The Adverse Event Landscape of Stem Cell Transplant: Evidence for aGVHD Driving Early Transplant Associated Toxicities.

Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (aGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of aGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n = 69, abatacept cohort, n = 73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 aGVHD, only aGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 aGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified aGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between aGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant aGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).

Evaluation of quality of life in patients with schizophrenia: An inpatient social welfare institution-based cross-sectional study.

Schizophrenia is a chronic mental illness with a poor quality of life (QoL). The main aim of this study was to measure the QoL and factors that affect the QoL of patients with schizophrenia placed in a social welfare institution. This cross-sectional study included 287 patients with schizophrenia who were treated in a long-stay social care institution in which QoL was assessed using five different instruments: the World Health Organization Quality of Life scale, the EuroQoL Five-Dimension-Five-Level scale (including the visual analog scale), the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form, and the Brief Psychiatric Rating Scale. To determine the impact of patients' characteristics on score values, multiple linear regression using backward elimination was employed. Due to non-normality in the distribution of the dependent variables, a Box-Cox power transformation was applied to each dependent variable prior to conducting multiple linear regression analysis. Results revealed that patients with schizophrenia have lower QoL. Our study revealed that age, level of education, type of accommodation, type of pavilion, age of onset of the disease, number of prescribed antipsychotics, number of psychiatric comorbidities, duration of therapy, and the number of daily doses of antipsychotics are dominant contributors to the QoL in patients with schizophrenia who were treated in social welfare institution.

Perceptions of and preparedness for cross-cultural care: a survey of final-year medical students in Ireland.

BACKGROUND: Migration is increasing globally, and societies are becoming more diverse and multi-ethnic. Medical school curricula should prepare students to provide high-quality care to all individuals in the communities they serve. Previous research from North America and Asia has assessed the effectiveness of medical cultural competency training, and student preparedness for delivery of cross-cultural care. However, student preparedness has not been explored in the European context. The aim of this study was to investigate how prepared final-year medical students in the Republic of Ireland (ROI) feel to provide care to patients from other countries, cultures, and ethnicities. In addition, this study aims to explore students' experiences and perceptions of cross-cultural care. METHODS: Final-year medical students attending all six medical schools within the ROI were invited to participate in this study. A modified version of the Harvard Cross-Cultural Care Survey (CCCS) was used to assess their preparedness, skill, training/education, and attitudes. The data were analysed using IBM SPSS Statistics 28.0, and Fisher's Exact Test was employed to compare differences within self-identified ethnicity groups and gender. RESULTS: Whilst most respondents felt prepared to care for patients in general (80.5%), many felt unprepared to care for specific ethnic patient cohorts, including patients from a minority ethnic background (50.7%) and the Irish Traveller Community (46.8%). Only 20.8% of final-year students felt they had received training in cross-cultural care during their time in medical school. Most respondents agreed that they should be assessed specifically on skills in cultural competence whilst in medical school (83.2%). CONCLUSIONS: A large proportion of final-year medical students surveyed in Ireland feel inadequately prepared to care for ethnically diverse patients. Similarly, they report feeling unskilled in core areas of cross-cultural care, and a majority agree that they should be assessed on aspects of cultural competency. This study explores shortcomings in cultural competency training and confidence amongst Irish medical students. These findings have implications for future research and curricular change, with opportunities for the development of relevant educational initiatives in Irish medical schools.

Overlap chronic GVHD is associated with adverse survival outcomes compared to classic chronic GVHD.

Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD ('ocGVHD'), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype.

Evaluation of Risk Factors for the Occurrence of Limb Fractures in Children Due to Unintentional Injury in Podgorica, Montenegro, Mediterranean.

