title: Migrants' primary care utilisation before and during the COVID-19 pandemic in England: An interrupted time series

abstract:
BackgroundHow international migrants access and use primary care in England is poorly understood. We aimed to compare primary care consultation rates between international migrants and non-migrants in England before and during the COVID-19 pandemic (2015- 2020).

MethodsUsing linked data from the Clinical Practice Research Datalink (CPRD) GOLD and the Office for National Statistics, we identified migrants using country-of-birth, visa-status or other codes indicating international migration. We ran a controlled interrupted time series (ITS) using negative binomial regression to compare rates before and during the pandemic.

FindingsIn 262,644 individuals, pre-pandemic consultation rates per person-year were 4.35 (4.34-4.36) for migrants and 4.6 (4.59-4.6) for non-migrants (RR:0.94 [0.92-0.96]). Between 29 March and 26 December 2020, rates reduced to 3.54 (3.52-3.57) for migrants and 4.2 (4.17-4.23) for non-migrants (RR:0.84 [0.8-0.88]). Overall, this represents an 11% widening of the pre-pandemic difference in consultation rates between migrants and non-migrants during the first year of the pandemic (RR:0.89, 95%CI:0.84-0.94). This widening was greater for children, individuals whose first language was not English, and individuals of White British, White non-British and Black/African/Caribbean/Black British ethnicities.

InterpretationMigrants were less likely to use primary care before the pandemic and the first year of the pandemic exacerbated this difference. As GP practices retain remote and hybrid models of service delivery, they must improve services and ensure they are accessible and responsive to migrants healthcare needs.

FundingThis study was funded by the Medical Research Council (MR/V028375/1) and Wellcome Clinical Research Career Development Fellowship (206602).


title: Risk of ESKD in related older living kidney donors

abstract: Living kidney donors who are biologically related to the recipient have higher risk for end-stage kidney disease (ESKD) compared with those who are unrelated to the recipient. This risk is greater for first-degree relatives than more distant relatives. To understand if this holds true for older donors, who were cleared for donation and might be past the peak-age for hereditary disease, we used donor data (SRTR) linked to ESKD registry data (CMS) and stratified donors by age (younger vs older [[≥]50 years]) and race (black, Hispanic, and white). Younger related donors of all racial groups had higher risk of ESKD compared with younger unrelated donors; however, only older related white and Hispanic donors had higher risk of ESRD compared with unrelated older donors (2.3-fold for white full-siblings and 1.9-fold for white parents/offspring; 3.3-fold for Hispanic full-siblings and 2.0-fold for Hispanic parents/offspring). Older related black donors did not have higher risk compared to older unrelated black donors (0.8-fold for black full-siblings and 0.5-fold for black parents/offspring). Our study points to an earlier age of onset of kidney disease in black donors with a family history of ESKD. Our findings call for programs that promote living donation among related older black donor candidates.

category: transplantation


title: Prevalence, determinants, and impact on general health and working capacity of post-acute sequelae of COVID-19 six to 12 months after infection: a population-based retrospective cohort study from southern Germany

abstract:
BackgroundPost-acute sequelae of SARS-CoV-2 infection have commonly been described after COVID-19, but few population-based studies have examined symptoms six to 12 months after acute SARS-CoV-2 infection and their associations with general health recovery and working capacity.

MethodsThis population-based retrospective cohort study in four geographically defined regions in southern Germany included persons aged 18-65 years with PCR confirmed SARS-CoV-2 infection between October 2020 and March 2021. Symptom frequencies (six to 12 months after versus before acute infection, expressed as prevalence differences [PD] and prevalence ratios [PR]), symptom severity and clustering, risk factors and associations with general health recovery, and working capacity were analysed.

FindingsAmong a total of 11 710 subjects (mean age 44{middle dot}1 years, 59{middle dot}8% females, 3{middle dot}5% previously admitted with COVID-19, mean follow-up time 8.5 months) the most prevalent symptoms with PDs >20% and PRs >5% were rapid physical exhaustion, shortness of breath, concentration difficulties, chronic fatigue, memory disturbance, and altered sense of smell. Female sex and severity of the initial infection were the main risk factors. Prevalence rates, however, appeared substantial among both men and women who had a mild course of acute infection, and PCS considerably affected also younger subjects. Fatigue (PD 37{middle dot}2%) and neurocognitive impairment (PD 31{middle dot}3%) as symptom clusters contributed most to reduced health recovery and working capacity, but chest symptoms, anxiety/depression, headache/dizziness and pain syndromes were also prevalent and relevant for working capacity, with some differences according to sex and age. When considering new symptoms with at least moderate impairment of daily life and [≤]80% recovered general health or working capacity, the overall estimate for post-COVID syndrome was 28{middle dot}5% (age- and sex-standardised rate 26{middle dot}5%).

InterpretationThe burden of self-reported post-acute symptoms and possible sequelae, notably fatigue and neurocognitive impairment, remains considerable six to 12 months after acute infection even among young and middle-aged adults after mild acute SARS-CoV-2 infection, and impacts general health and working capacity.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrevious studies have shown that post-acute sequelae of COVID-19 are common, in particular among patients who had been admitted to hospital for COVID-19. Post-acute self-reported complaints and symptoms often are diverse, nonspecific and sometimes of unknown severity and functional relevance. We searched PubMed and medRxiv for studies published between January 2021 and February 2022, using search terms describing "long covid, post-acute sequelae of COVID-19, prevalence, and systematic review", with no language restrictions. Searches with the terms "long covid", "post-acute sequelae of COVID-19", "post-covid condition" and "post-covid syndrome" were also done in PROSPERO, and we screened the website of the UK Office for National Statistics (www.ons.gov.uk) for long covid studies. We found more than 20 systematic reviews summarising post-acute symptom patterns among adults and a prevalence of "any" or "defined" symptoms (such as respiratory symptoms or symptoms related to mental health) or of medically assessed functional impairment (pulmonary or cardiac or neurocognitive function). Two reviews reported of health-related quality of life assessments. The prevalence of post-acute sequelae of COVID-19 or long covid/post-covid syndromes ranged between <10 to >70%, in part due to lack of uniform and clear case definitions, variable follow-up times, and non-inclusion of outpatients with initially mild disease. Most papers reviewed presented high heterogeneity and had a short follow-up, and there were very few papers estimating the prevalence of post-covid syndrome beyond six months after acute infection. The studies with the largest number of subjects were either including only patients after hospital admission, used online surveys of subjects with self-reported suspected and confirmed COVID-19 or electronic medical records only. We found one (small but) comprehensive population-based study from Switzerland assessing post-covid syndrome prevalence and associations with quality of life and health recovery with a follow-up time ranging from six to 10 months. Two further population-based studies from Switzerland and Norway investigated long covid symptoms among subgroups with [≥]6 months (n=498) and 11 to 12 months (n=170) of follow-up after acute infection, respectively.

Added value of this studyWith this large population-based study, we provide evidence of persistence of new symptom clusters (not present before acute infection) such as fatigue, neurocognitive impairment, chest symptoms, smell or taste disorder, and anxiety/depression beyond six months after acute infection, with a prevalence of >20% for each of these five clusters. We show that the three most frequent clusters (fatigue, neurocognitive impairment, chest symptoms) are often interfering with daily life and activities, often co-occur, and that both fatigue and neurocognitive impairment have the largest impact on working capacity, while long-term smell and taste disorders are reported relatively independent of other complaints. Age in this 18-65-year old adult population was not a major determinant of symptom prevalence, but we confirm severity of the initial infection and female sex as consistent risk factors for various manifestations of medium-term post-COVID syndrome, and age as risk factor for self-reported reduced working capacity, which overall and at population level exceeded 10%.

Implications of all the available evidenceFuture research should include the medical validation of the key symptom clusters of post-COVID syndrome, determine the possible causes, and urgently address prognostic factors and therapeutic options. The described key symptom clusters contributed most to reduced general health status and working capacity in middle-aged adults. The findings of this study may also help develop a more consistent and relevant definition of post-COVID syndrome with major implications for research and medical practice.

category: infectious diseases


title: Glucose and lipid profiles in men with non-obstructive azoospermia

abstract: The impact of a low testosterone level among men with non-obstructive azoospermia with various testicular histopathological patterns on the regulation of glucose and lipid metabolism is less well known than among the general population. The aim of this retrospective study was to examine the association between testicular histopathology and components of the metabolic profile among men with non-obstructive azoospermia. Participants were divided into two groups: men with non-obstructive azoospermia and men with obstructive azoospermia. Testicular biopsies were performed among those with non-obstructive azoospermia. We included 115 patients in this study: 83 (72.2%) had non-obstructive azoospermia and 32 (27.8%) had obstructive azoospermia. The plasma glucose concentration, glycated hemoglobin level, and lipid profile were similar between patients with non-obstructive azoospermia and those with obstructive azoospermia. Upon subgroup analysis of patients with non-obstructive azoospermia, those with Sertoli-cell-only syndrome had the lowest testosterone (431 {+/-} 238 ng/dL; P=0.039) and highest follicle-stimulating hormone (23.4 {+/-} 18.2 mIU/mL; P=0.002) concentrations. They also had the highest triglyceride concentration (163 {+/-} 114 mg/dL; P=0.001). Interestingly, patients with Sertoli-cell-only syndrome had a lower fasting plasma glucose concentration (92 {+/-} 11 mg/dL; P<0.001) and glycated hemoglobin level (5.9 {+/-} 0.8%; P=0.022) than those with histopathological patterns of maturation arrest and hypospermatogenesis. In conclusion, differences in glucose and lipid metabolism are evident between men with non-obstructive azoospermia with different spermatogenesis patterns.

category: urology


title: Mid-term subclinical myocardial injury detection in patients recovered from COVID-19 according pulmonary lesion severity.

abstract:
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV 2) may cause damage of the cardiovascular system during the acute phase of infection. However, Recent studies described a mid and long-term subtle cardiac injuries after recovery from acute Coronavirus disease 19 (COVID-19).The aim of this study was to determine the relationship between the severity of chest computed tomography (CT) lesions and the persistence of subtle myocardial injuries at mid-term follow-up of patients recovered from COVID-19 infection.

