Densely sampled viral trajectories for SARS-CoV-2 variants alpha (B.1.1.7) and epsilon (B.1.429) BackgroundThe alpha and delta SARS-CoV-2 variants have been responsible for major recent waves of COVID-19 despite increasing vaccination rates. The reasons for the increased transmissibility of these variants and for the reduced transmissibility of vaccine breakthrough infections are unclear.

MethodsWe quantified the course of viral proliferation and clearance for 173 individuals with acute SARS-CoV-2 infections using longitudinal quantitative RT-PCR tests conducted using anterior nares/oropharyngeal samples (n = 199,941) as part of the National Basketball Associations (NBA) occupational health program between November 28th, 2020, and August 11th, 2021. We measured the duration of viral proliferation and clearance and the peak viral concentration separately for individuals infected with alpha, delta, and non-variants of interest/variants of concern (non-VOI/VOC), and for vaccinated and unvaccinated individuals.

ResultsThe mean viral trajectories of alpha and delta infections resembled those of non-VOI/VOC infections. Vaccine breakthrough infections exhibited similar proliferation dynamics as infections in unvaccinated individuals (mean peak Ct: 20.5, 95% credible interval [19.0, 21.0] vs. 20.7 [19.8, 20.2], and mean proliferation time 3.2 days [2.5, 4.0] vs. 3.5 days [3.0, 4.0]); however, vaccinated individuals exhibited faster clearance (mean clearance time: 5.5 days [4.6, 6.6] vs. 7.5 days [6.8, 8.2]).

ConclusionsAlpha, delta, and non-VOI/VOC infections feature similar viral trajectories. Acute infections in vaccinated and unvaccinated people feature similar proliferation and peak Ct, but vaccinated individuals cleared the infection more quickly. Viral concentrations do not fully explain the differences in infectiousness between SARS-CoV-2 variants, and mitigation measures are needed to limit transmission from vaccinated individuals.
Estimating the elevated transmissibility of the B.1.1.7 strain over previously circulating strains in England using GISAID sequence frequencies The B.1.1.7 strain, also referred to as Alpha variant, is a variant strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Alpha variant is considered to possess higher transmissibility compared to the strains previously circulating in England. This paper proposes a new method to estimate the selective advantage of a mutant strain over another strain using the time course of strain frequencies and the distribution of the serial interval of infections. This method allows the instantaneous reproduction numbers of infections to vary over calendar time. The proposed method also assumes that the selective advantage of a mutant strain over previously circulating strains is constant. Applying the method to SARS-CoV-2 sequence data from England, the instantaneous reproduction number of the B.1.1.7 strain was estimated to be 26.6-45.9% higher than previously circulating strains in England. This result indicates that control measures should be strengthened by 26.6-45.9% when the B.1.1.7 strain is newly introduced to a country where viruses with similar transmissibility to the preexisting strain in England are predominant.
The effects of modifiable maternal pregnancy exposures on offspring molar-incisor hypomineralisation: A negative control study ObjectivesO_LITo explore the associations between modifiable maternal pregnancy exposures: pre-pregnancy body mass index (BMI), pregnancy smoking and alcohol consumption with offspring molar-incisor hypomineralisation (MIH).
C_LIO_LITo explore for the presence of residual confounding using negative control analyses.
C_LI

MethodsThis study used data from Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective birth cohort. We defined offspring MIH using prospectively collected questionnaire data. We used logistic regression to explore confounder adjusted associations between maternal pre-pregnancy BMI and smoking and alcohol consumption during pregnancy with MIH. We included negative control exposure (paternal BMI, smoking and alcohol around the time of pregnancy) and outcome (offspring dental trauma) analyses to explore for the presence of residual confounding.

Results5536 mother/offspring pairs were included (297 MIH cases [5.4%]). We found a positive association between maternal mean BMI and offspring MIH (OR per 1-kg/m2 difference in maternal BMI: 1.04, 95% CI: 1.00, 1.08). In subsequent analyses, we found evidence that this effect was non-linear and being driven by women in the highest BMI quintiles. In negative control analyses, we found no evidence of association between paternal BMI and offspring MIH (OR: 0.94, 95% CI: 0.89, 1.00) and maternal BMI and offspring dental trauma (OR: 0.99, 95% CI: 0.96, 1.02). There was no clear evidence of an association for maternal pregnancy smoking (OR: 0.76, 95%CI: 0.46, 1.22) and alcohol consumption (OR: 0.79, 95% CI: 0.56, 1.21) with offspring MIH with results imprecisely estimated.