Background and Objectives: Limb injuries in childhood are very common, with most of them being unintentional and often accompanied by soft tissue injuries. The aim of our study was to determine the risk factors that contribute to the occurrence of limb fractures as the most common type of accidental injury to children in our conditions. Materials and Methods: This study was designed as a prospective clinical analysis of predictive factors with a "nested" case-control study. It included all patients under the age of 18 who were diagnosed with unintentional limb injury and limb fracture due to accidental injury, at the Clinical Center of Montenegro, Podgorica, in the period of 7 January 2020-30 June 2021. Results: The gender of the child and the occurrence of the fracture are not related, and a statistically significant relationship was found between the occurrence of the fracture and the place of residence, the child's age, body mass index (BMI), the affected limb, the method of injury, and the mental state of the parents of the injured child, as well as their economic status. It was proved that the older the child was, the lower the chance of injury, while multivariate analysis proved that BMI could be a predictor of accidental fracture. The most common method of accidental limb fractures in children was a fall from a height. Conclusions: The analysis of factors that influence the occurrence of children's injuries is of great importance for public health. Such and similar research can enable a better understanding of the factors that influence accidental injuries, and therefore influence the prevention of these injuries by organizing various educational materials at the primary healthcare level or at the school level, for both children and parents.

Antidiabetic effects of polyherbal mixture made of Centaurium erythraea, Cichorium intybus and Potentilla erecta.

ETHNOPHARMACOLOGICAL RELEVANCE: The polyherbal mixture made of Centaurium erythraea aerial parts and Cichorium intybus roots and Potentilla erecta rhizomes has been used for centuries to treat both the primary and secondary complications of diabetes. AIM OF THE STUDY: As a continuation of our search for the most effective herbal mixture used as an ethnopharmacological remedy for diabetes, this study aimed to compare the in vitro biological activities of this polyherbal mixture and its individual ingredients, and, most importantly, to validate the ethnopharmacological value of the herbal mixture through evaluation of its phytochemical composition, its potential in vivo toxicity and its effect on diabetes complications. MATERIALS AND METHODS: Phytochemical analysis was performed using HPLC-UV. Antioxidant activity was estimated via the DPPH test. Potential cytotoxicity/anticytotoxicity was assessed using an in vitro RBCs antihemolytic assay and an in vivo sub-chronic oral toxicity method. Antidiabetic activity was evaluated using an in vitro α-amylase inhibition assay and in vivo using a chemically induced diabetic rat model. RESULTS: The HPLC-UV analysis revealed the presence of p-hydroxybenzoic acid, p-hydroxybenzoic acid derivative, catechin, five catechin derivatives, epicatechin, isoquercetin, hyperoside, rutin, four quercetin derivatives, caffeic acid, and four caffeic acid derivatives in the polyherbal mixture decoction. Treatment with the decoction has shown no toxic effects. The antioxidant and cytoprotective activities of the polyherbal mixture were higher than the reference's ones. Its antidiabetic activity was high in both in vitro and in vivo studies. Fourteen days of treatment with the decoction (15 g/kg) completely normalized blood glucose levels of diabetic animals, while treatments with insulin and glimepiride only slightly lowered glycemic values. In addition, lipid status of treated animals as well as levels of serum AST, ALT, ALP, creatinine, urea and MDA were completely normalized. In addition, the polyherbal mixture completely restored the histopathological changes of the liver, kidneys and all four Cornu ammonis regions of the hippocampus. CONCLUSIONS: The polyherbal mixture was effective in the prevention of both primary and secondary diabetic complications such as hyperlipidemia, increased lipid peroxidation, non-alcoholic fatty liver disease, nephropathy and neurodegeneration.

Seasonal Dynamics and Physiological Age of Ixodid Ticks Collected from Dogs.

