To evaluate equity in the allocation and distribution of vaccines for coronavirus disease 2019 (COVID-19) to countries and territories participating in the COVID-19 Vaccines Global Access (COVAX) Facility.We used publicly available data on the numbers of COVAX vaccine doses allocated and distributed to 88 countries and territories qualifying for COVAX-sponsored vaccine doses and 60 countries self-financing their vaccine doses facilitated by COVAX. We conducted a benefit–incident analysis to examine the allocation and distribution of vaccines based on countries’ gross domestic product (GDP) per capita. We plotted cumulative country-level per capita allocation and distribution of COVID-19 vaccines from COVAX against the ranked per capita GDP of the countries and territories to generate a measure of the equity of COVAX benefits.By 23 January 2022 the COVAX Facility had allocated a total of 1 678 517 990 COVID-19 vaccine doses, of which 1 028 291 430 (61%) doses were distributed to 148 countries and territories. Taking account of COVAX subsidies, we found that countries and territories with low per capita GDP benefited more than higher-income countries in the numbers of vaccines. The benefits increased further when the analysis was adjusted by population age group (aged 65 years and older).The COVAX Facility is helping to balance global inequities in the allocation and distribution of COVID-19 vaccines. However, COVAX alone has not been enough to reverse the inequality of total COVID-19 vaccine distribution. Future studies could examine the equity of all COVID-19 vaccine allocation and distribution beyond the COVAX-facilitated vaccines. Equitable vaccine distribution can be a major factor towards global control of the coronavirus disease 2019 (COVID-19) pandemic.,Established in June 2020, the COVAX Facility is a vaccine acquisition mechanism for countries and territories unable to bargain directly with manufacturers.,–COVAX-secured dose allocation follows the World Health Organization’s (WHO) allocation framework for fair and equitable access to COVID-19 health products.To assess the extent to which COVAX has fulfilled its commitment, we evaluated equity in the allocation and distribution of COVAX-facilitated COVID-19 vaccines to countries and territories by income group and by proportion of older people. The cross-country analysis will add to the evidence on whether collaborative efforts such as the COVAX Facility can contribute to the equitable international allocation and distribution of scarce global public goods  during international health emergencies. We analysed secondary data on countries’ COVID-19 vaccine purchases, allocation and distribution, including data on the COVAX Facility and donations by bilateral and multilateral agencies, international nongovernmental organizations and private firms. We extracted the data from the United Nations Children’s Fund’s (UNICEF) COVID-19 vaccine dashboard as of 23 January 2022 at 20:00 Eastern Standard Time.To understand the differences between actual and intended distribution of COVAX benefits, we obtained: (i) allocated dose counts from the COVAX deliveries category of the UNICEF dashboard and (ii) distributed dose counts from the doses shipped subset of the COVAX allocation values. Vaccine allocation describes the projected number of COVAX vaccine doses available to the country, based on potential supplies and the allocation framework. The doses distributed describes the quantities of COVID-19 vaccines delivered to countries by COVAX at a given point in time.Among the 148 countries and territories included on the dashboard, 88 countries qualified for COVAX-sponsored vaccine doses under the advance market commitment mechanism and 60 countries were self-financing their vaccine doses facilitated by COVAX. We grouped the countries into four income groups based on the World Bank country classification:In line with COVAX guidelines and WHO’s fair allocation framework, we assumed that COVAX will fully subsidize vaccines for 20% of the population in countries and territories qualifying for advance market commitment.We used standard benefit–incident analysis methods for doses allocated and doses distributed to evaluate differences between actual and intended distribution of COVAX benefits. We performed the following steps: (i) ranking countries and territories from poorest to richest via per capita GDP adjusted for PPP; (ii) obtaining both COVAX vaccine doses allocated and distributed by country; (iii) estimating total per capita benefits received from COVAX; (iv) estimating self-financed per capita benefits that were facilitated by COVAX; (v) deducting self-financed per capita benefit from total per capita benefits to obtain COVAX-sponsored per capita benefits; and (vi) aggregating COVAX-sponsored per capita benefits. We plotted COVAX-sponsored per capita benefits on Lorenz concentration curves to assesses whether benefits were distributed equitably. A 45° line on the curves represents perfect equality and enabled us to quantify deviation from perfect equality. μ is the average benefit from COVAX, and cov is the weighted covariance between per capita COVAX benefit h received by country i and the country’s rank r in the GDP per capita distribution. The number of countries and territories, N, are ranked from 1 to N, that is, from poorest to richest. For computation, a more convenient formula for the concentration index defines it in terms of the covariance between the vaccine doses allocated or distributed and the fractional rank in the GDP per capita.,We then calculated Wagstaff concentration index (C):,minh is the lower limit of ih.When data are categorical rather than continuous, calculation of a standard concentration index may be insufficient. We therefore also calculated the Erreygers modified concentration index (MC), which accounts for the chosen transformation:We analysed per capita COVAX benefits measured as country-level per capita COVAX expenditures on vaccines net of domestic expenditures on the vaccines, plotted against the ranked per capita GDP adjusted for PPP. We calculated Wagstaff and Erreygers concentration indices for total benefits, COVAX-sponsored benefits and self-financed per capita COVAX benefits for all countries and territories. We made the calculations for the total population of each country or territory. We also examined the distribution of COVAX benefits based on the proportion of the population aged 65 years and older as a proxy for the relative size of the most vulnerable population in each country or territory. For both indices, a concentration index of 0 to –1 reflects a pro-poor distribution, and an index of 0 to 1 reflects a pro-rich distribution.We used Excel  and Stata version 16  for the analysis.At the time of analysis COVAX had allocated a total of 1 678 517 990 COVID-19 vaccine doses among 148 countries and territories, of which 1 028 291 430 (61%) doses had been distributed . Fig. 1 The concentration curve for total per capita COVAX benefits shows a pro-poor distribution, which lies mostly along the line of equality . HoweverThe average total per capita COVAX benefit was US$ 3.37 while the average COVAX-sponsored and self-financed per capita benefits were US$ 1.40 and US$ 1.98, respectively. The Wagstaff concentration indices for total per capita benefits and COVAX-sponsored per capita benefits were −0.034 and −0.657, respectively, indicating that the poorest 50% nations were allocated about 3% and 49% more total and COVAX-sponsored doses, respectively, compared with the wealthiest 50% nations, after adjusting for need . In contThe concentration curves for per capita benefits from COVAX doses distributed mirror the trends seen in the curves for doses allocated . The conThe average per capita benefits were US$ 2.46 for total, US$ 1.16 for COVAX-sponsored and US$ 1.29 for self-financed benefits. The Wagstaff concentration indices for total and COVAX-sponsored per capita benefits were pro-poor at −0.014 and –0.518, respectively . MeanwhiBenefits from allocated doses were more pro-poor compared with distributed doses. Additionally, the analysis demonstrates that self-financed expenditure both for doses allocated and doses distributed disproportionately benefited the richest nations in the absence of COVAX’s subsidies. When we took account of COVAX subsidies, we found that total and COVAX-sponsored per capita benefits were pro-poor for both allocated and distributed doses.The concentration curves and indices for COVAX-sponsored benefits adjusted for the size of the population aged 65 years and older are presented in We found that for both allocated and distributed COVID-19 vaccine doses, the total per capita benefits from the COVAX initiative disproportionately benefited countries and territories with lower per capita GDP. This difference applied when analysing the overall population and after accounting for the relative size of vulnerable older populations within each country. The total per capita benefits after adjusting for the size of older populations within each country demonstrated even higher benefits towards countries and territories with lower GDP per capita. These results were similar for COVAX-sponsored per capita benefits for both allocated and distributed COVID-19 vaccine doses.The results also revealed that the benefits to poorer countries were greater for doses allocated than for doses distributed. This disparity can be explained by differences in the vaccine distribution systems across countries and territories. The differences include availability of cold-chain equipment, warehousing or storage capacities and human resources. Due to variations in supply-chain readiness, COVAX-eligible countries and territories may not receive their allocation from the COVAX Facility until minimum conditions are met. As such, WHO and UNICEF have developed a guidance note on COVID-19 vaccine supply and logistics management to help countries to prepare.We found variations in the benefits accrued across country income levels. Although total and COVAX-sponsored per capita benefits favoured poorer countries and territories, the benefits varied across country income levels, especially after adjusting for need using the size of the vulnerable older populations. In general, both total and COVAX-facilitated per capita benefits among self-financing countries disproportionately favoured countries with higher GDP per capita. This difference may be because nations with more resources can procure extra doses of COVID-19 vaccines in addition to the vaccines from the COVAX subsidy. These results also explain why the self-financed COVAX-facilitated per capita benefits accrued to nations with higher GDP per capita. However, the total benefits per capita favoured poorer countries when we took account of COVAX subsidies in the analysis. ,Despite substantial investments in vaccine delivery systems during the Global Vaccine Action Plan’s decade of vaccines (2010–2019), vaccine distribution systems of the poorest countries lag behind those of middle- and high-income countries.COVAX alone will not be sufficient to tackle future global inequity of vaccine access unless considerable reforms to the global system of vaccine governance are made. Although COVAX was able to allocate its COVID-19 vaccine doses among countries in an equitable manner, these efforts have not been enough to reverse the inequitable allocation and timely delivery of total COVID-19 vaccine. Inequities also still persist due to countries’ hoarding vaccine supplies for their own populations.There were some limitations to the study. First, we used PPP-adjusted GDP per capita to rank countries along a continuum. This country-level average does not reflect cross-country and in-country variations in living standards that may exist. Second, the analysis focused on the benefits received by countries and territories from COVAX in terms of the numbers of vaccine doses allocated and distributed. We were unable to determine how COVAX vaccine doses were allocated and distributed within the countries after the delivery by COVAX. Key issues such as human resources for health availability, geospatial access issues, internal stocking and cold-chain maintenance issues, and vaccine hesitancy may affect the ability of the countries and territories to eventually vaccinate their populations. As such, there may be significant variation in full vaccination coverage within and among the countries and territories. Another limitation is that we only examined doses from COVAX, omitting doses from other bilateral deals or non-COVAX sources. COVAX vaccines represent approximately 20% of all doses in circulation.In conclusion, global risk-sharing for pooled procurement can foster the equitable distribution of COVID-19 vaccines and help to balance global inequities in the allocation and delivery of COVID-19 vaccines. Without COVAX subsidies and the COVAX Facility as a whole, poorer countries and territories may struggle to access COVID-19 vaccines. Therefore, expanding COVAX subsidies beyond 20% of the population for the poorer countries may be important to further enhance equity in the allocation and delivery of COVID-19 vaccines. Future studies could examine the equity of vaccine distribution within countries and include vaccines beyond the COVAX-facilitated vaccines.


