog conditions, and the capsular profiles broaden the applicability of the findings. The frequency of task errors highlights the potential for mistakes in operational activities when performed by laypersons.Blue RS, Ong KM, Ray K, Menon A, Mateus J, Auñón-Chancellor S, Shah R, Powers W. Layperson physiological tolerance and operational performance in centrifuge-simulated spaceflight. Aerosp Med Hum Perform. 2023; 94(8):584-595.

An investigation of data from the first year of the interim Canada Dental Benefit for children <12 years of age.

Introduction: In 2022, the federal government announced a commitment of $5.3B to provide dental care for the uninsured, beginning with children <12 years of age. Now referred to as the Interim Canada Dental Benefit (CDB), the program targets those <12 years of age from families with annual incomes <$90,000 without private dental insurance. The purpose of this study was to review federal data from the Government of Canada on public uptake and applications made to the Canada Revenue Agency (CRA) during the first year of the Interim CDB. Methods: Data for the first year of the Interim CDB (up to June 30, 2023) were accessed from the Government of Canada Open Data Portal through Open Government Licence-Canada. Rates of children receiving the Interim CDB per 1,000 were calculated by dividing the number of beneficiaries by the total number of children 0-11 years by province or territory, available from Statistics Canada for the year 2021. Results: During the first year of the program, a total of 204,270 applications were approved, which were made by 188,510 unique applicants for 321,000 children <12 years of age. Over $197M was distributed by the CRA. Overall, the national rate for receiving the Interim CDB was 67.8/1,000 children. Ontario (82.5/1,000), Manitoba (77.1/1,000), Nova Scotia (73.4/1,000), and Saskatchewan (72.3%), all had rates of children with the Interim CDB above the national rate. Conclusions: Data from the first year of the Interim CDB suggests that this federal funding is increasing access to care for children <12 years by addressing the affordability of dental care. Governments and the oral health professions need to address other dimensions of access to care including accessibility, availability, accommodation, awareness, and acceptability of oral health care.

Spatial expression of aquaporin 5 in mammalian cornea and lens, and regulation of its localization by phosphokinase A.

PURPOSE: Aquaporins (AQPs) play a significant role in the movement of water across the plasma membrane. In the eye, the cornea and lens are avascular with unique microcirculatory mechanisms to meet the metabolic demands. We have previously shown that AQP0 and AQP1 water channels participate in maintaining lens transparency and homeostasis. In the present investigation, we explored the expression and spatial distribution of AQP5 in the cornea and lens, and its regulation during membrane localization. METHODS: AQP5 expression and cellular localization were investigated by reverse transcription polymerase chain reaction (RT-PCR) using gene-specific primers, and by western blot and immunocytochemistry analyses using specific antibodies. AQP5 phosphorylation was studied using calf intestinal alkaline phosphatase for dephosphorylation. Effects of phosphokinase A (PKA) agonist cyclic AMP (cAMP), and antagonist H-89 on AQP5 expression and localization were studied in vitro using MDCK (Madin-Darby Canine Kidney) cells, and ex vivo using isolated corneas from wild type mice. RESULTS: RT-PCR revealed the presence of AQP5 transcripts in the cornea, lens epithelial cells and fiber cells. Western blotting identified the presence of both non-phosphorylated and phosphorylated forms of AQP5 protein. Immunostaining showed the distribution of AQP5 in the epithelial layer and stromal keratocytes of the cornea, and epithelial and fiber cells of the lens. In vitro and ex-vivo experiments revealed PKA-induced AQP5 internalization; PKA inhibition prevented such internalization. CONCLUSIONS: This is the first report on the spatial expression of AQP5 in the corneal keratocytes and lens epithelial cells, as well as on the regulation of AQP5 localization by PKA in the corneal epithelial cells. PKA-mediated regulation of AQP5 holds promise for therapeutic intervention to control corneal and lens diseases.

Epistaxis, paroxysmal anxiety episodes, and hypertension in a child with SDHB-associated paraganglioma: A case report.

A child presented with anxiety and weight gain which were overlooked until she had epistaxis. She was found to have hypertension secondary to paraganglioma. She was managed with curative surgery involving multidisciplinary care. The tumor removal led to the amelioration of symptoms and marked control of hypertension.

Symptomatic hypoglycemia in a nondiabetic adult female recovering from mild COVID-19 infection: A case report.

A 38-year-old lady, recently recovered from SARS-CoV-2 infection and taking grape seed extract, suffered multiple episodes of severe postprandial hyperinsulinemic hypoglycemia. A careful evaluation ruled out the common etiologies of hypoglycemia and identified grape seed extract consumption as a possible cause. She recovered after stopping the nutritional supplements. In her, hypoglycemia could have resulted from transient beta cell dysfunction associated with SARS-CoV-2 infection or proanthocyanidins in the grape seed extract.

Fever of Unknown Origin and Hepatitis as the Initial Presentation of Anti-MDA-5 Positive Dermatomyositis: A Case Report.

Petersdorf and Beeson first defined fever of unknown origin (FUO) in 1961, and subsequently, over the next 60 years, the definition of FUO has changed considerably. In the western world, non-infectious inflammatory diseases are the most common cause of FUO; however, in developing countries, infections remain the leading cause of FUO. Dermatomyositis (DM) is an autoimmune inflammatory disease of unknown aetiology which mainly affects skin and muscles. Anti-melanoma differentiation-associated protein 5 (MDA-5) positive DM generally presents with classical cutaneous manifestations, early interstitial lung disease, and patients generally do not have clinical features of muscle involvement. We present a case of a 39-year-old male who presented with FUO and hepatitis and was diagnosed as clinically amyopathic DM after two weeks of admission. Subsequently, he was found to have a high titre of Anti-MDA-5 antibody. This is the first case of Anti-MDA-5 positive DM presenting as FUO and hepatitis with a favourable outcome to the best of our knowledge.