In order to reproduce and complete life cycles, ticks have to feed on different hosts, thus participating as vectors and reservoirs in the maintenance and circulation of different pathogens. Since dogs can serve as suitable hosts for numerous tick species, the aims of this study were to determine tick species and their seasonal occurrence on pet dogs and to compare the accuracy of three indices frequently used to calculate engorged female physiological age. Ticks were collected from dogs brought to veterinary clinics. Three indices were analyzed: scutal index, alloscutal/scutal index ratio, and physiological age index. Four tick species were identified: Ixodes ricinus, Dermacentor marginatus, D. reticulatus, and Rhipicephalus sanguineus group, and the last was the most abundant. The highest number of collected ticks was in April, but two species were continuously active throughout the year. The statistical analyses distinguished the physiological age index as more precise because of lower variability. Dog owners usually ignore regular dog anti-tick treatments throughout the year, as they are not aware that ticks could be active during the winter months. Tick surveillance is unquestionably important in order to monitor and prevent the distribution of these vectors and also the diseases they transmit.

Herring roe oil in treatment of psoriasis - influence on immune cells and cytokine network.

Background: Psoriasis is a chronic immune-mediated skin disease with systemic inflammation and comorbidities. Although the disease severity may vary over time, many patients suffer from mild to moderate disease. Often local treatment will be sufficient to control the symptoms, but they may have several side effects. ω-3 polyunsaturated fatty acids have shown promising results in clinical trials with mild-to-moderate psoriasis. Methods: We explored the impact of phospholipid bound docosahexaenoic acid and eicosapentaenoic acid in a 3:1 ratio on immune cells and cytokine networks in peripheral blood of patients with psoriasis. We investigated the inter-relation of plasma cytokine levels and disease severity in 58 patients, and explored the status of circulating immune cell activity in 18 patients with non-severe psoriasis before and during herring roe oil supplementation. Plasma concentration of 22 cytokines was measured by Luminex technology and circulating immune cells were analyzed by multicolor flow cytometry. Results: CCL2 levels decreased over time, and IFN-γR1 increased, possibly related to the action of ω-3 polyunsaturated fatty acids. We observed a shift from naïve to effector CD4+ T cells and decreases of CD38 expression on CD4+ and CD8+ T cells, CD56bright NK cells and CD14+CD16- classical monocytes. Conclusions: These findings support the beneficial effect of herring roe oil supplementation.

Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments. OBJECTIVE: We sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGD-IBD. METHODS: We conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium. RESULTS: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD. CONCLUSION: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.

Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events.

In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 µg/mL. However, a higher Ctrough_1 (≥39 µg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 µg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 µg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131.

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium.

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. INTERPRETATION: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. FUNDING: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.

A Registry Study of 240 Patients with X-Linked Agammaglobulinemia Living in the USA.

PURPOSE: To understand the natural history and clinical outcomes for patients with X-linked agammaglobulinemia (XLA) in the United States utilizing the United States Immunodeficiency Network (USIDNET) patient registry. METHODS: The USIDNET registry was queried for data from XLA patients collected from 1981 to 2019. Data fields included demographics, clinical features before and after diagnosis of XLA, family history, genetic mutation in Bruton's tyrosine kinase (BTK), laboratory findings, treatment modalities, and mortality. RESULTS: Data compiled through the USIDNET registry on 240 patients were analyzed. Patient year of birth ranged from 1945 to 2017. Living status was available for 178 patients; 158/178 (88.8%) were alive. Race was reported for 204 patients as follows: White, 148 (72.5%); Black/African American, 23 (11.2%); Hispanic, 20 (9.8%); Asian or Pacific Islander, 6 (2.9%), and other or more than one race, 7 (3.4%). The median age at last entry, age at disease onset, age at diagnosis, and length of time with XLA diagnosis was 15 [range (r) = 1-52 years], 0.8 [r = birth-22.3 years], 2 [r = birth-29 years], and 10 [r = 1-56 years] years respectively. One hundred and forty-one patients (58.7%) were < 18 years of age. Two hundred and twenty-one (92%) patients were receiving IgG replacement (IgGR), 58 (24%) were on prophylactic antibiotics, and 19 (7.9%) were on immunomodulatory drugs. Eighty-six (35.9%) patients had undergone surgical procedures, two had undergone hematopoietic cell transplantation, and two required liver transplantation. The respiratory tract was the most affected organ system (51.2% of patients) followed by gastrointestinal (40%), neurological (35.4%), and musculoskeletal (28.3%). Infections were common both before and after diagnosis, despite IgGR therapy. Bacteremia/sepsis and meningitis were reported more frequently before XLA diagnosis while encephalitis was more commonly reported after diagnosis. Twenty patients had died (11.2%). The median age of death was 21 years (range = 3-56.7 years). Neurologic condition was the most common underlying co-morbidity for those XLA patients who died. CONCLUSIONS: Current therapies for XLA patients reduce early mortality, but patients continue to experience complications that impact organ function. With improved life expectancy, more efforts will be required to improve post-diagnosis organ dysfunction and quality of life. Neurologic manifestations are an important co-morbidity associated with mortality and not yet clearly fully understood.