Firearms cause the most suicides (60%) and homicides (36%) in the US. The high lethality and availability of firearms make them a particularly dangerous method of attempted violence. The aim of this study was to study US trends in firearm suicide and homicide mortality and years of potential life lost before age 75 (YPLL-75) between 1981 and 2020.Data in this cross-sectional study were collected between 1981 and 2020 from the Centers for Disease Control and Prevention (CDC)’s WISQARS database for fatal injury and violence. Data from the US population were considered for all age groups and were divided by racial groups and sex for analysis.Those most heavily impacted by firearm homicide were Black, with homicide age-adjusted death rates almost seven times higher than White people. A spike in firearm homicide deaths occurred between 2019 and 2020, with Black people having the largest increase (39%). White people had the highest rates of firearm suicide, and suicide death rates increased between 2019 and 2020. Increases in homicide and suicide YPLL-75 between 2011 and 2020 had most heavily impacted minority populations. Men had a firearm suicide rate that was seven times higher than women, and a firearm homicide rate that was five times higher than women.This study demonstrated that Black and White men were most impacted by firearm deaths, and that firearm homicide and suicide rates increased between 2019 and 2020 for all racial groups except Asian/Pacific Islander. Our results suggest that prevention efforts should focus on specific demographic factors and articulate the urgency to mitigate firearm-related deaths in the US. Firearm injuries and deaths are increasingly recognized as a unique threat to the US population. Public attention focuses on mass shootings and their devastating impact on communities and has brought conversations on gun violence and ownership to the forefront of public health. Mass shootings represent only a small proportion of life lost to gun violence, as firearm suicide represents 60% and firearm homicide 36%  of all firearm-related deaths , 2. The Increasing rates of US firearm deaths have been attributed to the rising number of firearm suicides . ConsistThere are a limited number of studies that examine historic trends in US homicide and suicide rates , 18, as For this cross-sectional study, age-adjusted death rates and YPLL-75 were used to describe trends and disparities of firearm-related suicide and homicide deaths between 1981 and 2020 in the US.Data were collected from the CDC’s Web-based Injury and Statistics Query and Reporting System (WISQARS), utilizing Fatal Injury Reports and Years of Potential Life Lost (YPLL) . BecauseData collected from WISQARS were compiled into Microsoft Excel tables to organize age-adjusted death rates for firearm suicide and homicide by race, sex, and year of death. We also obtained firearm-related suicide and homicide YPLL-75 and stratified the data by year. First, we presented firearm-related suicide and homicide age-adjusted death rate trends and YPLL-75 by race between 1981 and 2020. We calculated ratios between racial groups for firearm homicide and suicide age-adjusted death rates between 1981 and 2020. The data were divided into 4 periods . Next, we calculated percent change of firearm YPLL-75 between each time period by the total US population and racial groups. We calculated yearly number of YPLL-75 by racial groups and their standard deviations using data between 1981 and 2020. We then calculated ratios between racial groups for firearm-related homicide and suicide YPLL-75 between 1981 and 2020. Finally, we showed firearm-related suicide and homicide age-adjusted death rate trends by sex between 1981 and 2020. We calculated age-adjusted death rates between 1981 and 2020 and found ratios between sex-specific firearm homicide and suicide death rates.Fig 1). The Black population had a firearm-related homicide death rate that was on average seven times higher than the White population. Rates of firearm-related homicide mortality within the Black population were five times higher than the next highest homicide death rate (American Indian/Alaska Native population). Among all populations, there was a rise and fall in firearm-related homicide death rates that occurred between 1990–1995. Between 2019 and 2020, a spike in firearm-related homicide death rates was seen in all racial groups except for Asian/Pacific Islander population . Firearm-related suicide death rate was highest among the White population. The rate of firearm-related suicide mortality in the White population was two times higher than the Black population and was 1.4 times higher than the next highest firearm-related suicide death rate (American Indian/Alaska Native population). Between 2019 and 2020, firearm-related suicide death rates increased among all populations except Asian/Pacific Islander population and had the larger increases in the American Indian/Alaska Native population (39%) and Black population (14%).The highest yearly firearm-related death rate between 1981 and 2020 within a racial group was consistently homicide of the US Black population . A rise and peak were observed in the early 1990s followed by a decline, with a recent increase in firearm homicide YPLL-75 between 2019 and 2020. The firearm homicide YPLL-75 were higher among the Black population  than the White population , with a 1.3 times higher value. On average, firearm homicide YPLL-75 in the White population were twenty-six times higher than the next highest (Asian/Pacific Islander). Table 1 shows firearm YPLL-75 and percent change between 4 time periods: 1981–1990, 1991–2000, 2001–2010, 2011–2020. Between 2011 and 2020, the largest increases in firearm homicide YPLL-75 occurred in the Black population (147%) and American Indian/Alaska Native population (90%). Overall, firearm suicide YPLL-75 had an upward trend since 2000 . However, firearm suicide YPLL-75 had increased the most among minority populations  as compared to the White population (16%), although White people made up the largest proportion of firearm suicide YPLL-75.Trends in firearm homicide YPLL-75 shown in Fig 3), and it closely resembled the White population’s firearm age-adjusted suicide death rate trend seen in Fig 1. The male firearm-related homicide rate was five times higher than the female rate. The male firearm suicide death rate was almost seven times higher than the female rate. Male firearm suicide death rate was 1.5 times higher than the male firearm homicide death rate. Female firearm suicide death rate was 1.1 times higher than the female firearm homicide death rate. Between 2019 and 2020, there was a 36% increase in male firearm homicide death rate and 29% increase in female firearm homicide death rate. During this same period, female firearm suicide death rate decreased by 3% and male firearm suicide death rate only increased by 2%.The highest firearm-related death rate between sexes was seen in firearm suicide rate in men  of the US population . BetweenPrevious studies have examined racial and sex-based disparities in firearm-related deaths, but our study is unique in analyzing 40-years of deaths and YPLL-75 to elucidate the increasing firearm impact on the US population, which might not otherwise be reflected in studies using short periods of mortality data. Furthermore, analyzing 2019–2020 mortality data also allowed us to assess the impact of increasing violence and firearm ownership during the COVID-19 pandemic. Fowler, et al. found that men of any race and Black people were most likely to be the victims of firearm-related deaths . Our resIn a report of global data from 2016, homicides accounted for 64% and suicides 27% of firearm-related deaths . There hChanges in age-adjusted death rates reflect the need to focus on minority (particularly Black and American Indian/Alaska Native) populations’ vulnerability to firearm-related violence. Results from our study suggested that firearm homicide was a leading cause of death within the US population and is of particular concern given a spike in firearm death rates between 2019 and 2020. Men are heavily affected by firearm-related violence, and it is important for prevention efforts to target the demographics of people most affected by firearm-related homicide and suicide, respectively. Understanding how policies impact death rates could help develop legislations to decrease US firearm-related deaths. Sen and Panjamapirom conducted a study to understand the relationship between background checks for gun purchases and rates of firearm deaths and reported that firearm homicide deaths were lower in states checking for restraining orders and fugitive status, whereas firearm suicide deaths were lower in states checking for mental status, fugitive status, and misdemeanors . StudiesThis study had several limitations. First, we examined historical trends in firearm-related mortality rates and YPLL-75 and therefore causation could not be established. Second, we did not consider US Hispanic versus non-Hispanic populations as there were no Hispanic origin data available on WISQARS prior to 1990. Third, WISQARS provided only 4 racial groups  and no multiracial considerations when choosing “race” as an output group in fatal injury data, leaving out other racial groups that might have been impacted by firearm-related homicide and suicide deaths.This study found a recent spike in firearm homicide death rates between 2019 and 2020, particularly affecting men and the Black population. A national priority in dismantling structural racism is important to address disparities in firearm violence as indicated by our study.


