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TiO, TiO-ZnO (TZ) nanocomposite and PANI (Poly aniline) have been synthesized by simple sol-gel and direct chemical method, respectively, for the application in Dye Sensitized Solar Cell (DSSC). Structural, morphological and optical analyses were carried out using XRD, SEM, EDAX, PL and FTIR. PANI film has been fabricated for solid state DSSC. The photovoltaic performance has been checked for both liquid state and solid state in outdoor and indoor environmental condition. The results show that for TZ showed better performance compared to the monophasic TiO. Stability test showed that the solid state DSSC shows a better stability under constant illumination. Liquid state DSSC loses its efficiency by about 52.5 % while solid state to DSSC by about 13.3 % after 5 h of constant illumination. [ABSTRACT FROM AUTHOR]

Harvesting solar energy to produce value-added chemicals from carbon dioxide (CO 2 ) presents a promising route for addressing the complexities of sustainable energy systems and environmental issues. In this context, the development of metal-coordinated porous organic polymers (POPs) offers a vital avenue for improving the photocatalytic performance of organic motifs. The current study presents a metal-integrated photocatalytic system (namely, Zn@BP-POP ) developed via a one-pot Friedel-Crafts (F.C.) acylation strategy, for solid-gas phase photochemical CO 2 reduction to CO (CO 2 RR). The postsynthetic incorporation of metal (Zn) active sites on the host polymeric backbone of BP-POP significantly influences the catalytic activity. Notably, Zn@BP-POP demonstrates good photocatalytic performance in the absence of any cocatalyst and photosensitizer yielding CO while impeding the competitive hydrogen evolution reaction (HER) from water. The experimental findings collectively propose that the observed catalytic activity and selectivity arise from the synergistic interplay between the singular zinc catalytic centers and the light-harvesting capacity of the highly conjugated polymeric backbone. Further, X-ray absorption spectroscopy (XAS) analysis has significantly highlighted the prominent role played by the ZnN 2 O 4 single sites in the polymeric framework for activating the gaseous CO 2 molecules. Further, time-dependent density functional theory (DFT) analysis also reveals the thermodynamic feasibility of CO 2 RR over HER under optimized reaction conditions. This work cumulatively presents an effective strategy to demonstrate the importance of metal-active sites and effectively establish their structure-activity relationship during photocatalysis.

The Istrian (IS) and the Pag sheep (PS) are local Croatian breeds which provide significant income for the regional economy and have a cultural and traditional importance for the inhabitants. The aim of this study was to estimate some important population specific genetic parameters in IS (N = 1293) and PS (N = 2637) based on genome wide SNPs. Estimates of linkage disequilibrium effective population size (N e ) evidenced more genetic variability in PS (N e = 838) compared to IS (N e = 197), regardless of historical time (both recent and ancient genetic variability). The discrepancy in the recent genetic variability between these breeds was additionally confirmed by the estimates of genomic inbreeding (F ROH ), which was estimated to be notably higher in IS (F ROH>2 = 0.062) than in PS (F ROH>2 = 0.029). The average F ROH2-4 , F ROH4-8 , F ROH8-16 , and F ROH>16 were 0.26, 1.65, 2.14, and 3.72 for IS and 0.22, 0.61, 0.75, and 1.58 for PS, thus evidencing a high contribution of recent inbreeding in the overall inbreeding. One ROH island with > 30% of SNP incidence in ROHs was detected in IS (OAR6; 34,253,440-38,238,124 bp) while there was no ROH islands detected in PS. Seven genes (CCSER1, HERC3, LCORL, NAP1L5, PKD2, PYURF, and SPP1) involved in growth, feed intake, milk production, immune responses, and resistance were associated with the found autozygosity. The results of this study represent the first comprehensive insight into genomic variability of these two Croatian local sheep breeds and will serve as a baseline for setting up the most promising strategy of genomic Optimum Contribution Selection.

Purpose: The aim of this study was to determine how sodium hydrogen carbonate (NaHCO 3 ) ingestion during a 1-h recovery period after a 200-m front-crawl swim affects blood-gas levels, acid-base balance, and performance during a successive trial., Methods: Fourteen national-level male swimmers (age: 21 ± 3 years, body mass (BM):77 ± 10 kg, stature: 181 ± 7 cm) performed four maximal 200-m front-crawl tests. On one of the two days, the swimmers swam two 200-m tests with a 1-h recovery break, during which they drank water (WATER); on the other day, they performed the same protocol but consumed 0.3 g min -1 NaHCO 3 solution during the recovery break (NaHCO 3 )., Results: The ingestion of NaHCO 3 before the second test had no effect on swim time despite a greater [ HCO 3 - ] (19.2 ± 2.3 mmol L -1 ) than that measured during the first test (NaHCO 3 ) (14.5 ± 1.1 mmol L -1 ) and the other two tests (WATER) (12.7 ± 2.4 and 14.8 ± 1.5 mmol L -1 ; F = 18.554; p = 0.000) and a higher blood pH (7.46 ± 0.03) than that measured during the first test (NaHCO 3 ) (7.39 ± 0.02) and the other two tests (WATER) (7.16 ± 0.04 and 7.20 ± 0.05); (F = 5.255; p = 0.004). An increase in blood pCO 2 (0.2 ± 0.3 kPa) between both tests (NaHCO 3 ) compared to unchanged pCO 2 values (- 0.1 ± 0.3 kPa) between the other two tests (WATER) (t = - 2.984; p = 0.011; power = 0.741) was confirmed., Conclusions: NaHCO 3 ingestion during the recovery period between two 200-m front-crawl time trials had a strong buffering effect that did not positively affect performance. An increase in pCO 2 may have counterbalanced this impact., (© 2024. The Author(s).)