MethodsAll COVID-19 patients were enrolled prospectively in this study. Sensitive troponin T (hsTnT) and chest CT scan was performed in all patients at the acute phase of Covid-19 infection. At the mid-term follow up, conventional transthoracic echocardiograph and global longitudinal strain (GLS) of left and right ventricles (LV and RV) were determined and compared between patients with chest CT scan lesions less than 50% (Group 1) and those with severe chest CT scan greater or equal to 50% (Group 2).

ResultsThe mean age was 55 more or less than 14 years. Both LV GLS and RV GLS were significantly decreased in the group 2 (p=0.013 and p=0.011, respectively). LV GLS value more than -18% was noted in 43% of all the patients and RV GLS value more than -20% was observed in 48% of them. The group with severe chest CT scan lesions included more patients with reduced LV GLS and reduced RV GLS than the group with mild chest CT scan lesions (G1:29% vs. G2:57%, p=0.002) and (G1:36% vs. G2:60 %, p=0.009) respectively).

ConclusionPatients with severe chest CT scan lesions are more likely to develop subclinical myocardial damage. TTE could be recommended in patients recovering from COVID-19 to detect subtle LV and RV lesions.

Trial registrationThe cohort of patients is a part of the research protocol (IORG 00093738 N{degrees}102/OMB 0990-0279) approved by the Hospital Ethics Committee.

category: cardiovascular medicine


title: Prospectively validated disease-agnostic predictive medicine with hybrid AI

abstract: Despite numerous superhuman achievements in complex challenges1,2, standalone AI does not free life science from the long-term bottleneck of linearly extracting new knowledge from exponentially growing new data3, severely limiting the success rate of drug discovery4. Inspired by the state-of-the-art AI training methods, we trained a human-centric hybrid augmented intelligence5 (HAI) to learn a foundation model6 that extracts all-encompassing knowledge of human physiology and diseases. To evaluate the quality of HAIs extracted knowledge, we designed the public, prospective prediction of pivotal ongoing clinical trial outcomes at large scale (PROTOCOLS) challenge to benchmark HAIs real-world performance of predicting drug clinical efficacy without access to human data. HAI achieved a 10.5-fold improvement from the baseline with 99% confidence7 in the PROTOCOLS validation, readily increasing the average clinical success rate of investigational new drugs from 7.9%8 to 90% for almost any human diseases9,10. The validated HAI confirms that exponentially extracted knowledge alone is sufficient for accurately predicting drug clinical efficacy, effecting a total reversal of Erooms law4. HAI is also the worlds first clinically validated model of human aging that could substantially speed up the discovery of preventive medicine for all age-related diseases11. Our results demonstrate that disruptive breakthroughs necessitate the smallest team size to attain the largest HAI for optimal knowledge extraction from high-dimensional low-quality data space, thus establishing the first prospective proof of the previous discovery that small teams disrupt12. The global adoption of training HAI provides a well-beaten economic path to mass-produce scientific and technological breakthroughs via exponential knowledge extraction and better designs of data labels for training better-performing AI13.

category: pharmacology and therapeutics


title: Prospectively validated disease-agnostic predictive medicine with augmented intelligence


title: Prospectively validated augmented intelligence for disease-agnostic predictions of clinical success for novel therapeutics


title: The impact of COVID-19 on pregnant and recently pregnant women in Malawi: A national facility-based cohort

abstract:
ObjectiveTo describe the demographic characteristics, clinical manifestations, and clinical outcomes of hospitalised pregnant and recently pregnant women with COVID-19 in Malawi, a low-income country in Sub-Saharan Africa. This study responds to a critical gap in the global COVID-19 data.

MethodsA national surveillance platform was established in Malawi by the Ministry of Health to record the impact of COVID-19 on pregnant and recently pregnant women and provide real-time data for decision making. We report this facility-based cohort that includes all pregnant and recently pregnant hospitalised women in Malawi suspected of having COVID-19 between 2nd June 2020 and 1st December 2021.

Results398 women were admitted to hospital with suspected COVID-19 based on presenting symptoms and were tested; 246 (62%) were confirmed to have COVID-19. In women with COVID-19, the mean age was 27 {+/-} 7 years.

The most common presenting symptoms were cough (74%), breathlessness (45%), Fever (42%), headache (17%), and joint pain (10%). 53% of the women had COVID-19 symptoms severe enough to warrant admission.

31% (76/246) of women admitted with COVID-19 suffered a severe maternal outcome, 47/246 (19%) died, and 29/246 (12%) had a near-miss event. 9/111 (8%) of recorded births were stillbirths, and 12/101 (12%) of the live births resulted in early neonatal death.

ConclusionA national electronic platform providing real-time information on the characteristics and outcomes of pregnant and recently pregnant women with COVID-19 admitted to Malawian government hospitals. These women had much higher rates of adverse outcomes than those suggested in the current global data. These findings may reflect the differences in the severity of disease required for women to present and be admitted to Malawian hospitals, limited access to intensive care and the pandemics disruption to the health system.

SUMMARY BOXO_ST_ABSWhat is already known?C_ST_ABSO_LIIn pregnant and recently pregnant women, COVID-19 is associated with increased complications such as admission to an intensive care unit, invasive ventilation, and maternal death.
C_LIO_LIIn pregnant women with confirmed COVID-19, the current global estimate of all-cause mortality is 0.02%.
C_LIO_LIMost countries in Africa rely on paper-based systems to collect key maternal health indicators such as maternal deaths and severe morbidity, which does not enable timely actions.
C_LI

What are the new findings?O_LIMaternal mortality and adverse perinatal outcomes are alarmingly high in a cohort of pregnant and recently pregnant women admitted to Malawian healthcare facilities located in a low-income country in Africa.
C_LIO_LIA national facility-based maternal surveillance platform can be implemented during a pandemic and provide real-time data to aid policymakers in understanding its impacts on this key population.
C_LI

What do the new findings imply?O_LIIn low-income countries in Sub-Saharan Africa, pregnant and recently pregnant women with COVID-19 admitted to hospital require enhanced care and a renewed focus on their needs to avert these adverse health outcomes.
C_LIO_LIGlobal and national surveillance systems must specifically record outcomes for pregnant, recently pregnant women and their infants to understand the impact of public health emergencies on these groups, as they may be disproportionately affected and may require special considerations.
C_LI

category: public and global health


title: Laboratory changes associated with medication non-adherence in patients with hypertension over six months of the COVID-19 pandemic

abstract: The coexistence of multiple diseases is common in the elderly and often accompanied by medication non-adherence. This study investigated the relationship between medication non- adherence and laboratory findings inpatients with hypertension and hypertensive comorbidities (i.e., diabetes and nephropathy) in southern Taiwan during 6 months of the coronavirus disease pandemic. This was a panel study and involved outpatients from three hospitals classified as regional hospitals or above. Questionnaireswere usedto collect information on patient demographics, diet, medication adherence, and laboratory data at the time of recruitment and 6 months after. A total of 140 patients with only hypertension and 98 patients with hypertension and comorbidities were recruited, and the changes inblood pressure andlaboratory data were assessed after 6 months. Analyses performed with generalized estimating equations showed that patients who had not forgotten to take medication had a higher estimated glomerular filtration rate. Moreover, patients who did not change their medication time arbitrarily had lower low- density lipoprotein levels. Furthermore, patients who did not stop or interrupt their medication arbitrarily had lower diastolic blood pressuresand low-density lipoprotein levels. Overall, patients with better medication adherence had better estimated glomerular filtration rates,lower low-density lipoprotein levels, and lower diastolic blood pressures.


title: Immunogenicity of the third and fourth BNT162b2 mRNA COVID-19 boosters and factors associated with immune response in systemic lupus erythematosus and rheumatoid arthritis patients

abstract:
ObjectivesTo evaluate the safety and immunogenicity of third and fourth BNT162b2 boosters in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients.

MethodsSLE and RA patients aged 18-65 years who completed a series of inactivated, adenoviral vector, or heterogenous adenoviral vector/mRNA vaccines for at least 28 days were enrolled. Immunogenicity assessment was done before and day 15 after each booster vaccination. The third BNT162b2 booster was administered on day 1. Patients with suboptimal humoral response to the third booster dose (anti-receptor binding domain (RBD) IgG on day 15 < 2,360 BAU/mL) were given a fourth BNT162b2 booster on day 22.

ResultsSeventy one SLE and 29 RA patients were enrolled. The third booster raised anti-RBD IgG by 15 fold and patients with positive neutralizing activity against the Omicron variant increased from 0% to 42%. Patients with positive cellular immune response also increased from 55% to 94%. High immunosuppressive load and initial inactivated vaccine were associated with lower anti-RBD IgG titer.

Fifty four patients had suboptimal humoral responses to the third booster and 28 received a fourth booster dose. Although anti-RBD IgG increased further by 7 fold, no significant change in neutralizing activity against the Omicron variant was observed. There were 2 severe SLE flares that occurred shortly after the fourth booster dose.

ConclusionsThe third BNT162b2 booster significantly improved humoral and cellular immunogenicity in SLE and RA patients. The benefit of a short interval fourth booster in patients with suboptimal humoral response was unclear.

Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABS- The SARS-CoV-2 omicron variant (B.1.1.159) has multiple mutations that have resulted in greater escape from immune protection elicited by COVID-19 vaccines.
- More attenuated immune response to SARS-CoV-2 vaccination has been observed in patients with autoimmune rheumatic diseases. The additional third dose of SARS-CoV-2 vaccine has been recommended in immunocompromised populations.
- Some immunocompromised patients have a suboptimal humoral response to a third booster dose. Factors associated with poor immune response have not been adequately studied.
- Administration of more than 3 doses has been shown to enhance immune response in some severely immunocompromised patients.

What does this study add?- The third BNT162b2 booster was well tolerated, and significantly improved both humoral and cellular immunogenicity in SLE and RA patients previously vaccinated with either inactivated, adenoviral vector, or heterogenous adenoviral vector/mRNA vaccines.
- High intensity of immunosuppressive therapy and initial inactivated vaccine were associated with lower humoral immune response to the third BNT162b2 booster.
- Administration of a fourth BNT162b2 booster in poor humoral immune responders may not offer additional protection against the omicron variant, and flares were observed in SLE patients.