ConclusionIn summary we found evidence of a possible intrauterine effect of high maternal pre-pregnancy BMI on offspring MIH. We did not find robust evidence for an intrauterine effect of maternal pregnancy smoking or alcohol consumption on offspring MIH. Our findings provide further support for women of reproductive age to maintain a healthy weight. Future studies are warranted to explore possible mechanisms on how the pregnancy environment may relate to offspring MIH. Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders. Arrhythmic Outcomes in Catecholaminergic Polymorphic Ventricular Tachycardia IntroductionCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. The aim of this study is to examine the genetic basis and identify pre-dictive factors for arrhythmic outcomes in CPVT patients from Hong Kong.

MethodsThis was a territory-wide retrospective cohort study of consecutive patients diagnosed with CPVT at public hospitals or clinics in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF).

ResultsA total of 16 (mean presentation age=11{+/-}4 years old) patients were included. All patients presented at or before 19 years of age. Fifteen patients (93.8%) were initially symptomatic. Ten patients had both premature ventricular complexes (PVCs) and VT/VF, whereas one patient had PVCs without VT/VF. Genetic tests were performed in 14 patients (87.5%). Eight (57.1%) tested positive for the RyR2 gene. Seven variants have been described else-where (c.14848G>A, c.12475C>A, c.7420A>G, c.11836G>A, c.14159T>C, c.10046C>T and c.7202G>A). c.14861C>G is a novel RyR2 variant that has not been reported outside this cohort. All patients were treated with beta-blockers, three patients received amiodarone and two received verapamil. Sympathectomy (n=8), ablation (n=1) and implantable-cardioverter defibrillator implantation (n=3) were performed. Over a median follow-up of 127 (IQR: 97-143) months, six patients suffered from incident VT/VF. No significant predictors were identified on Cox regression. Nevertheless, a random survival forest model identified initial VT/VF/sudden cardiac death, palpitations, QTc, initially symptomatic and heart rate as important variables for estimating the probability of developing incident VT/VF.

ConclusionAll CPVT patients who are from Hong Kong presented at or before 19 years of age. Clinical and electrocardiographic findings can be used to predict arrhythmic outcomes. A nonparametric machine learning survival analysis achieved high accuracy for predicting the probability of incident VT/VF. mRNA COVID-19 vaccine booster fosters B and T cell responses in immunocompromised patients SARS-CoV-2 vaccination has proven effective in inducing an immune response in healthy individuals and is progressively allowing to overcome the pandemic. Recent evidence has shown that response to vaccination in some vulnerable patients may be diminished, and it has been proposed a booster dose. We tested the kinetic of development of serum antibodies to the SARS-CoV-2 Spike protein, their neutralizing capacity, the CD4 and CD8 IFN-{gamma} T cell response in 328 subjects, including 131 immunocompromised individuals (cancer, rheumatologic, and hemodialysis patients), 160 healthcare workers (HCW) and 37 subjects older than 75 yo, after vaccination with two or three doses of mRNA vaccines. We stratified the patients according to the type of treatment. We found that immunocompromised patients, depending on the type of treatment, poorly respond to SARS-CoV-2 mRNA vaccines. However, an additional booster dose of vaccine induced a good immune response in almost all of the patients except those receiving anti-CD20 antibody. Similarly to HCW, previously infected and vaccinated immunocompromised individuals demonstrate a stronger SARS-CoV-2 specific immune response than those who are vaccinated without prior infection.