A biopolymer-based formulation for robust and active food packaging material was developed. This material consisted of a blend of three biopolymers (guar gum-sodium alginate-i-carrageenan) reinforced by cellulose nanocrystals (CNC) alongside the integration of silver nanoparticles (AgNPs) with varying sizes. The CNC utilized in this process was derived from cloth waste lint (CWL) generated from a household cloth dryer machine. This CNC synthesis underwent a series of solvent treatments to yield the CNC used in the composite. CNC and AgNPs were incorporated into the tribiopolymeric blend matrix to construct a nanocomposite film that showed excellent tensile strength (∼90 MPa). The nanocomposite film also exhibited antimicrobial activity against Escherichia coli ATCC 25922 and Bacillus cereus MTCC 1272. In this report, it was demonstrated that the zone of inhibition against E. coli and B. cereus depends on the variation of size and amount of AgNPs inside the polymeric matrix. The practical applicability of such a film was also demonstrated by applying it to sliced bread and the enhancement of the shelf life of the raped bread was compared with a control. Thus, the guar gum-sodium alginate-i-carrageenan tribiopolymer blend with a cloth waste lint extracted cellulose nanocrystal composite film is antimicrobial, hence, an excellent candidate as an active packaging film.

Ear length in sheep (Ovis aries) shows a wide range of natural variation, from the absence of an outer ear structure (anotia), to small outer ears (microtia), to regular ear length. Up until now, the underlying genetics of this phenotype has been studied in four sheep breeds from China, Jordan and Italy. These studies revealed a broad range of genes significantly associated with ear length, potentially indicating genetic heterogeneity across breeds or geographic regions. In the current study, we performed genome-wide SNP genotyping and haplotype-based mapping, in a population of 340 individuals, to identify loci influencing ear length variation in additional sheep breeds from Slovenia, Croatia, Cyprus and Greece. Additionally, two previously described candidate variants were also genotyped in our mapping population. The mapping model without candidate variant genotypes revealed only one genome-wide significant signal, which was located next to HMX1 on OAR6. This region was previously described as being associated with ear length variation in the Altay and Awassi sheep breeds. The mapping model including the candidate duplication genotype near HMX1 as a fixed effect explained the phenotypic variance on OAR6 and revealed an additional genome-wide significant locus on OAR13 associated with ear length. Our results, combined with published evidence, suggest that a duplication in the evolutionarily conserved region near HMX1 is the major regulator of ear length in sheep breeds descended from a larger region from Central Asia, to the Middle East, Cyprus, Greece and to the Alps. This distribution suggests an ancient origin of the derived allele., (© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

The inability of people living with HIV (PLWH) to eradicate human immunodeficiency virus (HIV) infection is due in part to the inadequate HIV-specific cellular immune response. The antiviral function of cytotoxic CD8+ T cells, which are crucial for HIV control, is impaired during chronic viral infection because of viral escape mutations, immune exhaustion, HIV antigen downregulation, inflammation, and apoptosis. In addition, some HIV-infected cells either localize to tissue sanctuaries inaccessible to CD8+ T cells or are intrinsically resistant to CD8+ T cell killing. The novel design of synthetic chimeric antigen receptors (CARs) that enable T cells to target specific antigens has led to the development of potent and effective CAR-T cell therapies. While initial clinical trials using anti-HIV CAR-T cells performed over 20 years ago showed limited anti-HIV effects, the improved CAR-T cell design, which enabled its success in treating cancer, has reinstated CAR-T cell therapy as a strategy for HIV cure with notable progress being made in the recent decade.Effective CAR-T cell therapy against HIV infection requires the generation of anti-HIV CAR-T cells with potent in vivo activity against HIV-infected cells. Preclinical evaluation of anti-HIV efficacy of CAR-T cells and their safety is fundamental for supporting the initiation of subsequent clinical trials in PLWH. For these preclinical studies, we developed a novel humanized mouse model supporting in vivo HIV infection, the development of viremia, and the evaluation of novel HIV therapeutics. Preclinical assessment of anti-HIV CAR-T cells using this mouse model involves a multistep process including peripheral blood mononuclear cells (PBMCs) harvested from human donors, T cell purification, ex vivo T cell activation, transduction with lentiviral vectors encoding an anti-HIV CAR, CAR-T cell expansion and infusion in mice intrasplenically injected with autologous PBMCs followed by the determination of CAR-T cell capacity for HIV suppression. Each of the steps described in the following protocol were optimized in the lab to maximize the quantity and quality of the final anti-HIV CAR-T cell products., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction : Central nervous system (CNS) tumours represent a significant public health issue worldwide, and their incidence and distribution vary across different populations. Although studies on CNS tumours have been conducted in various countries, there is a lack of information regarding their patterns in Macedonia. Therefore, this study is aimed at investigating the distribution, histopathological types and subtypes and demographic features of CNS tumours in our country. Materials and Methods : A cross sectional study was conducted using the electronic database of the Institute of Pathology - Medical Faculty, University "Ss. Cyril and Methodius" in Skopje which contains data from 3286 received and analysed surgical specimens, mainly from the University Clinic of Neurosurgery in Skopje, and a smaller number of surgical specimens from the University Surgical Centre "St. Naum Ohridski" in Skopje between 2012 and 2022. The collected and analysed data includes patient age, sex and histopathological types and subtypes of the tumours. Results : The majority of CNS tumours were diagnosed in adults aged between 50-70, with a male to female ratio of 1.5:1. The most common location of the tumours was the cerebrum, followed by the pituitary gland and cerebellum. The most frequent histological groups were gliomas, with glioblastoma as the most common diagnosis, followed by meningiomas. Conclusion : Following a detailed and thorough review of the CNS tumours in our study, we can conclude that the R. of Macedonia follows global statistics and trends regarding brain tumours., (© 2023 Panche Zdravkovski et al., published by Sciendo.)

