title: Molecular typing of breast cancer in Northern Henan Province

abstract:
ObjectiveInvestigating and analyzing the clinical features of breast cancer patients in Northern Henan Province, measuring expression of biomarkers (ER, PR, HER2 and Ki-67) and classified the molecular typing of breast cancer patients, to understand the molecular typing distribution and correlation between biomarkers of breast cancer patients in North Henan Province, which may provide the information for the local oncologist to make sound treatment plans.

MethodsWe collected the clinical data of breast cancer patients in Xinxiang Central Hospital from 2016 to 2021, those data was classified by gender and pathological types of breast cancer patients; and we also measured and analyzed the expression of breast cancer related biomarkers (ER, PR, HER2 and Ki-67) by immunohistochemistry, and based on expression of these biomarkers, the molecular typing of breast cancer were also classified.

Results3210 cases breast cancer patients were collected in this study; there were 3205 female patients and 5 male patients, accounting for 99.84% and 0.16% in total breast cancer patients, respectively. Classification according to pathological conditions of breast cancer patients, there were 2761 cases patients with invasive ductal carcinoma, accounting for 86.01% in total breast cancer patients, and then mucinous adenocarcinoma (109/3210, 3.40%), lobular carcinoma (106/3210, 3.30%), ductal carcinoma in situ (75/3210, 2.34%), papillary carcinoma (61/3210, 1.90%), intraductal carcinoma (40/3210, 1.25%), myeloid carcinoma (27/3210, 0.84%); There were also including some rare breast cancer types including cribriform carcinoma (6/3210, 0.19%), lymph node metastasis (7/3210, 0.22%), occult breast carcinoma (5/3210, 0.14%), invasive carcinoma (5/3210, 0.14%), squamous cell carcinoma (3/3210, 0.09%), fibroadenoma (3/3210, 0.09%), pleomorphic carcinoma (2/3210, 0.06%). Classification according to molecular typing of breast cancer, the number of breast cancer patients with Luminal A type [ER(+)/PR(+) HER2(-)Ki67<14%] were 207 cases, accounting for 6.45% in total breast cancer patients, the number of breast cancer patients with Luminal B type I [ER(+)/PR(+) HER2(-)] were 243 cases, accounting for 7.57% in total breast cancer patients, the number of breast cancer patients with Luminal B type II [(ER(+)/PR(+)HER2(+) any Ki67] was 254 cases, accounting for 7.91% in total breast cancer patients, and the number of Triple-negative breast cancer (TNBC) were 390 cases, accounting for 12.15% in total breast cancer patients.

The average expression rate of Ki-67 in ER (+) and/or PR (+) breast cancer patients was 20.39+27.33%, while the average expression rate of Ki-67 in ER(-)/PR(-) breast cancer patients was 36.35%+30.14%, and the difference between two patients was significant (p=0.0021); the average expression rate of Ki-67 in HER2 positive breast cancer patients was 23.01%+21.96%, the average expression rate of Ki-67 in HER2 negative breast cancer patients was 29.44%+24.16%, and there was no significant difference between the two groups (P=0.2589).

The main treatment methods of breast cancer patients in Northern Henan Province were antitumor drugs and chemotherapy, the results showed that 87.29% patients were treated by chemotherapy; and high frequency anti-tumor drugs used for breast cancer treatment were Epirubicin (1527/3210, 47.57%), Cyclophosphamide (1172/3210, 36.51%),Paclitaxel (1141/3210,35.55%), Tamoxifen (912/3210, 28.41%).

ConclusionsThe main pathological type of breast cancer are invasive ductal carcinoma, and the main treatment methods of breast cancer patients in Northern Henan Province were antitumor drugs and chemotherapy. In the four kinds of molecular typing of breast cancer, the incidence rate of TNBC is highest compared with Luminal B type II[(ER(+)/PR(+)HER2(+) any Ki67], Luminal B type I [ER(+)/PR(+)HER2(-)] and Luminal A type [ER(+)/PR(+) HER2(-) Ki67<14%]; these results may provide some suggestions for the local oncologist.

category: oncology


title: The effect of sample medication use on subsequent anti-VEGF agent selection for neovascular age-related macular degeneration

abstract:
PurposeTo examine the effect of medication sample use (ranibizumab or aflibercept) on future anti-vascular endothelial growth factor (VEGF) agent selection in neovascular age-related macular degeneration (nvAMD).

DesignRetrospective cohort study.

MethodsnvAMD patients who underwent an initial anti-VEGF injection with a sample medication were compared to nvAMD control patients who never received a medication sample. Charts from 2017 through 2020 were reviewed for data regarding demographics, anti-VEGF agent selection, and visual acuity outcomes for both groups. Anti-VEGF agent selection for the first four injections and at one year were examined in both the sample and control groups.

ResultsAdherence to the initial agent was high between first and subsequent injections (2nd, 3rd, 4th injection, and 1 year) in both sample (96.2%, 95.9%, 91.9%, 93.4%, respectively) and control groups (98.1%, 94.2%, 94.9%, 87.8%, respectively). Bevacizumab usage was significantly lower among eyes receiving samples relative to controls at the second (1.9% vs. 38.7%, p<0.001), third (3.1% vs. 41.3%, p<0.001), fourth injections (4.7% vs. 40.4%, p<0.001), and at 1 year (0% vs. 33.8%, p<0.001). Aflibercept usage was significantly higher in sample eyes relative to controls at the second (78.3% vs. 43.4%, p<0.001), third (76.3% vs. 41.5%, p<0.001), and fourth injections (76.7% vs. 43.4%, p<0.001), and at 1 year (77.0% vs. 52.7%, p<0.001).

ConclusionsEyes receiving a sample anti-VEGF agent (ranibizumab or aflibercept) for their initial injection were less likely to receive bevacizumab at future visits relative to eyes that did not receive an anti-VEGF sample, even after one year of treatment.

category: ophthalmology


title: A highly sensitive and specific SARS-CoV-2 spike- and nucleoprotein-based fluorescent multiplex immunoassay (FMIA) to measure IgG, IgA and IgM class antibodies

abstract:
BackgroundValidation and standardization of accurate serological assays are crucial for the surveillance of the coronavirus disease 2019 (COVID-19) pandemic and population immunity.

MethodsWe describe the analytical and clinical performance of an in-house fluorescent multiplex immunoassay (FMIA) for simultaneous quantification of antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein and spike glycoprotein. Furthermore, we calibrated IgG-FMIA against World Health Organisation (WHO) International Standard and compared FMIA results to an in-house enzyme immunoassay (EIA) and a microneutralisation test (MNT). We also compared the MNT results of two laboratories.

ResultsIgG-FMIA displayed 100% specificity and sensitivity for samples collected 13-150 days post-onset of symptoms (DPO). For IgA- and IgM-FMIA 100% specificity and sensitivity were obtained for a shorter time window (13-36 and 13-28 DPO for IgA- and IgM-FMIA, respectively). FMIA and EIA results displayed moderate to strong correlation, but FMIA was overall more specific and sensitive. IgG-FMIA identified 100% of samples with neutralising antibodies (NAbs). Anti-spike IgG concentrations correlated strongly ({rho}=0.77-0.84, P<2.2x10-16) with NAb titers. The NAb titers of the two laboratories displayed a very strong correlation ({rho}=0.95, P<2.2x10-16).

DiscussionOur results indicate good correlation and concordance of antibody concentrations measured with different types of in-house SARS-CoV-2 antibody assays. Calibration against WHO international standard did not, however, improve the comparability of FMIA and EIA results.

category: infectious diseases


title: Effect of vaccination and of prior infection on infectiousness of vaccine breakthrough infections and reinfections

abstract: SARS-CoV-2 breakthrough infections in vaccinated individuals and in those who had a prior infection have been observed globally, but the transmission potential of these infections is unknown. The RT-qPCR cycle threshold (Ct) value is inversely correlated with viral load and culturable virus. Here, we investigated differences in RT-qPCR Ct values across Qatars national cohorts of primary infections, reinfections, BNT162b2 (Pfizer-BioNTech) breakthrough infections, and mRNA-1273 (Moderna) breakthrough infections. Through matched-cohort analyses of the randomly diagnosed infections, the mean Ct value was higher in all cohorts of breakthrough infections compared to the cohort of primary infections in unvaccinated individuals. The Ct value was 1.3 (95% CI: 0.9-1.8) cycles higher for BNT162b2 breakthrough infections, 3.2 (95% CI: 1.8-4.5) cycles higher for mRNA-1273 breakthrough infections, and 4.0 (95% CI: 3.4-4.6) cycles higher for reinfections in unvaccinated individuals. Assuming a linear relationship between viral load and infectiousness, these differences imply that breakthrough infections are at least 50% less infectious than primary infections in unvaccinated individuals. Public health benefits of vaccination may have been underestimated, as COVID-19 vaccines not only protect against acquisition of infection, but also appear to protect against transmission of infection.

category: epidemiology


title: Viral loads observed under competing strain dynamics

abstract: A plausible mechanism for the increased transmissibility of SARS-CoV-2 variants of concern (VOCs) results from VOC infections causing higher viral loads in infected hosts. However, investigating this hypothesis using routine RT-qPCR testing data is challenging because the population-distribution of viral loads changes depending on the epidemic growth rate; lower cycle threshold (Ct) values for a VOC lineage may simply reflect increasing incidence relative to preexisting lineages. To understand the extent to which viral loads observed under routine surveillance systems reflect viral kinetics or population dynamics, we used a mathematical model of competing strain dynamics and simulated Ct values for variants with different viral kinetics. We found that comparisons of Ct values obtained under random cross-sectional surveillance were highly biased unless samples were obtained at times when the variants had comparable growth rates. Conversely, comparing Ct values from symptom-based testing was largely unaffected by epidemic dynamics, and accounting for the time between symptom onset and sample collection date further reduced the risk of statistical errors. Finally, we show how a single cross-sectional sample of Ct values can be used to jointly estimate differences in viral kinetics and epidemic growth rates between variants. Epidemic dynamics should be accounted for when investigating strain-specific viral kinetics using virologic surveillance data, and findings should be corroborated with longitudinal viral kinetics studies.


title: Changes in household food security, access to health services, and income in northern Lao PDR during the COVID-19 pandemic

abstract:
BackgroundThe COVID-19 pandemic is expected to exacerbate food insecurity in low- and middle-income countries, through loss of income and disrupted food supply chains. Lao PDR has among the highest rates of malnutrition in Southeast Asia. We assessed the relative difficulty in meeting food needs during the COVID-19 pandemic in rural districts of Luang Prabang Province, Lao PDR compared to before; determined associations between pandemic-associated difficulties in food access and household, maternal and child food security; and identified resiliency-promoting strategies.