How might this impact on clinical practice or future developments?- This study supported a third BNT162b2 booster dose administration in SLE and RA patients to enhance immune protection against the Omicron variant.
- Patients who receive a high dose of immunosuppressive therapy or initial inactivated vaccine could be unprotected from SARS-CoV-2 infection. Benefits and risks of additional boosters or second generation of SARS-CoV-2 vaccine should be further studied.

category: rheumatology


title: Reduced norepinephrine transporter binding in Parkinson's disease with dopa responsive freezing gait

abstract:
Freezing of gait (FOG) is a major cause of falling and leads to loss of independence in Parkinsons disease (PD). The pathophysiology of FOG is poorly understood - although there is a hypothesized link with NE systems. PD-FOG can present in levodopa-responsive and unresponsive forms.

We examined NE transporter (NET) binding via brain positron emission tomography (PET) to evaluate changes in NET density associated with FOG using the high affinity selective NET antagonist radioligand [11C]MeNER (2S,3S)(2-[-(2-methoxyphenoxy)benzyl]morpholine) in N=52 parkinsonian patients. We used a rigorous levodopa challenge paradigm to characterize patients as non-freezing PD (NO-FOG, N=16), levodopa responsive freezing (OFF-FOG, N=10), levodopa-unresponsive freezing (ONOFF-FOG, N=21), and primary progressive freezing of gait (PP-FOG, N=5).

Linear mixed models identified significant reductions in whole brain NET binding in the OFF-FOG group compared to the NO-FOG group (-16.8%, P=0.021). Additional contrasts tested post-hoc identified trends toward increased NET expression in ONOFF-FOG vs. OFF-FOG ({approx}10%; P=0.123). Linear mixed models with interaction terms identified significantly reduced NET binding in right thalamus in the OFF-FOG group (P=0.038). A linear regression analysis identified an association between reduced NET binding and more severe NFOG-Q score only in the OFF-FOG group (P=0.022).

This is the first study to examine brain noradrenergic innervation using NET-PET in PD patients with and without FOG. Based on the normal regional distribution of noradrenergic innervation and pathological studies in the thalamus of PD patients, the implications of our findings suggest that noradrenergic limbic pathways may play a key role in OFF-FOG in PD. This finding could have implications for clinical subtyping of FOG as well as development of therapies.

category: neurology


title: The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

abstract: Understanding the exact molecular mechanisms involved in the etiology of epileptogenic pathologies with or without tumor activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350x) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants (SNV) in low-grade epilepsy-associated tumors (LEAT; 7.92{+/-}5.65 SNV) than in brain tissue from malformations of cortical development (MCD; 6.11{+/-}4 SNV) or hippocampal sclerosis (HS; 5.1{+/-}3.04 SNV). Tumor tissues also had the largest number of likely pathogenic variant carrying cells. LEAT had the highest proportion of samples with one or more somatic copy number variants (CNV; 24.7%), followed by MCD (5.4%) and HS (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among LEAT. For germline variant-associated MCD genes such as TSC2, DEPDC5, and PTEN, germline SNV were frequently identified within large loss of heterozygosity regions, supporting the recently proposed  second hit disease mechanism in these genes. We detect somatic variants in twelve established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the etiology of LEAT (e.g., BRAF) and MCD (e.g., SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with LEAT and NRAS Q61 mutated protein with a complex MCD characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21-q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical genetic analyses showed that the numbers of somatic SNV across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with LEAT. Finally, we report that identifying a likely pathogenic variant enabled us to refine or reclassify previous histopathological classifications post hoc in 20.5% of diagnoses. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening, and guides future directions for clinical implementation of epilepsy surgery genetics.

category: genetic and genomic medicine


title: Estimating Cuff-less Continuous Blood Pressure from Fingertip Photoplethysmogram Signals with Deep Neural Network Model

abstract:
ObjectiveBlood pressure (BP) is an important physiological index reflecting cardiovascular function. Continuous blood pressure monitoring helps to reduce the prevalence and mortality of cardiovascular diseases. In this study, we aim to estimate systolic blood pressure (SBP) and diastolic blood pressure (DBP) values continuously based on fingertip photoplethysmogram (PPG) waveforms using deep neural network models.

MethodsTwo models were proposed and both models consisted of three stages. The only difference between them was the method of extracting features from PPG signals in the first stage. Model 1 adopted Bidirectional Long Short-Term Memory (BiLSTM), while the other used convolutional neural network. Then, the residual connection was applied to multiple stacked LSTM layers in the second stage, following by the third stage with two fully connected layers.

ResultsOur proposed models outperformed other methods based on similar dataset or framework, while in our proposed models, the model 2 was superior to model 1. It satisfied the standard of Association for the Advancement of the Medical Instrumentation (AAMI) and obtained grade A for SBP and DBP estimation according to the British Hypertension Society (BHS) standard. The mean error (ME) and standard deviation (STD) for SBP and DBP estimations were 0.21 {+/-} 6.40 mmHg and 0.19 {+/-}4.71 mmHg, respectively.

ConclusionOur proposed models could extract important features of fingertip PPG waveforms automatically and realize cuff-less continuous BP monitoring, which can be helpful in the identification and early treatment of abnormal blood pressure, thus may reduce the occurrence of cardiovascular malignant events.

category: health informatics


title: CDC (Cindy and David's Conversations) Game: Advising President to Survive Pandemic

abstract:
AO_SCPLOWBSTRACTC_SCPLOWOngoing debates on anti-COVID19 policies have been focused on coexistence vs. zero-out strategies, which can be simplified as "always open (AO)" vs. "always closed (AC)." We postulate that, the middle ground between the two extremes, dubbed LOHC (low-risk open and high-risk closed), is likely more favorable, precluding obviously irrational HOLC (high-open-low-closed). From a meta-strategy perspective, these four policies cover the full spectrum of anti-pandemic policies. We argue that, among numerous factors influencing strategic policy-making, the competence of advisory body such as CDC chief-scientist (say, Cindy) and politics in decision-making body such as president (David), and their cooperation/communication can be critical. Here we investigate anti-pandemic policy-making by harnessing the power of evolutionary game theory in modeling competition/cooperation/communication (three critical processes underlying biological and social evolutions). Specifically, we apply the Sir Philip Sydney (SPS) game, a 4x4 signaler-responder evolutionary game with 16 strategic interactions, which was devised to investigate the reliability of communication that can modulate competition and cooperation, to capture rich idiosyncrasies surrounding todays anti-pandemic policies. By emulating the reality of anti-pandemic policies today, the study aims to identify possible cognitive gaps and traps. The extended SPS, dubbed CDC (Cindy and Davids Conversations) game, offers a powerful cognitive model for investigating the coexistence/zero-out dichotomy and possible alternatives. The rigorous analytic solutions and extensive simulations suggest a take-home message--keep it persistently simple and rational: while apparently preferred middle-ground LOHC seems to be small-probability ([~]0.05) event counter-intuitively, the AO and AC policies appears to be large-probability ([~]0.41-0.53) events.

LO_SCPLOWAYC_SCPLOW SO_SCPLOWUMMARYC_SCPLOWOngoing debates on anti-COVID19 policies have been focused on coexistence-with vs. zero-out (virus) strategies, which can be simplified as "always open (AO)" vs. "always closed (AC)." We postulate that middle ground, dubbed LOHC (low-risk-open and high-risk-closed), is likely more favorable, precluding obviously irrational HOLC (high-risk-open and low-risk-closed). From a meta-strategy perspective, these four policies cover the full spectrum of anti-pandemic policies. By emulating the reality of anti-pandemic policies today, the study aims to identify possible cognitive gaps and traps by harnessing the power of evolutionary game-theoretic analysis and simulations, which suggest that (i) AO and AC seems to be "high-probability" events ([~]0.41-0.53); (ii) counter-intuitively, the middle ground--LOHC--seems to be small-probability event ([~]0.05), possibly due to its unduly complexity, mirroring its wide-range failures in practice.

category: health policy


title: Durability of second-line anti-retroviral therapy in a resource-limited setting: an 11-year analytical cohort

abstract:
BackgroundIt is projected that up to 19{middle dot}6% of patients on ART in Sub-Saharan Africa will need second-line treatment by 2030, but the durability of such therapy remains unclear. This study investigated the durability of second-line ART and the factors associated with the viral rebound among patients on second-line ART in Uganda.

MethodsA retrospective dynamic cohort of adults initiated on second-line ART after confirmed virological failure to first-line ART. Patients that had taken second-line for [≥]6 months between 2007 and 2017 were included. Patients were followed until they experienced a viral rebound (Viral load [≥]200copies/ml). Cumulative probability of viral rebounds and factors associated with viral rebound were determined using Kaplan-Meier methods and Cox proportional hazard models, respectively.

Findings1101 participants were enrolled. At base-line, 64% were female, the median age was 37 years (IQR 31-43), median duration on first-line ART was 44months (IQR 27-67), and the median CD4 and viral load were 128 cells/ul (IQR 58-244) and 45978 copies/ml (IQR 13827-139583), respectively. During the 4757{middle dot}21 person-years, the incidence density of viral rebound was 74{middle dot}62 (95% CI 67{middle dot}25- 82{middle dot}80) per 1000 person-years. The probability of a viral round at 5 and 10 years was 0{middle dot}29 (95% C: I 0{middle dot}26 -0{middle dot}32) and 0{middle dot}623 (95%CI:0{middle dot}55 -0{middle dot}69), respectively. The median survival without experiencing a viral rebound was 8{middle dot}7 years. Young adults (18-24) years (aHR 2{middle dot}31 95 CI 1{middle dot}25-4{middle dot}27), high switch viral load [≥]100,000copies/ml (aHR 1{middle dot}53 95 CI 1{middle dot}23- 1{middle dot}91) and ATV/r based second-line (aHR1{middle dot}53 95 CI 1{middle dot}18-2{middle dot}00) were associated with an increased risk viral rebound.

InterpretationSecond-line regimens are fairly durable for eight years followed a rapid increase in the incidence of rebounds. A high viral load at switch, ATV/r based second-line, and young adulthood are risk factors associated with a viral rebound, which underscores the need for differentiated care services.

category: hiv aids


title: Super-spreaders of novel coronaviruses that cause SARS, MERS and COVID-19 : A systematic review

abstract:
OBJECTIVEMost index cases with novel coronavirus infections transmit disease to just 1 or 2 other individuals, but some individuals  super-spread - they are infection sources for many secondary cases. Understanding common factors that super-spreaders may share could inform outbreak models.