Producing hydrogen peroxide (H 2 O 2 ) from H 2 O and O 2 under visible light irradiation is a promising solar-to-chemical energy conversion technology. Hydrogen peroxide has versatile applications as a green oxidant and liquid energy carrier but has been produced through energy-intensive and complex anthraquinone processes. Herein, we report the rational design of efficient and stable porous organic polymer (POP) containing redox centers, anthraquinone photocatalyst (ANQ-POP) for solar H 2 O 2 production. ANQ-POP is readily synthesized with stable dioxin-linkages via efficient one-pot, transition-metal-free nucleophilic aromatic substitution reactions between 1,2,3,4,5,6,7,8-octafluoro-9,10-anthraquinone (OFANQ) and 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP). Exhibiting a fibrillar morphology, ANQ-POP boasts a high surface area of 380 m 2 ∙g -1 and demonstrates thermal stability. With 10 % ethanol, ANQ-POP yields an H 2 O 2 production rate of 320 μmol g -1 under visible light irradiation. Moreover, ANQ-POP alone can efficiently produce H 2 O 2 without any photosensitizers and cocatalysts. Density functional theory calculations reveal that the quinone groups of the anthraquinone moieties can serve as redox centers for H 2 O 2 production under light irradiation. Furthermore, unlike most conventional photocatalysts, it can produce H 2 O 2 using only water and air by catalyzing both oxygen reduction and evolution reactions under light irradiation. Our findings provide an efficient, eco-friendly pathway for photocatalytic production of H 2 O 2 under mild reaction conditions using a dioxin-derived POP-based photocatalyst., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate the concentrations of essential trace and toxic elements in the milk of Lacaune sheep during lactation in intensive rearing systems. This research was conducted with 30 Lacaune sheep that were monitored in the early (60 days of lactation), medium (120 days of lactation), and late (180 days of lactation) stages of lactation. The sheep were fed a pelleted feed mixture (1 kg/day), a cereal mixture (600 g/day), and alfalfa hay (ad libitum). The essential (Fe, Zn, Cu, Co, Mn, Mo, Se, Cr, and Ni) and toxic element (heavy metals: Cd, Pb, As, and Hg) concentrations in the feed and milk were determined using an inductively coupled plasma mass spectrometer. Significant variations in the main essential trace and toxic elements, except for the Mo, Se, Ni, As, and Hg concentrations, were found in the milk of Lacaune sheep during lactation. As lactation progressed, in the late stage of lactation, significantly higher concentrations of Co, Mn, Mo, Cr, and Pb were found, while Zn and Cu in the milk of Lacaune sheep decreased significantly (4.15 and 0.21 mg/kg) compared to their concentrations in the early stage of lactation (5.66 and 0.43 mg/kg). Significantly lower concentrations of Fe and higher concentrations of Cd were found in the medium stage (0.23 mg/kg and 1.08 µg/kg) of lactation compared to both the early and late stages of lactation. An analysis of the correlation coefficients between the essential trace and toxic elements in Lacaune sheep milk during lactation determined a significantly positive correlation between Fe:Cr, Fe:Mn, Fe:Co, Fe:Se, Zn:Ni, Zn:Se, Cr:Mn, Cr:Co, Cr:Se, Cr:Mo, Mn:Co, Mn:Pb, Co:Ni, Co:Se, Ni:Se, Se:Mo, Se:Pb, and Cd:Pb. A significantly negative correlation was also found between Cu:Mn, Zn:Mo, Cg:Hg, and Hg:Pb. Based on the obtained results, it is recommended that the influence of the stage of lactation, as well as the breed of sheep, should be included when designing experiments. In general, sheep milk is rich in essential trace elements, but it also contains a very low content of toxic elements, which provides justification for increasing the breeding of Lacaune sheep and indicates the convenience of consuming their milk without risking the consumer's health.

Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor receptor 4 (FGFR4) is highly expressed in RMS and lowly expressed in healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen receptor (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as an adoptive T cell treatment for RMS. The 3A11 CAR T cells induced robust cytokine production and cytotoxicity against RMS cell lines in vitro. In contrast, a panel of healthy human primary cells failed to activate 3A11 CAR T cells, confirming the selectivity of 3A11 CAR T cells against tumors with high FGFR4 expression. Finally, we demonstrate that 3A11 CAR T cells are persistent in vivo and can effectively eliminate RMS tumors in two metastatic and two orthotopic models. Therefore, our study credentials CAR T cell therapy targeting FGFR4 to treat patients with RMS., Competing Interests: Declaration of interests J. Khan, R.J.O., D.S.D., and A.T.C. are inventors on international patent application no. PCT/US2016/052496. The 3A11 CAR sequence is in this patent application (see https://patents.justia.com/patent/11078286) filed on September 19, 2016, titled “Monoclonal antibodies specific for fibroblast growth factor receptor 4 (FGFR4) and methods of their use.”, (Published by Elsevier Inc.)