To quantify COVID-19 vulnerabilities for Californian residents by their legal immigration status and place of residence.Secondary data analysis of cross-sectional population-representative survey data.All adult respondents in the restricted version of the California Health Interview Survey .Relative Social Vulnerability Indices for COVID-19 by legal immigration status and census region across six domains: socioeconomic vulnerability; demography and disability; minority status and language barriers; high housing density; epidemiological risk; and access to care.Undocumented immigrants living in Southern California’s urban areas  have exceptionally high vulnerabilities due to low socioeconomic status, high language barriers, high housing density and low access to care. San Joaquin Valley is home to vulnerable immigrant groups and a US-born population with the highest demographic and epidemiological risk for severe COVID-19.Interventions to mitigate public health crises must explicitly consider immigrants’ dual disadvantage from social vulnerability and exclusionary state and federal safety-net policies. We adapted the Centers for Disease Control and Prevention Social Vulnerability Index to quantify immigrants’ vulnerability to COVID-19 by their legal immigration status and their geographic region of residence in California.Our analysis used the California Health Interview Survey , which contains direct measurements of immigrants’ legal status as well as detailed socioeconomic and health information.The data cover 2015–2020, and vulnerability indices may diverge from the pandemic’s peaks in 2021.Vulnerability indices are relative measures among California’s 50 immigrant status-region groups and cannot be generalised to the broader national population.The novel coronavirus, SARS-CoV-2, has spread across all parts of the USA, exacerbating entrenched social and health inequalities in its wake. This article uses sensitive immigration and geographic information from the restricted data in the California Health Interview Survey (CHIS) to quantify underlying socioeconomic, demographic and epidemiological vulnerabilities to COVID-19 by legal immigration status in California’s 10 census regions.Prior research on immigrants’ resources and health suggests that their vulnerability to COVID-19 may be higher than the US-born population.As the COVID-19 pandemic progressed, commentaries and limited research described the unique difficulties and high risk for adverse COVID-19 outcomes that undocumented immigrants faced. Reports from hospital emergency rooms detailed inpatient teams struggling to communicate with Spanish-speaking patients using language lines and through layers of personal protective equipment.In addition to the COVID-19 risk factors and other unique difficulties described above, undocumented immigrants also face greater structural barriers in accessing healthcare and safety-net programmes.When COVID-19 vaccines became available to the general public, the Department of Homeland Security released a statement that they fully support equal access to the vaccine for undocumented immigrants.Policies at the state and local levels can support inclusive public health programmes and outreach to address their immigrant communities’ specific needs.Conversely, exclusionary policies such as mandating the use of E-Verify, an electronic database of immigrants’ work authorisation, or barring states from issuing drivers’ licences, or granting college admission to undocumented immigrants aim to create obstacles for those who do not have legal status.This article identifies opportunities for local-level and community-level interventions that can address the immigrants’ unique challenges. Fractured policies that stratify people by immigration status stymie efforts that aim to mitigate the effects of the COVID-19 pandemic for all.We used the 2015–2020 survey data from CHIS, a collaborative data collection between UCLA Center for Health Policy Research, the California Department of Public Health and the Department of Health Care Service.Our analysis included 128 528 adult survey respondents 18 years or older and used individual weights to account for sampling design. The CHIS imputed missing values for almost all variables in their surveys using random selection or hot deck imputation used in census-published data sets.The article presents analyses of secondary survey data, and no patients were involved in the study.We categorised respondents by their nativity and legal immigration status: US-born citizens, naturalised citizens, legal permanent residents (LPR), documented temporary visa holders and undocumented immigrants. The first three categories, which accounted for almost 97% of our analysis sample, were determined directly for the entire study period 2015–2020 through a series of citizenship and immigration questions. All respondents answered whether they were born in the USA. If the response was no, they indicated whether they were naturalised citizens. Respondents who were not US citizens were then asked whether they were LPRs. Questions that can differentiate undocumented immigrants from documented temporary visa holders (non-LPRs) were only asked in 2015–2016. The large majority (98.4%) of our analysis sample had direct information on immigration status, including whether they were undocumented or living in the USA on valid visas. The remaining 1.6% of our sample non-citizens who were not LPRs in the years 2017–2020 accounted for about half of non-citizens and non-LPRs. They may have had a valid visa to live in the USA , but CHIS did not ask for specific details on visa status during those survey years. We used a multiple imputation procedure to differentiate the documented temporary visa holders from the likely undocumented based on the relationships between sociodemographic characteristics and documentation status derived from the complete survey years in 2015 and 2016.We adapted the validated US Centers for Disease Control and Prevention (CDC) Social Vulnerability Index (SVI)This domain captures the disproportionate crisis vulnerability associated with economic disadvantage. Households living below the poverty line face increased COVID-19 vulnerability due to structural health inequities and disproportionate distribution of underlying comorbidities.This domain captures the increased danger that vulnerable demographic groups face in disaster situations such as the COVID-19 pandemic. Older adults are at greater risk of requiring hospitalisation or dying if diagnosed with COVID-19, and single parents and individuals with disabilities may experience additional stressors of the pandemic.This domain captures minority and marginalised populations’ disproportionate vulnerability. About 33% of US-born and 60% of the foreign-born population in California self-reported as non-white,We included density factors associated with an increased risk of SARS-CoV-2 transmission: the proportion of respondents who live in a multifamily or mobile house, the proportion of respondents who live in an urban or metropolitan area and the proportion of households with three or more adults.This domain captures the medical and epidemiological risk factors associated with COVID-19 infection and its adverse outcomes. The medical risk factors for severe COVID-19 in this domain include cardiovascular conditions (high blood pressure and heart disease), respiratory conditions (asthma and smoking), obesity and diabetes.This domain encapsulates the additional vulnerability that healthcare barriers, such as the lack of health insurance, add during a widespread health crisis. Concerns about the cost of testing and treatment and uncertainty around where to seek medical attention lead to delayed patient care and disrupt our ability to control epidemics.We constructed a vulnerability index for each of the six domains by immigration status intersected with census region (5 immigrant groups × 10 regions=50 immigrant-region groups). First, we estimated groups’ proportions in the high vulnerability category for each of the 21 factors. Second, we averaged the proportions across factors within each domain. Third, we ranked immigrant status-region groups from the group with the highest proportion in the vulnerable category to the lowest. We then assigned a percentile rank using the following equation: Percentile Rank = (rank−1)/(N-1), where N equals 50 and represents the total number of immigrant status-region groups. A higher percentile indicates greater relative vulnerability. Our approach is the same as the method used by Acharya and Porwal,Undocumented immigrants have high vulnerability due to low socioeconomic status, the concentration of minorities and language barriers and low access to care across the entire state. Undocumented immigrants living in the San Joaquin Valleys have the highest socioeconomic vulnerability. In contrast, vulnerability due to minority status and language barriers is the highest among undocumented immigrants in San Diego County (0.98) and Central Coast (1.00).Naturalised citizens and US-born citizens share similar vulnerability profiles across the 10 regions, but unlike non-citizen immigrants, their sources of vulnerability are predominantly from demographic composition and disability. They also score high in vulnerability from epidemiological COVID-19 risk factors, especially in the North Coast and the San Joaquin Valleys.The wide range of vulnerability indices across California’s regions reflects documented temporary visa holders’ socioeconomic and demographic diversity that was obscured in Vulnerability due to high housing density is concentrated among non-citizen immigrants, including LPRs in Southern California—Los Angeles County, Orange County and San Diego-Imperial—and is likely linked to high housing costs in these regions. San Joaquin Valley is home to vulnerable non-citizen immigrants, including LPRs, due to their low socioeconomic status, high minority populations and language barriers.concentration of vulnerability for each immigrant status-region group. The values in Naturalised citizens had the fewest high-scoring (top 75th percentile) vulnerabilities with an average of 0.7 across 10 regions. Undocumented immigrants had the most high-scoring vulnerabilities. Undocumented immigrants living in urban centres surrounding San Francisco, Los Angeles and San Diego scored in the top 75th percentile for five out of six vulnerability domains. They also had a high concentration of vulnerabilities (four out of six) in non-urban regions where the vulnerability was low for other groups such as Superior California. North Coast and the Inland Empire regions had a relatively high concentration of vulnerability due to high scores among US-born citizens and naturalised citizens in addition to immigrants with liminal statuses.Our study highlights the unequal social vulnerabilities between people with different legal immigration statuses across California during the years leading up to the COVID-19 pandemic. Our domain-specific analyses showed that vulnerabilities from low socioeconomic status, language barriers, high housing density and low access to healthcare go hand in hand and that these vulnerabilities are concentrated among undocumented immigrants living in Southern California. The heightened social vulnerabilities among undocumented immigrants are not unique to COVID-19. Researchers have used the same factors to determine vulnerabilities in a wide range of crises, including the 2004 tsunami in Aceh, IndonesiaOur ecological approach also revealed regional disparities by immigration status. Such disparities may require parallel interventions to address the needs of a US-born population that is demographically and epidemiologically at risk for COVID-19, as well as an immigrant population that is healthy but socioeconomically disadvantaged.Researchers and policy makers should interpret the findings with caution. First, the data collected were aggregated across the years leading up to the COVID-19 pandemic. Thus, the vulnerabilities may diverge from the pandemic’s peak during the winter of 2020–2021. Still, the structural inequities that we measure in our analysis have been profound and persistent in immigrant communities.Despite these limitations, this article concretely examines immigrants’ unique and diverse vulnerabilities associated with the COVID-19 pandemic. Population-representative analysis of undocumented immigrants by subregion is scarce, and our analysis aims to inform future disaster preparations.Exclusionary policies against immigrants have created a nation that stratifies its people based on legal immigration status.