The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions.

BACKGROUND: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. OBJECTIVE: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. METHODS: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. RESULTS: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). CONCLUSIONS: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

Biological treatment in severe psoriasis: Influence on peripheral blood dendritic cells.

In-depth immunophenotyping by flow cytometry of peripheral blood dendritic cell (DC) populations of psoriasis vulgaris without (PsO; N = 23) or with psoriatic arthritis (PsA; N = 15), before (T1) and after 12 months (T2) therapy with the anti-TNF drugs infliximab, etanercept, the anti-IL-17A secukinumab and the anti-IL12/IL-23 ustekinumab. Compared to healthy donors (N = 38), patients with PsA displayed lower frequencies of dendritic cell subsets pDC, cDC1 and cDC2, which were normalized following treatment except pDC. In contrast, patients with PsO only displayed lower frequencies of pDC which were normalized following treatment. Figure created with BioRender.com.

Lentiviral Gene Therapy for Artemis-Deficient SCID.

BACKGROUND: The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation. METHODS: We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C, in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months. RESULTS: Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor ß chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report. CONCLUSIONS: Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).

Atropine and Scopolamine in Maize Products from the Retail Stores in the Republic of Serbia.

The cereal grains, which represent the cultivated grasses fruits, supply almost half of the total caloric requirements for humans and provide more nourishment compared with any other class of the food. Out of many cereals used for food, maize, rice, and wheat are the most important food resources for humans, representing 94% of the total cereals consumption. According to the data of the Republic Institute of Statistics for the year 2018, the harvested areas of corn amount to 906,753 hectares. The production of about 7 million tons was achieved with an average yield of 7.7 t/ha according to the Ministry of Agriculture of the Republic of Serbia. Serbia is still among the ten largest exporters of wheat and corn in the world for the period of 2014/15-2017/18. More precisely, it ranks seventh in the export of corn. Utilization of maize products for food animal nutrition (1000 t) is 491,48, and for industrial processing (1000 t) 278,862 expressed as the total consumption (1000 t) is 769,910. Therefore, a total of 103 samples of maize products were analyzed for the presence of toxins, i.e., tropane alkaloids (TAs). The samples were collected from the retail stores in the Republic of Serbia in 2021 and analyzed for the presence of atropine and scopolamine (33 corn grits, 39 polenta, and 31 semolina samples). Therefore, the Recommendation 2015/976/EU on the monitoring of TAs in food was adopted by the EU Commission to obtain more occurrence data on TAs in food. The monitoring extent, however, is restricted because reliable analytical methods and appropriate sensitivity are limited. There was a limit of 1 g/kg for each atropine and scopolamine in cereals containing millet, sorghum, buckwheat, or their derivatives. All the samples were analyzed by the LC-MS/MS. The LOQ was set at 1.0 µg/kg. Out of the total 103 tested samples, 32 samples (31.1%) were contaminated with atropine and scopolamine in concentrations above the LOQ. The highest concentrations of the studied TAs were observed in a semolina sample-atropine: 58.80 µg/kg, scopolamine: 10.20 µg/kg. The obtained results indicate that the TAs concentrations are above the LOQ which can be considered potential human and animal health hazards.

Aberrant signaling of immune cells in Sjögren's syndrome patient subgroups upon interferon stimulation.

Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, characterized by mononuclear cell infiltrates in the salivary and lacrimal glands, leading to glandular atrophy and dryness. Patient heterogeneity and lack of knowledge regarding its pathogenesis makes pSS a difficult disease to manage. Methods: An exploratory analysis using mass cytometry was conducted of MAPK/ERK and JAK/STAT signaling pathways in peripheral blood mononuclear cells (PBMC) from 16 female medication free pSS patients (8 anti-Sjögren's syndrome-related antigen A negative/SSA- and 8 SSA+) and 8 female age-matched healthy donors after stimulation with interferons (IFNs). Results: We found significant differences in the frequencies of memory B cells, CD8+ T central and effector memory cells and terminally differentiated CD4+ T cells among the healthy donors and patient subgroups. In addition, we observed an upregulation of HLA-DR and CD38 in many cell subsets in the patients. Upon IFNα2b stimulation, slightly increased signaling through pSTAT1 Y701 was observed in most cell types in pSS patients compared to controls, while phosphorylation of STAT3 Y705 and STAT5 Y694 were slightly reduced. IFNγ stimulation resulted in significantly increased pSTAT1 Y701 induction in conventional dendritic cells (cDCs) and classical and non-classical monocytes in the patients. Most of the observed differences were more prominent in the SSA+ subgroup, indicating greater disease severity in them. Conclusions: Augmented activation status of certain cell types along with potentiated pSTAT1 Y701 signaling and reduced pSTAT3 Y705 and pSTAT5 Y694 induction may predispose pSS patients, especially the SSA+ subgroup, to upregulated expression of IFN-induced genes and production of autoantibodies. These patients may benefit from therapies targeting these pathways.

The advantages of co-digestion of vegetable oil industry by-products and sewage sludge: Biogas production potential, kinetic analysis and digestate valorisation.

The production of edible vegetable oils generates considerable amounts of energy-rich waste, which is usually not utilised fully. Besides, inefficient management of such wastes can have a negative impact on the environment. On the other hand, this waste can also serve as a raw material for the production of high value-added products, such is biogas. The mono-digestion of seven different by-products and wastes from the vegetable oil industry was investigated in this study: Pumpkin seeds press cake (PSPC), grape seeds press cake (GSPC), olive mill pomace (OMP), coconut oil cake (CC), filtration additive (FA), spent bleaching earth (SBE) and sludge from a vegetable oil industry (SOI) wastewater treatment plant. In addition, co-digestion of these substrates was performed with municipal sewage sludge (SS). Besides inoculum, rumen fluid was added to the reactors to enhance biogas production. The biogas production potential of the tested substrates was monitored by measuring various parameters. A kinetic analysis was later carried out and a growth test was performed on the digestates to evaluate their potential for agricultural use. The highest biogas yields in the mono-digestion test were obtained with the substrates with the highest fat content: 1402, 1288, 830 and 750 mL of biogas/gVS for SOI, FA, PSPC and CC substrate, respectively. Co-digestion of SS with by-products of vegetable oil industry such as FA, SBE, CC, SOI and PSPC increased the biogas yields by 94.9%, 74.1%, 30.8%, 27.4% and 23.6% compared to SS mono-digestion. Furthermore, the data for mono-digestion of PSPC, GSPC, and FA, and co-digestion of SS with these substrates, CC and SBE, have not been found in the literature to date. The maximum methane content ranged from 61 to 74 vol%, while the chemical oxygen demand removal efficiency ranged from 42 to 78%. Relatively high fatty acids contents and ammonium concentrations were measured in the reactors. Kinetic analysis showed the best fit to the experimental data for the Cone kinetic model (R2 > 0.98). The First order kinetic model, Monod, and the modified Gompertz model also exhibited high R2 values. The digestates obtained from co-digestion proved to be excellent in the cress seeds growth test at digestate concentrations of 5-10 wt%, while higher concentrations had a toxic effect.

Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC.

Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.