MethodsIn November 2020, households (N = 1,122) with children under five years were interviewed. Respondents reported the relative ease of access of food and health care as well as changes in income and expenditures compared to before March 2020. We used generalized linear models with cluster robust standard errors to assess univariate and multivariate associations.

ResultsNearly four-fifths (78.5%) found it harder to meet household food needs during the pandemic. The most common reasons were increased food prices (51.2%), loss of income (45.3%), and decreased food availability (36.6%). Adjusting for demographics, households with increased difficulty meeting food needs had lower food consumption scores and child dietary diversity. Over 85% of households lost income during the pandemic. Decreased expenditures was associated with reliance on more extreme coping strategies to meet food needs. The households who experienced no change in meeting food needs produced a greater percentage of their food from homegrown methods (4.22% more, 95% CI: 1.28, 7.15), than households who found it more difficult. We estimated that decreases in child bodyweight by 0.5 - 1% would increase wasting in this population by 1.7 - 2.1 percentage points.

ConclusionsPandemic-associated shocks may have large effects on malnutrition prevalence. Action is needed to mitigate consequences of the pandemic on nutrition. Local food production and safety net programs that offset income losses may help.

Summary BoxO_ST_ABSWhat is already known?C_ST_ABSThe COVID-19 pandemic has disrupted food supply chains and livelihoods, causing concerns that a global nutrition crisis is imminent and prompting leaders from United Nations agencies to issue an immediate call to action to direct funds towards prevention of child malnutrition. While documented COVID-19 transmission in Lao PDR was lower than that of surrounding counties, malnutrition rates are high, particularly in the northern province of Luang Prabang, which is heavily reliant on tourism for livelihoods.

What are the new findings?Nearly four-fifths of those interviewed in Luang Prabang Province, Lao PDR reported that it was harder to meet their households food needs, compared to before the pandemic, with 51% attributing the reason to increased food prices. Over 85% of households reported losing income. Lower expenditures and increased difficulty obtaining food were both associated with lower household food consumption scores and higher household coping strategies, in adjusted analyses. Households who obtained a greater proportion of their foods through home production appeared more resilient than households who obtained a greater proportion of their foods through purchasing.

What do the new findings imply?The pandemic may deeply exacerbate food insecurity in Lao PDR, potentially leading to increases in child wasting. Increased local food production and establishment of safety net programs that offset income losses may be two strategies that address this problem among this population.


title: An investigation of spatial-temporal patterns and predictions of the COVID-19 pandemic in Colombia, 2020-2021

abstract:
Colombia announced the first case of severe acute respiratory syndrome coronavirus 2 on March 6, 2020. Since then, the country has reported a total of 4,240,982 cases and 106,544 deaths as of June 30, 2021. This motivates an investigation of the SARS-CoV-2 transmission dynamics at the national and regional level using case incidence data. Mathematical models are employed to estimate the transmission potential and perform short-term forecasts of the COVID-19 epidemic trajectory in Colombia. Furthermore, geographic heterogeneity of COVID-19 in Colombia is examined along with the analysis of mobility and social media trends, showing that the increase in mobility in July 2020 and January 2021 were correlated with surges in case incidence. The estimation of national and regional reproduction numbers shows sustained disease transmission during the early phase of the pandemic, exhibiting sub-exponential growth dynamics. Moreover, most recent estimates of reproduction number are >1.0 at the national and regional levels as of May 30, 2021. Further, the 30-day ahead short-term forecasts obtained from Richards model present a sustained decline in case counts in contrast to the sub-epidemic and GLM model. Nevertheless, our spatial analysis in Colombia shows distinct variations in incidence rate patterns across different departments that can be grouped into four distinct clusters. Lastly, the correlation of social media trends and adherence to social distancing measures is observed by the fact that a spike in the number of tweets indicating the stay-at-home orders was observed in November 2020 when the case incidence had already plateaued.

Author summaryAs the COVID-19 pandemic continues to spread across Colombia, studies highlighting the intensity of the pandemic become imperative for appropriate resource allocation and informing public health policies. In this study we utilize mathematical models to infer the transmission dynamics of SARS-CoV-2 at the regional and national level as well as short-term forecast the COVID-19 epidemic trajectory. Moreover, we examine the geographic heterogeneity of the COVID-19 case incidence in Colombia along with the analysis of mobility and social media trends in relation to the observed COVID-19 case incidence in the country. The estimates of reproduction numbers at the national and regional level show sustained disease transmission as of May 30, 2021. Moreover, the 30-day ahead short-term forecasts for the most recent time-period (June 1-June 30, 2021) generated from the mathematical models needs to be interpreted with caution as the Richards model point towards a sustained decline in case incidence contrary to the GLM and sub-epidemic wave model. Nevertheless, the spatial analysis in Colombia shows distinct variations in incidence rate patterns across different departments that can be grouped into four distinct clusters. Lastly, the social media and mobility trends explain the occurrence of case resurgences over the time.


title: Genomic epidemiology of SARS-CoV-2 divulge B.1, B.1.36, and B.1.1.7 as the most dominant lineages in first, second, and third wave of SARS-CoV-2 infections in Pakistan

abstract: The present study aims to investigate the genomic variability and epidemiology of SARS-CoV-2 in Pakistan along with their role in the spread and severity of infection during the three waves of COVID-19. A total of 453 genomic sequences of Pakistani SARS-CoV-2 were retrieved from GISAID and subjected to MAFFT-based alignment and QC check which resulted in removal of 53 samples. The remaining 400 samples were subjected to Pangolin-based genomic lineage identification. And to infer our SARS-CoV-2 time-scaled and divergence phylogenetic trees, 3,804 selected global reference sequences plus 400 Pakistani samples were used for the Nextstrain analysis with Wuhan/Hu-1/2019, as reference genome. Finally, maximum likelihood based phylogenetic tree was built by using the Nextstrain & coverage map was created by employing Nextclade. And by using the amino acid subsitutions the maximum likelihood phylogenetic trees were developed for each wave, separately. Our results reveal the circulation of 29 lineages, belonging to following 7 clades G, GH, GR, GRY, L, O, & S in the three waves. From first wave, 16 genomic lineages of SARS-CoV-2 were identified with B.1(24.7%), B.1.36(18.8%), & B.1.471(18.8%) as the most prevalent lineages respectively. The second wave data showed 18 lineages, 10 of which were overlapping with the first wave suggesting that those variants could not be contained during the first wave. In this wave, a new lineage, AE.4, was reported from Pakistan for the very first time in the world. However, B.1.36 (17.8%), B.1.36.31 (11.9%), B.1.1.7 (8.5%) & B.1.1.1 (5.9%) were the major lineages in second wave. Third wave data showed the presence of 9 lineages with Alpha/B.1.1.7 (72.7%), Beta/B.1.351 (12.99%), & Delta/B.1.617.2 (10.39%) as the most predominant variants. It is suggested that these VOCs should be contained at the earliest in order to prevent any devastating outbreak of SARS-CoV-2 in the country.


title: Higher polygenic scores for empathy increase posttraumatic stress severity in response to certain traumatic events

abstract:
BackgroundPosttraumatic stress disorder (PTSD) is triggered by environmental stressors. Empathy may predispose an individual to respond to life events differently if high empathizers are emotionally more sensitive to trauma. For the first time, we test this hypothesis at the genetic level.

MethodsWe applied polygenic scoring (PGS) to investigate the shared genetics linking empathy (measured using the Empathy Quotient (EQ), a self-report measure of empathy; N=46,861) and PTSD symptom severity (measured using the 6-item PTSD Checklist 6-item (PCL-6)) in the UK Biobank (N=126,219). Follow-up analyses were performed in the context of (1) experiencing any of 16 potential traumas, (2) the total number of traumas endorsed, and (3) the context of trauma. Autism, depression, generalized anxiety, and PCL-17 PGS were included as covariates to verify the specificity of the effect.

ResultsEQPGS associated with PCL-6 (R2=0.012%, P=9.35x10-5). This effect remained significant after accounting for autism, depression, PTSD, and anxiety PGS but was observed only in those who endorsed experiencing at least one traumatic event. EQPGS showed the strongest effect on PCL-6 ({beta}=2.32, s.e.=0.762, P=0.002) among those who endorsed childhood neglect/abuse (felt hated as a child). In the highest EQPGS decile, feeling hated as a child was associated with lower odds of healthy adulthood interpersonal relationships (OR=0.623, 95%CI 0.443-0.885) but this association was not seen in the lowest EQPGS decile.

ConclusionsA genetic predisposition to higher empathy, which may index greater emotional sensitivity, predisposes an individual to more severe PTSD symptoms, specifically in the presence of early negative life events.

category: psychiatry and clinical psychology


title: Resting State Functional Connectivity Alterations in Individuals with Autism Spectrum Disorders: A Systematic Review

abstract: Many studies investigate the alterations in resting state functional connectivity in autism. Most of these studies focus on different regions of the brain to find the connectivity differences between autism spectrum disorder and typically developing populations. The present review quantitatively extracts this data from all the seed based studies on autism spectrum disorder and uses it to build, for the first time, an Autism Altered Functional Connectome (AAFC) which summarizes the alterations in functional connectivity consistently reported in the literature. The data extracted from all the studies matching the inclusion criteria are presented at one place in human as well as a machine-readable format for further interpretation and analysis. Systematically reviewing 41 publications on 2818 subjects comprising 1459 typically developing and 1359 subjects with autism spectrum disorder, a total of 932 altered functional connectivity links were employed to construct an AAFC. The AAL atlas mapping of these links resulted in 71 replicated links of which 49 were consistent, and 574 unreplicated links that were reported just once. Out of 49, 38 were replicated across different non overlapping datasets. Majority of the studies analyzed the functional connectivity of the Default Mode Network (DMN) and its regions. Two important DMN regions, namely precuneus and posterior cingulate cortex were reported to exhibit different connectivity profiles with former majorly underconnected and later majorly overconnected consistently reported across multiple studies. After mapping the AAFLs to an atlas of brain networks, poor integration within DMN regions, and poor segregation of DMN regions with extra-DMN regions was observed.


title: Association between COVID-19 infection rates by region and implementation of non-pharmaceutical interventions: A cross-sectional study in Japan

abstract:
BackgroundDuring a pandemic, non-pharmaceutical interventions (NPIs) play an important role in protecting oneself from infection and preventing the spread of infection to others. There are large regional differences in COVID-19 infection rates in Japan. We hypothesized that the local infection incidence may affect adherence to individual NPIs.