Summary blurbImmunocompromised patients poorly respond to two doses of SARS-CoV-2 mRNA vaccines. However, an additional booster dose elicits a strong humoral and cellular immune response in these subjects. Human lipoproteins comprise at least 12 different classes that are lognormally distributed. Lipoproteins in medical samples have been measured by enzymatic methods that coincide with conventional ultracentrifugation. However, the high gravity and time required for ultracentrifugation can cause sample degradation. This study presents the results of HPLC, a gentler and rapid separation method, for 55 human serum samples. The elution patterns were analysed parametrically, and the attribute of each class was confirmed biochemically. Human samples contained 12 classes of lipoproteins, each of which may consist primarily of proteins. There are three classes of VLDLs. The level of each class was distributed lognormally, and the standard amount and the 95% range were estimated. Enzymatic methods measure the levels of several mixed classes. This lognormal character suggests that the levels are controlled by the synergy of multiple factors. The Association of Opening K-12 Schools with the Spread of COVID-19 in the United States: County-Level Panel Data Analysis AO_SCPLOWBSTRACTC_SCPLOWThis paper empirically examines how the opening of K-12 schools and colleges is associated with the spread of COVID-19 using county-level panel data in the United States. Using data on foot traffic and K-12 school opening plans, we analyze how an increase in visits to schools and opening schools with different teaching methods (in-person, hybrid, and remote) is related to the 2-weeks forward growth rate of confirmed COVID-19 cases. Our debiased panel data regression analysis with a set of county dummies, interactions of state and week dummies, and other controls shows that an increase in visits to both K-12 schools and colleges is associated with a subsequent increase in case growth rates. The estimates indicate that fully opening K-12 schools with in-person learning is associated with a 5 (SE = 2) percentage points increase in the growth rate of cases. We also find that the positive association of K-12 school visits or in-person school openings with case growth is stronger for counties that do not require staff to wear masks at schools. These results have a causal interpretation in a structural model with unobserved county and time confounders. Sensitivity analysis shows that the baseline results are robust to timing assumptions and alternative specifications. Validation of a remote and fully automated story recall task to assess for early cognitive impairment in older adults: a longitudinal case-control observational study BACKGROUNDStory recall is a simple and sensitive cognitive test commonly used to measure changes in episodic memory function in early Alzheimers disease (AD). Recent advances in digital technology and natural language processing methods make this test a candidate for automated administration and scoring. Convenient and low-burden daily assessments may provide more reliable data than one-off lengthy assessments and be suitable for longer-term disease monitoring.

OBJECTIVESDevelop and validate a remote and fully automated story recall task, suitable for longitudinal assessment, in a population of older adults with and without mild cognitive impairment (MCI) or mild AD.

METHODSParticipants from AMYPRED-UK (NCT04828122) and AMYPRED-US (NCT04928976) studies were asked to complete optional daily self-administered assessments remotely on their smart devices over 7-8 days. Assessments included immediate and delayed recall of three stories from the Automatic Story Recall Task (ASRT), a test with multiple parallel stimuli (18 short stories, and 18 long stories) balanced for key linguistic and discourse metrics. Verbal responses were recorded and securely transferred from participants personal devices, and automatically transcribed and scored using text similarity metrics between the source text and retelling to derive a generalised matching score (G-match). Adherence and task performance differences were examined with logistic mixed models and linear mixed models, respectively. Correlational analysis examined parallel forms reliability of ASRTs, and convergent validity with established cognitive tests (Logical Memory Test, and Preclinical Alzheimers Cognitive Composite with semantic processing (PACC5)). Acceptability and usability data were obtained via remotely administered questionnaire.

RESULTSOut of 200 participants recruited into the AMYPRED studies, a total of 151 participants (75.5%, 78 cognitively unimpaired (CU), 73 MCI/mild AD) engaged in optional remote assessments. In these participants, adherence to daily assessment was moderate, did not decline over time, but was higher in cognitively unimpaired participants (66% MCI/mild AD and 78% CU participants completed at least one ASRT story per day). Participants reported favourable task usability: few technical problems, that the application was easy to use, and the tasks were broadly interesting. Task performance improved modestly across the week and was better for immediate recall. G-match scores were lower in participants with MCI/mild AD. Parallel forms reliability of ASRTs were moderate to strong for immediate recall (mean rho=0.73), and delayed recall (mean rho=0.73). ASRTs showed moderate convergent validity with established cognitive tests.