METHODSWe conducted a comprehensive search in MEDLINE, Scopus and preprint servers to identify studies about persons who were each documented as transmitting SARS, MERS or COVID-19 to at least nine other persons. We extracted data from and applied quality assessment to eligible published scientific articles about super-spreaders to describe them demographically: by age, sex, location, occupation, activities, symptom severity, any underlying conditions and disease outcome. We included scientific reports published by mid June 2021.

RESULTSThe completeness of data reporting was often limited, which meant we could not identify traits such as patient age, sex, occupation, etc. Where demographic information was available, for these coronavirus diseases, the most typical super-spreader was a male age 40+. Most SARS or MERS super-spreaders were very symptomatic and died in hospital settings. In contrast, COVID-19 super-spreaders often had a very mild disease course and most COVID-19 super-spreading happened in community settings.

CONCLUSIONAlthough SARS and MERS super-spreaders were often symptomatic, middle- or older-age adults who had a high mortality rate, COVID-19 super-spreaders often had a mild disease course and were documented to be any adult age (from 18 to 91 years old). More outbreak reports should be published with anonymised but useful demographic information to improve understanding of super-spreading, super-spreaders, and the settings that super-spreading happens in.


title: Area-level social and structural inequalities determine mortality related to COVID-19 diagnosis in Ontario, Canada: a population-based explanatory modeling study of 11.8 million people

abstract:
ImportanceSocial determinants of health (SDOH) play an important role in COVID-19 outcomes. More research is needed to quantify this relationship and understand the underlying mechanisms.

ObjectivesTo examine differential patterns in COVID-19-related mortality by area-level SDOH accounting for confounders; and to compare these patterns to those for non-COVID-19 mortality, and COVID-19 case fatality (COVID-19-related death among those diagnosed).

Design, setting, and participantsPopulation-based retrospective cohort study including all community living individuals aged 20 years or older residing in Ontario, Canada, as of March 1, 2020 who were followed through to March 2, 2021.

ExposureSDOH variables derived from the 2016 Canada Census at the dissemination area-level including: median household income; educational attainment; proportion of essential workers, racialized groups, recent immigrants, apartment buildings, and high-density housing; and average household size.

Main outcomes and measuresCOVID-19-related death was defined as death within 30 days following, or 7 days prior to a positive SARS-CoV-2 test. Cause-specific hazard models were employed to examine the associations between SDOH and COVID-19-related mortality, treating non-COVID-19 mortality as a competing risk.

ResultsOf 11,810,255 individuals included, 3,880 (0.03%) died related to COVID-19 and 88,107 (0.75%) died without a positive test. After accounting for demographics, baseline health, and other SDOH, the following SDOH were associated with increased hazard of COVID-19-related death (hazard ratios [95% confidence intervals]) comparing the most to least vulnerable group): lower income (1.30[1.09-1.54]), lower educational attainment (1.27[1.10-1.47]), higher proportion essential workers (1.28[1.10-1.50]), higher proportion racialized groups (1.42[1.16-1.73]), higher proportion apartment buildings (1.25[1.11-1.41]), and larger vs. medium household size (1.30[1.13-1.48]). In comparison, areas with higher proportion racialized groups were associated with a lower hazard of non-COVID-19 mortality (0.88[0.85-0.92]). With the exception of income, SDOH were not independently associated with COVID-19 case fatality.

Conclusions and relevanceArea-level social and structural inequalities determine COVID-19-related mortality after accounting for individual demographic and clinical factors. COVID-19 has reversed the pattern of lower non-COVID-19 mortality by racialized groups. Pandemic responses should include prioritized and community-tailored intervention strategies to address SDOH that mechanistically underpin disproportionate acquisition and transmission risks and shape barriers to the reach of, and access to prevention interventions.

Key pointsO_ST_ABSQuestionC_ST_ABSAre area-level social determinants of health factors independently associated with coronavirus disease 2019 (COVID-19)-related mortality after accounting for demographics and clinical factors?

FindingsIn this population-based cohort study including 11.8 million adults residing in Ontario, Canada and 3,880 COVID-19-related death occurred between Mar 1, 2020 and Mar 2, 2021, we found that areas characterized by lower SES (including lower income, lower educational attainment, and higher proportion essential workers), greater ethnic diversity, more apartment buildings, and larger vs. medium household size were associated with increased hazard of COVID-19-related mortality compared to their counterparts, even after accounting for individual-level demographics, baseline health, and other area-level SDOH.

MeaningPandemic responses should include prioritized and community-tailored intervention strategies to address SDOH that mechanistically underpin inequalities in acquisition and transmission risks, and in the reach of, and access to prevention interventions.

category: epidemiology


title: Long-term survival analysis of HIV patients on antiretroviral therapy in Congo: a 14 years retrospective cohort analysis, 2003-2017

abstract:
BackgroundThe long-term survival of patients on antiretroviral treatment in Congo remains less documented. Our study aimed to analyze the long-term survival of adults living with HIV on ART (Antiretroviral Therapy).

MethodsWe conducted a historical cohort study on 2,309 adult PLHIV (People Living with HIV) followed between January 1, 2003 and December 31, 2017 whose viral load and date of initiation of ART were known. The Kaplan Meier method was used to estimate the probability of survival and the Cox regression model to identify factors associated with death.

ResultsThe median age was 49 years; the female sex was predominant with 68.56%. The probability of survival at 14 years was 83%, (95% CI (Confidence Interval) [78-87]). On the other hand, when the lost to follow-up died, it was 66% (95% CI [62-70]) in the worst scenario. Stratified cox regression analysis showed that: being male, AHR (Adjusted Hazard Ratio) = 1.65 (95% CI [1.26-2.17]) was significantly associated with death, p-value <0.0001. Furthermore, having a viral load> 1000 copies / ml, AHR = 2.56 (95% CI [1.93-3.40]), be in the advanced WHO clinical stage, in particular: stage II, AHR = 4.07 (95% CI [2.36-7.01]); stage III, AHR = 13.49 (95% CI [8.99-20.27]) and stage IV, AHR = 34.45 (95% CI [23.74-50]) were also significantly associated with death; p-value <0.0001.

ConclusionThe long-term survival of PLHIV is worrying despite the offer of ARVs.


title: People underestimate the change of airborne Corona virus exposure when changing distance to an infected person: On interpersonal distance, exposure time, face masks and perceived virus exposure.

abstract: Participants judged airborne Corona virus exposure following a change of inter-personal distance and time of a conversation with an infected person with and without a face mask. About 75% of the participants underestimated how much virus exposure changes when the distance to an infected person changed. The smallest average face to face distance from an infected person without a mask that a participant judged as sufficiently safe was about 12 feet (3.67 m). Correlations showed that the more a person underestimated the effects of change of distance on exposure the shorter was that persons own safety distance. On average the effects of different lengths of a conversation on exposure were correct, but those who judged the effects of time as smaller tended to select longer safety distances. Worry of own COVID-19 infection correlated with protective behaviors: keeping longer safety distances, avoiding public gatherings, postponement of meetings with friends. The results showed that the protective effects of both distancing and wearing a face mask were under-estimated by a majority of the participants. Implications of these results were discussed last.


title: Biomarkers Selection for Population Normalization in SARS-CoV-2 Wastewater-based Epidemiology

abstract:
Wastewater-based epidemiology (WBE) has been one of the most cost-effective approaches to track the SARS-CoV-2 levels in the communities since the COVID-19 outbreak in 2020. Normalizing SARS-CoV-2 concentrations by the population biomarkers in wastewater can be critical for interpreting the viral loads, comparing the epidemiological trends among the sewersheds, and identifying the vulnerable communities. In this study, five population biomarkers, pepper mild mottle virus (pMMoV), creatinine (CRE), 5-hydroxyindoleacetic acid (5-HIAA), caffeine (CAF) and its metabolite paraxanthine (PARA) were investigated for their utility in normalizing the SARS-CoV-2 loads through developed direct and indirect approaches. Their utility in assessing the real-time population contributing to the wastewater was also evaluated. The best performed candidate was further tested for its capacity for improving correlation between normalized SARS-CoV-2 loads and the clinical cases reported in the City of Columbia, Missouri, a university town with a constantly fluctuated population. Our results showed that, except CRE, the direct and indirect normalization approaches using biomarkers allow accounting for the changes in wastewater dilution and differences in relative human waste input over time regardless flow volume and population at any given WWTP. Among selected biomarkers, PARA is the most reliable population biomarker in determining the SARS-CoV-2 load per capita due to its high accuracy, low variability, and high temporal consistency to reflect the change in population dynamics and dilution in wastewater. It also demonstrated its excellent utility for real-time assessment of the population contributing to the wastewater. In addition, the viral loads normalized by the PARA-estimated population significantly improved the correlation (rho=0.5878, p<0.05) between SARS-CoV-2 load per capita and case numbers per capita. This chemical biomarker offers an excellent alternative to the currently CDC-recommended pMMoV genetic biomarker to help us understand the size, distribution, and dynamics of local populations for forecasting the prevalence of SARS-CoV2 within each sewershed.

HIGHLIGHT (bullet points)O_LIThe paraxanthine (PARA), the metabolite of the caffeine, is a more reliable population biomarker in SARS-CoV-2 wastewater-based epidemiology studies than the currently recommended pMMoV genetic marker.
C_LIO_LISARS-CoV-2 load per capita could be directly normalized using the regression functions derived from correlation between paraxanthine and population without flowrate and population data.
C_LIO_LINormalizing SARS-CoV-2 levels with the chemical marker PARA significantly improved the correlation between viral loads per capita and case numbers per capita.
C_LIO_LIThe chemical marker PARA demonstrated its excellent utility for real-time assessment of the population contributing to the wastewater.
C_LI


title: Neonatal AKI profile using KDIGO guidelines: A cohort study in tertiary care hospital ICU of Lahore, Pakistan

abstract:
BackgroundAKI is witnessed in sick neonates and is associated with poor outcomes. Our cohort represents the profile of neonates who were diagnosed with AKI using KDIGO guidelines during intensive care unit stay.