MethodsThis cross-sectional study was conducted online among full-time workers in Japan in December 2020. Data from a total of 27,036 participants were analyzed. The questionnaire asked the respondents to identify their habits regarding seven well-known NPIs.

ResultsCompared to the region with the lowest infection rate, the odds ratios for the region with the highest infection rate were 1.24 (p<0.001) for wearing a mask in public, 1.08 (p=0.157) for washing hands after using the bathroom, 1.17 (p=0.031) for disinfecting hands with alcohol sanitizers when entering indoors, 1.54 (p<0.001) for gargling when returning home, 1.45 (p<0.001) for ventilating the room, 1.33 (p<0.001) for disinfecting or washing hands after touching frequently touched surfaces, and 1.32 (p<0.001) for carrying alcohol sanitizers when outdoors. Five of the seven NPIs showed statistically significant trends across regional infection levels, the two exceptions being wearing a mask in public and washing hands after using the bathroom. Multivariate adjustment did not change these trends.

ConclusionsThis study found that NPIs were more prevalent in regions with higher incidence rates of COVID-19 in Japanese workers. The findings suggest that the implementation of NPIs was influenced not only by personal attributes but also by contextual effects of the local infection level.

category: public and global health


title: Interventional Neurorehabilitation for Promoting Functional Recovery Post-Craniotomy: A Proof-of-Concept

abstract:
PurposeThe human brain is a highly plastic  complex network -it is highly resilient to damage and capable of self-reorganisation after a large perturbation. Clinically, neurological deficits secondary to iatrogenic injury have very few active treatments. New imaging and stimulation technologies, though, offer promising therapeutic avenues to accelerate post-operative recovery trajectories. In this study, we sought to establish the safety profile for  interventional neurorehabilitation: connectome-based therapeutic brain stimulation to drive cortical reorganisation and promote functional recovery post-craniotomy.

MethodsIn n=34 glioma patients who experienced post-operative motor or language deficits, we used connectomics to construct single-subject cortical networks. Based on their clinical and connectivity deficit, patients underwent network-specific Transcranial Magnetic Stimulation (TMS) sessions daily over five consecutive days. Patients were then assessed for TMS-related side effects and improvements.

Results31/34 (91%) patients were successfully recruited and enrolled for TMS treatment within two weeks of glioma surgery. No seizures or serious complications occurred during TMS rehabilitation and one-week post-stimulation. Transient headaches were reported in 4/31 patients but improved after a single session. No neurological worsening was observed while a benefit was noted in 28/31 patients post-TMS. We present two clinical vignettes and a video demonstration of interventional neurorehabilitation.

ConclusionsFor the first time, we demonstrate the safety profile and ability to recruit, enrol, and complete TMS acutely post-craniotomy in a high seizure risk population. Given the lack of randomisation and controls in this study, prospective randomised sham-controlled stimulation trials are now warranted to establish the efficacy of interventional neurorehabilitation following craniotomy.

category: rehabilitation medicine and physical therapy


title: Metal concentrations in breastmilk of Fuzhou nursing mothers associates with dietary and lifestyle factors

abstract:
Metal intake greatly influences physiological development during infancy. For infants, breastmilk is the major route of metal exposure. The metal status of their nursing mothers is affected by lifestyle and nutritional factors. However, the relationship between these factors and breastmilk metal concentration is largely unknown.

The present study provided food frequency questionnaires to be completed by 113 nursing mothers from Fujian Provincial Hospital. Their breastmilk samples were analysed for the metal concentrations using inductively coupled plasma mass spectrometery (ICP-MS). Based on the outcome of the questionnaires and ICP-MS results, a total of 94 samples were deemed valid for further data analyses.

Results showed levels of breastmilk lead (Pb) and iron (Fe) were outside the reference range from authoritative data. Correlation analyses found Pb levels to negatively associate with dietary fibre intake. Additionally, Fe levels were negatively associated with alcohol and dairy consumption. In terms of Zn levels, it was positively associated with tea and vitamin B1 intake. Zn was also negatively associated with seafood consumption.

The study concluded dietary factors to associate with metal levels within breastmilk. Recommendations were made to increase consumption of dietary fibre, tea and foods rich in vitamin B1 for gestational and postpartum women. Conversely, alcohol consumption continues to be discouraged for this population. Furthermore, careful considerations need to be taken for levels of dairy and seafood intake to minimize metal metabolism disruptions. Infant metal exposure requires critical attention and this needs to be initiated through the diet and lifestyle of their nursing mothers.

category: nutrition


title: HPV 51: A candidate for type-replacement following vaccination?

abstract:
BackgroundHuman papilloma virus (HPV) infection is known to be a necessary cause of cervical cancer and is found in 99.7% of invasive cervical carcinomas. Current HPV vaccines protect against infection from strains 16 and 18. Baseline prevalence studies are important for the measurement of prophylactic vaccine impact and type-replacement monitoring. Between 2009-2010 the HPV research group in collaboration with Cervical Screening Wales conducted the  Base HPV 2009 study to determine baseline prevalence in unvaccinated women aged 20-22 in Wales. Preliminary analysis of results showed that in single HPV infection, 16 was the most prevalent high-risk strain followed by 18 and 51. This high prevalence of HPV 51 has not been observed in previous studies from Wales and is not a common finding elsewhere. This study aims to determine whether the high prevalence of HPV 51 observed in the Base HPV 2009 study is a true finding and if HPV 51 should be considered a candidate for type-replacement post-vaccination.

MethodsThe first 100 single and 100 multiple HPV 51 positive liquid-based cytology (LBC) samples from the Base HPV 2009 study were selected for re-analysis. Each sample underwent DNA extraction and was tested using two methods: 1) Repeat of original methodology using GP5+/6+ HPV 51 PCR-ELISA. 2) HPV 51 E7 PCR. Data were then correlated with age, social deprivation score and cytology. 5 samples were excluded from analysis.

ResultsDirect repeat of HPV 51 PCR-EIA identified 146 of 195 (75.0%) samples as HPV 51 positive. E7 PCR identified 166 of 195 (85.1%) samples as HPV 51 positive. When classified by cytological grade, the prevalence of confirmed HPV 51 increased with grade.

ConclusionsThis study confirms that the prevalence of HPV 51 observed in the Base HPV 2009 study population is truly high and warrants further consideration. There is limited evidence on the cross-protection for 51 offered by the current HPV vaccine and it represents a potential candidate for type-replacement following vaccination. This study highlights the need for further longitudinal investigation into the regional and global prevalence of HPV 51. The data would recommend HPV 51 to be considered in future multivalent vaccines.

category: obstetrics and gynecology


title: Diagnostic performance of a novel digital immunoassay (RapidTesta SARS-CoV-2): a prospective observational study with 1,127 nasopharyngeal samples

abstract:
IntroductionDigital immunoassays are generally regarded as superior tests for the detection of infectious disease pathogens, but there have been insufficient data concerning SARS-CoV-2 immunoassays.

MethodsWe prospectively evaluated a novel digital immunoassay (RapidTesta SARS-CoV-2). Two nasopharyngeal samples were simultaneously collected for antigen tests and RT-PCR. Real-time RT-PCR for SARS-CoV-2, using a method developed by the National Institute of Infectious Diseases, Japan, served as the reference RT-PCR method.

ResultsDuring the study period, 1,127 nasopharyngeal samples (symptomatic patients: 802, asymptomatic patients: 325) were evaluated. For digital immunoassay antigen tests, the sensitivity was 78.3% (95% CI: 67.3%-87.1%) and the specificity was 97.6% (95% CI: 96.5%-98.5%). When technicians visually analyzed the antigen test results, the sensitivity was 71.6% (95% CI: 59.9%-81.5%) and the specificity was 99.2% (95% CI: 98.5%-99.7%). Among symptomatic patients, the sensitivity was 89.4% (95% CI; 76.9%-96.5%) with digital immunoassay antigen tests, and 85.1% (95% CI; 71.7%-93.8%) with visually analyzed the antigen test, respectively.

ConclusionsThe findings indicated that RapidTesta SARS-CoV-2 analysis with the DIA device had sufficient analytical performance for the detection of SARS-CoV-2 in nasopharyngeal samples. When positive DIA results are recorded without a visually recognizable red line at the positive line location on the test cassette, additional RT-PCR evaluation should be performed.


title: Correlates of Neutralizing/SARS-CoV-2-S1-binding Antibody Response with Adverse Effects and Immune Kinetics in BNT162b2-Vaccinated Individuals

abstract:
BackgroundWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the features of immune response remain to be clarified.

MethodsIn the present prospective observational study, 225 healthy individuals in Kumamoto General Hospital, Japan, who received two BNT162b2 doses in February 2021, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions and live target cells) with SARS-CoV-2-S1-binding-IgG and -IgM levels, adverse effects (AEs), ages, and genders were examined. The average half-life of neutralizing activity and the average time length for the loss of detectable neutralizing activity were determined and the potency of serums against variants of concerns was also determined.

FindingsSignificant rise in NT50s was seen in serums on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation was seen between NT50s and AEs. NT50s and IgG levels on day 28 post-1st dose and pain scores following the 2nd shot were greater in women than in men. The average half-life of neutralizing activity in the vaccinees was approximately 67.8 days and the average time length for their serums to lose the detectable neutralizing activity was 198.3 days. While serums from elite-responders (NT50s>1,500-fold: the top 4% among all participants NT50s) potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain.

