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Abstract Background We assessed the prognostic value of serological humoral markers measured one month after the last dose of the primary COVID-19 vaccine course for predicting the risk of severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection over the following six months in specific populations. Methods ANRS0001SCOV-POPART is a French nationwide multicenter prospective observational cohort study assessing the immune response to Covid-19 vaccines routinely administered to 11 subgroups of patients with chronic disease and a control group. Participants from the ANRS0001S COV-POPART were included if they received at least two doses of Covid-19 vaccine for the primary vaccine course, had measurements of anti-Spike, anti-receptor binding domain (RBD) IgG-specific or neutralizing antibodies one month after the end of the primary vaccine course, without being infected by SARS-CoV-2 before the measurement. SARS-CoV-2 infections defined by a positive PCR/antigenic test or seroconversion to detectable anti nucleocapsid antibodies were evaluated until the first COVID-19 booster injection. Cox proportional hazards models taking into account interval-censored data were implemented to estimate the association between each antibody level and the risk of SARS-CoV-2 infection. Predictive performances were evaluated by the area under the receiving operating characteristic curve (AUROC). Results Two thousand five hundred seventy adults from a specific population and 1,123 from the control group were included. The cumulative probabilities of SARS-CoV-2 infections at five months after serological measurement were 6.0% 95% confidence interval: [5.0; 7.9] and 10.1% 95% confidence interval: [8.3; 11.9], respectively. Higher levels of anti-Spike IgG antibody were associated with a lower risk of SARS-CoV-2 infections in the control group, but not in the specific populations. Among the specific populations, AUROC were 74.5%, 74.9%, and 72.4% for anti-Spike IgG, anti-RBD IgG, and neutralizing antibodies, respectively. AUROC were superior in the specific populations, 82.0%, 81.2%, and 81.4% for anti-Spike IgG, anti-RBD IgG, and neutralizing antibodies, respectively. Conclusions Vaccine-induced antibody response after the primary course of Covid-19 infection only moderately discriminated between participants developing a SARS-CoV-2 infection during the Omicron wave. Trial registration NCT04824651 (first posted: 2021-04-01).

Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans.

Abstract The use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II–IV and III–IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III–IV aGVHD was lower with BM than with PB + ATG. All outcomes were similar in PB and PB + ATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II–IV; 16% for aGVHD III–IV) than with BM (28% for aGVHD II–IV; 8% for aGVHD III–IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III–IV remained higher with PB than with BM graft (HR = 2.0; range [1.17–3.43], p = 0.012).

Abstract Since the emergence of the Omicron variant of SARS-CoV-2, though considered less virulent, hospitalization and death rates among immunocompromised patients remain high, especially for poor responders to vaccination. We conducted a retrospective multicentric study to evaluate pre-exposure prophylaxis with AZD7442 (tixagevimab/cilgavimab) for preventing COVID-19 in adult allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Among the 161 patients of our cohort, 22 (14%) contracted COVID-19 after a median follow-up of 105 days, but no severe form was observed. Only one major adverse event was reported: an acute coronary syndrome, resolved without sequelae. Pending randomized controlled trial results, our data support the use of AZD7442 as pre-exposure prophylaxis for COVID-19 during Omicron wave in allo-HSCT patients who failed to develop humoral immunity to vaccination, to prevent severe and potentially lethal forms of SARS-CoV-2 infection.

The combination of chemotherapy and broad-spectrum antibiotics induces gut microbiota (GM) dysbiosis in acute myeloid leukaemia (AML) leading to additional complications. Here, the authors report the efficacy in GM restoration and safety of autologous faecal microbiota transfer in treated AML patients in a phase II clinical trial.

Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors.