MethodologyA cohort study was conducted in the NICU of FMH from June 2019 to May 2021. Data were collected on standardized proforma. Serum creatinine was measured within 24 hours after enrollment in the study by cytometric analysis using the C311 Rosch machine and subsequently after 24 to 48 hours. Data analysis was done using SPSS v 20.0. All continuous variables were not normally distributed and were expressed as the median and interquartile range (IQR). Categorical variables were analyzed by proportional differences with either the Pearson chi-square test or Fishers exact tests. A multinomial logistic regression model was used to explore the independent risk factors of AKI. Time to the event (death) and survival curves for the cohort were plotted by using Cox proportional hazard model.

ResultsAKI occurred in 473 (37.6%) of neonates and 15.7%, 16.3% and 5.6% had stage 1, 2 and 3 respectively. The outborn birth (p 0.000, AOR 3.987, 95%CI 2.564 - 6.200), birth asphyxia (p 0.000, AOR 3.567, 95%CI 2.093 - 6.080), inotropic agent (p 0.000, AOR 2.060, 95%CI 1.436 - 2.957), antenatal steroids (p 0.002, AOR 1.721, 95%CI 1.213 - 2.443), central lines (p 0.005, AOR 1.630, 95%CI 1.155 - 2.298), IVH/ICH/DIC (p 0.009, AOR1.580, 95%CI 1.119 - 2.231) and NEC (p 0.054, AOR 1.747, 95%CI 0.990 - 3.083) were independently associated with AKI. Protective factors of neonatal AKI were normal sodium levels, maternal diabetes mellitus as well Hb>10.5 mg/dl. Duration of stay (7 vs 9 days) and mortality rates (3.9% vs16.5%) were significantly higher in neonates with AKI (p <0.001).

ConclusionAbout one-third of critically sick neonates had AKI. Significant risk factors for AKI were outborn birth (298%), birth asphyxia (256%), inotropic agents (106%) %, NEC 74.7%, antenatal steroids 72%, central lines 63% and IVH/ICH/DIC 58%. AKI prolongs the duration of stay and reduces the survival of sick neonates.

category: pediatrics


title: Health behaviours and their determinants among immigrants residing in Italy

abstract:
BackgroundThe mechanisms that influence the uptake of risky behaviours among immigrants are influenced by the interrelation between characteristics operating in different phases of their migratory experience. Characterizing their behavioural risk profile is needed to prioritize actions for prevention and health services organization. We therefore analysed health behaviours and their determinants among immigrants in Italy, jointly accounting for sociodemographic factors, migration pathways and integration indicators.

MethodsData come from a national survey conducted in 2011-2012 on a sample of about 12000 households with at least one foreigner residing in Italy. The independent impact of a variety of sociodemographic, migratory and integration characteristics on obesity, smoking and daily alcohol consumption was assessed using multivariable Poisson models.

ResultsThe survey involved more than 15,000 first generation immigrants. Unhealthy lifestyles are more common among men than among women and vary widely by ethnic group. There is a significant impact of employment status and family composition, while the educational level loses importance. Longer duration of residence and younger age at arrival are associated with an increased behavioural risk. Among women we also observed an independent impact of the integration indicators, less important for men.

ConclusionsThe profile of the main unhealthy lifestyles among migrants is shaped by cultural, socioeconomic and migratory characteristics, which differ by gender. Understanding these factors can help to design tailored preventive messages, necessary to interrupt the deterioration of migrants health capital. Low levels of integration have an additional negative impact on health, so inclusion and integration policies should complement health promotion strategies.


title: Patterns of rates of mortality in the Clinical Practice Research Datalink

abstract:
The Clinical Practice Research Datalink (CPRD) is a widely used data resource, representative in demographic profile, with accurate death recordings but it is unclear if mortality rates within CPRD are similar to rates in the general population. Rates may additionally be affected by selection bias caused by the requirement that a cohort have a minimum lookback window, i.e. observation time prior to start of at-risk follow-up.

Standardised Mortality Ratios (SMRs) were calculated incorporating published population reference rates from the Office for National Statistics (ONS), using Poisson regression with rates in CPRD contrasted to ONS rates, stratified by age, calendar year and sex. An overall SMR was estimated along with SMRs presented for cohorts with different lookback windows (1, 2, 5, 10 years). SMRs were stratified by calendar year, length of follow-up and age group. Mortality rates in a random sample of 1 million CPRD GOLD patients were slightly lower than the national population [SMR=0.980 95% confidence interval (CI) (0.973, 0.987)]. Cohorts with observational lookback had SMRs below one [1 year of lookback; SMR=0.905 (0.898, 0.912), 2 years; SMR=0.881 (0.874, 0.888), 5 years; SMR=0.849 (0.841, 0.857), 10 years; SMR=0.837 (0.827, 0.847)]. Mortality rates in the first two years after patient entry into CPRD were higher than the general population, while SMRs dropped below one thereafter.

Mortality rates in CPRD, using simple entry requirements, are similar to rates seen in the English population. The requirement of at least a single year of lookback results in lower mortality rates compared to national estimates.


title: Employer Requirements and COVID-19 Vaccination and Attitudes among Healthcare Personnel in the U.S.: Findings from National Immunization Survey Adult COVID Module, August - September 2021

abstract:
IntroductionEmployer vaccination requirements have been used to increase vaccination uptake among healthcare personnel (HCP). In summer 2021, HCP were the group most likely to have employer requirements for COVID-19 vaccinations as healthcare facilities led the implementation of such requirements. This study examined the association between employer requirements and HCPs COVID-19 vaccination status and attitudes about the vaccine.

MethodsParticipants were a national representative sample of United States (US) adults who completed the National Immunization Survey Adult COVID Module (NIS-ACM) during August-September 2021. Respondents were asked about COVID-19 vaccination and intent, requirements for vaccination, place of work, attitudes surrounding vaccinations, and sociodemographic variables. This analysis focused on HCP respondents. We first calculated the weighted proportion reporting COVID-19 vaccination for HCP by sociodemographic variables. Then we computed unadjusted and adjusted prevalence ratios for vaccination coverage and key indicators on vaccine attitudes, comparing HCP based on individual self-report of vaccination requirements.

ResultsOf 12,875 HCP respondents, 41.5% reported COVID-19 vaccination employer requirements. Among HCP with vaccination requirements, 90.5% had been vaccinated against COVID-19, as compared to 73.3% of HCP without vaccination requirements--a pattern consistent across sociodemographic groups. Notably, the greatest differences in uptake between HCP with and without employee requirements were seen in sociodemographic subgroups with the lowest vaccination uptake, e.g., HCP aged 18-29 years, HCP with high school or less education, HCP living below poverty, and uninsured HCP. In every sociodemographic subgroup examined, vaccine uptake was more equitable among HCP with vaccination requirements than in HCP without. Finally, HCP with vaccination requirements were also more likely to express confidence in the vaccines safety (68.3% vs. 60.1%) and importance (89.6% vs 79.6%).

ConclusionIn a large national US sample, employer requirements were associated with higher and more equitable HCP vaccination uptake across all sociodemographic groups examined. Our findings suggest that employer requirements can contribute to improving COVID-19 vaccination coverage, similar to patterns seen for other vaccines.


title: Short-chain fatty acid concentrations in the incidence and risk-stratification of colorectal cancer: a systematic review and meta-analysis

abstract:
The beneficial role of gut microbiota and bacterial metabolites, including short-chain fatty acids (SCFAs), is well recognized; although the available literature around their role in colorectal cancer (CRC) has been inconsistent.

We performed a systematic review and meta-analysis to examine associations of fecal SCFA concentrations to the incidence and risk of CRC.

Data extraction through Medline, Embase, and Web of Science was carried out from database conception to May 21, 2021. Predefined criteria included human clinical observational studies, while excluding cell/animal model studies, conference proceedings, and reviews. Quality assessment of selected 16 case-control and six cross-sectional studies is reported using PRISMA 2020 guidelines. Studies were categorized for CRC risk or incidence, and RevMan 5.4 was used to perform the meta-analyses. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated using a random-effects model.

Combined analysis of acetic-, propionic-, and butyric-acid revealed significantly lower concentrations of these SCFAs in individuals with high-risk of CRC (SMD = 2.02, 95% CI 0.31 to 3.74, P = 0.02). Further, CRC incidence increased in individuals with lower levels of SCFAs (SMD = 0.45, 95% CI 0.19 to 0.72, P = 0.0009), compared to healthy individuals.

Overall, lower fecal concentrations of the three major SCFAs is associated with higher risk and incidence of CRC.

category: oncology


title: Identification of probiotic responders in cross-over trials using the Bayesian statistical model considering lags of effect period

abstract: Recent advances in microbiome research have led to the further development of microbial interventions, such as probiotics and prebiotics, which are potential treatments for constipation. However, the effects of probiotics vary from person to person; therefore, the effectiveness of probiotics needs to be verified for each individual. Individuals showing significant effects of the target probiotic is called responders. A statistical model for the evaluation of responders was proposed in a previous study. However, the previous model does not consider the lag in the effect of the probiotic. It is expected that there are lags between the period of time when probiotics are administered and when they are effective. In this study, we propose a Bayesian statistical model to estimate the probability that a subject is a responder, by considering the lag of the effect period. In synthetic dataset experiments, the proposed model was found to outperform the base model, which did not factor in the lag. Further, we found that the proposed model could distinguish responders showing large uncertainty in terms of the lag of the effect period against the intake period.


title: Safety and immunogenicity of SARS-CoV-2 vaccine MVC-COV1901 in adolescents in Taiwan: A double-blind, randomized, placebo-controlled phase 2 trial

abstract:
BackgroundMVC-COV1901 is a subunit SARS-CoV-2 vaccine based on the prefusion spike protein S-2P and adjuvanted with CpG 1018 and aluminum hydroxide. Although MVC-COV1901 has been licensed for emergency use for adults in Taiwan, the safety and immunogenicity of MVC-COV1901 in adolescents remained unknown. As young people play an important role in SARS-CoV-2 transmission and epidemiology, a vaccine approved for adolescents and eventually, children, will be important in mitigating the COVID-19 pandemic.

