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The Omicron variant of SARS-CoV-2 infected many vaccinated and convalescent individuals1–3. Despite the reduced protection from infection, individuals who received three doses of an mRNA vaccine were highly protected from more serious consequences of infection4. Here we examine the memory B cell repertoire in a longitudinal cohort of individuals receiving three mRNA vaccine doses5,6. We find that the third dose is accompanied by an increase in, and evolution of, receptor-binding domain (RBD)-specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the second dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared with antibodies obtained after the second dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells, which differed from persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analysed neutralizing antibodies in the memory compartment after the third mRNA vaccine dose neutralized the Omicron variant. Thus, individuals receiving three doses of an mRNA vaccine have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help to explain why a third dose of a vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease.

Individuals who receive a third mRNA vaccine dose show enhanced protection against severe COVID-19, but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a third or fourth antigenic exposure by Delta or Omicron BA.1 infection, respectively. A third exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a third mRNA vaccine dose. A fourth antigenic exposure with Omicron BA.1 infection increased variant-specific plasma antibody and memory B cell responses. However, the fourth exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a third mRNA vaccine dose. In conclusion, a third antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.

The SARS-CoV-2 pandemic prompted a global vaccination effort and the development of numerous COVID-19 vaccines at an unprecedented scale and pace. As a result, current COVID- 19 vaccination regimens comprise diverse vaccine modalities, immunogen combinations and dosing intervals. Here, we compare vaccine-specific antibody and memory B cell responses following two-dose mRNA, single-dose Ad26.COV2.S and two-dose ChAdOx1 or combination ChAdOx1/mRNA vaccination. Plasma neutralizing activity as well as the magnitude, clonal composition and antibody maturation of the RBD-specific memory B cell compartment showed substantial differences between the vaccination regimens. While individual monoclonal antibodies derived from memory B cells exhibited similar binding affinities and neutralizing potency against Wuhan-Hu-1 SARS-CoV-2, there were significant differences in epitope specificity and neutralizing breadth against viral variants of concern. Although the ChAdOx1 vaccine was inferior to mRNA and Ad26.COV2.S in several respects, biochemical and structural analyses revealed enrichment in a subgroup of memory B cell neutralizing antibodies with distinct RBD-binding properties resulting in remarkable potency and breadth.

Individuals that receive a 3rd mRNA vaccine dose show enhanced protection against severe COVID19 but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a 3rd or 4th antigenic exposure by Delta or Omicron BA.1 infection, respectively. A 3rd exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a 3rd mRNA vaccine dose. A 4th antigenic exposure with Omicron BA.1 infection increased variant specific plasma antibody and memory B cell responses. However, the 4th exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a 3rd mRNA vaccine dose. In conclusion, a 3rd antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a 4th antigenic exposure with Omicron BA.1 is limited to increased strain specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.

Feedback inhibition of humoral immunity by antibodies was initially documented in guinea pigs by Theobald Smith in 1909, who showed that passive administration of excess anti-Diphtheria toxin inhibited immune responses1. Subsequent work documented that antibodies can enhance or inhibit immune responses depending on antibody isotype, affinity, the physical nature of the antigen, and engagement of immunoglobulin (Fc) and complement (C’) receptors2, 3. However, little is known about how pre-existing antibodies might influence the subsequent development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity IgG1 anti-SARS-CoV-2 receptor binding domain (RBD)-specific monoclonal antibodies, C144-LS and C135-LS, and subsequently two doses of a SARS-CoV-2 mRNA vaccine. The two antibodies target Class 2 and 3 epitopes that dominate the initial immune response to SARS-CoV-2 infection and mRNA vaccination4–8. Antibody responses to the vaccine in C144-LS and C135-LS recipients produced plasma antigen binding and neutralizing titers that were fractionally lower but not statistically different to controls. In contrast, memory B cells enumerated by flow cytometry after the second vaccine dose were present in higher numbers than in controls. However, the memory B cells that developed in antibody recipients differed from controls in that they were not enriched in VH3-53, VH1-46 and VH3-66 genes and predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations. These antibodies showed altered RBD target specificity consistent with epitope masking, and only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The results indicate that pre-existing high-affinity antibodies bias memory B cell selection and have a profound effect on the development of immunological memory in humans that may in part explain the shifting target profile of memory antibodies elicited by the 3rd mRNA vaccine dose.