Abstract Background Peripheral T cell lymphomas form a heterogeneous group with a usually dismal prognostic. The place of allogeneic stem cell transplantation to treat PTCL is debated. Methods We retrospectively analyzed the overall survival (OS), event-free survival (EFS), relapse, and transplant-related mortality (TRM) and associated variables in 285 adults with non-primary cutaneous PTCL (PCTL-NOS (39%), angioimmunoblastic T cell lymphomas (29%), anaplastic T cell lymphomas (15%), and other subtypes (17%)), who received alloSCT in 34 centers between 2006 and 2014. Results AlloSCT was given as part of front-line therapy (n = 138) to 93 patients in first complete response (CR) and 45 in first partial response (PR), and of salvage therapy (n = 147) to 116 patients for second or more CR/PR and 31 for progressive disease. Reduced-intensity conditioning (RIC) was given to 172 patients (62%), while 107 (38%) received myeloablative conditioning (MAC). The median follow-up was 72.4 months. The 2- and 4-year OS were 65% and 59%, respectively, and the cumulative incidence of relapse was 18% after 1 year and 19% after 2 years. TRM was 21% at 1 year, 24% after 2 years, and 28% after 4 years. In multivariate analysis, grade III–IV acute GvHD (HR = 2.57, 95% CI 1.53–4.31; p = 0.00036), low Karnofsky score < 80% (HR = 5.14, 95% CI 2.02–13.06; p = 0.00058), and progressive disease status before transplant (HR = 2.21, 95% CI 1.25–3.89; p = 0.0062) were significantly associated with a reduced OS. Conclusions The data demonstrate in the largest retrospective cohort of non-cutaneous PTCL so far reported that alloSCT after RIC or MAC is an effective strategy, even in chemoresistant patients.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative and useful strategy in high-risk relapsing CLL. Minimal Residual Disease (MRD) assessment at 12 months post-HSCT is predictive of relapse. This phase 2 study aimed to achieve M12 MRD negativity (MRDneg) using MRD-driven immune-intervention (Md-PII) algorithm based on serial flow-cytometry blood MRD, involving cyclosporine tapering followed if failure by donor lymphocytes infusions. Patients had high-risk CLL according to 2006 EBMT consensus, in complete or partial response with lymphadenopathy < 5 cm and comorbidity score ≤ 2. Donors were HLA-matched sibling or matched unrelated (10/10). Forty-two enrolled patients with either 17p deletion (front-line, n=11; relapse n=16) or other high-risk relapse (n=15) received reduced intensity-conditioning regimen before HSCT and were submitted to Md-PII. M12-MRDneg status was achieved in 64% versus 14.2% before HSCT. With a median follow-up of 36 months (range, 19-53), 3-year overall survival, non-relapse mortality and cumulative incidence of relapse are 86.9% (95%CI, 70.8-94.4), 9.5% (95%CI, 3.7-23.4) and 29.6% (95%CI, 17.3-47.7). Incidence of 2-year limited and extensive chronic graft versus host disease (cGVHD) is 38% (95%CI, 23-53) and 23% (95%CI, 10-36) including 2 cases post Md-PII. Fifteen patients converted to MRDneg either after CsA withdrawal (n=12) or after cGVHD (n=3). As a time-dependent variable, MRDneg achievement at any time-point correlates with reduced relapse (HR=0.14 [0.04-0.53], p=0.004) and improvement of both progression free (HR=0.18 [0.06-0.6], p

We explored the molecular evolution of the spike gene after the administration of anti-spike monoclonal antibodies in patients with mild or moderate forms of COVID-19. Four out of the 13 patients acquired a mutation during follow-up; two mutations (G1204E and E406G) appeared as a mixture without clinical impact, while the Q493R mutation emerged in two patients (one receiving bamlanivimab and one receiving bamlanivimab/etesevimab) with fatal outcomes. Careful virological monitoring of patients treated with mAbs should be performed, especially in immunosuppressed patients.

Usually self-limited, hepatitis E virus (HEV) infection may evolve to chronicity and cirrhosis in immunosuppressed patients. HEV infection has been described in solid-organ transplantation and hematology patients, but for allogeneic hematopoietic stem cell transplant (alloHSCT) recipients, only small cohorts are available. This retrospective nationwide multi-center series aimed to describe HEV diagnostic practices in alloHSCT French centers, and the course of infection in the context of alloHSCT. Twenty-nine out of 37 centers participated. HEV search in case of liver function tests (LFT) abnormalities was never performed in 24% of centers, occasionally in 55%, and systematically in 21%. Twenty-five cases of active HEV infection were diagnosed in seven centers, all because of LFT abnormalities, by blood nucleic acid testing. HEV infection was diagnosed in three patients before alloHSCT; HEV infection did not influence transplantation planning, and resolved spontaneously before or after alloHSCT. Twenty-two patients were diagnosed a median of 283 days after alloHSCT. Nine patients (41%) had spontaneous viral clearance, mostly after immunosuppressive treatment decrease. Thirteen patients (59%) received ribavirin, with sustained viral clearance in 11/12 evaluable patients. We observed three HEV recurrences but no HEV-related death or liver failure, nor evolution to cirrhosis.