The physical properties of nanomagnetic particles are expected to be highly dependent on their size. In this study, besides the promising applications of nanocrystalline Ni-Zn spinel ferrites in the area of photocatalysis and free radical scavenging, we present a detailed study with appropriate scientific explanations on the role of size change in modifying and tuning the microstructural, optical and magnetic properties. Three nanostructured Zn 0.3 Ni 0.7 Fe 2 O 4 samples of different particle sizes were prepared via the chemical co-precipitation method. Crystallographic phase purity and formation of the spinel cubic phase for all the samples were tested by X-ray diffraction studies. The magnetic properties of the as-synthesized ferrite nanoparticles have been examined thoroughly at 5 K and 300 K. Emergence of superparamagnetic behavior has been observed for the sample with the smallest size ferrite nanoparticles (ZNF-1). The photocatalytic efficiency of all the nanocatalysts was tested on methylene blue (MB) dye and the smallest sized nanocatalyst (ZNF-1) was identified as the most efficient catalyst in degrading MB dye under light illumination. The degradation efficiency was found to decrease with increasing mean particle size of the prepared samples. The antioxidant properties of the prepared ferrite samples were also studied. Here, too, the ZNF-1 sample with the smallest sized nanoparticles exhibited maximum scavenging of free radicals compared to other samples. Hence, the present study clearly demonstrates that smaller-sized Ni-Zn spinel ferrites are efficient materials for tuning the physical properties as well as for use in photocatalytic and antioxidant applications., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

The development of efficient metal-free photocatalysts for the generation of reactive oxygen species (ROS) for sulfur mustard (HD) decontamination can play a vital role against the stockpiling of chemical warfare agents (CWAs). Herein, one novel concept is conceived by smartly choosing a specific ionic monomer and a donor tritopic aldehyde, which can trigger linker-independent regioselective protonation/deprotonation in the polymeric backbone. In this context, the newly developed vinylene-linked ionic polymers (TPA/TPD-Ionic) are further explored for visible-light-assisted detoxification of HD simulants. Time-resolved-photoluminescence (TRPL) study reveals the protonation effect in the polymeric backbone by significantly enhancing the life span of photoexcited electrons. In terms of catalytic performance, TPA-Ionic outperformed TPD-Ionic because of its enhanced excitons formation and charge carrier abilities caused by the donor-acceptor (D-A) backbone and protonation effects. Moreover, the formation of singlet oxygen ( 1 O 2 ) species is confirmed via in-situ Electron Spin Resonance (ESR) spectroscopy and density functional theory (DFT) analysis, which explained the crucial role of solvents in the reaction medium to regulate the ( 1 O 2 ) formation. This study creates a new avenue for developing novel porous photocatalysts and highlights the crucial roles of sacrificial electron donors and solvents in the reaction medium to establish the structure-activity relationship., (© 2023 Wiley-VCH GmbH.)

With greater accessibility and an increased number of patients being treated with CAR T cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood-derived (UCB) regulatory T cells (Tregs) can resolve inflammation and treat acute and immune-mediated lung injuries. Allogeneic, cryopreserved UCB Tregs have shown a clinical benefit in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Treg cells include a lack of plasticity under inflammatory micro-environments, no requirement for HLA matching, a long shelf life of cryopreserved cells, and immediate product availability, which makes them attractive for treating acute inflammatory syndromes. Therefore, we hypothesized that adjunct therapy with UCB Tregs may resolve the undesirable inflammation responsible for CAR T cell therapy-associated toxicity. In in vitro analysis, no interference from the addition of UCB Tregs was observed on CD19 CAR T cells' ability to kill CD19 Raji cells at different CAR T: Raji cell ratios of 8:1 (80.4% vs. 81.5%); 4:1 (62.0% vs. 66.2%); 2:1 (50.1% vs. 54.7%); and 1:1 (35.4% vs. 44.1%). In the xenogeneic B-cell lymphoma model, multiple injections of UCB Tregs were administered 3 days after CD19 CAR T cell injection, and no detrimental effect of add-on Tregs was noted on the circulating CD8 + T effector cells. The distribution of CAR T cells in multiple organs remained unaffected by the addition of the UCB Tregs. Specifically, no difference in the overall tumor burden was detected between the UCB Treg + CAR T vs. CAR T alone recipients. No tumor was detected in the liver or bone marrow in CAR T cells + UCB Tregs recipients, with a notable corresponding decrease in multiple circulating inflammatory cytokines when compared to CART alone recipients. Here we show the proof of concept for adjunct therapy with UCB Tregs to mitigate the hyper-inflammatory state induced by CAR T cells without any interference in their on-target anti-tumor activity. Administration of UCB Tregs after CAR T cells allows sufficient time for their synapse formation with tumor cells and exerts cytotoxicity, such that the UCB Tregs are diverted to interact with the antigen-presenting cells at the site of inflammation. Such a differential distribution of cells would allow for a two-pronged strategy of a UCB Treg "cooling blanket" effect and lay the groundwork for clinical study.

In recent times, a self-complementary balanced characteristic feature with the combination of both covalent bonds (structural stability) and open metal sites (single-site catalysis) introduced an advanced emerging functional nanoarchitecture termed metalated porous organic polymers (M-POPs). However, the development of M-POPs in view of the current interest in catalysis has been realized still in its infancy and remains a challenge for the years to come. In this work, we built benzothiazole-linked Fe-metalated porous organic polymer ( Fc-Bz-POP ) using ferrocene dicarboxaldehyde ( FDC ), 1,3,5-tris(4-aminophenyl) benzene ( APB ), and elemental sulfur (S 8 ) via a template-free, multicomponent, cost-effective one-pot synthetic approach. This Fc-Bz-POP is endowed with unique features including an extended network unit, isolated active sites, and catalytic pocket with a possible local structure, in which convergent binding sites are positioned in such a way that substrate molecules can be held in close proximity. Prospective catalytic application of this Fc-Bz-POP has been explored in executing catalytic allylic "C-H" bond functionalization of cyclohexene ( CHX ) in water at room temperature. Catalytic screening results identified that a superior performance with a CHX conversion of 95% and a 2-cyclohexene-1-ol selectivity ( COL ) of 80.8% at 4 h and 25 °C temperature has been achieved over Fc-Bz-POP , thereby addressing previous shortcomings of the other conventional catalytic systems. Comprehensive characterization understanding with the aid of synchrotron-based extended X-ray absorption fine structure (EXAFS) analysis manifested that the Fe atom with an oxidation state of +2 in our Fc-Bz-POP catalytic system encompasses a sandwich structural environment with the two symmetrical eclipsed cyclopentadienyl (Cp) rings, featuring nearest-neighbor (NN) Fe-C (≈2.05 Å) intramolecular bonds, as validated by the Fe L 3 -edge EXAFS fitting result. Furthermore, in situ attenuated total reflection-infrared spectroscopy (ATR-IR) analysis data for liquid-phase oxidation of cyclohexene allow for the formulation of a molecular-level reaction mechanistic pathway with the involvement of specific reaction intermediates, which is initiated by the radical functionalization of the allyl hydrogen. A deep insight investigation from density functional theory (DFT) calculations unambiguously revealed that the dominant pathway from cyclohexene to 2-cyclohexene-1-ol is initiated by an allyl-H functionalization step accompanied by the formation of 2-cyclohexene-1-hydroperoxide species as the key reaction intermediate. Electronic properties obtained from DFT simulations via the charge density difference plot, Bader charge, and density of state (DOS) demonstrate the importance of the organic polymer frame structure in altering the electronic properties of the Fe site in Fc-Bz-POP , resulting in its high activity. Our contribution has great implications for the precise design of metalated porous organic polymer-based robust catalysts, which will open a new avenue to get a clear image of surface catalysis.