CONCLUSIONSThe unsupervised, self-administered ASRT task is sensitive to cognitive impairments in MCI/mild AD. The task shows good usability, high parallel forms reliability and convergent validity with established cognitive tests. Remote, low cost, low burden and automatically scored speech assessments could be used to support diagnostic screening, healthcare and treatment monitoring. The socioeconomic factors that led to unemployment under COVID-19 pandemic among Japanese workers: a prospective cohort study ObjectivesTo examine the relationship between socioeconomic factors and unemployment among workers during COVID-19 pandemic in Japan.

DesignA prospective cohort study, follow-up from December 22-25, 2020 through February 18-19, 2021.

SettingThe panelists registered with an Internet survey company

ParticipantsA cluster random sample of 33,087 workers with stratification by sex, job type, and region among Japans working population

Main outcomes and measuresUnemployment between December 2020 and February 2021

ResultsAmong the 19,941 participants, 725 (3.6%) had experienced unemployment. Multivariate analysis showed that the significant high unemployment for women (compared to men); younger age (compared to older age); being married (spouse not working), bereaved or divorced, and unmarried (compared to married (spouse working)); annual household income less than 6 million yen, (compared to more than 10 million yen); junior high or high school, vocational school, junior college, or technical school (compared to graduate school); and temporary or contract employees, self-employed, agriculture, forestry, or fishing (compared to general employees).

ConclusionsCOVID-19 appears to have created difficulties for the vulnerable groups. This suggests the need for employment and economic support for such individuals.

Strengths and limitations of this studyUnder the pandemic of COVID-19, we found that unemployment was associated with socioeconomic factors such as age, sex, marriage, income, education and occupation.

Our findings suggest that in the event of a major epidemic, resulting in unemployment among vulnerable segments of the labour market, regardless of whether workers themselves are infected.

It was unclear why the participants had experienced unemployment

This study was conducted as an Internet survey, so the generalizability of our results is limited. Stability of the stroke code during the COVID-19 pandemic in the region of Madrid: a retrospective cohort study Acute Stroke (AS) is the most common time-dependent disease attended in the Emergency Medicine Service (EMS) of Madrid (SUMMA 112). Community of Madrid has been one of the most affected regions in Spain by the coronavirus disease 2019 (COVID19) pandemic. A significant reduction in AS hospital admissions has been reported during the COVID-19 pandemic compared to the same period one year before. As international clinical practice guidelines support those patients with suspected acute stroke should be accessed via EMS, it is important to know whether the pandemic has jeopardized urgent pre-hospital stroke care, the first medical contact for most patients. We aimed to examine the impact of the COVID-19 in stroke codes (SC) in our EMS among three periods of time: the COVID-19 period, the same period the year before, and the 2019-2020 seasonal influenza period. Methods: We compared the SC frequency among the periods with high cumulative infection rate (above the median of the series) of the first wave of COVID-19, seasonal influenza, and also with the same period of the year before. Results: 1,130 SC were attended during the three periods. No significant reduction in SC was found during the COVID-19 pandemic. The reduction of hospital admissions might be attributable to patients attending the hospital by their means. The maximum SC workload seen during seasonal influenza has not been reached during the pandemic. We detected a non-significant deviation from the SC protocol, with a slight increase in hospitals transfers to hospitals without stroke units. Early prediction of preeclampsia in pregnancy with circulating cell-free RNA Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an unprecedented opportunity to noninvasively study the development of pregnancy-related complications and to bridge gaps in clinical care. Here, we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia (PE), a multi-organ syndrome which is the second largest cause of maternal death globally. We find that changes in cfRNA gene expression between normotensive (NT) and preeclamptic mothers are striking and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial, and immune cell types and tissues that reflect important aspects of PE physiology and suggest new hypotheses for disease progression. This enabled identification and independent validation of a panel of 18 genes whose measurement between 5-16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of PE well before the clinical symptoms manifest themselves. Finally, we demonstrate that cfRNA changes reflect the multifactorial nature of PE and provide a means to non-invasively monitor maternal organ health. Tests based on these observations could help predict and manage who is at risk for PE, an important and until now unachieved objective for obstetric care. A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) Vaccination or restriction?: COVID-19 vaccine hesitancy and vaccine passports ObjectivesWhile the development of vaccines against the novel coronavirus (COVID-19) brought the hope of establishing herd immunity, which might help end the global pandemic, vaccine hesitancy can hinder the progress towards herd immunity. In this study, we assess the determinants of vaccine hesitancy, reasons for hesitation, and effectiveness of vaccine passports in relaxing public health restrictions.