Feedback inhibition of humoral immunity by antibodies was first documented in 19091. Subsequent studies showed that, depending on the context, antibodies can enhance or inhibit immune responses2,3. However, little is known about how pre-existing antibodies influence the development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity anti-SARS-CoV-2 monoclonal antibodies and subsequently two doses of an mRNA vaccine4–8. We found that the recipients of the monoclonal antibodies produced antigen-binding and neutralizing titres that were only fractionally lower compared than in control individuals. However, the memory B cells of the individuals who received the monoclonal antibodies differed from those of control individuals in that they predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations and showed altered receptor binding domain (RBD) target specificity, consistent with epitope masking. Moreover, only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The mechanism underlying these findings was examined in experiments in mice that showed that germinal centres formed in the presence of the same antibodies were dominated by low-affinity B cells. Our results indicate that pre-existing high-affinity antibodies bias germinal centre and memory B cell selection through two distinct mechanisms: (1) by lowering the activation threshold for B cells, thereby permitting abundant lower-affinity clones to participate in the immune response; and (2) through direct masking of their cognate epitopes. This may in part explain the shifting target profile of memory antibodies elicited by booster vaccinations9.

IntroductionCancer is the second leading cause of death among women in the United States. Previous studies demonstrate a higher prevalence of cancer among female orthopaedic surgeons. This study aimed to provide an updated prevalence of breast and all-cause cancer among female orthopaedic surgeons using a larger and more current study population.MethodsWe distributed surveys to female orthopaedic surgeons in national orthopaedic specialty societies. Six hundred seventy-two survey responses were collected. We calculated standardized prevalence ratios (SPRs) and 95% confidence intervals (CIs) based on gender-specific, race-specific, and age-specific cancer prevalence statistics in the US population. We compared the distribution of breast cancer risk factors with that of women in the 2018 and 2009 California Health Interview Survey.ResultsFifty-one of the 672 surveyed surgeons reported a diagnosis of invasive cancer. Twenty reported breast cancer with a prevalence higher among female orthopaedic surgeons compared with the US female population (SPR: 2.89, 95% CI: 2.16 to 3.81, P < 0.001). The breast cancer prevalence was also higher among orthopaedic surgeons compared with the US female population (SPR: 3.97, 95% CI: 2.43 to 6.14, P = 0.003).DiscussionThe increased prevalence of breast and all-cause cancer among a larger and more diverse cohort of female orthopaedic surgeons confirms previous studies and provides an update regarding a concerning public health issue within this specialty.

The single dose Ad.26.COV.2 (Janssen) vaccine elicits lower levels of neutralizing antibodies and shows more limited efficacy in protection against infection than either of the available mRNA vaccines. In addition, the Ad.26.COV.2 has been less effective in protection against severe disease during the Omicron surge. Here, we examined the memory B cell response to single dose Ad.26.COV.2 vaccination. Compared to mRNA vaccines, Ad.26.COV.2 recipients had significantly lower numbers of RBD-specific memory B cells 1.5 or 6 months after vaccination. Memory antibodies elicited by both vaccine types show comparable neutralizing potency against SARS-CoV-2 and Delta. However, the number of memory cells producing Omicron neutralizing antibodies was somewhat lower after Ad.26.COV.2 than mRNA vaccination. The data help explain why boosting Ad.26.COV.2 vaccine recipients with mRNA vaccines is effective, and why the Janssen vaccine appears to have been less protective against severe disease during the Omicron surge than the mRNA vaccine.One-Sentence SummaryAd.26.COV.2 vaccine results in lower quantity but comparable quality of protective memory B cells compared to mRNA vaccines.