Among repairs for ventriculoarterial discordance, ventricular septal defect, and pulmonary stenosis, aortic root translocation (Nikaidoh operation) offers the most anatomic result. With a diminutive pulmonary annulus or hypoplastic left ventricular outflow tract, the distance gained posteriorly with aortic translocation is negligible. We developed the “hemi-Nikaidoh” procedure as an alternative. Geometric shift is achieved by mobilizing the anterior two-thirds of the aortic root, and posterior aortic translocation is performed by plicating the left ventricular outflow tract without dividing the conus. The right ventricular outflow tract is reconstructed with an orthotopic conduit. Herein, we describe the hemi-Nikaidoh operation.

Abstract Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990–1994) to 58 years (2015–2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990–1994) to 54 (2015–2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015–2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990–1994) to 70% (2015–2021), p 40,000 transplants, providing insights for evaluating emerging DLBCL therapies.

Not available.

Penetrating chest trauma may result in significant intracardiac injury. A traumatic ventricular septal defect is a rare complication that requires surgical management, particularly if heart failure ensues. We report a case of delayed repair of an outlet-type ventricular septal defect and perforation of the aortic and pulmonary valve leaflets following a stab wound. This report highlights diagnostic and surgical considerations and also presents an opportunity to review the conotruncal anatomy, which may be relatively unfamiliar to many adult cardiac surgeons.

Objective: Ebstein's anomaly is a rare congenital heart malformation for which surgical and medical management are still controversial. The cone repair has transformed surgical outcomes in many of these patients. We aimed to present our results on the outcomes of patients with Ebstein's anomaly who underwent a cone repair or tricuspid valve replacement. Methods: A total of 85 patients who underwent a cone repair (mean age, 16.5 years) or tricuspid valve replacement (mean age, 40.8 years) between 2006 and 2021 were included. Univariate, multivariate, and Kaplan–Meier analyses were used to evaluate operative and long-term outcomes. Results: Residual/recurrent greater than mild-to-moderate tricuspid regurgitation at discharge was higher after cone repair compared with tricuspid valve replacement (36% vs 5%; P = .010). However, at last follow-up, the risk of greater than mild-to-moderate tricuspid regurgitation was not different between groups (35% in the cone group vs 37% in the tricuspid valve replacement group; P = .786). The tricuspid valve replacement group had a higher risk of tricuspid valve reoperation (37% vs 9%; P = .005) and tricuspid stenosis (21% vs 0%; P = .002) compared with the cone repair group. Kaplan–Meier freedom from reintervention was 97%, 91%, and 91% at 2, 4, and 6 years after cone repair, respectively, and 84%, 74%, and 68% at 2, 4, and 6 years after tricuspid valve replacement, respectively (P = .0191). At last follow-up, right ventricular function was significantly worse from baseline in the tricuspid valve replacement group (P = .0294). There were no statistical differences between age-stratified cohorts or surgeon volume in the cone repair group. Conclusions: The cone procedure offers excellent results, with stable tricuspid valve function and low reintervention and death rates at last follow-up. The rate of greater than mild-to-moderate residual tricuspid regurgitation at discharge was higher after cone repair compared with tricuspid valve replacement, but this did not expose the patient to a higher risk of reoperation or death at last follow-up. Tricuspid valve replacement was associated with a significantly higher risk of tricuspid valve reoperation and tricuspid valve stenosis, and worse right ventricular function at last follow-up.