MethodsThrough an online survey that includes a conjoint experiment of a demographically representative sample of 5,000 Japanese adults aged 20-74, we assess the determinants of vaccine hesitancy, reasons for hesitation, and effectiveness of hypothetical vaccine passports.

ResultsWe found that about 30% of respondents did not intend to vaccinate or have not yet decided, with major reasons for vaccine hesitancy being related to concerns about the safety and side effects of the vaccine. In line with previous findings, younger age, lower socioeconomic status, and psychological factors such as weaker COVID-19 fear were associated with vaccine hesitancy. The easing of public health restrictions such as travel, wearing face masks, and dining out at night was associated with an increase in vaccine acceptance by 4-10%.

ConclusionVaccine hesitancy can be reduced by mitigating the concerns about vaccine safety and side effects, as well as by relaxing public health restrictions. However, the feasibility of vaccine passports needs to be sufficiently assessed, taking the ethical issues of passports and the public health impacts of the relaxation of restrictions into careful consideration.

Strengths and limitations of this study{square} This study includes timely data on COVID-19 vaccine hesitancy, obtained from a demographically representative sample of 5,000 Japanese adults.
{square}A conjoint experiment allows assessing the effectiveness of easing public health restrictions on vaccine acceptance.
{square}Actual behaviour may diverge from the survey responses or fluctuate due to the pandemic situation and the timing of the survey.
{square}Results may not be applicable in other countries, since the pandemic situation, government responses to the pandemic, and reasons for vaccine hesitancy can vary across countries. "What do you mean I can't have a doctor? This is Canada!" - A Qualitative Study of the Myriad Consequences for Unattached Patients Awaiting Primary Care Attachment BackgroundPatient access to primary healthcare (PHC) is the foundation of a strong healthcare system and healthy populations. Attachment to a regular PHC provider, a key to healthcare access, has seen a decline in some jurisdictions. This study explored the consequences of unattachment from a patient perspective, an under-studied phenomenon to date.

MethodsA realist-informed qualitative study was conducted with unattached patients in Nova Scotia, Canada. Semi-structured interviews with nine participants were conducted and transcribed for analysis. The framework method was used to carry out analysis, which was guided by Donabedians model of assessing healthcare access and quality.

ResultsFive key findings were noted in this study: 1) Participants experienced a range of consequences from not having a regular PHC provider. Participants used creative strategies to 2) attempt to gain attachment to a regular PHC provider, and, to 3) address their health needs in the absence of a regular PHC provider. 4) Participants experienced negative feelings about themselves and the healthcare system, and 5) stress related to the consequences and added work of being unattached and lost care.

ConclusionsUnattached patients experienced a burden of care related to lost care and managing their own health and related information, due to the download of medical record management and system navigation to them. These findings may underestimate the consequences for further at-risk populations who would not have been included in our recruitment. This may result in poorer health outcomes, which could be mitigated by interventions at the structural level, such as enhanced centralized waitlists to promote attachment. Such waitlists may benefit from a triage approach to appropriately attach patients based on need. Characteristic and Sex Differences in Auditory Function and Cochlear Pathophysiology in a Noise-exposed Cohort: A Cross-sectional Study BackgroundTo determine the characteristics and sex differences of auditory perception and cochlear function in individuals with long-term occupational noise exposure.

MethodsYoung workers with long-term occupational noise exposure from a shipyard were recruited in the current study as the hidden hearing loss (HHL) risk group. Age-matched office workers in the same shipyard who had no occupational noise-exposure history were enrolled in the control group. The auditory processing ability of speech-in-noise (SIN) score and gap detection threshold (GDT) were further examined by sex. The cochlear function of action potential (AP) and summating potential (SP)/AP values were tested and compared by sex and side. The correlation between the SIN score and cochlear function was studied by sex. The correlation between either auditory processing ability or cochlear function and occupational-noise working length (OWL) was also analysed in the HHL risk group.