The omicron variant of SARS-CoV-2 infected very large numbers of SARS-CoV-2 vaccinated and convalescent individuals1–3. The penetrance of this variant in the antigen experienced human population can be explained in part by the relatively low levels of plasma neutralizing activity against Omicron in people who were infected or vaccinated with the original Wuhan-Hu-1 strain4–7. The 3rd mRNA vaccine dose produces an initial increase in circulating anti-Omicron neutralizing antibodies, but titers remain 10-20-fold lower than against Wuhan-Hu-1 and are, in many cases, insufficient to prevent infection7. Despite the reduced protection from infection, individuals that received 3 doses of an mRNA vaccine were highly protected from the more serious consequences of infection8. Here we examine the memory B cell repertoire in a longitudinal cohort of individuals receiving 3 mRNA vaccine doses9,10. We find that the 3rd dose is accompanied by an increase in, and evolution of, anti-receptor binding domain specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the 2nd vaccine dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared to antibodies obtained after the 2nd vaccine dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells that differed from the persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analyzed neutralizing antibodies in the memory compartment obtained from individuals receiving a 3rd mRNA vaccine dose neutralized Omicron. Thus, individuals receiving 3 doses of an mRNA vaccine encoding Wuhan-Hu-1, have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help explain why a 3rd dose of an mRNA vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease.

Aims Diabetic ketoacidosis (DKA) is an emergency with high morbidity and mortality. This study examined patient factors associated with hospitalization for recurrent DKA. Methods Characteristics of 265 subjects admitted for DKA at Hennepin County Medical Center between January 2017 and January 2019 were retrospectively analyzed. Differences between subjects with a single admission versus multiple were reviewed. Results Forty-eight out of 265 patients had recurrent DKA. Risk factors included African American race (adjusted odds ratio (aOR) versus white non-Hispanic = 4.6, 95% CI 1.8–13, p = 0.001) or other race/ethnicity (aOR = 8.6, 2.9–28, p p = 0.10; aOR 53-99y versus 18-36y = 0.37, 0.12–0.99, p = 0.05), type 1 diabetes mellitus (aOR = 2.4, 1.1–5.5, p = 0.04), ever homeless (aOR = 2.5, 1.1–5.4, p = 0.03), and drug abuse (aOR = 3.2, 1.3–7.8, p = 0.009). DKA cost a median of $29,981 per admission. Conclusions Recurrent DKA is costly, and social determinants are strong predictors of recurrence. This study highlights the need for targeted preventative care programs.

BACKGROUND While often grouped with other noise aversions, fearful behaviour during storms is considered more complex than noise aversion alone. The objective here was to assess the effect of imepitoin for the treatment of storm anxiety in dogs. METHODS In this double-blind, placebo-controlled randomised study, eligible dogs completed a baseline then were randomised to receive either imepitoin (n = 30; 30 mg/kg BID) or placebo (n = 15) for 28 days. During storms, owners rated their dog's intensity for 16 behaviours using a Likert scale. Weekly, owners rated intensity and frequency of these behaviours. Summary scores were compared to baseline and between groups. RESULTS AND CONCLUSIONS Imepitoin was significantly superior to placebo in storm logs and weekly surveys for weeks 2 and 4, and in the end-of-study survey. Mild/moderate adverse events were reported in 26 patients (24 active: two placebo); the most frequent adverse event was ataxia. Owners of dogs in the imepitoin group, compared to placebo, were significantly more likely to report that treatment reduced their dogs fear and anxiety during storms (p

While often grouped with other noise aversions, fearful behaviour during storms is considered more complex than noise aversion alone. The objective here was to assess the effect of imepitoin for the treatment of storm anxiety in dogs.In this double-blind, placebo-controlled randomised study, eligible dogs completed a baseline then were randomised to receive either imepitoin (n = 30; 30 mg/kg BID) or placebo (n = 15) for 28 days. During storms, owners rated their dog's intensity for 16 behaviours using a Likert scale. Weekly, owners rated intensity and frequency of these behaviours. Summary scores were compared to baseline and between groups.Imepitoin was significantly superior to placebo in storm logs and weekly surveys for weeks 2 and 4, and in the end-of-study survey. Mild/moderate adverse events were reported in 26 patients (24 active: two placebo); the most frequent adverse event was ataxia. Owners of dogs in the imepitoin group, compared to placebo, were significantly more likely to report that treatment reduced their dogs fear and anxiety during storms (p 0.001) and other noise events (p 0.001). Twice daily administration of imepitoin decreased anxiety scores in dogs with storm anxiety. Future work may evaluate optimal dosage regimens.