MethodsThis study is a prospective, double-blind, multi-center phase 2 trial evaluating the safety, tolerability and immunogenicity of two doses of the SARS-CoV-2 vaccine MVC-COV1901 in adolescents. Healthy adolescents from age of 12 to 17 years were recruited and randomly assigned (6:1) to receive two intramuscular doses of either MVC-COV1901 or placebo at 28 days apart. The primary outcomes were safety and immunogenicity from the day of first vaccination (Day 1) to 28 days after the second vaccination (Day 57), and immunogenicity of MVC COV1901 in adolescents as compared to young adult vaccinees in terms of neutralizing antibody titers and seroconversion rate. The secondary outcomes were safety and immunogenicity of MVC-COV1901 as compared to placebo in adolescents in terms of immunoglobulin titers and neutralizing antibody titers over the study period.

ResultsBetween July 21, 2021 and December 22, 2021, a total of 399 adolescent participants were included for safety evaluation after enrollment to receive at least one dose of either MVC-COV1901 (N=341) or placebo (N=58). Of these, 334 and 46 participants went on to receive two doses of either MVC-COV1901 or placebo, respectively, and were included in the per protocol set (PPS) for immunogenicity analysis. Adverse events were mostly mild and were similar in MVC-COV1901 and placebo groups. The most commonly reported adverse events were pain/tenderness and malaise/fatigue. All immunogenicity endpoints in the adolescent group were non-inferior to the endpoints seen in the young adult and placebo groups.

ConclusionsThe safety and immunogenicity data presented here showed that MVC-COV1901 has similar safety profile and non-inferior immunogenicity in adolescents compared to young adults.

ClinicalTrials.gov registrationNCT04951388.


title: Deep kinetoplast genome analyses result in a novel molecular assay for detecting Trypanosoma brucei gambiense-specific minicircles

abstract: The World Health Organization targeted Trypanosoma brucei gambiense (Tbg) human African trypanosomiasis for elimination of transmission by 2030. Sensitive molecular markers that specifically detect Tbg type 1 (Tbg1) parasites will be important tools to assist in reaching this goal. Here, we aim at improving molecular diagnosis of Tbg1 infections by targeting the abundant mitochondrial minicircles within the kinetoplast of Trypanosoma brucei parasites. Using Next-Generation Sequencing of total cellular DNA extracts, we assembled and annotated the kinetoplast genome and investigated minicircle sequence diversity in 38 animal- and human-infective trypanosome strains. Computational analyses recognized a total of 241 Minicircle Sequence Classes as Tbg1-specific, of which three were shared by the 18 studied Tbg1 strains. We then developed a novel multiplex quantitative PCR assay (g-qPCR3) targeting one Tbg1-specific minicircle and three Tbg1-specific or Trypanozoon-specific markers. Molecular analyses revealed that the minicircle-based assay is applicable on animals and is as specific as the TgsGP-based assay, the current golden standard for molecular detection of Tbg1. The median copy number of the targeted minicircle was equal to eight, suggesting that our minicircle-based assay may be used for the sensitive detection of Tbg1 parasites. Finally, annotation of the targeted minicircle sequence indicated that it encodes genes essential for the survival of the parasite, and will thus likely be preserved in natural Tbg1 populations. These results demonstrated that our minicircle-based assay is a promising new tool for reliable and sensitive detection of Tbg1 infections in humans and animals.


title: Neutralizing responses in fully vaccinated with BNT162b2, CoronaVac, ChAdOx1, and Ad26.COV2.S against SARS-CoV-2 lineages in Colombia, 2020-2021

abstract:
BackgroundBy March 2022, around 34 million people in Colombia had received a complete scheme of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including, mRNA-based vaccines, viral vectored coronavirus vaccines, or the inactivated whole virus vaccine. However, as several SARS-CoV-2 variants of concern (VOC) and interest (VOI) co-circulate in the country, determining the resistance level to vaccine-elicited neutralizing antibodies (nAbs) is useful to improve the efficacy of COVID-19 vaccination programs.

MethodsMicroneutralization assays with the most prevalent SARS-CoV-2 lineages in Colombia during 2020-2021 were performed using serum samples from immunologically naive individuals between 9 and 13 weeks after receiving complete regimens of CoronaVac, BNT162b2, ChAdOx1, or Ad26.COV2.S. The mean neutralization titer (MN50) was calculated by the Reed-Muench method and used to determine differences in vaccine-elicited nAbs against the SARS-CoV-2 lineages B.1.111, P.1 (Gamma), B.1.621 (Mu), and AY.25.1 (Delta).

ResultsThe most administered vaccines in the country, BNT162b2 and CoronaVac, elicited significantly different nAb responses against Mu, as the GMTs were 75.7 and 5.9-fold lower relative to the control lineage (B.1.111), while for Delta were 15.8 and 1.1-fold lower, respectively. In contrast, nAb responses against Mu and Delta were comparable between ChAd0x1-s and Ad26.COV2.S as the GMTs remained around 5 to 7-fold lower relative to B.1.111.

ConclusionsThe emergence of SARS-CoV-2 variants in Colombia with a significant capacity to escape from vaccine-elicited nAbs indicates that a booster dose is highly recommended. Furthermore, other non-pharmacological measures should be retained in the vaccinated population.


title: Integrated Bile Acid Profile Analysis for The Non-invasive Staging Diagnosis of Ulcerative Colitis

abstract: Clinical staging diagnosis and progression tracking for ulcerative colitis (UC) is challenging as poor patient compliance of endoscopic biopsy, we aimed to explore a non-invasive integrative biochemical index to quantitative track and monitor pathological activity. Here we perform a study that integrates bile acid metabolomic profiling, metagenomic sequencing and clinical monitoring on serum and feacal samples from 24 active-state UC patients, 25 remission-state UC patients and 20 healthy volunteers from China. Besides known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with UC, we found several bile acid-transforming species, including 7-dehydroxygenase and 7/{beta}-dehydrogenase expressing microbiota, were significant correlated with UC pathological activity. We identified 7 microbial gene markers that differentiated active and remission-stage UC and healthy control microbiomes. Relevantly, decreased serum deoxycholic acid /cholic acid ratio and increased fecal ursodeoxycholic acid/chenodeoxycholic acid ratio were associated with pathological activity of UC. Moreover, receiver operating characteristic analysis based on serum/fecal bile acids ratios was much accurate in prediction of active and remission stage outcome. This species-specific temporal change and bile acid dysregulation pattern linked to disease severity indicating that integrated microbiome-bile acid profile maybe implied for disease activity prediction, and that targeting microbiome-mediated restoring gut flora and bile acids homeostasis may be implicative of therapy efficacy. Collectively, these insights will help improve clinical diagnosis and optimize existing medical treatments.

category: gastroenterology


title: METHYLATION BIOMARKERS ASSOCIATED WITH DRUG-RESISTANT EPILEPSY

abstract: Epilepsy is a disabling neurological disease that affects 2% of the population. Drug-resistant epilepsy (DRE) affects 25-30% of epilepsy patients. Understanding its underlying mechanisms is key to adequately manage this condition. To analyze the main epigenetic marks of DRE an epigenome-wide association study was carried out including samples from different regions of DRE patients brain and peripheral blood. An Illumina Infinium MethylationEPIC BeadChip array including cortex, hippocampus, amygdala, and peripheral blood from DRE subjected to neurosurgical resection of the epileptogenic zone was used. Overall, 32, 59, 3210, and 6 differentially methylated probes (DMPs) associated with DRE were found in the hippocampus, amygdala, cortex, and peripheral blood, respectively. These DMPs harbored 19, 28, 1574, and 7 genes, respectively, which play different roles in processes such as neurotrophic or calcium signaling. Three of the top DMPs observed in cortex were validated with methylation specific qPCR. Moreover, 163 DMPs associated with neurosurgery response at 6 months were found in the hippocampus. Genes located on these DMPs were involved in diverse processes such as synaptic signaling and central nervous system development. Besides 3 DMPs in blood samples were associated with response to neurosurgery at 12 months. In conclusion, the present study reports genome-wide DNA methylation changes across different regions of the DRE brain. These changes could be useful for further studies to disentangle the bases of DRE to search for therapeutic alternatives for this disease. Furthermore, they could also help identify patients likely to respond to neurosurgery.


title: Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure

abstract: COVID-19-related severe respiratory failure (SRF) leads to mechanical ventilation increasing the in-hospital mortality substantially. Abundancy of lung fibroblasts (LFs) in injured lung tissue has been associated with the progression of respiratory failure in COVID-19. Aiming to reduce mortality in patients with SRF (PaO2/FiO2<100 mmHg) and considering the multi-mechanistic nature of severe COVID-19 pathogenesis, we applied a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone and heparin) comprised inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, such as anti-IL-6 receptor tocilizumab and selective JAK1/2 inhibitor baricitinib. COMBI (n=22) was compared with SOC (n= 26), and with two previously and consecutively used therapeutic approaches, including either IL-1 receptor antagonist anakinra (ANA, n=19), or tocilizumab (TOCI, n=11), on top of SOC. In parallel, evaluation of immunothrombosis was assessed in vitro in human LFs, treated with the applied therapeutic agents upon stimulation with COVID-19 plasma. COMBI was associated with lower in-hospital mortality (p=0.014) and intubation rate (p=0.013), shorter duration of hospitalization (p=0.019), and prolonged overall survival after a median follow-up of 110{+/-}4 days (p=0.003). In vitro, COVID-19 plasma markedly induced tissue factor/thrombin pathway in LFs, while this effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results suggest the design of randomized trials using combined immunomodulatory therapies in COVID-19-associated SRF targeting multiple interconnected pathways of immunothrombosis.