InterpretationBNT162b2-elicited immune response has no significant association with AEs. BNT162b2-efficacy is likely diminished to under detection limit by 6-7 months post-1st shot. High-level neutralizing antibody-containing serums potently to moderately block the infection of SARS-CoV-2 variants; however, a few moderate-level neutralizing antibody-containing serums failed to do so. If BNT162b2-elicited immunity memory is short, an additional vaccine or other protective measures would be needed.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the salient features of immune response including the persistence of protection remain to be clarified. There is a report that anti-SARS-CoV-2 antibodies persist through 6 months after the second dose of mRNA-1273 vaccine (Doria-Rose et al. N Engl J Med. 2021;384:2259-2261); however, more definite immune kinetics following mRNA-vaccine-elicited protection have to be clarified. The mRNA-vaccine-elicited protection against SARS-CoV-2 variants are also to be determined.

Added value of this studyIn the present prospective study, 225 twice-BNT162b2-dose-receiving individuals in Japan were enrolled. No significant correlation was seen between 50% neutralizing titers (NT50s), determined by using infectious SARS-CoV-2 virions and live target cells, and adverse effects. Largely, NT50s and IgG levels were greater in women than in men. Following 28 days post-2nd shot, significant reduction was seen in NT50s, IgG, and IgM levels. The average half-life of NT50s was [~]68 days and the average time-length for participants serums to lose the detectable activity was [~]198 days. Although serums from elite-responders potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain.

Implications of all the available evidenceBNT162b2 efficacy is likely to be diminished to under detection limit by 6-7 months post-1st shot on average. Individuals with moderate NT50s may fail to block beta variants. If BNT162b2-elicited immune memory is lost soon, additional vaccine(s) or other protective means would be needed.


title: Estimation of the onset rate and the number of asymptomatic patients of COVID-19 from the proportion of untraceable patients

abstract: A simple method is devised to estimate the onset ratio of COVID-19 patients from the proportion of untraceable patients tested positive, which allows us to obtain the number of asymptomatic patients, the number of infectious patients and the effective reproduction number. The recent data in Tokyo indicate that there are about six to ten times as many infectious patients in the city as the daily confirmed new cases. It is shown that, besides social distancing and use of effective masks, a quarantine measure on non-symptomatic patients is critically important in controlling the pandemic.


title: Sex-specific trajectories of molecular cardiometabolic trait concentrations through childhood, adolescence and young adulthood: a cohort study

abstract:
BackgroundCausal risk factors and predictive biomarkers for cardiometabolic diseases are increasingly being identified from comprehensive metabolomic profiling in epidemiological studies. The changes which typically occur in molecular cardiometabolic traits across early life are not well characterised.

MethodsWe quantified sex-specific trajectories of 148 metabolic trait concentrations including various lipoprotein subclasses from age 7y to 25y. Data were from offspring of the Avon Longitudinal Study of Parents and Children birth cohort study. Outcomes included concentrations of 148 traits quantified using nuclear magnetic resonance spectroscopy measured at 7y, 15y, 18y and 25y. Sex-specific trajectories of each trait concentration were modelled using linear spline multilevel models with robust standard errors.

Findings7,065-7,626 participants (11,702-14,797 repeated measures) were included in analyses. Females had higher very-low-density lipoprotein (VLDL) particle concentrations at 7y. VLDL particle concentrations decreased from 7y to 25y with larger decreases in females, leading to lower VLDL particle concentrations at 25y in females. For example, females had 0.25 SD (95% Confidence Interval (CI), 0.20, 0.31) higher very small VLDL particle concentration at 7y; mean levels decreased by 0.06 SDs (95% CI, -0.01, 0.13) in males and 0.85 SDs (95% CI, 0.79, 0.90) in females from 7y to 25y leading to 0.42 SD (95% CI, 0.35, 0.48) lower very small VLDL particle concentrations in females at 25y. Females also had higher low-density lipoprotein (LDL) particle concentrations at 7y; these increased from 7y to 25y in both sexes and increases were larger among males. By age 25y, LDL particle concentrations remained higher in females but the sex difference was smaller than in early childhood. Females had lower high-density lipoprotein (HDL) particle concentrations at 7y. HDL particle concentrations increased from 7y to 25y with larger increases among females leading to higher HDL particle concentrations in females at 25y.

InterpretationChildhood and adolescence are important periods for the emergence of sex differences in atherogenic lipids and predictive biomarkers for cardiometabolic disease, mostly to the detriment of males.

FundingWellcome Trust, Medical Research Council UK, Health Research Board, Ireland

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCausal risk factors and novel predictive biomarkers for cardiometabolic diseases are increasingly being identified from the recent application of comprehensive metabolomic profiling in epidemiological studies but the change which typically occur in these traits across childhood, adolescence and early adulthood is not well u understood.

Added value of this studyIn this prospective cohort study with repeat assessments of 148 molecular cardiometabolic traits from comprehensive metabolomic profiling at age 7y, 15y, 18y and 25y, we demonstrate that marked change in levels of causal risk factors and novel predictive biomarkers for cardiometabolic diseases occur from childhood to early adulthood. In addition, our findings suggest that childhood and adolescence are an important life stage for the development of sex differences in atherogenic lipids and predictive biomarkers for cardiometabolic disease, mostly to the detriment of males.

Implications of all the available evidenceFindings suggest that cardiometabolic disease prevention targeting childhood and adolescence should be prioritised for both lifelong cardiometabolic disease prevention and sex differences in cardiometabolic risk to the disadvantage of males across the life course.


title: Overlapping Time Scales Obscure Early Warning Signals for the Second COVID-19 Wave

abstract: Early warning indicators based on critical slowing down have been suggested as a model-independent and low-cost tool to anticipate the (re)emergence of infectious diseases. We studied whether such indicators could reliably have anticipated the second COVID-19 wave in European countries. Contrary to theoretical predictions, we found that characteristic early warning indicators generally decreased rather than increased prior to the second wave. A model explains this unexpected finding as a result of transient dynamics and the multiple time scales of relaxation during a non-stationary epidemic. Particularly, if an epidemic that seems initially contained after a first wave does not fully settle to its new quasi-equilibrium prior to changing circumstances or conditions that force a second wave, then indicators will show a decreasing rather than an increasing trend as a result of the persistent transient trajectory of the first wave. Our simulations show that this lack of time scale separation was to be expected during the second European epidemic wave of COVID-19. Overall, our results emphasize that the theory of critical slowing down applies only when the external forcing of the system across a critical point is slow relative to the internal system dynamics.


title: Overlapping Time Scales Obscure Early Warning Signals of the Second COVID-19 Wave


title: Can Vaccine Prioritization Reduce Disparities in Covid-19 Burden for Historically Marginalized Populations?

abstract:
1.ImportanceNationally stated goals for distributing SARS-CoV-2 vaccines included to reduce COVID-19 mortality, morbidity, and inequity using prioritization groups. However, the impact of these prioritization strategies is not well understood, particularly their effect on health inequity in COVID-19 burden for historically marginalized racial and ethnic populations.

ObjectiveTo assess the impact of vaccination prioritization and operational strategies on disparities in COVID-19 burden among historically marginalized populations, and on mortality and morbidity by race and ethnicity.

DesignWe use an agent-based simulation model of North Carolina to project SARS-CoV-2 infections and COVID-19-associated deaths (mortality), hospitalizations (morbidity), and cases over 18 months (7/1/2020-12/31/2021) with vaccine distribution beginning 12/13/2020 to frontline medical and people 75+, assuming initial uptake similar to influenza vaccine. We study two-stage subsequent prioritization including essential workers ("essential"), adults 65+ ("age"), adults with high-risk health conditions, HMPs, or people in low income tracts, with eligibility for the general population in the third stage. For age-essential and essential-age strategies, we also simulated maximal uptake (100% for HMP or 100% for everyone), and we allowed for distribution to susceptible-only people.

ResultsPrioritizing Age then Essential had the largest impact on mortality (2.5% reduction from no prioritization); Essential then Age had the lowest morbidity and reduced infections (4.2% further than Age-Essential) without significantly impacting mortality. Under each prioritization scenario, the age-adjusted mortality burden for HMPs is higher (e.g., 33.3-34.1% higher for the Black population, 13.3%-17.0% for the Hispanic population) compared to the White population, and the gap grew under some prioritizations. In the Age-Essential strategy, the burden on HMPs decreases only when uptake is increased to 100% in HMPs. However, the Black population still had the highest mortality rate even with the Susceptible-Only distribution.

Conclusions and RelevanceSimulation results show that prioritization strategies have differential impact on mortality, morbidity, and disparities overall and by race and ethnicity. If prioritization schemes were not paired with increased uptake in HMPs, disparities did not improve and could worsen. Although equity was one of the tenets of vaccine distribution, the vaccination strategies publicly outlined are insufficient to remove and may exacerbate disparities between racial and ethnic groups, thus targeted strategies are needed for the future.

category: health policy


title: Influence of social determinants of health and county vaccination rates on machine learning models to predict COVID-19 case growth in Tennessee

abstract:
The SARS-CoV-2 (COVID-19) pandemic has exposed health disparities throughout the United States, particularly among racial and ethnic minorities. As a result, there is a need for data-driven approaches to pinpoint the unique constellation of clinical and social determinants of health (SDOH) risk factors that give rise to poor patient outcomes following infection in US communities.

We combined county-level COVID-19 testing data, COVID-19 vaccination rates, and SDOH information in Tennessee. Between February-May 2021, we trained machine learning models on a semi-monthly basis using these datasets to predict COVID-19 incidence in Tennessee counties. We then analyzed SDOH data features at each time point to rank the impact of each feature on model performance.

Our results indicate that COVID-19 vaccination rates play a crucial role in determining future COVID-19 disease risk. Beginning in mid-March 2021, higher vaccination rates significantly correlated with lower COVID-19 case growth predictions. Further, as the relative importance of COVID-19 vaccination data features grew, demographic SDOH features such as age, race, and ethnicity decreased while the impact of socioeconomic and environmental factors, including access to healthcare and transportation, increased.