The FreeStyle Libre flash glucose monitor (FGM) has made the use of continuous glucose monitors more accessible to the typical diabetes patient in an outpatient setting given the significantly lower cost and ease of use of FGM as compared to other systems. However, FGM is not labeled for use in a critically ill population. The critical care department at our institution queried the endocrine department about studying the use of FGM in critically ill patients. The interest of the critical care department was due to the potential of decrease in patient discomfort and decrease in time and effort of nursing and support staff related to the performance of fingerstick capillary glucoses if FGM was an adequate replacement measure. As of yet, there has been only minimal study of flash glucose monitoring in critically ill patients. One Australian study evaluated 8 patients in an ICU setting and determined that as compared with arterial blood glucose monitoring, flash glucose monitoring provided acceptable numerical and clinical accuracy.1 A Swedish study evaluated a total of 26 patients undergoing cardiac surgery and compared the use of FGM to use of a microdialysis intravascular system and concluded that the microdialysis system was more accurate, though in this study, only 25% of patients had diabetes. 2 To further investigate use of FGM in a critically ill population, we plan to undertake a single center, prospective, single arm study enrolling at least 20 and up to 40 patients. Inclusion criteria include a known diagnosis of type 1 or type 2 diabetes, age of 18 or older, and admission to the medical intensive care unit (MICU) with expected MICU stay of at least 48 hours. Participating subjects will have a sensor applied by a study investigator. After confirmation that the sensor is operational, the investigator will place opaque tape over the monitor to blind the monitor data. Nurses or medical assistants will conduct the standard of care fingerstick glucose monitoring per hospital protocol but will also have been notified of request to also pass FGM reader over the sensor at time of fingerstick glucose data collection. The primary objectives are to determine numerical accuracy in a critical care setting using the mean absolute relative difference and to determine clinical accuracy in a critical care setting using the surveillance error grid and the clarke error grid analyses. Preliminary data should be available by March, 2020. 1. Ancona P, Eastwood GM, Lucchetta L, Ekinci EI, Bellomo R, Martensson J. The performance of flash glucose monitoring in critically ill patients with diabetes. Crit Care Resusc 2017; 19: 167-174, June 2017. 2. Schierenbeck F, Franco-Cereceda A, Liska J. Accuracy of 2 Different Continuous Glucose Monitoring Systems in Patients Undergoing Cardiac Surgery: Intravascular Microdialysis Versus Subcutaneous Tissue Monitoring. Journal of Diabetes Science and Technology 2017, Vol. 11(1) 108–116

Bucket chlorination (where workers stationed at water sources manually add chlorine solution to recipients’ water containers during collection) is a common emergency response intervention with litt...

Scholars have identified many determinants of regulatory outcomes in unconventional oil and gas development, but few have focused on industry structure. We examine the effects of company size and ownership on revenue sharing outcomes in North Dakota (ND), drawing on political economy bargaining models. We examine firm-level characteristics of ND’s oil producers from 2005 to 2015, matching these data against revenue sharing outcomes and estimating effects using graphical and statistical methods. Along with this core analysis, we conduct key informant interviews with four elite actors in the unconventional oil and gas sector in ND, to provide supplementary details on industry structure and voluntary contributions to local communities. Our findings suggest that when industry is dominated by larger, publicly-traded firms, there is more revenue sharing between firms and the state government. However, we find anecdotal evidence that smaller, local firms may better target resources towards local needs. Our work contributes to a better understanding of the varied outcomes at the sub-national and sub-state level and expands the “resource curse” literature that suggests that industry characteristics shape local outcomes.