The photovoice literature has focused mainly on research collaborations between researchers in academia and community partners. There is limited evidence of undergraduate students facilitating photovoice research projects with underserved Black, Indigenous, and persons of color (BIPOC). Students’ participation in photovoice research increases their understanding of local issues and can empower them to engage with local communities to create change. This qualitative study explored students’ experiences facilitating photovoice research with BIPOC older adults and frontline healthcare workers. In this study, we trained college students in photovoice methodological skills by introducing photovoice as a participatory qualitative methodology, explained ethics issues and the informed consent process, and clarified the steps and requirements for the photovoice project. Students were paired with BIPOC older adults and frontline healthcare workers. They facilitated the photovoice research project in four stages. Throughout the study, students critically reflected and wrote about the various aspects of their experience facilitating the photovoice research activities based on weekly structured reflection questions. In their weekly journal, student facilitators commented on how both older and younger BIPOC participants were friendly and kind, flexible with the research activity scheduling, inspiring with their stories, and selfless. Students’ reflections indicated that their participants experienced greater emotional and psychological burdens during the COVID-19 pandemic, exacerbated by the long-standing epidemic of systemic racism. Student facilitators overwhelmingly recognized participants’ resilience and perseverance despite these life challenges. Our findings highlight the importance of photovoice in developing and strengthening college students’ qualitative research skills and stimulating critical thinking and creativity, a sense of critical consciousness about social issues and society, and a sense of empowerment. Our results will be relevant to hospital/long-term care managers, policymakers, and researchers.

Introduction Despite consensus on climate change's impact on humans, medical schools have not widely adopted inclusion of environmental topics into their mandatory curriculum. This educational activity explicitly addresses climate change as one of the environmental determinants of health (EDH). Methods We developed a required, 1-hour module for all first-year medical students. This interactive, case-based, small-group activity was incorporated into a curriculum within an advising program but could be run independently. Before and after the session, participants completed evaluations assessing knowledge gains and attitude shifts. Results Of 183 first-year students, 155 completed both pre- and postmodule surveys. Participants' rating increased on the postmodule survey item “priority should be given to the discussion of EDH in medical education.” The Wilcoxon signed rank test determined this difference in priority was statistically significant (p < .001). Reported strengths of this activity included the cases, informative content on EDH, the video, the discussion, and highlighted EDH resources. Suggested areas for improvement included more information on how to apply concepts to clinical contexts, guidance on how to engage in EDH concepts, and more discussion time. As a result of the module, students planned to engage in recycling, reduced consumption, advocacy, and changes to mode of transportation. Discussion Climate change remains the greatest global threat to human health, and future physicians must be equipped to educate patients and policymakers on the harms of environmental hazards. This brief yet effective module offers one approach to incorporating this topic into medical school curricula.

Introduction Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is a major treatment for many haematological malignancies. The procedure has a good success rate but high transplant-related toxicity (TRM). TRM is mostly related to graft-versus-host disease (GvHD) and infectious complications. Alterations of the intestinal microbiota plays a major role in the development of allo-HSCT complications. The gut microbiota could be restored by faecal microbiota transplantation (FMT). However, there are no published randomised studies assessing the efficacy of FMT for GvHD prophylaxis.Methods and analysis This prospective, open-label, multi-centre, parallel-group, randomised phase-II clinical trial has been designed to assess the effect of FMT on toxicity in patients treated with myeloablative allo-HSCT for haematological malignancy. Based on Fleming’s single-stage sample size estimation procedure, the design plans to include 60 male and female patients aged 18 or over per arm, to be randomly assigned to two groups, one with and one without (control group) FMT. The primary endpoint is GvHD-free relapse-free survival rate at 1 year after allo-HSCT. Secondary endpoints are outcome measures of the impact of FMT on allo-HSCT-related morbidity and mortality (overall survival and progression-free survival at 1 and 2 years, haematological parameters, infectious complications, tolerance and safety of FMT). The primary endpoint will be evaluated according to assumptions of the single-stage Fleming design, compared between groups by a log-rank test and further investigated in a multivariate marginal structural Cox model taking into account centre effect. The proportional-hazard hypothesis will be verified using Schoenfeld’s test and by plotting residuals.Ethics and dissemination The local institutional review board (CPP Sud-Est II, France) issued approval on 27 January 2021. The French national authorities issued approval on 15 April 2021. The outcome of the study will be disseminated via peer-reviewed publications and at congresses.Trial registration number NCT04935684.