Perceived self-efficacy has been associated with psychological well-being, health behaviours and health outcomes. Little is known about the influence of self-efficacy on oral health outcomes for Aboriginal adults in Australia, a population experiencing high levels of oral health conditions. This study examines associations between oral health-related self-efficacy and oral health outcomes in a regional Aboriginal Australian population and investigates whether the associations persist after adjusting for sociodemographic characteristics and other general and oral health-related psychosocial factors.Cross-sectional data were obtained from the baseline questionnaire of the Indigenous Oral Heath Literacy Project, South Australia. Oral health-related self-efficacy was measured using a six item scale, with total sum scores dichotomised into high/low self-efficacy. Oral health outcomes included self-rated oral health and oral health impacts, measured using the Oral Health Impact Profile (OHIP-14). Generalized linear models with a log-Poisson link function were used to estimate Prevalence Ratios (PR) of poor self-rated oral health according to levels of oral health-related self-efficacy. Multivariable linear regressions were used to estimate the association between oral health-related self-efficacy and OHIP-14 scores. Blocks of confounders were subsequently added into the models, with the final model including all factors.Complete data were available for 252 participants (63%) aged 18 to 82 years (mean age of 37.6 years). Oral health-related self-efficacy was associated with poor self-rated oral health, with a 43% ) greater prevalence of poor self-rated oral health among those with low self-efficacy. Oral health-related self-efficacy was associated with OHIP-14 severity scores, with a score over six points higher for those with low self-efficacy . Although addition of perceived stress into the models attenuated the relationship, associations remained in the final models.Lower levels of oral health-related self-efficacy were associated with a higher prevalence of poor self-rated oral health and greater impacts of oral health among Aboriginal adults in regional South Australia. These associations persisted after controlling for sociodemographic and psychosocial confounders, suggesting that increasing self-efficacy may provide an opportunity for improving oral health outcomes for Aboriginal adults. Oral health is fundamental to overall health and wellbeing. Oral conditions affect quality of life, with physical, social and psychological impacts in addition to economic consequences for individuals and communities . In AustA key psychosocial dimension related to health and oral health outcomes reported extensively in the literature is perceived self-efficacy, with an individual’s perceived self-efficacy shown to influence a broad range of health-related behaviours . Self-efPerceived self-efficacy assesses an individual’s belief in their ability to have control over their own behaviours and therefore their ability to engage in healthy behaviours irrespective of other external and internal factors. For example, a common approach to evaluating an individual’s perceived self-efficacy involves asking how confident a person is that they will perform a certain behaviour when they are stressed, busy or tired , 16. ThiWe therefore aimed to address this gap in the literature pertaining to self-efficacy and oral health outcomes for Aboriginal adults specifically in regional South Australia. This Aboriginal community resides in a regional centre of around 13, 800 residents, with just over 18% (2500 adults and children) identifying as Aboriginal or Torres Strait Islander . This AbSpecifically this study aimed to:describe the prevalence of high/low oral health-related self-efficacy according to sociodemographic characteristics;investigate whether oral health-related self-efficacy is associated with oral health impacts and self-rated oral health;if the association in (b) was supported, determine if associations between oral health related self-efficacy and oral health outcomes persisted after controlling for sociodemographic and other psychosocial characteristics of perceived stress, perceived coping and oral health-related fatalism.We hypothesised that study participants with low self-efficacy would report more oral health impacts and poorer self-rated oral health, and that these associations would remain after controlling for sociodemographic and other psychosocial characteristics.Data were obtained from the Indigenous Oral Health Literacy Project (IOHLP), a randomised controlled trial utilising a delayed intervention design  based inThe exposure of interest, oral health-related self-efficacy (OH-SE), was measured using six items adapted from a self-efficacy scale developed by Finlayson and colleagues . The sixOral health outcomes included (1) the self-reported impact of oral health conditions using the shortened form of the Oral Health Impact Profile (OHIP-14) , previouConfounding factors were identified based on the literature and theoretical associations with both exposures (OH-SE) and oral health outcomes –32, as dPerceived stress and coping were measured using an adapted Perceived Stress Scale (PSS), developed by Cohen and colleagues  and usedOral health-related fatalism (OH-F) was based on a single item used by Finlayson and colleagues . In thisAll analyses were conducted for a complete case sample. Descriptive analyses were performed, including distribution of participants according to the exposure, confounding factors and outcomes.Generalized linear models with a log-Poisson link function and robust standard errors were used to estimate Prevalence Ratios (PR) and their 95% confidence intervals (CI) of poor SROH according to levels of OH-SE. Adjusted PRs and their respective 95% CIs were assessed after blocks of confounders were added into the models. The final model included all factors.Multivariable linear regressions were used to estimate the association between OH-SE and OHIP-14 scores, using Beta coefficients and their 95% confidence intervals (CI). Blocks of confounders were subsequently added into the models, with the final model including all factors.Sensitivity analysis was conducted to identify if including those with the median score in the high or low OH-SE group impacted on the results. The sensitivity analysis confirmed that patterns of associations remained for both approaches. Analyses were carried out using STATA 15.0.fair or poor (poor SROH).Complete data were available for 252 participants (63%) aged 18 to 82 years and a mean age of 37.6 years . Table Table Table Oral health-related self-efficacy was associated with poor SROH, with over 40%  greater prevalence of poor SROH among those with low OH-SE  (Table This study assessed associations between OH-SE and subjective measures of oral health among a regional Aboriginal population in South Australia. Levels of OH-SE varied by age and some, but not all, socioeconomic variables. The prevalence of poor SROH was greater among those with lower OH-SE. Adjusting for confounders attenuated the relationship. Perceived stress had the most notable impact on the relationship between OH-SE and OHIP-14 scores, however, in the final model higher levels of oral health impacts remained for those with lower efficacy beliefs.The association between levels of self-efficacy and oral health outcomes is an important finding adding to the developing body of literature demonstrating the importance of psychosocial determinants of oral health for Aboriginal Australian populations. This finding is consistent with that among pregnant Aboriginal women in South Australia, whereby low self-efficacy persisted as a risk indicator for poor self-rated oral health after controlling for a range of sociodemographic and psychosocial confounders . The OH-For both outcome measures, the addition of perceived stress into multivariable models resulted in the most substantial attenuation in the association with OH-SE. While this was modest for the prevalence of poor SROH, the reduction in the association with the OHIP-14 severity score was 2.24 units, a relative attenuation of 35%. This indicates that perceived stress is an important psychosocial factor to consider when investigating determinants of oral health for Aboriginal people. Despite this role of perceived stress, OH-SE remained significant in all models, indicating that even among more highly stressed individuals, self-efficacy is likely to be an important factor in evaluating oral health outcomes. This is consistent with the findings for pregnant Aboriginal women in South Australia, with a group of psychosocial factors including perceived stress, attenuating the odds of poor SROH by 17% . This isThe weaknesses of this study must be acknowledged and interpretation of findings assessed in light of the small sample size and, in particular, the high proportion of study participants excluded from this analysis due to missing data. Nearly one third of the original sample had missing data for the OH-SE. This was a result of the response option of “I never feel like this”, treated as a missing response. The original scale from which ours was derived did not include this option. It was added in our study based on feedback from the expert and Aboriginal advisory groups. The second reason for missing data was the OH-F scale, as an option of “I don’t know”, also treated as a missing response, also added on the advice of the expert and Aboriginal reference groups. Validation of the OH-SE scale  involvedDespite these weaknesses, this study has key strengths and is an important addition to the sparse literature investigating psychosocial factors and oral health outcomes for Aboriginal people in Australia. The fact that 400 Aboriginal adults in a regional location completed baseline questionnaires involving questions pertaining to psychosocial factors, with a complete data set for over 250 participants, is a successful study outcome. This indicates the cultural acceptability of the survey instruments and study design. The inclusion of a broad range of sociodemographic variables known to be associated with general and oral health outcomes for Aboriginal people ensured these factors were not explaining the association between OH-SE and oral health outcomes.Lower levels of OH-SE were associated with a higher prevalence of SROH and greater impacts of oral health among Aboriginal adults in regional South Australia. These associations persisted after controlling for sociodemographic and general and oral health-specific psychosocial confounders. Perceived stress resulted in the most significant attenuation in the association between OH-SE and oral health outcomes. The findings indicate that self-efficacy beliefs may provide an opportunity for intervention to improve oral health outcomes for Aboriginal adults in regional South Australia.