The gene and cell therapy field saw its first approved treatments in Europe in 2012 and the United States in 2017 and is projected to be at least a $10B USD industry by 2025. Despite this success, a massive gap exists between the companies, clinics, and researchers developing these therapeutic approaches, and their availability to the patients who need them. The unacceptable reality is a geographic exclusion of low-and middle-income countries (LMIC) in gene therapy development and ultimately the provision of gene therapies to patients in LMIC. This is particularly relevant for gene therapies to treat human immunodeficiency virus infection and hemoglobinopathies, global health crises impacting tens of millions of people primarily located in LMIC. Bridging this divide will require research, clinical and regulatory infrastructural development, capacity-building, training, an approval pathway and community adoption for success and sustainable affordability. In 2020, the Global Gene Therapy Initiative was formed to tackle the barriers to LMIC inclusion in gene therapy development. This working group includes diverse stakeholders from all sectors and has set a goal of introducing two gene therapy Phase I clinical trials in two LMIC, Uganda and India, by 2024. Here we report on progress to date for this initiative., (© 2021. The Author(s).)

Chimeric Antigen Receptor (CAR) T cell therapy is an accepted standard of care for relapsed/refractory B cell malignancies. However, the high cost of existing industry-driven centralized production makes this therapy unaffordable in low and middle-income countries. Decentralized or point of care manufacturing has the potential to overcome some of these challenges. Here we demonstrate a decentralized manufacturing process for anti-CD19-CAR-T cells using a fully automated closed system (Miltenyi CliniMACS Prodigy®) is feasible in a developing country setting. Validation run data, as part of a pre-clinical trial safety evaluation, demonstrates the successful and robust manufacturing of anti-CD19 CAR-T cells with T cell expansion of 25 to 47-fold. The median transduction efficiency was 48.8%, with a median viability of 98% and fulfillment of all standard release criteria assays for clinical application. Evaluation of production costs in an academic, not for profit setting in India provide a benchmark for low and middle-income pricing which could greatly increase access to this therapy. Based on our analysis, the cost per product would be approximately $35,107 US dollars. Our data highlights the safety, efficacy, and reproducibility of the process for use in planned future clinical trials., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The landscape of therapeutic options for B cell malignancies has fundamentally changed with regulatory and marketing approval of chimeric antigen receptor (CAR)-engineered T cell products. The cell types used for CAR-T production, the length of time of manufacture, the stimulation matrix, and the nature of the gene vector used to transduce human T cells all are significant variables that require adequate quality control before infusion. Having approved products available to clinicians using a centralized production paradigm has not stopped innovation in investigator-initiated trials. Moreover, the high costs of the commercial products have been a significant wake-up call to those concerned about rising costs in health care, and the ability of developing nations, and nations with managed care systems to support these costs. Place-of-care manufacturing is a clear alternative to the approved products created in a centralized manufacturing approach. It is supported by continued technological innovation and the willingness of clinicians to develop new ways to decrease costs and make these curative therapies equitably available., Competing Interests: Declaration of Competing Interest RO serves on the Scientific Advisory Board of Abound Bio, and Umoja Biopharma. MDL has consulted for Pfizer, Novartis and BMS, and serves on DSMB for AbbVie., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

We aimed to identify potential physiological and performance differences of trained cross-country skiers (V˙o 2max =60±4 ml ∙ kg -1  ∙ min -1 ) following two, 3-week long altitude modalities: 1) training at moderate altitudes (600-1700 m) and living at 1500 m (LMTM;N=8); and 2) training at moderate altitudes (600-1700 m) and living at 1500 m with additional nocturnal normobaric hypoxic exposures (FiO 2  =0.17;LHTM; N=8). All participants conducted the same training throughout the altitude training phase and underwent maximal roller ski trials and submaximal cyclo-ergometery before, during and one week after the training camps. No exercise performance or hematological differences were observed between the two modalities. The average roller ski velocities were increased one week after the training camps following both LMTM (p=0.03) and LHTM (p=0.04) with no difference between the two (p=0.68). During the submaximal test, LMTM increased the Tissue Oxygenation Index (11.5±6.5 to 1.0±8.5%; p=0.04), decreased the total hemoglobin concentration (15.1±6.5 to 1.7±12.9 a.u.;p=0.02), and increased blood pH (7.36±0.03 to 7.39±0.03;p=0.03). On the other hand, LHTM augmented minute ventilation (76±14 to 88±10 l·min -1 ;p=0.04) and systemic blood oxygen saturation by 2±1%; (p=0.02) with no such differences observed following the LMTM. Collectively, despite minor physiological differences observed between the two tested altitude training modalities both induced comparable exercise performance modulation., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