title: Optical Genome Mapping: Clinical Validation and Diagnostic Utility for Enhanced Cytogenomic Analysis of Hematological Neoplasms

abstract: Hematological neoplasms are predominantly defined by chromosomal aberrations that include structural variations (SVs) and copy number variations (CNVs). The current standard-of-care (SOC) genetic testing for the detection of SVs and CNVs relies on a combination of traditional cytogenetic techniques that include karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarrays (CMA). These techniques are labor-intensive, time and cost-prohibitive, and often do not reveal the genetic complexity of the tumor. Optical genome mapping (OGM) is an emerging technology that can detect all classes of SVs in a single assay. We report the results from our clinical validation (in a CLIA setting) of the OGM technique for hematological neoplasms. The study included 92 sample runs (including replicates) using 69 well-characterized unique samples (59 hematological neoplasms and 10 controls). The technical (QC metrics and first-pass rate) and analytical performance [sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV)] were evaluated using the clinical samples. The reproducibility was evaluated by performing inter-run, intra-run, and inter-instrument comparisons using six samples run in triplicates. The limit of detection (LoD) for aneuploidy, translocation, interstitial deletion, and duplication was assessed. To confirm the LoD, samples at 12.5%, 10%, and 5% allele fractions (theoretical LoD range) were run in triplicates. The technical performance resulted in a 100% first-pass rate with all samples meeting the minimum QC metrics. The analytical performance showed a sensitivity of 98.7%, specificity of 100%, accuracy of 99.2%, PPV of 100%, and NPV of 98%, which included the detection of 61 aneuploidies, 34 deletions, 28 translocations, 11 duplications/amplifications, 15 insertions/additional material not identified with karyotyping, 12 marker chromosomes, and one each of ring chromosome, inversion and isochromosome. OGM demonstrated robust technical and analytical inter-run, intra-run, and inter-instrument reproducibility. The LoD was determined to be at 5% allele fraction for all the variant classes evaluated in the study. In addition, OGM demonstrated higher resolution to refine breakpoints, identify the additional genomic material, marker, and ring chromosomes. OGM identified several additional SVs, revealing the genomic architecture in these neoplasms that provides an opportunity for better tumor classification, prognostication, risk stratification, and therapy selection. This study is the first CLIA validation report for OGM for genome-wide structural variation detection in hematological neoplasms. Considering the technical and analytical advantages of OGM compared to the current SOC methods used for chromosomal characterization, we highly recommend OGM as a potential first-tier cytogenetic test for the evaluation of hematological neoplasms.


title: Estimating the burden of malaria and soil-transmitted helminth co-infection in sub-Saharan Africa: a geospatial study

abstract:
BackgroundLimited understanding exists about the interactions between malaria and soil-transmitted helminths (STH), their potential geographical overlap and the factors driving it. This study characterised the geographical and co-clustered distribution patterns of malaria and STH infections among vulnerable populations in sub-Saharan Africa (SSA).

Methodology/Principal findingsWe obtained continuous estimates of malaria prevalence from the Malaria Atlas Project and STH prevalence surveys from the WHO-driven Expanded Special Project for the Elimination of NTDs (ESPEN) covering 2000-2018 and used spatial autocorrelation methods to identify statistically significant clusters for both diseases across SSA. We used the inverse distance weighted kriging (interpolation) methods to estimate STH prevalence. We calculated the population-weighted prevalence of malaria and STH co-infection, and used the bivariate local indicator of spatial association (LISA analysis) to explore potential co-clustering of both diseases at the implementation unit levels.

Our analysis shows spatial variations in the estimates of the prevalence of Plasmodium falciparum-STH co-infections and identified hotspots across many countries in SSA with inter-and intra-country variations. High P. falciparum and high hookworm co-infections were more prevalent in West and Central Africa, whereas high P. falciparum, high Ascaris lumbricoides, high P. falciparum, and high Trichuris trichiura co-infections were more predominant in Central Africa, compared to other sub-regions in SSA.

Conclusions/SignificanceWide spatial heterogeneity exists in the prevalence of malaria and STH co-infection within the regions and within countries in SSA. The geographical overlap and spatial co-existence of malaria and STH could be exploited to achieve effective control and elimination agendas through the integration of the vertical programmes designed for malaria and STH into a more comprehensive and sustainable community-based paradigm.

Author SummaryMalaria and worms frequently co-exist together among children living in the poorest countries of the world, but little is known about the specific locations of the combined infections involving the two major parasitic diseases and how they interact and change over the years.

We used open access data collected by two public registries, that is, the Malaria Atlas Project and Expanded Special Project for the Elimination of NTDs, to understand the overlap of the two diseases in different parts of Africa, where their burden are more predominant.

We found significant differences in the distributions of the combined diseases across different parts of Africa, with large concentrations identified in Central and West Africa. For example, double infections with malaria and hookworm were more common in West and Central Africa, whereas malaria and roundworm, and malaria and whipworm were predominantly found in Central Africa. A large collection of the dual infections was also found in some localities within the countries which appeared to have low burden of the two diseases.

These findings provide a useful insight into the areas which could be serving as a reservoir to propagating the transmission of the two diseases. The results of this study could also be used to develop and implement integrated control programmes for malaria and worms, and this could help to achieve the WHO NTD roadmap to ending the neglect to attain Sustainable Development Goals by 2030.


title: Withdrawal of Assisted Ventilation at the Patient's Request in MND: A Retrospective Exploration of the Ethical and Legal Issues Concerning Relatives, Nurses and Allied Health Care Professionals

abstract:
BackgroundThere is little literature focusing on the issues relatives and health professionals encounter when withdrawing assisted ventilation at the request of a patient with MND/ALS.

AimTo explore with relatives, nurses and allied health professionals the ethical and legal issues that they had encountered in the withdrawal of ventilation at the request of a patient with MND/ALS.

MethodA retrospective qualitative interview study with 16 family members and 26 professionals. Data was analysed thematically and compared with results from a previous study with doctors.

ResultsThe events surrounding ventilation withdrawal were extraordinarily memorable for both HCPs and family members with clear recall of explicit details, even from years previously. The events had had a profound and lasting effect due to the emotional intensity of the experiences. Withdrawal of ventilation posed legal, ethical and moral challenges for relatives and health are professionals. Relatives looked to health care professionals for knowledge, guidance and reassurance on these issues, worried about how the withdrawal would be perceived by others, and found professional ignorance and disagreement distressing. Many health care professionals lacked theoretical knowledge and confidence on the legal and ethical considerations of withdrawal and struggled morally knowing the outcome of the withdrawal would be death. Health care professionals also worried about the perception of others of their involvement, which in turn influenced their practice. There was a lack of consistency in understanding across professions, and professionals often felt uncomfortable and anxious

ConclusionsLegal, ethical and practical guidance is needed and open discussion of the ethical challenges as well as education and support for health care professionals and relatives would improve the experience of all involved.

category: palliative medicine


title: Predicting refugee flows from Ukraine with an approach to Big (Crisis) Data: a new opportunity for refugee and humanitarian studies

abstract:
BackgroundThis paper shows that Big Data and the so-called tools of digital demography, such as Google Trends (GT) and insights from social networks such as Instagram, Twitter and Facebook, can be useful for determining, estimating, and predicting the forced migration flows to the EU caused by the war in Ukraine.

ObjectiveThe objective of this study was to test the usefulness of Google Trends indexes to predict further forced migration from Ukraine to the EU (mainly to Germany) and gain demographic insights from social networks into the age and gender structure of refugees.

MethodsThe primary methodological concept of our approach is to monitor the digital trace of Internet searches in Ukrainian, Russian and English with the Google Trends analytical tool (trends.google.com). Initially, keywords were chosen that are most predictive, specific, and common enough to predict the forced migration from Ukraine. We requested the data before and during the war outbreak and divided the keyword frequency for each migration-related query to standardise the data. We compared this search frequency index with official statistics from UNHCR to prove the significations of results and correlations and test the models predictive potential. Since UNHCR does not yet have complete data on the demographic structure of refugees, to fill this gap, we used three other alternative Big Data sources: Facebook, Twitter and Instagram.

ResultsAll tested migration-related search queries about emigration planning from Ukraine show the positive linear association between Google index and data from official UNHCR statistics; R2 = 0.1211 for searches in Russian and R2 = 0.1831 for searches in Ukrainian. It is noticed that Ukrainians use the Russian language more often to search for terms than Ukrainian. Increase in migration-related search activities in Ukraine such as "[gcy][p][a][ncy][icy][tscy][a]" (Rus. border), [kcy][o][p][dcy][o][ncy][u] (Ukr. border); "[Pcy][o][lcy][softcy][shchcy][a]" (Poland); "[Gcy][e][p][m][a][ncy][icy][yacy]" (Rus. Germany), "[H]i[m][e][chcy][chcy][icy][ncy][a]" (Ukr. Germany) and "[U][gcy][o][p][shchcy][icy][ncy][a]" and "[V][e][ncy][gcy][p][icy][yacy]" (Hungary) correlate strongly with officially UNHCR data for externally displaced persons from Ukraine. All three languages show that the interest in Poland is the highest. When refugees arrive in nearby countries, the search for terms related to Germany, such as "crossing the border + Germany", etc., is proliferating. This result confirms our hypothesis that one-third of all refugees will cross into Germany. According to Big Data insights, the estimate of the total number of expected refugees is to expect 5,4 Million refugees. The age group most represented is between 24 and 45 years (data for children are unavailable), and over 65% are women.