The cell lines were derived from patients with Sjogren’s disease (SjD) and were compared to the results from cell lines from females lacking autoimmune disease.Shaw et al.   . XIST bio of 9:1 . A minorInterestingly, despite the majority of patients experiencing disease onset around the time of menopause, SjD is characterized by autoantibodies (anti-SS A and anti-SS B) that may precede the onset of clinical SjD by many years . FinallyExtensive genome-wide association studies (GWAS) have been published in SjD, and none of the associations comes anywhere close to the female predominance. The usual explanation to medical students is that female preponderance in autoimmune disease is due to Darwinian natural selection that has shaped the female immune system to accept the implantation and gestation of a semi-allogeneic fetus. The hypothesis dates back to the time of Sir Burnet , who invAdditional evidence has been provided to support this hypothesis by many studies that demonstrated skewed X-linked genes that promote escape from tolerance induction during thymic development, and subsequently play a role in triggering autoimmune disease . Other snew potential therapeutic targets [However, this study by Shaw and co-workers makes us ask this question more critically. The potential escape of certain X-linked genes from inactivation in patients with autoimmune disease leads not only to clues for pathogenesis (triggers) but also to  targets .Toll-like 7 or Toll-like 8 receptors which are known to be located on the X-chromosome [One immediate candidate might be the romosome . Howevernot observed in 4 control female cell lines. Interestingly, the set of silenced genes was not identical in all the SjD cell lines, although overlap was noted . Also, skewing was noted in samples from Systemic Lupus Erythematosus patients  in comparison to control females.This unequal silencing was not an artifact of a single cell line, but was found in 4 differently established salivary mesenchymal cell lines derived from SjD subjects, while They have excluded artifacts introduced in maintaining cell lines by allele-specific PCR .These intriguing studies have identified a new batch of candidate deregulated genes that have emerged in at least 1 SjD patient . Other findings such as alteration in H3K27me3 deposition and decreased level of miR6891-5p (a HLA expressed miRNA) may provide further candidates. The role of miR6981 in this inhibition leading to H3K27me3 and the allelic skewing are new challenges for understanding pathogenesis of the female-predominant autoimmunity.In summary, this article points out possible mechanisms by which environmental triggers can lead to clinically significant autoimmune manifestations in genetically suspectable individuals. In fact, it focuses our attention on the often overlooked observation that these autoimmune diseases occur predominantly in women.


The worldwide use of prone position (PP) for invasively ventilated patients with COVID-19 is progressively increasing from the first pandemic wave in everyday clinical practice. Among the suggested treatments for the management of ARDS patients, PP was recommended in the Surviving Sepsis Campaign COVID-19 guidelines as an adjuvant therapy for improving ventilation. In patients with severe classical ARDS, some authors reported that early application of prolonged PP sessions significantly decreases 28-day and 90-day mortality.Since January 2021, the COVID19 Veneto ICU Network research group has developed and implemented nationally and internationally the “PROVENT-C19 Registry”, endorsed by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care…’(SIAARTI). The PROVENT-C19 Registry wishes to describe 1. The real clinical practice on the use of PP in COVID-19 patients during the pandemic at a National and International level; and 2. Potential baseline and clinical characteristics that identify subpopulations of invasively ventilated patients with COVID-19 that may improve daily from PP therapy. This web-based registry will provide relevant information on how the database research tools may improve our daily clinical practice.This multicenter, prospective registry is the first to identify and characterize the role of PP on clinical outcome in COVID-19 patients. In recent years, data emerging from large registries have been increasingly used to provide real-world evidence on the effectiveness, quality, and safety of a clinical intervention. Indeed observation-based registries could be effective tools aimed at identifying specific clusters of patients within a large study population with widely heterogeneous clinical characteristics.NCT04905875) on May 28,2021.The registry was registered (ClinicalTrial.Gov Trials Register  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized mainly by moderate/severe pneumonia associated with progressive endothelial damage and coagulopathy . Acute rProne position (PP) is a well established treatment for acute respiratory distress syndrome (ARDS), that has been use for many years and is now recommended for invasively ventilated patients with moderate to severe ARDS . Indeed,Despite these promising evidence and the guidelines recommendation , the useIn patients with COVID-19 requiring mechanical ventilation, the PRONA-COVID group reported that PP was widely used in this population and that overall PP led to a significant increase in oxygenation, although no significant change in respiratory mechanics was reported . In a reSince January 2021, the COVID19 Veneto ICU Network research group has developed, implemented, and nationally and internationally spread the “PROVENT-C19 Registry”, endorsed by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI) with the aim to describe the subpopulations of invasively ventilated patients with COVID-19 that benefit the most from PP therapy . This web-based registry will provide a clear example of translational medicine and translational research where data from clinical practice feed a database for clinical research and, at the same time, the database research tools may improve daily practice.Since January 2021, the SIAARTI Society has developed, implemented, nationally and internationally promoted the “PROVENT-C19 Registry”, endorsed by Coordination of Intensive Care - Veneto Region. The Ethics Committee of the St. Bortolo Hospital, Vicenza, Italy (Study ID Numbers: 22/21) and all other participating centers have approved the protocol. Each eligible participant has provided written informed consent. For each enrolled patient, their personal information were been recorded and kept in a secure folder. To protect their privacy, the patients’ personal information were only made accessible to the researchers. The registry was registered  on May 28,2021; the study was designed in accordance with the Declaration of Helsinki. The PROVENT registry with protocol amendment has gone international and has obtained company endorsements European Society of Intensive Care Medicine (ESICM) and European Society of Anaesthesiology and Intensive Care (ESAIC). Almost fifty centers joined the registry and a number of registered patients that has exceeded a thousand for which the results will certainly be encouraging.This registry enrolls all patients diagnosed with COVID-19 infection requiring invasive mechanical ventilation and undergoing PP who meet the inclusion (but not the exclusion) criteria. Each hospital will designate two intensivists for patient enrollment. Inclusion criteria are the following: Adult patients (age > 18 years old) fulfilling all the following inclusion criteria can be included in this study: Laboratory-confirmed COVID-19 infection; Pronation of intensive care patients undergoing invasive mechanical ventilation. Exclusion criteria were contraindications to PP and patients in PP but undergoing non-invasive ventilation must be excluded. Please note that the lack of consensus regarding the timing and duration of PP leads to variability in clinical practice, and treatment is undertaken depending on the decision of the clinician in charge. In these circumstances, it is advisable to keep the inclusion criteria as broad as possible to obtain an accurate picture of clinical practice worldwide.. InformeThe Primary Outcome is represented by the identification of patient profiles in terms of outcomes based on specific PP models and their intermediate surrogate endpoints. However, Secondary Outcomes are:Gas exchange and respiratory mechanics before and after the first positioning manoeuvre and during the initial and final phases of PP. A positive response was defined a priori as an increase in partial oxygen tension (PaO2)/ fractional inspired oxgen (FiO2) ≥20%Pao2 / Fio2, before and after each PP manoeuvre. A positive response was defined a priori as an increase in the Pao2 / Fio2 ratio of ≥20%Duration of PPVentilatory parameters  after repeated prone positioningMortality: ICU mortality and hospital mortality, 28 days of free ventilationAll clinical variables at each PP cycle (starting with the patient’s Case Report Forms)The clinical variables relevant for the application of PP treatment will be described, as well as the starting time of the treatment. In particular, the absolute and relative frequencies of those clinical variables relevant to the application and the starting time of PP treatment will be describedPP usage rates (number of PP admissions / ICU) will be described in terms of annual absolute frequencies and cumulative incidence among all patients enrolled from all participating centresThe study recruits all patients diagnosed with COVID-19 infection requiring invasive mechanical ventilation and undergoing PP at the participating centers will be retrospectively or prospectively enrolled. Patient enrollment will coincide with PP treatment start date . Study duration is one year, starting presumably from 01/03/2021. Patients enrollment at each center will start at different times depending on the spread of the registry and local IRB approval. The first patient might be expected to be enrolled prospectively on 01/05/2021. Retrospectively patient might be enrolled since 01/12/2020. Final results of this study will be available in 31/12/2022. Descriptive statistics will be reported using I quartile/median/III quartile for continuous variables and percentages (absolute numbers) for categorical variables. Wilcoxon-Kruskal-Wallis and Chi-squared tests will be employed to compare the distribution of continuous and categorical variables, respectively.Joint models will be estimated to evaluate the association between PP maneuvers and short and long -term outcomes. Traditionally, linear mixed models for longitudinal data, i.e., changes in respiratory parameters collected repeatedly during the ICU stay according to clinical choice, and Cox Proportional Hazard models for time-to-event outcomes, i.e., in-hospital death, are estimated separately. However, such an approach does not allow for taking into account of the dependency between respiratory parameters changes and the outcome of interests. Joint models overcome such a limitation