HIV-specific chimeric antigen receptor-T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. Paramount to translating such therapeutic candidates successfully into the clinic will require anti-HIV CAR T cells to localize to lymphoid tissues in the body and eliminate reactivated HIV-infected cells such as CD4+ T cells and monocytes/macrophages. Here we show that i.v. injected anti-HIV duoCAR T cells, generated using a clinical-grade anti-HIV duoCAR lentiviral vector, localized to the site of active HIV infection in the spleen of humanized mice and eliminated HIV-infected PBMCs. CyTOF analysis of preinfusion duoCAR T cells revealed an early memory phenotype composed predominantly of CCR7+ stem cell-like/central memory T cells (TSCM/TCM) with expression of some effector-like molecules. In addition, we show that anti-HIV duoCAR T cells effectively sense and kill HIV-infected CD4+ T cells and monocytes/macrophages. Furthermore, we demonstrate efficient genetic modification of T cells from PWH on suppressive ART into anti-HIV duoCAR T cells that subsequently kill autologous PBMCs superinfected with HIV. These studies support the safety and efficacy of anti-HIV duoCAR T cell therapy in our presently open phase I/IIa clinical trial (NCT04648046).

Background: Life satisfaction (LS), a useful construct in the study of psycho-social well-being, is an important indicator of healthy aging. With a view to investigate whether the improved longevity in India is accompanied by commensurate levels of well-being and contentment among the older adults , this study aimed to examine (1) the association between LS and sleep quality among older Indian adults aged 60 years and above (2) the mediating role of depression that accounts for the association and (3) the moderating role of functional limitation in this mediation., Methods: Cross-sectional data from the Longitudinal Ageing Study in India (LASI), Wave-1 (2017-18) was used. Pearson's correlation coefficients were calculated to investigate the pair-wise relationship between sleep quality, depressive symptoms, functional limitation, and LS. Structural Equation Model was employed to analyse the moderated-mediated association between sleep quality and the level of LS., Results: Sleep quality had a direct effect (β=-0.12) as well as an indirect effect (β=-0.024) via depressive symptoms on LS, accounting for 83.6 and 16.4 per cent of the total effects, respectively. Also, the interaction term between poor seep quality and functional limitation was positive (β = 0.03, p < 0.001) in determining depressive symptoms, suggesting that higher level of functional limitation aggravated the indirect effect of poor sleep quality on LS., Conclusion: The findings of the study suggested that ensuring both the physical as well as the mental well-being of the population during the life course may confer in later life the desired level of life satisfaction., (© 2022. The Author(s).)

Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB-based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL., Significance: This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone. This article is highlighted in the In This Issue feature, p. 1825., (©2022 American Association for Cancer Research.)