Incorporating a data framework to track the evolving patterns of community-level SDOH risk factors could provide policymakers with additional data resources to improve health equity and resilience to future public health emergencies.

category: health informatics


title: Identification of muscle weakness in older adults from normalized lower and upper limbs strength

abstract:
IntroductionWeakness is a natural age-related condition meaning the loss of muscle strength that impairs older adults mobility and quality of life. Because the relationship between muscle strength and body-size variables is non-linear, weakness is misclassified in older adults with extreme body size (e.g., light, short, heavy, or tall). This misclassification can be overcome using the allometric approach.

ObjectivesTo propose cut-off points for older adults weakness for upper and lower limbs muscle strength normalized by body size with the ratio standard and allometric scaling.

MethodsNinety-four community-dwelling older adults (69.1% women) were assessed for 49 body-size variables (anthropometry, body composition and body indexes), handgrip strength (HGS), one maximum repetition measurement for knee extensors (1RMknee extensors), isokinetic knee extension peak torque at 60{degrees}/s (knee extensionPT60{degrees}/s), and six-minute walk test (6MWT). Ratio standard (muscle strength/body size) and allometric scaling (muscle strength/body sizeb; when b is the allometric exponent) were applied for body-size variables that significantly were correlated with HGS, 1RMknee extensors and knee extensionPT60{degrees}/s. Cut-off points were computed based on ROC curve and Youden index. When there was mobility limitation (6MWT<400m) cut-off were computed according to sex.

ResultsAbsolute HGS, 1RMknee extensors and knee extensionPT60{degrees}/s cut-off points were not adequate because they were associated with body size (r>0.30). But it was corrected with muscle strength normalization according to body size-variables: HGS (n=1); 1RMknee extensors (n=24) and knee extensionPT60{degrees}/s (n=24). The best cut-off points, with the highest area under the curve (AUC), were found after normalization for men: HGS/forearm circumference (1.33 kg/cm, AUC=0.74), 1RMknee extensors/triceps skinfold (4.22 kg/mm, AUC=0.81), and knee extensionPT60{degrees}/s/body mass*height0.43 (13.0 Nm/kg*m0.43, AUC=0.94); and for women: HGS/forearm circumference (1.04 kg/cm, AUC=0.70), 1RMknee extensors/body mass (0.54 kg/kg, AUC=0.76); and knee extensionPT60{degrees}/s/body mass0.72 (3.14 Nm/kg0.72; AUC=0.82).

ConclusionNormalization removes the effect of extreme body size on muscle strength and improves the accuracy to identify weakness at population level, reducing the risk of false-positive cases.

HighlightsO_LIThis study proposed a new approach to identify muscle weakness in older adults based on upper and lower limbs muscle strength normalized by body size (ratio standard and allometry).
C_LIO_LIThe identification of functional limitation is more precise when procedures of muscle strength normalization is applied.
C_LI

category: geriatric medicine


title: Effects of Various Policy Options on COVID-19 Cases in Nova Scotia including Vaccination Rollout Schedule: A Modelling Study

abstract:
BackgroundThe COVID-19 pandemic presents a significant challenge to minimize mortality and hospitalizations due to this disease. Vaccinations have begun to roll-out; however, restriction policies required during and after the rollout remain uncertain. A susceptible-exposed-infected-recovered (SEIR) model was developed for Nova Scotia, and it accounted for the provinces policy interventions, demographics, and vaccine rollout schedule.

MethodsA modified SEIR model was developed to simulate the spread and outcomes from COVID-19 in Nova Scotia under different policy options. The model incorporated the age distribution and co-morbidity of the province. A system dynamics model was developed in Vensim. Several scenarios were run to determine the effects of various policy options and loosening of restrictions during and after the vaccine roll-out period.

ResultsWhen restrictions policy include moderate closure of businesses, restricting travel to Atlantic Canada, and the mandating of masks and physical distancing, the number of cumulative infections after 110 days was less than 120. However, if national travel was opened by July 5 2021 and there were no restrictions by September 2021, the number of active infections will peak at 6,114 by February 16 2022, and there will be a peak of 104 hospitalizations on February 16 2022. Immediate opening of travel and all restrictions on March 15, 2021 will result in 71,731 active infections by June 4 2021.

DiscussionModerate restrictions will be required even after the population is fully vaccinated in order to avoid a large number of infections and hospitalizations because herd immunity is not reached due to children under 12 not being vaccinated, the efficacy of the vaccine, and the portion of the population that will choose not to be vaccinated.


title: Transmission of SARS-CoV-2 from pre and asymptomatic infected individuals. A systematic review

abstract:
BackgroundThe transmission role of SARS-Cov-2 infected persons who develop symptoms post testing (pre symptomatics) or not at all throughout the course of positivity (asymptomatics) is unknown. We carried out a systematic review of available evidence to determine whether they were infectious or not and if so for how long and their probable contribution to the pandemic spread of SARS-CoV-2.

MethodsWe searched LitCovid, medRxiv, Google Scholar and the WHO Covid-19 databases and reference lists of included studies. Search terms were COVID-19, SARS-CoV-2, transmission, asymptomatic, presymptomatic and appropriate synonyms. Searches were carried out to 31 March 2021. We included studies on people exposed to SARS CoV-2 within 2-14 days (incubation time) of close contact or suspected community or institutional exposure to index asymptomatic (at the time of observation) infected individuals, as defined in the study. We included studies with a proven or hypothesised chain of transmission with secondary case infected based on fulfilling a confirmed or probable case definition and confirmation of infectiousness and transmission outcome based either on serial PCR cycle threshold readings or viral culture or gene sequencing or any combination thereof and adequate follow up. We assessed the reliability of eliciting symptom and signs compatible with contemporary knowledge and extracted documentation of the likelihood of transmission, presence of replicating virus and/or documentation of phylodynamics (genetic sequence lineage) and/or adequate follow-up and reporting of symptoms and signs. We wrote to all included studies corresponding authors to request further details and assessed likelihood of transmission using adapted causality criteria.

ResultsWe included 18 studies from a variety of settings. Because of the current lack of standardized methodology and clear reporting criteria there was substantial methodological variation in transmission studies. Asymptomatic prevalence at the time of initial testing varied from 12.5% to 100% and of these 6% to 100% were pre-symptomatic cases, depending on the setting and the methods of case ascertainment and the population. Nursing/care home facilities reported high rates of presymptomatic: 50% - 100% (n=3 studies). Fifteen studies were classified as high risk and three studies at moderate risk of symptom ascertainment bias. In practice, this assessment means that high-risk studies may be less likely to distinguish between pre-symptomatic and asymptomatic cases. Six of the asymptomatic studies and four presymptomatic studies reported growing infectious virus although the data was too sparse to determine duration of infectiousness. Three studies were judged as providing possible and three of probable/likely evidence of asymptomatic transmission of SARs-CoV-2. Five studies provided evidence of possible and two of probable/likely presymptomatic transmission of SARs-CoV-2. Author response rate was 100%.

ConclusionsReliable studies included here provide probable evidence of transmission of SARS-CoV-2 from presymptomatic and asymptomatic individuals. Single point in time estimates and binary PCR testing alone cannot provide reliable information on symptom status and information on infectivity. The number of studies and asymptomatic and presymptomatic cases eligible for inclusion was low, with more data and international standardisation of methods needed to further reduce uncertainty.


title: In situ transcriptional profile of a germinal center plasmablastic burst hints at an unfavorable Diffuse Large B-cell Lymphoma subset.

abstract:
The germinal center (GC) reaction results in the selection of B-cells acquiring effector Ig secreting ability by progressing towards plasmablastic differentiation. This transition is associated with exclusion from the GC microenvironment. The aberrant expansion of plasmablastic elements within the GC fringes configures an atypical condition, the biological characteristics of which have not been defined yet. We investigated the in situ immunophenotypical and transcriptional characteristics of a non-clonal germinotropic expansion of plasmablastic elements (GEx) occurring in the tonsil of a young patient. Compared to neighboring GC and peri-follicular regions, the GEx showed a distinctive signature featuring key regulators of plasmacytic differentiation, cytokine signaling, and cell metabolism. The GEx signature was tested in the setting of diffuse large B-cell lymphoma (DLBCL) as a prototypical model of lymphomagenesis encompassing transformation at different stages of GC and post-GC functional differentiation. The signature outlined DLBCL clusters with different immune microenvironment composition and enrichment in genetic subtypes.

SignificanceThis report represents the first insight into the transcriptional features of a germinotropic plasmablastic burst, shedding light into the molecular hallmarks of B cells undergoing plasmablastic differentiation and aberrant expansion within the non-canonical setting of the GC microenvironment.

category: pathology


title: In situ transcriptional profile of a germinal center plasmablastic burst hints at MYD88/CD79B mutants-enriched Diffuse Large B-cell Lymphomas.


title: Predictors of COVID-19 vaccination uptake and reasons for decline of vaccination: a systematic review

abstract:
BackgroundVarious COVID-19 vaccines with proven safety and effectiveness are available now but vaccine hesitancy remains a public threat. COVID-19 vaccines uptake appears to have an essential role in the successful control of the COVID-19 pandemic.

ObjectiveTo examine predictors of COVID-19 vaccination uptake and reasons for decline of vaccination.

MethodsWe followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines for this systematic review. We searched Medline, PubMed, Web of Science, Scopus, ProQuest, CINAHL, and a pre-print service (medRxiv) from inception to July 12, 2021. We used the following key-words: vaccin*, COVID-19, and uptake. We included all types of studies (quantitative, qualitative, and mixed methods) reporting COVID-19 vaccination uptake. The review protocol was registered with PROSPERO (CRD42021267460).

ResultsTwelve studies met the inclusion and exclusion criteria. COVID-19 vaccination uptake ranged from 28.6% to 98% in the general population, while among healthcare workers ranged from 33.3% to 94.5%, and among patients ranged from 36% to 80%. The main predictors of COVID-19 vaccination uptake were male gender, white race, older age, higher socioeconomic status, higher self-perceived COVID-19 vulnerability, increased information about COVID-19 vaccines, and chronic illness. The most important reasons for decline of vaccination were concerns about the safety and effectiveness of vaccines, illness, medication, pregnancy, fertility, breastfeeding, religious reasons, ethical reasons, previous COVID-19 diagnosis, self-estimation that COVID-19 is not a severe disease, and limited knowledge about the vaccines.