since they allow for modelling longitudinal and time-to-event data simultaneously . The bas◆ A longitudinal mixed-effects model that analyses changes in the respiratory parameters collected repeatedly during the ICU stay ;◆ A survival or time-to-event model which analyses the time until the in-hospital death , 23.The joint estimation of these sub-models will be performed by assuming a mutual correlation between repeated observations through individual-level random-effects parameters. All these analyses might guide indications for PP in patients with COVID-19 to personalize treatments and to improve patients’ long-term outcomes.The workflow methodology and software solution of research electronic data capture (REDCap) , 22 was The following data will be collected anonymously on a case report form: Date and time of admission; Demographic data and comorbidities; Type of respiratory support in progress before intubation; Clinical parameters and respiratory exchanges before intubation and analytical blood gas parameters; assessment of the performance of several organ systems in the body ; Consciousness assessment (Glasgow Coma Score); Evaluation of blood chemistry tests ;Total number of pronation and for each pronation cycle will be assessed arterial blood gas values at T1 , T2 , T3 , T4 , T5 . Long-term outcome after discharge from intensive care and complications  related to PP will be recorded. Local investigators will transfer all the data to an electronic collection card that coincides with the paper card . Each local investigator received instructions on how to use the eCRF and a personal username and password. Each patient will be identified through a patient identification number (PIN).The term "registry" emphasizes and enhances the aspect of data retention with the aim of describing epidemiological relationships and differences, supporting quality assurance and improvement, as well as clinical research. In addition, registry should allow an evaluation of efficacy in medical clinical practice, but also a monitoring of patient safety as well as economic evaluation . The webClinical quality records enable to monitor the quality of health care provided to the present specific group of patients with COVID-19 by collecting, analysing and reporting relevant health information, but also identifying benchmarks for clinical performance and related variation in clinical outcomes. Generally, ongoing reporting of clinical data from the registry completes the clinical outcome feedback loop which is a defining feature of clinical quality registries. Feedbacks have been identified as one of the most effective interventions to improve practices and management in health care institutions. Clinical feedbacks provided by the web-based platform of this international registry will represent a summary of a care performance over a given period of time that can be transmitted a posteriori to the healthcare professional in any form. These feedbacks, by objectifying the level of individual and collective performance, will encourage a potential modification in practice improving performance. The efficacy of usual treatments performed in the ICU  is easily perceived by the physician and local coordinators. On the other hand, for treatments with restricted indications (as PP in patients with COVID-19), clinical efficacy is based on the results of few PP performed over a broad period of time. An objective recording process of specific outcomes and patients/treatments characteristics allow the physician to go over a subjective perception of efficacy. Stratification for other confounding factors recorded in this registry  may further increase the reliability of the overall treatment effectiveness. A clinical quality registry could be an opportunity to improve understanding of pathophysiologic mechanisms and to facilitate both predictive and prognostic enrichment , 26.The rationale behind the PROVENT-C19 Registry recognizes a new approach based on the real-life observation of the application of the PP for invasively ventilated patients with COVID-19. This approach is based on the concept of precision medicine based on the implementation of a large multidisciplinary and multi-parametric database aimed at identifying clusters of patients with COVID-19 with specific features who would benefit the most from PP, based also on real-time clinical feedbacks as clinical decision support system useful for improving process of care or patient outcomes.ricerca@siaarti.it; https://www.siaarti.it).The Registry l started in October 2021 in the coordinating centre, the St. Bortolo Hospital, Vicenza, Italy with the inclusion of the first patient. Fifty-nine other centres in Italy joined the registry. As of June 2021, the amendment was approved as an international registry. Several other centres have indicated that they are interested in participating (S1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.


Plasmodium infection strongly alters the frequency of these regulatory B cells indicating the immunoregulatory function of B cells in malarial. It is important to note that these subsets, taken together, form the cellular basis of humoral immune responses, allowing protection against a wide array of Plasmodium antigens to be achieved. However, it remains a challenge and an important area of investigation to understand how these B-cell subsets work together to provide protection against Plasmodium infection.In the past several decades, our understanding of how B cells are generated and what function they perform has continued to advance. It is widely accepted that B-cell subsets play a critical role in mediating immune response. Surprisingly, human and murine malarial infections cause major alterations in the composition of B-cell subsets in both the spleen and periphery. Multiple B-cell subsets are well characterized in murine models following primary and secondary infection, although in human malarial infection, these subsets are not well defined. Furthermore, a rare known function of B cells includes the potential role of regulating the activities of other cells in the body as regulatory cells.  Plasmodium parasite, along with multiple strains of the parasite, has resulted in the identification and characterization of important vaccine candidates  and Natural Killer T (NKT) cells are major contributors to innate immunity at the liver stage of infection  to activate T cells and produce various cytokines to participate in the effector immune system .The development of B-cells takes place in the bone marrow under a complex process that involves the positive selection of functional B cells and apoptosis of autoreactive B cells. B cells are characterized phenotypically by the expression of CD19 which are divided into B-1 and B-2 cells based on their potential to switch immunoglobulin isotype and expression of surface markers  and the symptomatic blood stage (erythrocytic stage) , follicular B cells (FoBs), major players of the germinal center (GC) reactions, or marginal zone B cells (MZBs)  and multiple antigens expressed by the  B cells .Naive mature B lymphocytes are classically divided based on surface marker expression and function into either B 1 cells or B cells. Transitional B1 cells (B1a and B1b) are mainly present in pleural cavities along with their presence in other organs such as the spleen and the liver. On the contrary, the B2 fraction mainly found in the spleen and lymph nodes further splits into follicular and marginal zone B cells in the periphery. Follicular B cells are the major B lymphocytes in mice, forming germinal centers with follicular T helper cells that trigger highly precise responses to antigens of a protein nature  B cells during infection of malarial  or T-cell-dependent immune response (TD), FoB cells reside close to T-cell zones in the follicles of secondary lymphoid organs, where at the interface between these two sites these two populations interact  and interleukin-3 (IL-3) cytokines during malarial pathogenesis  with their investigation in T-cell receptor α mutant (TCRα-/-) mice  which exert regulatory function through IL-10 and TGF-β secretion, the regulatory effect of regulatory B cells is exerted Various studies involving the blocking of either IL-10 or the IL-10 receptor have demonstrated the importance of IL-10-producing regulatory cells. Furthermore, it also has been described that not all IL-10-producing B cells may contribute equally to immune suppression.Plasmodium infection and IL-10-producing regulatory B cells which are purely based on experimental/murine models of malarial. A very recent study has investigated the dynamics of regulatory B cells during lethal and non-lethal Plasmodium yoelii infection in Balb/c mice. It was observed that regulatory B-cell frequency increases in the spleen following infection with each lethal and non-lethal infection. Furthermore, the protective effect of the adoptive transfer of regulatory B cells has been explained in terms of enhanced survival and inhibited the growth of parasites through inhibiting excess inflammation  were also observed during infection, and a significant increase in the frequency of these Tim-1+ Breg cells was seen in both strains of mice at day 8 of infection. Breg cells also have been investigated for their role in resolving neuropathology and preventing experimental cerebral malarial (ECM) during P. berghei ANKA infection in a murine model by counteracting the excess of inflammatory immune response  in Plasmodium berghei ANKA-infected mice resulted in a significant reduction in NK and CD8+ T-cell accumulation in the brain and also prevented cerebral hemorrhage, whereas, using the same susceptible model of experimental cerebral malarial C57BL/6, a different study reported that there is need of three cycles of infections followed by treatment for the development of mice resistant to cerebral malarial. Further analysis of cytokines in these resistant mice indicated more anti-inflammatory response through exacerbated IL-10 production at day 7 of infection and suppressed level of IFN-γ from Day 5. The predominant source of IL-10 production found CD19+ B cells in the spleen. Adoptive transfer of these CD19+ B cells that are negative for CD5 expression which were isolated from resistant mice provided protection from experimental cerebral malarial (ECM)  levels in plasma  and anti-inflammatory cytokines are suggested to play an important role in preventing excess inflammation effects in the host. Developing a better understanding of the role of regulatory B cells in malarial may contribute to the development of vaccines and immunotherapy, which can aid in the fight against malarial disease.However, the mechanism of Breg cell-mediated immune suppression in malarial remains poorly understood and ambivalent. Generally, the regulatory mechanism of Bregs cells involves a diverse array of immunomodulatory cytokines of which IL-10 is the most frequently investigated in the pathogenesis of malarial. Although IL-10 is produced by various immune cell types and exhibits several pleiotropic effects, it is