Background: Specialty training in plastic, reconstructive and aesthetic surgery is a prerequisite for safe and effective provision of care. The aim of this study was to assess and portray similarities and differences in the continuing education and specialization in plastic surgery in Europe., Material and Methods: A detailed questionnaire was designed and distributed utilizing an online survey administration software. Questions addressed core items regarding continuing education and specialization in plastic surgery in Europe. Participants were addressed directly via the European Leadership Forum (ELF) of the European Society of Plastic, Reconstructive and Aesthetic Surgery (ESPRAS). All participants had detailed knowledge of the organization and management of plastic surgical training in their respective country., Results: The survey was completed by 29 participants from 23 European countries. During specialization, plastic surgeons in Europe are trained in advanced tissue transfer and repair and aesthetic principles in all parts of the human body and within several subspecialties. Moreover, rotations in intensive as well as emergency care are compulsory in most European countries. Board certification is only provided for surgeons who have had multiple years of training regulated by a national board, who provide evidence of individually performed operative procedures in several anatomical regions and subspecialties, and who pass a final oral and/or written examination., Conclusion: Board certified plastic surgeons meet the highest degree of qualification, are trained in all parts of the body and in the management of complications. The standard of continuing education and qualification of European plastic surgeons is high, providing an excellent level of plastic surgical care throughout Europe., Hintergrund: Die Facharzt-Weiterbildung für Plastische und Ästhetische Chirurgie ist eine Grundvoraussetzung für sichere und effektive Patientenversorgung. Ziel der vorliegenden Studie war die Darstellung von Gemeinsamkeiten und Unterschieden in der Weiterbildung für Plastische Chirurgie innerhalb von Europa., Materialien Und Methoden: Ein internetbasierter Fragebogen wurde mit Hilfe eines kostenlosen Formularerstellungstools erstellt und verteilt. Die Fragen betrafen Kernpunkte der Weiterbildung für Plastische Chirurgie in Europa. Die Teilnehmer wurden direkt über das European Leadership Forum (ELF) der European Society of Plastic, Reconstructive and Aesthetic Surgery (ESPRAS) kontaktiert. Alle Teilnehmer hatten weitreichende Kenntnisse über die Organisation und Struktur der plastisch-chirurgischen Weiterbildung in ihrem jeweiligen Land., Ergebnisse: 29 Teilnehmer*innen aus 23 europäischen Ländern nahmen an der Umfrage teil. Die Weiterbildung für Plastische Chirurgie beinhaltet grundlegende Prinzipien und Techniken zur Wiederherstellung von Form und Funktion innerhalb der verschiedenen Säulen der Plastischen Chirurgie, sowie in allen Körperregionen. In den meisten europäischen Ländern ist eine Rotation in der Intensiv- und Notfallmedizin und die Behandlung kritisch kranker Patienten obligatorisch. Voraussetzung für die Facharztbezeichnung ist die mehrjährige, national organisierte Weiterbildung, der Nachweis einer festgelegten Anzahl selbstständig durchgeführter Operationen, sowie die mündliche und/oder schriftliche Abschlussprüfung., Schlussfolgerung: Fachärzte für Plastische und Ästhetische Chirurgie sind hochqualifiziert und auch im Umgang mit Komplikationen geschult. Der Standard der Weiterbildung der europäischen Plastischen Chirurgen ist hoch, so dass innerhalb Europas eine hohe Qualität plastisch-chirurgischer Versorgung gewährleistet ist., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Although awareness and treatment rates of hypertension have significantly improved in recent years, the prevalence of undiagnosed and untreated hypertension remains a major public health concern for Indian policymakers. While the urban-rural variation in the prevalence, diagnosis, control, and treatment of hypertension is reasonably well-documented, the explanation behind such variation remains poorly understood given the dearth of studies conducted on exploring the determinants of the rural-urban gap in the prevalence of undiagnosed, untreated, and uncontrolled hypertension in India. In view of this research gap, our paper aims to decompose the inter-group differences between rural and urban areas in undiagnosed, untreated, and undertreated hypertension among older adults in India into the major contributing factors., Methods: Nationally representative data collected in the Longitudinal Ageing Study of India, Wave-1 (2017-18), was utilized for this study. Maximum-likelihood binary logistic-regression models were employed to capture the crude and adjusted associations between the place of residence and prevalence of undiagnosed, untreated, and undertreated hypertension. Fairlie's decomposition technique was used to decompose the inter-group differences between rural and urban residents in the prevalence of undiagnosed, untreated, and undertreated hypertension among the older population in India, into the major contributing factors, in order to explore the pathways through which these differences manifest., Results: The overall prevalence rates of undiagnosed, untreated, and undertreated hypertension among older adults were 42.3%, 6%, and 18.7%, respectively. However, the prevalence of undiagnosed and untreated hypertension was higher in rural areas, by 12.4 and 1.7 percentage-points, respectively, while undertreated hypertension was more prevalent in the urban areas (by 7.2 percentage-points). The decomposition analysis explained roughly 41% and 34% of the urban advantage over rural areas in the case of undiagnosed and untreated hypertension, while it explained 51% of the urban disadvantage in respect of undertreated hypertension. The rural-urban differentials in education and comorbidities accounted for the majority of the explained rural disadvantage in the prevalence of undiagnosed hypertension, explaining 13.51% and 13.27% of the gap, respectively. The regional factor was found to be the major driver behind urban advantage in the prevalence of untreated hypertension, contributing 37.47% to the overall gap. In the case of undertreated hypertension, education, comorbidities, and tobacco consumption were the major contributors to the urban-rural inequality, which accounted for 12.3%, 10.6%, and 9.8% of the gap, respectively., Conclusion: Socio-economic and lifestyle factors seemed to contribute significantly to the urban-rural gap in undiagnosed, untreated and undertreated hypertension in India among older adults. There is an urgent need of creating awareness programmes for the early identification of hypertensive cases and regular treatment, particularly in under-serviced rural India. Interventions should be made targeting specific population groups to tackle inequality in healthcare utilization., (© 2022. The Author(s).)

This study deals with the biomonitoring of cadmium (Cd) heavy metal in the three selected Tricholoma mushroom species collected from wild habitats of central and coastal Croatia. For this, mushroom (T. columbetta: n = 38, T. portentosum: n = 35, and T. terreum: n = 34) and surface soil samples were collected from nine forest localities of Croatia and analyzed for Cd concentration using inductively coupled plasma−optical emission spectrometry (ICP−OES) through the acid digestion method. The findings revealed that Cd was present in Tricholoma spp. and surface soil. However, the maximum mean Cd concentration (mg/kg dry weight) was recorded in T. portentosum (cap: 0.98; stipe: 0.72), followed by T. columbetta (cap: 0.96; stipe: 0.73) and T. terreum (cap: 0.81; stipe: 0.63). The bioconcentration factor (BCF) value (>1) revealed that the selected Tricholoma spp. had the potential for Cd accumulation. Moreover, the principal component (PC) and hierarchical cluster (HC) analyses were used to derive the interactions and similarities between Cd levels Tricholoma spp. and sampling localities. The multivariate analysis suggested that central sampling localities had higher Cd levels as compared to coastal localities. However, the daily intake of metals (DIM < 0.426) and health risk index (HRI < 1) showed that there was no potential health risk associated with the consumption of selected Tricholoma spp. The findings of this study are helpful to understand the Cd accumulation behavior of wild edible Tricholoma spp. collected from Croatia.

The rational synthesis of durable, earth-abundant efficient electrocatalysts for the oxygen evolution reaction (OER) from water is one of the most important routes for storing renewable energy and minimizing fossil fuel combustion. The prime hurdles for effectively utilizing commercial RuO 2 as (OER) electrocatalysts are its very low stability, catalyst deactivation, and high cost. In this work, we explored a Ru-integrated porous organic polymer (Ru@Bpy-POP) by a facile one-pot Friedel-Crafts alkylation strategy between redox-active (Ru(demob)3Cl2) and a carbazole unit, which is composed of unique features including an extended framework unit, isolated active sites, and tunable electrode kinetics. Ru@Bpy-POP can serve as a bridge between a Metal-Organic Framework (MOF) and POP-based catalytic systems with a balanced combination of covalent bonds (structural stability) and open metal sites (single site catalysis). Ru@Bpy-POP, deposited on a three-dimensional nickel foam electrode support, exhibits a promising electrocatalytic OER activity with an ultra-low ruthenium loading compared to a benchmark RuO 2 catalyst, providing an overpotential of about 270 mV to reach 10 mA cm -2 in an alkaline medium. Moreover, a high current density of 248 mA cm -2 was achieved for the Ru@Bpy-POP catalyst at only 1.6 V ( vs. RHE), which is much higher than 91 mA cm -2 for commercial RuO 2 . The robust, albeit highly conjugated, POP framework not only triggered facile electro-kinetics but also suppressed aggregation and metallic corrosion during electrolysis. In particular, the benefits of covalent integration of distinct Ru sites into the framework can modulate intermediate adsorption and charge density, which contributes to its exceptional OER activity. All of the critical steps involved in OER are complemented by Density Functional Theory (DFT) calculations, which suggest that electrocatalytic water oxidation proceeds from a closed-shell configuration to open-shell electronic configurations with high-spin states. These open-shell configurations are more stable than their closed-shell counterparts by 1 eV, improving the overall catalytic activity.