ConclusionsSeveral factors affect COVID-19 vaccination uptake, while various reasons affect peoples decision to refuse to take a COVID-19 vaccine. These findings are essential to further enhance our understanding of COVID-19 vaccination uptake and design specific interventions. Given the high prevalence of COVID-19 vaccine hesitancy, our findings have major implications for the delivery of COVID-19 vaccination programmes in the public with special attention to people who are undecided or unlikely to take a COVID-19 vaccine.


title: All-cause and cause-specific mortality during and following incarceration in Brazil: a retrospective cohort study

abstract:
BackgroundMortality during and after incarceration is poorly understood in low- and middle-income countries. The need to address this knowledge gap is especially urgent in South America, which has the fastest growing prison population in the world. In Brazil, data on mortality during and after incarceration are lacking.

Methods and FindingsWe linked incarceration and mortality databases for the Brazilian state of Mato Grosso do Sul to obtain a cohort of 114,751 individuals with recent incarceration. Between January 1, 2009 and December 31, 2018, we identified 3127 deaths of individuals with recent incarceration (705 in detention; 2422 following release). We analyzed age-standardized, all-cause and cause-specific mortality rates among individuals detained in different facility types and following release, compared to non-incarcerated residents. Deaths in custody were 2.2 times the number reported by the national prison administration (n = 317). Incarcerated men and boys experienced elevated mortality, compared with the non-incarcerated population, due to increased risk of death from violence, suicide, and communicable diseases, with the highest standardized incidence rate ratio (IRR) in semi-open prisons (2.4; 95% CI, 2.0-2.8), police stations (3.1; 95% CI, 2.5-3.9), and youth detention (8.1; 95% CI, 5.9-10.8). Incarcerated women had increased mortality from suicide (IRR = 6.0, 95% CI 1.2-17.7) and communicable diseases (IRR = 2.5, 95% CI 1.1-5.0). We additionally modeled mortality rates over time during and after incarceration from all causes, violence, or suicide. Following release from prison, mortality was markedly elevated for men (IRR=3.0; 95% CI, 2.8-3.1) and women (IRR=2.4; 95% CI, 2.1-2.9). The risk of violent death and suicide was highest immediately post-release and declined over time; however, all-cause mortality remained elevated eight years post-release. The limitations of this study include inability to establish causality, uncertain reliability of data during incarceration, and underestimation of mortality rates due to imperfect database linkage.

ConclusionsIncarcerated individuals in Brazil experienced increased mortality from violence, suicide, and communicable diseases. Mortality was heightened following release for all leading causes of death, with particularly high risk of early violent death and elevated all-cause mortality up to eight years post-release. These disparities may have been under-recognized in Brazil due to underreporting and insufficient data.

Author SummaryO_ST_ABSWhy Was This Study Done?C_ST_ABSO_LIThe global prison population is growing rapidly, particularly in Latin America
C_LIO_LIIncarcerated and formerly incarcerated individuals may be at high risk of death from illness and external causes (i.e. homicide, suicide)
C_LIO_LIMortality during and after incarceration has been described in high-income countries but is poorly understood in low- and middle-income countries, including those in Latin America
C_LIO_LIIn Brazil, deaths during incarceration may be underreported, and there are no data on deaths after incarceration
C_LI

What Did the Researchers Do and Find?O_LIWe retrospectively followed over 114,000 individuals with recent incarceration in a Brazilian state and used database linkage to identify deaths between 2009 and 2018 occurring during or after incarceration
C_LIO_LIWe calculated rates of death from all causes and specific causes among incarcerated and formerly incarcerated individuals, and we compared them to those in the general population
C_LIO_LIWe found elevated mortality from violence, suicide, and communicable diseases during incarceration, which was underreported by national and state sources
C_LIO_LIFollowing release, individuals were at increased risk of mortality from nearly all leading causes of death, with particularly high risk of violent death and suicide among men in the first two years post-release
C_LI

What Do These Findings Mean?O_LIWhile we could not establish causality between incarceration and mortality, many of our findings indicate increased mortality risk associated with exposure to the carceral environment
C_LIO_LIThe exorbitant rates of violent deaths during and after incarceration point to deep-rooted social problems that cannot be solved by incarceration
C_LIO_LIAccurate and comprehensive data on mortality during and after incarceration are needed in Brazil and other low- and middle-income countries where this issue remains poorly understood
C_LIO_LIStructural interventions are needed to reduce the mortality risk in this population, including immediate improvement of conditions and healthcare within carceral facilities, supportive programs and services for the early transition period post-release, and implementation of alternatives to incarceration
C_LI


title: COVID-19 outcomes in hospitalized puerperal, pregnant, and neither pregnant nor puerperal women: a population study

abstract:
ObjectiveTo compare hospitalized reproductive age women with COVID-19 who were pregnant, puerperal, or neither one nor the other in terms of demographic and clinical characteristics and disease progression using Brazilian epidemiological data.

MethodsA retrospective analysis of the records of the Information System of the Epidemiological Surveillance of Influenza of the Health Ministry of Brazil was performed. It included the data of female patients aged 10 to 49 years hospitalized because of severe COVID-19 disease (RT-PCR+ for SARS-CoV-2), from February17, 2020 to January 02, 2021.They were separated into 3 groups: pregnant, puerperal, and neither pregnant nor puerperal. General comparisons and then adjustments for confounding variables (propensity score matching [PSM]) were made, using demographic and clinical characteristics, disease progression (admission to the intensive care unit [ICU] and invasive or noninvasive ventilatory support), and outcome (cure or death). Deaths were analyzed in each group according to comorbidities, invasive or noninvasive ventilatory support, and admission to the ICU.

ResultsAs many as 40,640 reproductive age women hospitalized for COVID-19 were identified: 3,372 were pregnant, 794 were puerperal, and 36,474 were neither pregnant nor puerperal. Groups were significantly different in terms of demographic data and comorbidities. Pregnant and puerperal women were less likely to be symptomatic than the women who were neither one nor the other. Pregnant women, however, had a higher frequency of cough, anosmia, and ageusia. Puerperal women had a worse prognosis than pregnant women with respect to admission to the ICU, invasive ventilatory support, and death.

ConclusionPuerperal women were at a higher risk for serious outcomes (need for the ICU, need for invasive and noninvasive ventilatory support, and death) than pregnant women.


title: Robust image-based risk predictions from the deep learning of lung tumors in motion

abstract:
IntroductionDeep learning (DL) models that use medical images to predict clinical outcomes are poised for clinical translation. For tumors that reside in organs that move, however, the impact of motion (i.e. degenerated object appearance or blur) on DL model accuracy remains unclear. We examine the impact of tumor motion on an image-based DL framework that predicts local failure risk after lung stereotactic body radiotherapy (SBRT).

MethodsAn IRB-approved study (NU00212113) was used to identify patients treated with lung SBRT. Pre-therapy free breathing (FB) CT images from 849 patients were input into a multi-task deep neural network to generate an image fingerprint (or DL score) that predicts time-to-event local failure outcomes. The impact of tumor motion was examined on the DL scores for a hold-out set comprising 228 image series from 19 patients comprising: (1) FB CT, (2) four-dimensional (4D) CT, and (3) maximum-intensity projection (MIP) images.

FindingsVariance in image-derived DL scores were associated with tumor motion (R2 = 0.45). Specifically, DL score variance was deterministic with undulations in phase with the respiratory cycle (R2 = 0.77-0.99). DL scores, but not tumor volumes, peaked near end-exhalation ([~]50% phase). The mean of the scores derived from 4D CT images and the score obtained from FB CT images were highly associated (Pearson r = 0.99). MIP-derived DL scores were significantly higher than 4D- or FB-derived risk scores (p < 0.0001).

InterpretationWe show that an image-based DL risk score derived from a series of four-dimensional CT images varies in a deterministic, sinusoidal trajectory in phase with the respiratory cycle. These results indicate that deep learning models of tumors in motion can be robust to fluctuations in object appearance due to movement and can guide standardization processes in the clinical translation of DL models for patients with lung cancer.


title: A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

abstract:
PRDM13 (PR Domain containing 13) is a putative chromatin modifier and transcriptional regulator that functions downstream of the transcription factor PTF1A, which in turn controls GABAergic fate in the spinal cord and neuronal development in the hypothalamus. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. We investigated the development of hypothalamic neurons and the cerebellum in mice homozygous for a Prdm13 mutant allele.

A significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone were observed. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Phenotypically, mice lacking PRDM13 displayed cerebellar hypoplasia, normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of kisspeptin neuron development in the hypothalamus, providing a mechanistic explanation for the co-occurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

category: genetic and genomic medicine


title: Leveraging video data from a digital smartphone autism therapy to train an emotion detection classifier

abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting one in 40 children in the United States and is associated with impaired social interactions, restricted interests, and repetitive behaviors. Previous studies have demonstrated the promise of applying mobile systems with real-time emotion recognition to autism therapy, but existing platforms have shown limited performance on videos of children with ASD. We propose the development of a new emotion classifier designed specifically for pediatric populations, trained with images crowdsourced from an educational mobile charades-style game: Guess What?. We crowdsourced the acquisition of videos of children portraying emotions during remote game sessions of Guess What? that yielded 6,344 frames from fifteen subjects. Two raters manually labeled the frames with four of the Ekman universal emotions (happy, scared, angry, sad), a "neutral" class, and "n/a" for frames with an indeterminable label. The data were pre-processed, and a model was trained with a transfer-learning and neural-architecture-search approach using the Google Cloud AutoML Vision API. The resulting classifier was evaluated against existing approaches (Microsofts Azure Face API and Amazon Web Services Rekognition) using the standard metrics of F1 score. The resulting classifier demonstrated superior performance across all evaluated emotions, supporting our hypothesis that a model trained with a pediatric dataset would outperform existing emotion-recognition approaches for the population of interest. These results suggest a new strategy to develop precision therapy for autism at home by integrating the model trained with a personalized dataset to the mobile game.


title: Staffing and Capacity Planning for SARS-CoV-2 Monoclonal Antibody Infusion Facilities: A Performance Estimation Calculator based on Discrete-Event Simulations

abstract:
ObjectiveThe COVID-19 pandemic has significantly stressed healthcare systems. The addition of monoclonal antibody (mAb) infusions, which prevent severe disease and reduce hospitalizations, to the repertoire of COVID-19 countermeasures offers the opportunity to reduce system stress but requires strategic planning and use of novel approaches. Our objective was to develop a web-based decision-support tool to help existing and future mAb infusion facilities make better and more informed staffing and capacity decisions.