important to note that the pro-inflammatory immune response mediated by the release of pro-inflammatory cytokines and other mediators during in vitro conditions that multiple soluble factors and cytokines induce the generation of distinct Breg cell populations through multiple B-cell pathways involving CD40, BCR, and TLRs. This heterogeneity in phenotype is the main reason behind the classification of regulatory B cells based on their immunosuppressive function in the immune system.After the development of progenitor B cells from hematopoietic stem cells, immature B cells enter the spleen. The development of regulatory B cells and the developmental stage at which they acquire their regulatory capacity are still not clear. Two different models have been defined to explain the development of B cells with regulatory ability  is the most broadly identified marker that plays an important role in the induction maintenance of regulatory B cells. It is expressed by the majority of IL-10-producing regulatory B cells (Ding et al., In mice, a multitude of Breg subsets having functional similarity and even expression of surface markers have been defined in response to various stimuli. However, the most widely investigated and adapted subset of regulatory B cells in mice is B10 cells with phenotype CD19Interestingly, the role of Tim-1 appears to be critical for the maintenance of regulatory properties of regulatory B cells. Moreover, B cells that are defective in Tim-1 are more inflammatory rather than regulatory and produce more IL-6, IL-12, and IL-1β than wild-type B cells (Xiao et al., During malarial pathogenesis, regulatory B cells have been phenotypically characterized with the limited evidence available. The following table summarizes the phenotypic characteristics of regulatory B cells during malarial pathogenesis. In the following section, a more detailed description of these regulatory B cells and their importance in malarial pathogenesis has been discussed. Plasmodium parasite infection. Human and animal models reflect the role of various immune cells across the globe in malarial pathogenesis. Nevertheless, a limited number of studies have explained the role of B cells in Plasmodium infections. For instance, some preliminary experimental investigations have witnessed changes in the dynamics and expansion of B cells during P. falciparum human infection. B cells are considered important for providing humoral immune response although antibodies generated during malarial Plasmodium infection are considered very inefficient and short-lived. In addition, atypical memory B cells are generated in response to malarial infection which is an important area of research for the scientific community. Other subsets of B cells along with their mechanism of differentiation into mature B cells need attention for further investigation during malarial that will help us to better understand the malarial vaccine strategies. Studies involving regulatory B cells are not much adequate to understand their role during malarial pathogenesis. Therefore, it is also important to explore the role of regulatory B cells, a novel subset of B cells capable of immunoregulating the immune response during Plasmodium infection.Significant progress has been made in understanding the immune response initiated by Plasmodium infection. Multiple B-cell subpopulations actively participate to provide protection against the different stages of the malarial parasite and are responsible for the generation of an effective immune response. B cells in the germinal center further provide more insights toward the generation of antibodies and the formation of long-lived plasma B cells against the malarial parasite. The functional characterization of Plasmodium antigen-specific antibodies may provide new opportunities to identify antigenic epitopes that will enable us to identify novel vaccine candidates.Numerous studies in humans and mice involving B cells very well explain the different immunological functions performed by these cells during In addition, adoptive transfer studies involving murine models of malarial have explained the immunoregulatory ability of IL-10-producing regulatory B cells. Understanding the immunosuppressive function of Breg cells may open a new way to overcome the excess of inflammatory immune response generated during lethal malarial infection. Overall, it was noticed that B-cell-mediated immune response plays a critical role during malarial pathogenesis. Although several different therapeutic approaches are being explored in the treatment of malarial, it is important to note that these approaches involving B cells are still in the early stages of development. Further research is needed to determine their safety and effectiveness in humans. Moreover, the potential for targeting B cells in the treatment of malarial is an exciting area of research that holds promise for the development of new and improved therapies for this serious and life-threatening disease.Plasmodium infection. Therefore, new investigations must be performed to understand the development and activation of B cells along with the establishment of germinal centers. Moreover, the mechanism of immunosuppression of regulatory B cells in the pathogenesis of malarial is also important to the purpose of cell-based immunotherapy. Overall understanding of B-cell subpopulation during malarial infection will be a boost in reducing the mortality associated with the disease, and the novel insights will prove fundamental for effective vaccine design strategies.The information available in the study explained the important B-cell subpopulations in malarial. It was observed that B-cell-mediated immune response has not been characterized very well during MK and JD conceptualized the topic and content of the manuscript. MK reviewed the literature and wrote the manuscript. JD provided valuable feedback that helped to revise the manuscript. All authors contributed to the article and approved the submitted version.


Previous studies indicate a role of dopamine in spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not well understood whether dopamine directly affects these representations, or only impacts other aspects of spatial brain function. Moreover, both dopamine and spatial cognition decline sharply during age, raising the question which effect dopamine has on directional signals in the brain of older adults. To investigate these questions, we used a double-blind cross-over L-DOPA/Placebo intervention design in which 43 younger and 37 older adults navigated in a virtual spatial environment while undergoing functional magnetic resonance imaging (fMRI). We studied the effect of L-DOPA, a dopamine precursor, on fMRI activation patterns that encode spatial walking directions that have previously been shown to lose specificity with age. This was done in predefined regions of interest, including the early visual cortex, retrosplenial cortex, and hippocampus. Classification of brain activation patterns associated with different walking directions was improved across all regions following L-DOPA administration, suggesting that dopamine broadly enhances neural representations of direction. No evidence for differences between regions was found. In the hippocampus these results were found in both age groups, while in the retrosplenial cortex they were only observed in younger adults. Taken together, our study provides evidence for a link between dopamine and the specificity of neural responses during spatial navigation.The sense of direction is an important aspect of spatial navigation, and neural representations of direction can be found throughout a large network of space-related brain regions. But what influences how well these representations track someone’s true direction? Using a double-blind cross-over L-DOPA/Placebo intervention design, we find causal evidence that the neurotransmitter dopamine impacts the fidelity of direction selective neural representations in the human hippocampus and retrosplenial cortex. Interestingly, the effect of L-DOPA was either equally present or even smaller in older adults, despite the well-known age related decline of dopamine. These results provide novel insights into how dopamine shapes the neural representations that underlie spatial navigation. Anatomically, spatial cognition depends on a network of brain regions centered around the hippocampus (HC) and retrosplenial cortex (RSC) , both ofMuch less is known about how DA might change the neural representations that support spatial navigation. Particularly interesting for human neuroscience are direction selective representations , which hNext to its role in spatial navigation, DA has also received much attention in the context of aging, where reduced DA functions are prevalent and are thought to underlie age-related cognitive declines . ComputaThese roles of DA in spatial navigation and aging might contribute to the pronounced decline in spatial cognition with age , and to Finally, we expected that DA could also influence the shape of population-based tuning functions of direction. Although direction-sensitive cells often have a preferred direction, they also fire in response to non-preferred directions in proportion to their similarity to the preferred direction . Hence, 22.1This study was part of a larger project in which the same participants performed multiple tasks, including a sequential decision making task and a virtual reality spatial memory task inside the scanner and other decision tasks outside of the scanner.Here, we only report results from the MRI analysis of the VR task described below. Specifically, following our previous publication , our anaNote that the relatively low number of female OA reflects difficulties in recruitment after the onset of the COVID-19 pandemic.2.2During each session of fMRI data collection participants had to complete a similar variant of a spatial memory task that was used in previous studies . AnalyseBriefly, participants were placed in a virtual, circular arena in which they could move around freely using a custom-made MRI-compatible joystick. The arena consisted of a circular grass plane surrounded by a wall. Participants could also see distal cues  as well as a local cue (traffic cone) to aid orientation see . We aske2.3Following a double-blind drug administration design, participants were given either a total of 225 mg of L-DOPA  or a placebo  before each MRI session in the form of two orally administered dosages. A first dosage (150 mg L-DOPA/Placebo) was given about 10 min before subjects entered the MRI scanner, roughly one hour before the spatial navigation task began. To assure high dopamine availability during the task, a second booster dosage (75 mg L-DOPA/Placebo) was administered roughly ten minutes before task onset cf. . Partici2.4All data was collected on a 3 Tesla Siemens Magnetom Trio  MRI scanner. T1-weighted structural images were collected at the beginning of the first session using a MP-RAGE pulse sequence  pulse sequence Quality of all collected functional sequences was