ConclusionThe increase in migration-related search queries is correlated with the rise in the number of refugees from Ukraine in the EU. Thus this method allows reliable forecasts. Understanding the consequences of forced migration from Ukraine is crucial to enabling UNHCR and governments to develop optimal humanitarian strategies and prepare for refugee reception and possible integration. The benefit of this method is reliable estimates and forecasting that can allow governments and UNHCR to prepare and better respond to the recent humanitarian crisis.

category: occupational and environmental health


title: Pan-cancer Analyses reveal functional similarities of three lncRNAs across multiple tumors

abstract: Long non-coding RNAs (lncRNAs) are emerging as key regulators in many biological processes. The dysregulation of lncRNA expression has been associated with many diseases, including cancer. Mounting evidence suggests that lncRNAs are involved in cancer initiation, progression, and metastasis. Thus, understanding the functional implications of lncRNAs in tumorigenesis can aid in developing novel biomarkers and therapeutic targets. Rich cancer datasets, documenting genomic and transcriptomic alterations together with advancement in bioinformatics tools, have presented an opportunity to perform pan-cancer analyses across different cancer types. This study is aimed at conducting a pan-cancer analysis of lncRNAs by performing differential expression and functional analyses between tumor and normal adjacent samples across eight cancer types. Among dysregulated lncRNAs, seven were shared across all cancer types. We focused on three lncRNAs, found to be consistently dysregulated among tumors. It has been observed that these three lncRNAs of interest are interacting with a wide range of genes across different tissues, yet enriching substantially similar biological processes, found to be implicated in cancer progression and proliferation.


title: HDMAX2: A framework for High Dimensional Mediation Analysis with application to maternal smoking, placental DNA methylation and birth outcomes

abstract: Most high dimensional mediation epigenetic studies evaluate each mediator indirect effects independently. These approaches are underpowered to detect multiple mediators and the overall indirect effect remains poorly quantified. We developed HDMAX2, an efficient algorithm for high dimensional mediation analysis using max-squared tests, considering CpGs and aggregated mediator regions. HDMAX2 outperformed existing approaches in simulated and real data, detected true mediators with increased power, and assessed the overall indirect effect of several mediators from a high dimension matrix. We showed a polygenic architecture for placenta CpGs and regions mediating the effects of maternal smoking during pregnancy on babys birth weight.


title: Sub-cellular level resolution of common genetic variation in the photoreceptor layer identifies continuum between rare disease and common variation

abstract: Photoreceptor cells (PRCs) are the light-detecting cells of the retina. Such cells can be non-invasively imaged using optical coherence tomography (OCT) which is used in clinical settings to diagnose and monitor ocular diseases. Here we present the largest genome-wide association study of PRC morphology to date utilising quantitative phenotypes extracted from OCT images within the UK Biobank. We discovered 111 loci associated with the thickness of one or more of the PRC layers, many of which had prior associations to ocular phenotypes and pathologies. We further identified 10 genes associated with PRC thickness through gene burden testing using exome data. In both cases there was a significant enrichment for genes involved in rare eye pathologies, in particular retinitis pigmentosa. There was evidence for an interaction effect between common genetic variants, VSX2 involved in eye development and PRPH2 known to be involved in retinal dystrophies. We further identified a number of genetic variants with a differential effect across the macular spatial field. Our results suggest a continuum between normal and rare variation which impacts retinal structure, sometimes leading to disease.


title: Contribution of Mendelian disorders in a population-based pediatric neurodegeneration cohort

abstract:
ObjectivesTo evaluate Mendelian causes of neurodegenerative disorders in a cohort of pediatric patients as pediatric neurodegenerative disorders are a rare, diverse group of diseases. As molecular testing has advanced, many children can be diagnosed, but the relative contribution of various disorders is unclear.

Study DesignPatients enrolled in the Center for Applied Genomics (CAG) Biobank at the Childrens Hospital of Philadelphia with neurodegenerative symptoms were identified using an algorithm that consisted of including and excluding selected ICD9 and ICD10 codes. A manual chart review was then performed to abstract detailed clinical information.

ResultsOut of approximately 100,000 patients enrolled in the CAG Biobank, 76 had a neurodegenerative phenotype. Following chart review, 7 patients were excluded. Of the remaining 69 patients, 42 had a genetic diagnosis (60.9%) and 27 were undiagnosed (39.1%). There were 32 unique disorders. Common diagnoses included Rett syndrome, mitochondrial disorders and neuronal ceroid lipofuscinoses.

ConclusionsThe disorders encountered in our cohort demonstrate the diverse diseases and pathophysiology that contribute to pediatric neurodegeneration. Establishing a diagnosis often informed clinical management, although curative treatment options are lacking. Many patients who underwent genetic evaluation remained undiagnosed, highlighting the importance of continued research efforts in this field.


title: Plasma alkaline phosphatase is associated to mortality risk in aortic valve stenosis patients.

abstract:
Backgroundaortic valve stenosis is an important clinical condition, with a significant mortality rate in the elderly. Plasma values of alkaline phosphatase (ALP) have been shown to act as a marker of prognosis in different clinical conditions and in the general population.

MethodsPlasma levels of alkaline phosphatase were studied in a cohort of patients with aortic valve stenosis, and a five-year survival evaluation was carried out.

Results24 patients were under study, of which 12 were dead at 5-year follow-up. The median age at baseline evaluation was 79 years (interquartile range, 72-85 years), and 11 patients were of the female sex (13 were male). The median value of ALP, of 83 IU/L, was used to separate patients into two groups; 2 patients died in the group with low ALP values versus 10 patients who died in the group with high ALP values. Using ALP with the same cut-off level, Kaplan Meyer study with log-rank analysis showed a significance level <0.01. Cox regression analysis showed an overall significant result, with a significant level for plasma ALP (significance level 0.03), but not for age, sex or transvalvular gradient (assessed by echocardiography).

ConclusionsElevated plasma ALP is associated to increased mortality risk in aortic valve stenosis patients. This finding may merit evaluation in studies with a larger number of patients.


title: IgG N-glycans are associated with prevalent and incident complications of type 2 diabetes

abstract:
Aims/hypothesisInflammation is important in development of type 2 diabetes complications. The N-glycosylation of IgG influences its role in inflammation. Until now, the association of IgG N-glycosylation with type 2 diabetes complications has not been extensively investigated. We hypothesized that N-glycosylation of IgG may be related to development of complications of type 2 diabetes.

MethodsIn three independent type 2 diabetes cohorts, IgG N-glycosylation was measured by UPLC (DiaGene n=1815, GenodiabMar n=640) and mass spectrometry (DCS n=1266). We investigated the associations of IgG N-glycosylation (fucosylation, galactosylation, sialylation and bisection) with incident and prevalent nephropathy, retinopathy and macrovascular disease using Cox- and logistic regression, followed by meta-analyses. The models were adjusted for age, sex and additionally for clinical risk factors.

ResultsIgG galactosylation was negatively associated with prevalent and incident nephropathy after adjustment for clinical risk factors. Sialylation was negatively associated with incident diabetic nephropathy. For retinopathy, similar associations were found for galactosylation in the basic model. For macrovascular complications, negative associations with galactosylation and sialylation were confined to the cross-sectional analyses.

ConclusionsWe showed that IgG N-glycosylation traits are associated with higher prevalence and future development of nephropathy, after correction for clinical risk factors. For other complications, IgG N-glycosylation was associated with their prevalence only, possibly reflecting ongoing vascular inflammation. These findings indicate the predictive potential of IgG N-glycosylation in nephropathy.


title: SARS-CoV-2 infection during the Omicron surge among patients receiving dialysis: the role of circulating receptor-binding domain antibodies and vaccine doses

abstract:
BackgroundIt is unclear whether a third dose of mRNA platform vaccines, or antibody response to prior infection or vaccination confer protection from the Omicron variant among patients receiving dialysis.

MethodsMonthly since February 2021, we tested plasma from 4,697 patients receiving dialysis for antibodies to the receptor-binding domain (RBD) of SARS-CoV-2. We assessed semiquantitative median IgG index values over time among patients vaccinated with at least one dose of the two mRNA vaccines. We ascertained documented COVID-19 diagnoses after December 25, 2021 and up to January 31, 2022. We estimated the relative risk for documented SARS-CoV-2 infection by vaccination status using a log-binomial model accounting for age, sex, and prior clinical COVID-19. Among patients with RBD IgG index value available during December 1-December 24, 2021, we also evaluated the association between the circulating RBD IgG titer and risk for Omicron variant SARS-CoV-2 infection.

ResultsOf the 4,697 patients we followed with monthly RBD assays, 3576 are included in the main analysis cohort; among these, 852 (24%) were unvaccinated. Antibody response to third doses was robust (median peak index IgG value at assay limit of 150, equivalent to 3270 binding antibody units/mL). Between December 25-January 31, 2022, SARS-CoV-2 infection was documented 340 patients (7%), 115 (36%) of whom were hospitalized. The final doses of vaccines were given a median of 272 (25th, 75th percentile, 245-303) days and 58 (25th, 75th percentile, 51-95) days prior to infection for the 1-2 dose and 3 dose vaccine groups respectively. Relative risks for infection were higher among patients without vaccination (RR 2.1 [95%CI 1.6, 2.8]), and patients with 1-2 doses (RR 1.3 [95%CI 1.0, 1.8]), compared with patients with three doses of the mRNA vaccines. Relative risks for infection were higher among patients with RBD index values < 23 (506 BAU/mL), compared with RBD index value [≥] 23 (RR 2.4 [95%CI 1.9, 3.0]). The higher risk for infection among patients with RBD index values < 23 was present among patients who received three doses (RR 2.1 [95%CI 1.3, 3.4]).

ConclusionsAmong patients receiving hemodialysis, patients unvaccinated, without a third mRNA vaccine dose, or those lacking robust circulating antibody response are at higher risk for Omicron variant infection. Low circulating antibodies could identify the subgroup needing intensified surveillance, prophylaxis or treatment in this patient population.


title: Community-level characteristics of COVID-19 vaccine hesitancy in England: A nationwide cross-sectional study

abstract: One year after the start of the COVID-19 vaccination programme in England, more than 43 million people older than 12 years old had received at least a first dose. Nevertheless, geographical differences persist, and vaccine hesitancy is still a major public health concern; understanding its determinants is crucial to managing the COVID-19 pandemic and preparing for future ones. In this cross-sectional population-based study we used cumulative data on the first dose of vaccine received by 01-01-2022 at Middle Super Output Area level in England. We used Bayesian hierarchical spatial models and investigated if the geographical differences in vaccination uptake can be explained by a range of community-level characteristics covering socio-demographics, political view, COVID-19 health risk awareness and targeting of high risk groups and accessibility. Deprivation is the covariate most strongly associated with vaccine uptake (Odds Ratio 0.55, 95%CI 0.54-0.57; most versus least deprived areas). The most ethnically diverse areas have a 38% (95%CI 36-40%) lower odds of vaccine uptake compared with those least diverse. Areas with the highest proportion of population between 12 and 24 years old had lower odds of vaccination (0.87, 95%CI 0.85-0.89). Finally increase in vaccine accessibility is associated with higher COVID-19 uptake (OR 1.07, 95%CI 1.03-1.12). Our results suggest that one year after the start of the vaccination programme, there is still evidence of inequalities in uptake, affecting particularly minorities and marginalised groups. Strategies including prioritising active outreach across communities and removing practical barriers and factors that make vaccines less accessible are needed to level up the differences.