Category: Sports Introduction/Purpose: Osteochondral lesions of the talus (OLT) are common injuries, however management remains challenging. Lesion size remains a common determinant of treatment and microfracture remains common for smaller lesions. Microfracture provides access to mesenchymal stem cells within the subchondral bone. Dehydrated micronized allogenic cartilage (DMAC) (BioCartilage, Arthrex, Naples, FL) utilizes a single stage attempt to augment microfracture with a scaffold over the defect to improve hyaline cartilage restoration. DMAC requires hydration with plasma rich protein (PRP) or bone marrow aspirate concentrate (BMAC). Currently, there is limited literature on pain scores and return-to-activities and satisfactory return- to-sport following DMAC treatments. The purpose of this study is to report pain scores, percent and time return-to -activities, percent and time to satisfactory return-to-sport following microfracture + DMAC and isolated microfracture. Methods: We reviewed a series of 65 cases (37 female and 28 male; mean age 34.6 (SD 14.1); mean BMI 27.3 (SD 6.2)) between 2010 and 2019 in which surgical treatment for OLT consisted of microfracture + DMAC, or isolated microfracture. Surgical procedure was determined by treating surgeon. Demographic, visual analog scale (VAS) pain scores (0-10), return-to-activities, and satisfactory-return-to-sport were collected preoperatively and postoperatively at 3-months, 6-months, and 1 year. Return-to- activities was defined as any engagement in desired activities, whereas satisfactory-return-to-sport was determined by patient- report. T-tests were used to determine between group differences. Results: Sixty-five cases (DMAC 25; isolated-microfracture: 40) demonstrated mean pain score at 3-months for DMAC and isolated-microfracture of 0.8 and 2.0, respectively, (p=0.04). There were no significant differences in remaining pain scores. By 1- year, 100% of DMAC and 87.5% of isolated-microfracture returned-to-activities, p=0.09. Of those that returned-to-activities there was no difference in time-to-return-to-activities between groups 82.9 days vs 82.4 days. By 1-year, patients that return-to-sport demonstrated a patient-reported satisfactory-level-of-return of 52.0% in DMAC and 37.5% in isolated-microfracture. Of those that returned satisfactorily-to-sport, the time-to-satisfactory-return-to-sport was similar (mean 139.5 and 135.7 days, p=0.66). A subgroup analysis of microfracture + DMAC group determined that PRP (n=16) had less pain at 3 months than BMAC (n=9), mean 0.8 vs 2.0, respectively; p=0.03, with no other differences noted (p>0.05). Conclusion: The use of microfracture + DMAC may improve early post-operative pain scores and improve ability to return to a patient-reported satisfactory level of sport by 1-year. Isolated microfracture and DMAC augmentation had similar rates and times to return-to-activities, and pain levels after 6-months post-operatively. The use of PRP to supplement DMAC improved early post- operative pain scores compared to BMAC which may be related to donor-site morbidity. Otherwise PRP and BMAC supplementation of DMAC had similar subsequent pain scores, and rate and time to return to activities. Augmentation of microfracture with DMAC for OLTs may improve outcomes compared to microfracture alone.

Ebola virus disease outbreaks in animals (including humans and great apes) start with sporadic host switches from unknown reservoir species. The factors leading to such spillover events are little explored. Filoviridae viruses have a wide range of natural hosts and are unstable once outside hosts. Spillover events, which involve the physical transfer of viral particles across species, could therefore be directly promoted by conditions of host ecology and environment. In this report, we outline a proof of concept that temporal fluctuations of a set of ecological and environmental variables describing the dynamics of the host ecosystem are able to predict such events of Ebola virus spillover to humans and animals. We compiled a data set of climate and plant phenology variables and Ebola virus disease spillovers in humans and animals. We identified critical biotic and abiotic conditions for spillovers via multiple regression and neural network-based time series regression. Phenology variables proved to be overall better predictors than climate variables. African phenology variables are not yet available as a comprehensive online resource. Given the likely importance of phenology for forecasting the likelihood of future Ebola spillover events, our results highlight the need for cost-effective transect surveys to supply phenology data for predictive modelling efforts. Electronic supplementary material The online version of this article (10.1007/s10393-017-1288-z) contains supplementary material, which is available to authorized users.

Past studies have indicated strong family bonds may act to buffer against adolescent substance abuse. However, this relationship is not clear, particularly when multiple substances and family dysfunction are examined. In this study, the relationship between alcohol use, marijuana use, and tobacco use and parental relationships were examined in 570 elementary and high school students. Results indicated that support in parent– child relationships was found to be inversely correlated with teen substance use. Clinical implications are discussed in light of these results.

Two theories exist on the relationship between bicuspid aortic valve (BAV) and aortapathy: Hemodynamic - aortic dilation results from shear stress of diseased BAV; Genetic - aorta is genetically abnormal and dilates independently of BAV disease progression. We explored these theories in patients