Materials and MethodsUsing real-world observations from three medical centers operating with federal field team support, we developed a discrete-event simulation model and performed simulation experiments to assess performance of mAb infusion sites under different conditions.

Results162,000 scenarios were evaluated by simulations. Our analyses revealed that it was more effective to add check-in staff than to add additional nurses for middle-to-large size sites with [≥] 2 infusion nurses; that scheduled appointments performed better than walk-ins when patient load was not high; and that reducing infusion time was particularly impactful when load on resources was only slightly above manageable levels.

DiscussionPhysical capacity, check-in staff, and infusion time were as important as nurses for mAb sites. Health systems can effectively operate an infusion center under different conditions to provide mAb therapeutics even with relatively low investments in physical resources and staff.

ConclusionSimulations of mAb infusion sites were used to create a capacity planning tool to optimize resource utility and allocation in constrained pandemic conditions, and more efficiently treat COVID-19 patients at existing and future mAb infusion sites.

category: health systems and quality improvement


title: Vaccinated and unvaccinated individuals have similar viral loads in communities with a high prevalence of the SARS-CoV-2 delta variant

abstract: The SARS-CoV-2 Delta variant is highly transmissible and contains mutations that confer partial immune escape. We compared RT-PCR cycle threshold (Ct) data from 699 test-positive anterior nasal swab specimens from fully vaccinated (n = 310) or unvaccinated (n=389) individuals. We observed low Ct values (<25) in 212 of 310 fully vaccinated (68%) and 246 of 389 (63%) unvaccinated individuals. Testing a subset of these low-Ct samples revealed infectious SARS-CoV-2 in 15 of 17 specimens (88%) from unvaccinated individuals and 37 of 39 (95%) from vaccinated people. To determine whether infectious virus titers differed in vaccinated and unvaccinated persons, we performed plaque assays on an additional set of 48 samples with Ct <25, finding no difference in infectious virus titer between groups.


title: Shedding of Infectious SARS-CoV-2 Despite Vaccination when the Delta Variant is Prevalent - Wisconsin, July 2021


title: Shedding of Infectious SARS-CoV-2 Despite Vaccination


title: Impact of B.1.351 (beta) SARS-CoV-2 variant on BNT162b2 mRNA vaccine effectiveness in long-term care facilities of eastern France: a retrospective cohort study

abstract:
BackgroundWe aimed to assess the effectiveness of the BNT162b2 mRNA vaccine against B.1.351 (beta) variant among residents of long-term care facilities (LCTFs) in eastern France.

MethodsWe used routinely collected surveillance and COVID-19 vaccination data to conduct a retrospective cohort study of SARS-CoV-2 B.1.351 infection incidence and vaccine effectiveness among LCTFs residents in eastern France between 15 January and 19 May 2021. Data from secondary RT-PCR screening were used to identify B.1.351 variants.

FindingsIncluded in our analysis were 378 residents from five LCTFs: 287 (76%) females, with median (IQR) age of 89 (83-92) years. Two B.1.351 outbreaks took place in LTCFs in which more than 70% of residents had received two doses of BNT162b2 mRNA vaccine, which included 11 cases of severe disease and six deaths among those who had received two doses. Vaccine effectiveness (95% CI) seven days after the second dose of vaccine was 49% (14-69) against any infection with B.1.351 and 86% (67-94) against severe forms of COVID-19. In multivariable analysis, females were less likely to develop severe forms of disease (IRR = 0.35, 95% CI = 0.20-0.63).

InterpretationWe observed reduced vaccine effectiveness associated with B.1.351, as well as B.1.351 outbreaks in two LTCFs among individuals who had received two doses of vaccine. Our findings highlight the need to maintain SARS-CoV-2 surveillance in these high-risk settings beyond the current COVID-19 mass vaccination campaign, and advocate for a booster vaccine dose prior to the next winter season.


title: An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19

abstract:
AbstractThe worldwide outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an established global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to counter the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity, and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse- adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency, in a phase I clinical trial in healthy human participants.

ClinicalTrials.gov Identifier: NCT04756531

One-Sentence SummaryPF-07321332 is disclosed as a novel, orally active, investigational small-molecule inhibitor of the SARS-CoV-2 main protease, which is being evaluated in clinical trials for the treatment of COVID-19.


title: Clinical Determinants and Predictors for Prognosis of SARS-CoV-2 Infected Pediatric Patients in Saudi Arabia

abstract:
BackgroundThe significant variations in clinical characteristics and outcomes of COVID-19 that range from asymptomatic to severe fatal illness entail searching for potential prognostic determinants to help predict the disease course and early detection of patients at risk of developing life-threatening complications. Although children are less commonly infected by SARS-CoV-2 than their adult counterparts, and their symptoms are generally milder, a severe type of COVID-19 cannot be precluded.

MethodsAt first, demographic, clinical, laboratory measurement data, and outcomes for 26 COVID-19 infected children of less than 12 years of age, admitted to King Abdallah Hospital, Bisha, Saudi Arabia, were retrieved from the electronic medical records for the observational retrospective study.

Later, electronic and manual database searches were carried out for pediatric severe COVID-19-related articles. The relevant data from 20 eligible studies and the present retrospective study were analyzed to assess the association of demographic characteristics and comorbidities with COVID-19 severity.

ResultsIn the retrospective study, 5 (19%) of the children presented with severe symptoms admitted to PICU, 18 (69%) presented with cough, 5 (19%) with diarrhea, 7 (27%) with underlying comorbidities, 4 (15%) with respiratory illnesses, 3 (12%) with cardiovascular diseases and 2 (8%) were obese. None of the patient characteristics showed any significant association with COVID-19 severity.

Of the 21 studies selected for meta-analyses, 14 studies were included in the analysis of the association between any comorbidity and disease severity, resulting in OR: 2.69, 95%CI: 1.38 - 5.26, P < 0.05, for analysis of the association between cardiovascular comorbidities and disease severity 14 studies were included giving OR: 4.06, 95%CI: 1.86 - 8.87, P < 0.05, for analysis of the association between respiratory comorbidity and disease severity 15 studies were included giving OR: 2.05, 95%CI: 1.54 - 2.74, P < 0.05, for analysis of the association between obesity and disease severity 10 studies were included, giving OR: 2.48, 95%CI: 1.16 - 5.32, P < 0.05, for analysis of the association between age <10 years old and diseases severity, 16 studies were included, giving OR: 0.80, 95%CI: 0.65 - 0.97, P < 0.05, and for analysis of the association between female gender and disease severity, 19 studies were included, giving OR: 0.83, 95%CI: 0.59 - 1.18, P > 0.05.

ConclusionIt can be concluded that COVID-19 pediatric patients with underlying comorbidities, being cardiovascular, respiratory, or obesity, are at high risk of developing severe illness, and young age has a protective role against the disease severity.


title: Transcriptomic signature on Hantavirus Cardiopulmonary Syndrome patients, reveals an increased interferon response as a hallmark of critically ill patients

abstract:
New World hantaviruses are important human pathogens that can cause a severe zoonotic disease called hantavirus cardiopulmonary syndrome (HCPS). HCPS patients can progress quickly to a severe condition with respiratory failure and cardiogenic shock that can be fatal in 30% of the cases. The role of the hosts immune responses in this progression towards HCPS remains elusive. In this study, 12 patients hospitalized with severe HCPS were analyzed using a transcriptome approach combined with clinical laboratory data to gain a better insight into factors associated with a severe clinical course. Patients were further classified in two levels of severity, a first group that required mechanical ventilation and vasoactive drugs (VM+VD) and a second group that also needed ECMO or died (ECMO/Fatal). Their transcriptional profile was compared during acute (early and late) and convalescent phases. Our results showed that overexpression of the interferon response is correlated with a worse (ECMO/Fatal) outcome and an increased viral load and proinflammatory cytokines in the early-acute-phase. This report provides insights into the differences in innate immune activation between severe patients that associates with different clinical outcomes, using a non-biased approximation.

Author SummaryHantavirus are rodent-borne zoonotic pathogens that when transmitted to humans cause two diseases: hantavirus renal syndrome in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. The latter, the goal of this work, is a highly lethal disease with a case fatality rate of 30%. Moreover no specific treatment or vaccine is available for this disease. In this study, we analyzed hospitalized HCPS patients with severe disease, to understand how they respond to hantavirus infection. We used a method that can measure every mRNA that is being transcribed in one moment (transcriptome analysis) and thus provide an accurate idea of how cells (specifically peripheral blood mononuclear cells) are responding to infection. The knowledge gained in this study helps us further understand the pathogenesis of this disease and might help us to design specific therapies to treat it.


title: DERIVATION AND VALIDATION OF A CLINICAL SCORE TO PREDICT DEATH AMONG NON-PALLIATIVE COVID-19 PATIENTS PRESENTING TO EMERGENCY DEPARTMENTS: THE CCEDRRN COVID MORTALITY SCORE

abstract:
BackgroundPredicting mortality from coronavirus disease 2019 (COVID-19) using information available when patients present to the Emergency Department (ED) can inform goals-of-care decisions and assist with ethical allocation of critical care resources.

MethodsWe conducted an observational study to develop and validate a clinical score to predict ED and in-hospital mortality among consecutive non-palliative COVID-19 patients. We recruited from 44 hospitals participating in the Canadian COVID-19 ED Rapid Response Network (CCEDRRN) between March 1, 2020 and January 31, 2021. We randomly assigned hospitals to derivation or validation, and pre-specified clinical variables as candidate predictors. We used logistic regression to develop the score in a derivation cohort, and examined its performance in predicting ED and in-hospital mortality in a validation cohort.

ResultsOf 8,761 eligible patients, 618 (7{middle dot}01%) died. The score included age, sex, type of residence, arrival mode, chest pain, severe liver disease, respiratory rate, and level of respiratory support. The area under the curve was 0{middle dot}92 (95% confidence intervals [CI] 0{middle dot}91-0{middle dot}93) in derivation and 0{middle dot}92 (95%CI 0{middle dot}89-0{middle dot}93) in validation. The score had excellent calibration. Above a score of 15, the observed mortality was 81{middle dot}0% (81/100) with a specificity of 98{middle dot}8% (95%CI 99{middle dot}5-99{middle dot}9%).