ResultsSignificantly decreased SIN scores and a higher GDT of the 4 kHz gap marker were only found in men in the HHL risk group. Although the hearing thresholds of the women in the HHL risk group were slightly but significantly worse than those of the women in the control group, no significant defects in auditory processing or temporal resolution were found between the two groups. Significantly decreased cochlear function and increased SP/AP values in the left ear were only found in men in the HHL risk group. Neither the AP amplitude nor the AP latency differed significantly between the two groups by sex. A correlation study indicated that only the correlation between the SIN score and the AP amplitude of the right ear in men was significant. No significant difference was found between the SIN score and cochlear function in women. The AP latency of the right ear was only significantly correlated with OWL in men.

ConclusionIn long-term occupational working exposure individuals with normal hearing, defects in auditory processing, temporal resolution and cochlear function showed sex differences, none of which were significant in women. In men, a weak correlation between the SIN score and the AP amplitude of the right ear was found. There was only a weak correlation between OWL and the AP latency of the right ear in men. Our findings indicate men are more vulnerable to occupational noise than women. Considering the noise-exposure dose differences between the control and HHL risk groups, our measures are insensitive to cochlear synaptopathy in humans. Effectiveness of a short term induction regimen of a biosimilar Adalimumab in the long term management of symptomatic Ankylosing Spondylitis Symptomatic Ankylosing Spondylitis: A Community Based Proof of Concept Observational Study IntroductionCost and drug toxicity often deter prolonged therapeutic use of anti-TNF agents in ankylosing spondylitis (AS). A planned study was completed to endorse our clinic based observation of long term relief following short-term administration of anti-TNF agent.

Methods50 consenting patients with symptomatic active chronic AS under rheumatology care in a community clinic were enrolled. They had no past history of anti-TNF use. 40 mg standard biosimilar adalimumab (BS-ADA, Exemptia trade name)was injected subcutaneously every fortnight for six injections (10 weeks). Patients were monitored at several time points. Improvement was assessed at regular interval as per protocol which included standard indices (Bath and Assessment Spondyloarthritis International Society /ASAS). An intention to treat analysis with significant p<0.05 was carried out.

ResultsPatients showed early and substantial significant improvement in pain, NSAID requirement, function and in several indices (ASAS 20 & 40, ASAS partial remission, BASDAI, BASFI, ASDAS) which persisted after stopping injections. 84% and 52 % of patients respectively showed ASAS 20 improvement at week 12 and 48: corresponding ASAS partial remission 34% and 24%. Over 50% patients maintained prolonged improvement and provided proof of concept (defined a-priori). Serum Interleukin-6 assay showed a sharp reduction at 24 weeks. None developed TB or serious drug toxicity. 11 patients withdrew (mostly inadequate response). Absence of control was a limitation.

ConclusionA ten-week administration of biosimilar adalimumab in difficult to treat AS showed early substantial improvement which often persisted for 24 weeks. This unconventional strategy was socioeconomically appealing. It merits further validation and acceptance especially in resource strained settings. Serum Vitamin D levels are associated with increased COVID-19 severity and mortality independent of whole-body and visceral adiposity INTRODUCTIONCoronavirus disease (COVID-19) is a global pandemic. Vitamin D deficiency has been associated with susceptibility to infectious disease. In this study, the association between COVID-19 outcomes and vitamin D levels in patients attending a COVID-19 reference center in Mexico City are examined.

METHODSConsecutive patients with confirmed COVID-19 were evaluated. All patients underwent clinical evaluation and follow-up, laboratory measurements and a thoracic computerized tomography, including the measurement of epicardial fat thickness. Low vitamin D was defined as levels <20ng/mL (<50nmol/L) and deficient Vitamin D as a level [&le;]12ng/mL (<30nmol/L)

RESULTSOf the 551 patients included, low vitamin D levels were present in 45.6% and deficient levels in 10.9%. Deficient Vitamin D levels were associated with mortality (HR 2.11, 95%CI 1.24-3.58, p=0.006) but not with critical COVID-19, adjusted for age, sex, body-mass index and epicardial fat. Using model-based causal mediation analyses the increased risk of COVID-19 mortality conferred by low vitamin D levels was partly mediated by its effect on D-dimer and cardiac ultrasensitive troponins. Notably, increased risk of COVID-19 mortality conferred by low vitamin D levels was independent of BMI and epicardial fat.