Abstract There is a dearth of research on cognitive aging and dementia in Asian Americans, particularly Vietnamese Americans, who are the fourth largest Asian subgroup in the United States. The National Institutes of Health is mandated to make certain that racially and ethnically diverse populations are included in clinical research. Despite the widespread recognition to ensure that research findings can be generalizable to all groups, there are no estimates of the prevalence or incidence of mild cognitive impairment and Alzheimer's disease and related dementias (ADRD) in Vietnamese Americans, nor do we understand ADRD risk and protective factors in this group. In this article, we posit that studying Vietnamese Americans contributes to a better understanding of ADRD in general and offers unique opportunities for elucidating life course and sociocultural factors that contribute to cognitive aging disparities. That is, the unique context of Vietnamese Americans may provide understanding in terms of within‐group heterogeneity and key factors in ADRD and cognitive aging. Here, we provide a brief history of Vietnamese American immigration and describe the large but often ignored heterogeneity of Asian Americans in the United States, elucidate how early life adversity and stress might influence late‐life cognitive aging, and provide a basis for the role of sociocultural and health factors in the study of Vietnamese cognitive aging disparities. Research with older Vietnamese Americans provides a unique and timely opportunity to more fully delineate the factors that contribute to ADRD disparities for all populations.

This study investigates how students experienced a sense of place and a sense of belonging in both in-person and virtual learning environments by analyzing student interview data. As educators and university students grapple with the ongoing COVID-19 pandemic, we consider how students experience the presence and absence of sense of place and belonging, and how this could inform faculty and staff practices. We conclude by offering recommendations for university educators, with a particular focus on the benefits of building communities of practice.

Immunoglobulin (IgG) Fc glycosylation has been shown to be important for the biological activity of antibodies. Fc sialylation is important for the anti-inflammatory activity of IgGs. However, evaluating the structure–activity relationship (SAR) of antibody Fc glycosylation has been hindered using simplified in vitro models in which antibodies are often displayed in monomeric forms. Presenting antibodies in monomeric forms may not accurately replicate the natural environment of the antibodies when binding their antigen in vivo. To address these limitations, we used different Fc-containing molecules, displaying their Fc domains in monovalent and multivalent fashion. Given the inhibitory role of Fc gamma receptor IIb (FcγRIIb) in autoimmune and inflammatory diseases, we focused on evaluating the impact of Fc sialylation on the activation of FcγRIIb. We report for the first time that in human cellular systems, sialic acid mediates the induction of FcγRIIb phosphorylation by IgG-Fc when the IgG-Fc is displayed in a multivalent fashion. This effect was observed with different types of therapeutic agents such as sialylated anti-TNFα antibodies, sialylated IVIg and sialylated recombinant multivalent Fc products. These studies represent the first report of the specific effects of Fc sialylation on FcγRIIb signaling on human immune cells and may help in the characterization of the anti-inflammatory activity of Fc-containing therapeutic candidates.

Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD (n=35) or at relapse (n=38). Among MRD patients, 91% had MRD >0.01% before blinatumomab, and 89% achieved complete MRD response after blinatumomab. High pre-blinatumomab MRD levels were associated with shorter relapse-free survival (P=0.049) and overall survival (OS) (P=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between MRD 0.1- 1% and

BackgroundSocial media enables the rapid consumption of news related to COVID-19 and serves as a platform for discussions. Its richness in text-based data in the form of posts and comments allows researchers to identify popular topics and assess public sentiment. Nonetheless, the vast majority of topic extraction and sentiment analysis based on social media is performed on the platform or country level and does not account for local culture and policies. ObjectiveThe aim of this study is to use location-based subreddits on Reddit to study city-level variations in sentiments toward vaccine-related topics. MethodsComments on posts providing regular updates on COVID-19 statistics in the Vancouver (r/vancouver, n=49,291), Toronto (r/toronto, n=20,764), and Calgary (r/calgary, n=21,277) subreddits between July 13, 2020, and June 14, 2021, were extracted. Latent Dirichlet allocation was used to identify frequently discussed topics. Sentiment (joy, sadness, fear, and anger) scores were assigned to comments through random forest regression. ResultsThe number of comments on the 250 posts from the Vancouver subreddit positively correlated with the number of new daily COVID-19 cases in British Columbia (R=0.51, 95% CI for slope 0.18-0.29; P