InterpretationThe CCEDRRN COVID Mortality Score is a simple score that accurately predicts mortality with variables that are available on patient arrival without the need for diagnostic tests.

Trial registrationClinicaltrials.gov, NCT04702945

category: emergency medicine


title: Individual Preparedness for Distant Wildfires and the Delta Variant in the United States: A Survey of 2,250 US Residents

abstract:
BackgroundCOVID-19 virus travels in the air and collects indoors through tiny particles from exhaled breath, and remains a growing concern globally especially since case studies of vaccine breakthrough infections are being reported. Last years wildfires resulted in the worst air quality on record in the Western US due to toxic wildfire smoke (PM 2.5 pollution) traveling from distant wildfires and this year can potentially be even worse due to extremely dry conditions. Aerosol precautions such as high-filtration (Hi-Fi) masks and HEPA air purifiers are useful to effectively reduce inhalation of most of these toxic aerosols. Whereas the lack of fit or filtration in a mask or use of an air purifier of insufficient size (capacity) for the room can inadvertently render these precautions ineffective. Here we investigate the publics concerns about wildfires and the COVID-19 variants (e.g. delta), their use of aerosol precautions, and whether these are being done in an effective manner.

MethodsWe conducted a national survey of 2,250 US residents in order to understand public concerns about airborne threats and their usage of airborne (aerosol) precautions.

ResultsWe find over 66% of US residents surveyed are worried about inhaling COVID-19 and its variants, and 52% are worried about toxic wildfire particles in the air. In the mountain and pacific regions the latter rises to 73%. Only a quarter are using masks with higher filtration and high level of fit (or Hi-Fi masks e.g. N95 or similar such as elastomeric N95 or KF94). Two-thirds are still using loose-fitting cloth or surgical masks. Just over 40% of respondents report using air purifiers at home, and of this group only 40% use it in their bedroom where they sleep. Of those using air purifiers, the majority said they chose the size of their air purifier based on "most popular" models, "recommendations," or "reviews." However, of those using air purifiers only 42% reported doing a calculation (or using a calculator) to estimate the right size of air purifier needed for the room they are using it in. Notably, a much higher percentage of people (than average) reported use of Hi-Fi masks and home air purifiers in certain occupations such as doctors, healthcare, first responders, public safety, engineering, military, and construction.

ConclusionNational survey data suggests most US residents are worried about wildfire smoke and Covid variants (e.g. delta variant) but a majority are not prepared for it. Preparation with aerosol precautions will also be useful for future pandemics and national biodefense.


title: Multi-omics insights into the biological mechanisms underlying gene-by-lifestyle interactions with smoking and alcohol consumption detected by genome-wide trans-ancestry meta-analysis

abstract: Gene-lifestyle interaction analyses have identified genetic variants whose effect on cardiovascular risk-raising traits is modified by alcohol consumption and smoking behavior. The biological mechanisms of these interactions remain largely unknown, but may involve epigenetic modification linked to perturbation of gene expression. Diverse, individual-level datasets including genotypes, methylation and gene expression conditional on lifestyle factors, are ideally suited to study this hypothesis, yet are often unavailable for large numbers of individuals. Summary-level data, such as effect sizes of genetic variants on a phenotype, present an opportunity for multi-omic study of the biological mechanisms underlying gene-lifestyle interactions. We propose a method that unifies disparate, publicly available summary datasets to build mechanistic hypotheses in models of smoking behavior and alcohol consumption with blood lipid levels and blood pressure measures. Of 897 observed genetic interactions, discovered through genome-wide analysis in diverse multi-ethnic cohorts, 48 were identified with lifestyle-related differentially methylated sites within close proximity and linked to target genes. Smoking behavior and blood lipids account for 37 and 28 of these signals respectively. Five genes also showed differential expression conditional on lifestyle factors within these loci with mechanisms supported in the literature. Our analysis demonstrates the utility of summary data in characterizing observed gene-lifestyle interactions and prioritizes genetic loci for experimental follow up related to blood lipids, blood pressure, and cigarette smoking. We show concordance between multiple trait-or exposure-related associations from diverse assays, driving hypothesis generation for better understanding gene-lifestyle interactions.


title: Monitoring COVID-19 spread in Prague local neighborhoods based on the presence of SARS-CoV-2 RNA in wastewater collected throughout the sewer network

abstract:
Many reports have documented that the presence of SARS-CoV-2 RNA in the influents of municipal wastewater treatment plants (WWTP) correlates with the actual epidemic situation in a given city. However, few data have been reported thus far on measurements upstream of WWTPs, i.e. throughout the sewer network. In this study, the monitoring of the presence of SARS-CoV-2 RNA in Prague wastewater was carried out at selected locations of the Prague sewer network from August 2020 through May 2021. Various locations such as residential areas of various sizes, hospitals, city center areas, student dormitories, transportation hubs (airport, bus terminal), and commercial areas were monitored together with four of the main Prague sewers. The presence of SARS-CoV-2 RNA was determined by reverse transcription - multiplex quantitative polymerase chain reaction (RT-mqPCR) after the precipitation of nucleic acids with PEG8000 and RNA isolation with TRIzol Reagent. The number of copies of the gene encoding SARS-CoV-2 nucleocapsid (N1) per liter of wastewater was compared with the number of officially registered COVID-19 cases in Prague. Although the data obtained by sampling wastewater from the major Prague sewers were more consistent than those obtained from the small sewers, the correlation between wastewater-based and clinical-testing data was also good for the residential areas with more than 1 000 registered inhabitants. It was shown that monitoring SARS-CoV-2 RNA in wastewater sampled from small sewers could identify isolated occurrences of COVID-19-positive cases in local neighborhoods. This can be very valuable while tracking COVID-19 hotspots within large cities.

HighlightsO_LISARS-CoV-2 RNA presence was measured at 24 locations in the Prague sewer network
C_LIO_LIResidential areas (100-13 000 inhab.), transport hubs, hospitals etc. were included
C_LIO_LIConsistent wastewater monitoring by RT-mqPCR took place from August 2020 - May 2021
C_LIO_LIThe sampling of major Prague sewers correlated well with clinical-based data
C_LIO_LIGrab samples can identify COVID-19 hotspots in local neighborhoods
C_LI

Graphical abstract

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title: Estimates of Single Dose and Full Dose BNT162b2 Vaccine Effectiveness among USAF Academy cadets, 1 Mar - 1 May 2021

abstract: Beginning in early March 2021 and continuing through May 2021, the USAF Academy began vaccinating cadets for protection against the SARS-CoV-2 virus with the BNT162b2 (Pfizer-BioNTech) mRNA vaccine. During this period, vaccination of the almost 4200 cadet population increased from 3% to 85% and prevalence of COVID-19 in the cadet population was constant at approximately 0.4% as indicated by weekly surveillance testing. In this study, vaccine effectiveness at preventing infection is estimated by comparing infection risk as a function of time since vaccination. A statistically significant four-fold reduction in infection risk was observed 14 days after the first vaccine dose and an eleven-fold reduction in infection risk was observed in fully vaccinated cadets. Overall, the Pfizer-BioNTech vaccine was 91% (95% confidence interval = 55-99%) effective at preventing infection in healthy young adults (17-26 years of age) in a university setting and military training environment.


title: Motivators and barriers to research participation for individuals with cerebral palsy and their families

abstract:
Objective(s)Our objective was to investigate the motivators and barriers associated with the individual or family decision to participate in cerebral palsy research. Based on this information, we offer suggestions to increase the likelihood of participation in future CP studies.

MethodsA digital survey was administered to stakeholders affected by cerebral palsy across the US. Our analysis focused on variables related to personal interests, travel, and study-specific elements. Statistical tests investigated the effects of responder type, cerebral palsy type, and Gross Motor Function Classification System level on travel and study-specific element variables. Recommendations were informed by responses reflecting the majority of respondents.

ResultsBased on 233 responses, we found that respondents highly valued research participation (on average 88.2/100) and compensation (on average 62.3/100). Motivators included the potential for direct benefit (62.2%) and helping others (53.4%). The primary barriers to participation were schedule limitations (48.9%) and travel logistics (32.6%). Schedule limitations were especially pertinent to caregivers, while individuals with more severe cerebral palsy diagnoses reported the necessity of additional items to comfortably travel.

ConclusionsOverall, we encourage the involvement of stakeholders affected by cerebral palsy in the research process. Researchers should consider offering flexible study times, accommodating locations, and compensation for time and travel expenses. We recommend a minimum compensation of $15/hour and a maximum time commitment of 4 hours/day to respect participants time and increase likelihood of research participation. Future studies should track how attitudes toward research change with time and experience.

category: pediatrics


title: Differential Deep Brain Stimulation Sites and Networks for Cervical vs. Generalized Dystonia

abstract:
Dystonia is a debilitating disease with few conservative treatment options but many types of isolated dystonia can be effectively treated using deep brain stimulation (DBS) to the internal pallidum.

While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations between optimal stimulation sites and potential network effects in the two types of dystonia have not been carried out.

Here, we retrospectively investigate clinical results following DBS for cervical and generalized dystonia in a multi-center cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce a novel approach to map optimal stimulation sites to anatomical space. Second, we analyse stimulation in context of a detailed pathway model of the subcortex to investigate the modulation of which tracts accounts for optimal clinical improvements. Third, we investigate stimulation in context of a broad-lense whole-brain functional connectome to illustrate potential multisynaptic network effects. Finally, we construct a joint model using local, tract- and network-based effects to explain variance in clinical outcomes in cervical and generalized dystonia.

Our results show marked differences in optimal stimulation sites that map to the somatotopic structure of the internal pallidum. We further highlight that modulation of the pallidofugal main axis of the basal ganglia may be optimal for treatment of cervical dystonia, while pallidothalamic bundles account for effects in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in form of connectivity to cerebellum and somatomotor cortex.

Our results suggest a multi-level model that could account for effectivity of treatment in cervical and generalized dystonia and could potentially help guide DBS programming and surgery, in the future.

category: neurology