assessed using MRI quality control MRIQC; . The qua2.5Each ROI was created from anatomical labels obtained from Mindboggle’s FreeSurfer-based segmentation of each participant’s individual T1-weighted images . We inve2.6Copyright WaiverfMRIPrep 20.0.6 , using OASIS30ANTs as target template. Brain tissue segmentation of cerebrospinal fluid (CSF), white-matter (WM) and gray-matter (GM) was performed on the brain-extracted T1w using fast  Stereotaxic Registration Model  image was corrected for intensity non-uniformity (INU) with N4BiasFieldCorrection , distribFunctional data preprocessingfMRIPrep. Susceptibility distortion correction (SDC) was omitted. The BOLD reference was then co-registered to the T1w reference using bbregister (FreeSurfer) which implements boundary-based registration  were resampled onto their original, native space by applying the transforms to correct for head-motion. These resampled BOLD time-series will be referred to as preprocessed BOLD in original space, or just preprocessed BOLD. The BOLD time-series were resampled into standard space, generating a preprocessed BOLD run in MNI152Lin space. The first step in this process was that a reference volume and its skull-stripped version were generated using a custom methodology of fMRIPrep. Several confounding time-series were calculated based on the preprocessed BOLD: framewise displacement (FD), DVARS and three region-wise global signals. FD and DVARS are calculated for each functional run, both using their implementations in Nipype  for the two CompCor variants: temporal (tCompCor) and anatomical (aCompCor). tCompCor components are then calculated from the top 5% variable voxels within a mask covering the subcortical regions. This subcortical mask is obtained by heavily eroding the brain mask, which ensures it does not include cortical GM regions. For aCompCor, components are calculated within the intersection of the aforementioned mask and the union of CSF and WM masks calculated in T1w space, after their projection to the native space of each functional run (using the inverse BOLD-to-T1w transformation). Components are also calculated separately within the WM and CSF masks. For each CompCor decomposition, the k components with the largest singular values are retained, such that the retained components’ time series are sufficient to explain 50 percent of variance across the nuisance mask . The remaining components are dropped from consideration. The head-motion estimates calculated in the correction step were also placed within the corresponding confounds file. The confound time series derived from head motion estimates and global signals were expanded with the inclusion of temporal derivatives and quadratic terms for each . Gridded (volumetric) resamplings were performed using antsApplyTransforms (ANTs), configured with Lanczos interpolation to minimize the smoothing effects of other kernels For each of the 4 BOLD runs collected per subject (two task related runs reported here and 2 resting state runs not reported here), the following preprocessing was performed. First, a reference volume and its skull-stripped version were generated using a custom methodology of stration . Co-registration . BOLD rufor each . Frames fMRIPrep use Nilearn 0.6.2  and relied on scikit-learn  was applied to the resulting activation patterns in order to test whether walking direction could be classified. Cross-validation was done separately for L-DOPA and placebo sessions.Participants’ walking direction was extracted from navigated paths within the virtual environment. The complete 360Each session was split into into three folds, and cross-validated decoding was performed across these folds from the same session. We ensured a balanced number of training examples for each class by upsampling underrepresented classes if necessary. A balanced accuracy score was calculated for each test set and results were pooled across all cross-validation runs. To asses above-chance classification accuracy the resulting scores were tested to exceed a chance baseline (16.66%) using one-sided, one-sample t-tests and one-sided comparisons to permutation distributions. Said distributions resulted from repeating individual classification procedures 1000 times with randomly permuted class labels in the training set. A permutation distribution of sample means was obtained by following the same averaging procedure as for the true values, just for each iteration of the permutation. To test whether classification accuracy was influenced by the various design factors , linear mixed models (LMM) were used to asses possible main effects and their interactions. Specifically, the model included fixed main effects of intervention (L-DOPA vs. Placebo), age group (OA vs. YA), ROI , and session order (L-DOPA – Placebo vs. Placebo – L-DOPA), as well as their interaction. The random effects included a participant wise intercept and random slope of intervention. For models including data only from one ROI, the random slope of intervention had to be dropped to avoid singularity (same number of random effects as there are data points).Additionally, we included several control factors in our models: A drug dosage relative to body weight and dosage/kg Influence of spatial angular difference on fMRI pattern similarityconfusion function. A simple Gaussian curve in the form ofTo test if neural representations of walking direction show the same circular similarity structure as directions in geometrical space, we analysed the structure of classifiers predictions as in The Gaussian model allowed us to assess age-differences in directional tuning specificity, which were captured by the precision parameter 2.8Task performance during the feedback phase was measured by the distance error: the Euclidean distance between the true location of an object and the location the participant placed the respective object . Performance for each trial was given by the average distance error across all five presented objects within a trial (missing responses due to exceeding the time limit were excluded). Kolmogorov–Smirnov tests indicated that performance scores of YA were not normally distributed . The increase in task performance was given by the session difference (L-DOPA – Placebo) of the log-transformed performance in the last trial of the task.33.1We first asked whether age group and intervention (L-DOPA vs. Placebo) affected participants’ object location memory, as expressed in distance errors on the last trial after learning. This this end, we ran a linear mixed model with fixed effects of interest for intervention and age group and a random effect of participant. This analysis showed a significant main effect of age group . A first analysis revealed that, averaged across sessions, decoding in our main areas of interest EVC (23.6%), RSC (18.4%) and HC (17.3%) was above chance baseline  on the last trial, in addition to age group and intervention. Because performance on the last trial was highly confounded with age group see  performaA model within the EVC revealed a significant main effect of distance error on the last trial on direction decoding  was related to EVC direction decoding in younger adults, and L-DOPA related changes in EVC decoding were related to changes in the same spatial memory measure. Moreover, these results showed that L-DOPA had comparable effects on HC walking direction signals in both age groups, but in the RSC these DA effects were present only in YA. An investigation of tuning specificity revealed no main effects of L-DOPA or L-DOPA Investigating age group differences, we found higher classification accuracy and precision of tuning functions in the EVC of YA compared to OA, a sign of neural dedifferentiation. No age effects on decoding in the HPC or RSC were found. These results confirm our previous finding that neural representations of walking direction can be found in EVC and RSC, and that strong age-related differentiation is present particularly in EVC Importantly, our results also offer a number of novel insights. First, we show a causal influence of L-DOPA on how walking directions are encoded in the brain. No statistical evidence for ROI difference were found, but the pattern of results suggests that this effect was mainly driven by effects in the HC and the RSC. Hence, further investigations are needed in this regard. Both areas have been linked to directional and other spatial information , and havSecond, the positive effects of DA on decoding are in line with computational models and empirical findings which suggest that DA affects neuronal gain . AccordiOther than individual differences in baseline DA level, task demand may also affect the inverted-U function of DA modulation . The spaBeyond these main implications, a number of interesting observation arose that warrant further investigation. Although we did not find any main effects of session order, we found some indications that session order could influence the effect of L-DOPA on neural signals that underlie spatial navigation. Age-differences in learning were stronger when L-DOPA was administered in the second compared to the first session. In addition, we found tuning specificity in EVC and RSC to be enhanced by L-DOPA only in participants who received the drug in the second session. Stronger effects when DA is administered in a second session have previously been reported in the context of spatial navigation . The reaOne open question is why the effect of L-DOPA on decoding in HC and RSC was not reflected in task performance, where no L-DOPA effect was found. In addition to generally small effects on neural representations, another explanation might be that task performance did not only depend on direction signals, but also relies on distance estimation and using distal and local cues, processes which themselves are affected by age . The tasWe would also like to point out a set of limitations that should be considered when interpreting the results of the presented work. While our results were statistically significant, and decoding performance compared to chance was broadly in line with previous studies e.g. , the repIn summary, we provide first causal insights into the role of dopamine in the encoding of spatial direction signals in the human brain. In addition, as suggested by exploratory data analysis, this enhancing effect of dopamine on the specificity of neural signals involved in navigation might mainly be present in the hippocampus and in the retrosplenial cortex, albeit there exclusively in younger adults. In combination with the replication of our own previous results , these fhttps://github.com/koch-means-cook/damson.All code of the involved analyses will be published and made openly available at The data supporting the findings of this study will be shared in preprocessed or aggregated form that ensures full anonymity of subjects, in line with funding and ethical regulations. Given the drug intervention and double blind nature of this work, the precise constraints on data sharing are currently evaluated.The authors declare no conflicts of interest.