The coronavirus disease 2019 (COVID-19) pandemic intensified the stressful and already difficult circumstances of communities of color. Yet, there is no current photovoice research highlighting the lived experiences of these communities from two perspectives—the older adults (OAs) and the frontline healthcare workers (FLHWs). This qualitative study used photovoice to visually portray the struggles of Black, Indigenous, and persons of color (BIPOC) OAs (n = 7) and younger FLHWs (n = 5) who worked with older adults during the pandemic and how they coped and recovered from the challenges of the pandemic. The investigators conducted a three-day training of ten research assistants (RAs) who were paired with either an OA or an FLHW for the photovoice sessions conducted in four stages. Upon examination of the narratives, focus group transcriptions, and photo stories, it became clear that participants faced different challenges during the pandemic, such as the fear of COVID-19 exposure, struggles to adopt COVID-19 mitigation strategies, workplace challenges, and social isolation. Amid this crisis of suffering, isolation, and sadness, participants employed two major strategies to deal with the challenges of the pandemic: positive reappraisal and self-care practices. The findings have implications for clinical social workers, mental health counselors, faith communities, nurse managers and administrators, and policymakers.

Abstract Background Vanishing white matter (VWM) is a leukodystrophy, caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B)‐subunit genes (EIF2B1–EIF2B5); 80% are missense mutations. Clinical severity is highly variable, with a strong, unexplained genotype–phenotype correlation. Materials and Methods With information from a recent natural history study, we severity‐graded 97 missense mutations. Using in silico modeling, we created a new human eIF2B model structure, onto which we mapped the missense mutations. Mutated residues were assessed for location in subunits, eIF2B complex, and functional domains, and for information on biochemical activity. Results Over 50% of mutations have (ultra‐)severe phenotypic effects. About 60% affect the ε‐subunit, containing the catalytic domain, mostly with (ultra‐)severe effects. About 55% affect subunit cores, with variable clinical severity. About 36% affect subunit interfaces, mostly with severe effects. Very few mutations occur on the external eIf2B surface, perhaps because they have minor functional effects and are tolerated. One external surface mutation affects eIF2B‐substrate interaction and is associated with ultra‐severe phenotype. Conclusion Mutations that lead to (ultra‐)severe disease mostly affect amino acids with pivotal roles in complex formation and function of eIF2B. Therapies for VWM are emerging and reliable mutation‐based phenotype prediction is required for propensity score matching for trials and in the future for individualized therapy decisions.

The impact of invasive fungal infections on human health is a serious, but largely overlooked, public health issue. Commonly affecting the immunocompromised community, fungal infections are predominantly caused by species of Candida, Cryptococcus, and Aspergillus. Treatments are reliant on the aggressive use of pre-existing antifungal drug classes that target the fungal cell wall and membrane. Despite their frequent use, these drugs are subject to unfavorable drug-drug interactions, can cause undesirable side-effects and have compromised efficacy due to the emergence of antifungal resistance. Hence, there is a clear need to develop novel classes of antifungal drugs. A promising approach involves exploiting the metabolic needs of fungi by targeted interruption of essential metabolic pathways. This review highlights potential antifungal targets including enolase, a component of the enolase-plasminogen complex, and enzymes from the mannitol biosynthesis and purine nucleotide biosynthesis pathways. There has been increased interest in the enzymes that comprise these particular pathways and further investigation into their merits as antifungal targets and roles in fungal survival and virulence are warranted. Disruption of these vital processes by targeting unconventional pathways with small molecules or antibodies may serve as a promising approach to discovering novel classes of antifungals.

Postcopulatory sexual selection is credited as a principal force behind the rapid evolution of reproductive characters, often generating a pattern of correlated evolution between interacting, sex-specific traits. Because the female reproductive tract is the selective environment for sperm, one taxonomically widespread example of this pattern is the co-diversification of sperm length and female sperm-storage organ dimension. In Drosophila, having testes that are longer than the sperm they manufacture was believed to be a universal physiological constraint. Further, the energetic and time costs of developing long testes have been credited with underlying the steep evolutionary allometry of sperm length and constraining sperm length evolution in Drosophila. Here, we report on the discovery of a novel spermatogenic mechanism—sperm cyst looping—that enables males to produce relatively long sperm in short testis. This phenomenon (restricted to members of the saltans and willistoni species groups) begins early during spermatogenesis and is potentially attributable to heterochronic evolution, resulting in growth asynchrony between spermatid tails and the surrounding spermatid and somatic cyst cell membranes. By removing the allometric constraint on sperm length, this evolutionary innovation appears to have enabled males to evolve extremely long sperm for their body mass while evading delays in reproductive maturation time. On the other hand, sperm cyst looping was found to exact a cost by requiring greater total energetic investment in testes and a pronounced reduction in male lifespan. We speculate on the ecological selection pressures underlying the evolutionary origin and maintenance of this unique adaptation.