CONCLUSIONVitamin D deficiency ([&le;]12ng/mL or <30nmol/L), is independently associated with COVID-19 mortality after adjustment for visceral fat (epicardial fat thickness). Low vitamin D may contribute to a pro-inflammatory and pro-thrombotic state, increasing the risk for adverse COVID-19 outcomes. Estimating Vaccination Effects and Variant Strains on COVID-19 outbreak course in Japan, as of August, 2021 BackgroundAs of the end of 2021 year, the rate of completion for second-dose administration was almost 80% in Japan.

ObjectWe evaluated waning of vaccine effectiveness for COVID-19 in Japan, controlling for mutated strains, the Olympic Games, and countermeasures.

MethodThe effective reproduction number R(t) was regressed on current vaccine coverage and data of a certain number of days prior, as well as shares of mutated strains, and an Olympic Games dummy variable along with data of temperature, humidity, mobility, and countermeasures. The study period was February, 2020 through December 7, as of December 28, 2021.

ResultsEstimation results indicate that the past vaccine coverage of older than 60 days prior raises R(t) significantly and cancelled vaccine effectiveness completely.

Discussion and ConclusionResults indicate significant waning of vaccine effectiveness from 60 days after the second dose. Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. The role of classroom volume, occupancy, voice reduction and ffp2 masks in transmission risk of SARS-CoV2 in schools Issues linked to aerosol physics within school buildings and related infection risk still lack a proper recognition in school safety regulations. In this theoretical work we try to shed more light on the critical role of air ventilation, classroom volume, occupancy, and face mask types (surgical vs ffp2) in controlling airborne transmission risk in educational settings. Limited spaces available in many schools require to precisely assess the occupancy/volume ratio in each classroom and to investigate the specific risk levels from aerosolization of viral loads from infective sources. Moreover, most schools are not provided with mechanical HVAC systems. Fundamental questions are therefore: how the specific classroom volume affects the long-range contagion risk in a given classroom? is linear social distancing the right way to assess a volumetric risk problem? How effective are other countermeasures like reduced speaking volume or equipping teachers with microphones? We present here the results of a numerical analysis based on the Gammaitoni-Nucci infection risk model and the consolidated Wells-Riley like approach, with SARS-CoV2 input data and geometric data from a typical high-school classroom in Italy. We investigated separately the case of infective asymptomatic student and infective asymptomatic teacher as source of viral quanta, taking into account thermal gradient effects on the air ventilation rates. First recommendations based on the volumetric nature of aerosol risk are suggested to extend the linear social distancing approach applied so far. Finally we discuss the concept of "cumulative infection risk" over multiple lesson+break cycles in Wells-Riley-like infection models. We believe that any attempt to proper model infection risk in closed environments with cycled changes of the source and the susceptible individuals, should carefully consider this point, particularly when modelling air ventilation breaks in classrooms. Macular vascular complexity analysis of diabetes mellitus by swept-source optical coherence tomographic angiography PurposeTo evaluate the associations of retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), with the severity of diabetic retinopathy (DR) by using noninvasive optical coherence tomographic angiography (OCTA).

MethodsThis prospective cross-sectional study recruited ocular-treatment-naive patients with type 2 diabetes mellitus (DM) registered in the community of Guangzhou, China. OCTA was used to obtain the measurements of FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression was used to analyse the correlation of FD and BVT in different layers with DR severity.

ResultsA total of 1282 patients with DM (1282 eyes), with a mean age of 64.2{+/-}7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in DR patients compared to non-DR patients, even after adjusting for confounding factors (P< 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, while the BVT progressively increased with worsening DR severity (P< 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group and severe DR group (P< 0.01).

ConclusionFD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression. I wanna live and not think about the future; What place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study BackgroundLittle is known about how people with multiple sclerosis and their families comprehend advance care planning (ACP) and its relevance in their lives.

AimTo explore under what situations, with whom, how, and why do people with MS and their families engage in ACP

MethodsWe conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach.

ResultsParticipants narratives focused on three major themes :(i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate discussions. Some shared concerns of a lack of confidence when having ACP discussions.

ConclusionThese findings support the need for a whole systems strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services.