Summary: N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition. : Nguyen et al. show that NAAG is more abundant in higher grade cancers and a source of glutamate in cancers expressing GCPII, the enzyme that hydrolyzes NAAG to glutamate and NAA. The results suggest that GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition. Keywords: N-acetyl-aspartyl-glutamate, NAAG, glutamate carboxypeptidase II, GCPII, glutaminase inhibitor, glutamate deprivation, glutamate reservoir, stable isotope resolved, metabolomics

Psychogenic polydipsia is a well-described phenomenon in those with a diagnosed psychiatric disorder such as schizophrenia and anxiety disorders. Primary polydipsia is differentiated from psychogenic polydipsia by the lack of a clear psychotic disturbance. We present a case of a 27-month-old boy who presented with polyuria and polydipsia. Laboratory studies, imaging, and an observed water deprivation test were consistent with primary polydipsia. Polydipsia resolved after family limited his fluid intake and began replacing water drinking with other transition objects and behaviors for self-soothing. This case highlights the importance of water deprivation testing to differentiate between causes of polyuria, thereby avoiding misdiagnosis and iatrogenic hyponatremia. Secondly, primary polydipsia can result during the normal stages of child development without overt psychiatric disturbances.

Chronic inflammation is an important risk factor for the development of colorectal cancer; however, the mechanism of tumorigenesis especially tumor progression to malignancy in the inflamed colon is still unclear. Our study shows that epithelial signal transducer and activator of transcription 3 (STAT3), persistently activated in inflamed colon, is not required for inflammation-induced epithelial overproliferation and the development of early-stage tumors; however, it is essential for tumor progression to advanced malignancy. We found that one of the mechanisms that epithelial STAT3 regulates in tumor progression might be to modify leukocytic infiltration in the large intestine. Activation of epithelial STAT3 promotes the infiltration of the CD8+ lymphocyte population but inhibits the recruitment of regulatory T (Treg) lymphocytes. The loss of Stat3 in epithelial cells promoted the expression of cytokines/chemokines including CCL19, CCL28, and RANTES, which are known to be able to recruit Treg lymphocytes. Linked to these changes was the pathway mediated by sphingosine 1-phosphate receptor 1 and sphingosine 1-phosphate kinases, which is activated in colonic epithelial cells in inflamed colon with functional STAT3 but not in epithelial cells deleted of STAT3. Our data suggest that epithelial STAT3 plays a critical role in inflammation-induced tumor progression through regulation of leukocytic recruitment especially the infiltration of Treg cells in the large intestine.

Although allogeneic stem cell transplantation is not a standard therapy for multiple myeloma, some patients can benefit from this intense therapy. There are few reports on outcomes after umbilical cord blood transplantation in multiple myeloma, and investigation of this procedure is warranted. We retrospectively analyzed 95 patients, 85 with multiple myeloma and 10 with plasma cell leukemia, receiving single or double umbilical cord blood transplantation from 2001 to 2013. Median follow up was 41 months. The majority of patients received a reduced intensity conditioning. The cumulative incidence of neutrophil engraftment was 97%±3% at 60 days, and that of 100-day acute graft-versus-host disease grade II-IV was 41%±5%. Chronic graft-versus-host disease at two years was 22%±4%. Relapse and non-relapse mortality was 47%±5% and 29%±5% at three years, respectively. Three-year progression-free survival and overall survival were 24%±5% and 40%±5%, respectively. Anti-thymocyte globulin was associated with decreased incidence of acute graft-versus-host disease, higher non-relapse mortality, decreased overall and progression-free survival. Patients with high cytogenetic risk had higher relapse, and worse overall and progression-free survival. In conclusion, umbilical cord blood transplantation is feasible for multiple myeloma patients.

Double cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free-survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host-disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were € 165,253 and €191,827, respectively. The corresponding costs after myeloablative conditioning were € 192,566 and € 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of € 21,302 and € 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of € 34,581 and €66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality-adjusted life-years.