Objective: To examine the association of multimorbidity and physical activity among older adults in India., Design: A cross-sectional study was conducted using large representative survey data., Setting and Participants: The study used data from the nationally representative 'Longitudinal Ageing Study in India (LASI),' conducted during 2017-2018. The study included a total sample of 65 336 older adults aged 45 years and above in India., Methods: Moderate and vigorous physical activities were measured separately by self-reported questionnaires. Physical activity was calculated as minutes of metabolic equivalent tasks per week. The outcome variable was a categorical variable where 2=the prevalence of more than one morbidity, 1=presence of one morbidity and 0=none. Bivariate analysis and multinomial logistic regression were applied to fulfil the objectives., Results: 27.39% of older adults in India had multimorbidity. 31.02% of older adults did not engage in any moderate physical activities. Also, 59.39% of older adults did not engage in any vigorous physical activities. Older adults reporting low (adjusted relative risk ratio (A RRR): 1.10, 95% CI 1.03 to 1.18) and moderate (A RRR): 1.05, 95% CI 0.98 to 1.13) level of moderate physical activity were significantly more likely to suffer from multimorbidity compared with no involvement in moderate physical activity. However, older adults who reported high (A RRR: 0.79, 95% CI 0.75 to 0.84), moderate (A RRR: 0.88, 95% CI 0.80 to 0.98) and low level of vigorous physical activity (A RRR: 0.94, 95% CI 0.86 to 1.02) had significantly less multimorbidity in comparison to those who never engaged in vigorous physical activity., Conclusion: Lack of physical activity is associated with multimorbidity among older adults. Physical activity promotion should be adopted as a primary strategy in reducing the burden of morbidity and multimorbidity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: With the rising number of chimeric antigen receptor (CAR) T cell treated patients, it is increasingly important to understand the treatment's impact on patient-reported outcomes (PROs) and, ideally, identify biomarkers of central nervous system (CNS) adverse effects., Methods: The purpose of this exploratory study was to assess short-term PROs and serum kynurenine metabolites for associated neurotoxicity among patients treated in an anti-CD20, anti-CD19 (LV20.19) CAR T cell phase I clinical trial (NCT03019055). Fifteen CAR T treated patients from the parent trial provided serum samples and self-report surveys 15 days before and 14, 28, and 90 days after treatment., Results: Blood kynurenine concentrations increased over time in patients with evidence of neurotoxicity ( p  = 0.004) and were increased in self-reported depression ( r  = 0.52, p  = 0.002). Depression improved after CAR T infusion ( p  = 0.035). Elevated 3-hydroxyanthranilic acid (3HAA) concentrations prior to cell infusion were also predictive of neurotoxicity onset ( p  = 0.031), suggesting it is a biomarker of neurotoxicity following CAR T cell therapy., Conclusions: Elevated levels of kynurenine pathway metabolites among CAR T cell recipients are associated with depressed mood and neurotoxicity. Findings from this exploratory study are preliminary and warrant validation in a larger cohort., Competing Interests: Competing interestsThe authors declare the following competing interests. P.H. reports receiving honoraria from Incyte, BMS, Legend, Jannsen, Takeda, Amgen, Karyopharm, GSK, Pfizer. C.J.H. is a member of the Scientific Advisory Boards of Phytecs, Inc, and has equity in Formulate Biosciences. B.J. reports receiving research support and honoraria and travel support from Miltenyi Biotec. D.S. and B.D. are authors on a patent for the 20.19 CAR. N.N.S. reports receiving honoraria and/or travel support from Incyte, Celgene, Lily, and Miltenyi Biotec; serving on scientific advisory boards for Lily, Kite, Celgene, Legend, Epizyme, Seattle Genetics, and TG therapeutics; equity ownership in Exelixis, Geron; receiving institutional research support for clinical trials from Miltenyi Biotec. The remaining authors declare no competing interests., (© The Author(s) 2022.)

Background: HIV cure research involving cell and gene therapy has intensified in recent years. There is a growing need to identify ethical standards and safeguards to ensure cell and gene therapy (CGT) HIV cure research remains valued and acceptable to as many stakeholders as possible as it advances on a global scale., Methods: To elicit preliminary ethical and practical considerations to guide CGT HIV cure research, we implemented a qualitative, in-depth interview study with three key stakeholder groups in the United States: (1) biomedical HIV cure researchers, (2) bioethicists, and (3) community stakeholders. Interviews permitted evaluation of informants' perspectives on how CGT HIV cure research should ethically occur, and were transcribed verbatim. We applied conventional content analysis focused on inductive reasoning to analyze the rich qualitative data and derive key ethical and practical considerations related to CGT towards an HIV cure., Results: We interviewed 13 biomedical researchers, 5 community members, and 1 bioethicist. Informants generated considerations related to: perceived benefits of CGT towards an HIV cure, perceived risks, considerations necessary to ensure an acceptable benefit/risk balance, CGT strategies considered unacceptable, additional ethical considerations, and considerations for first-in-human CGT HIV cure trials. Informants also proposed important safeguards to developing CGT approaches towards an HIV cure, such as the importance of mitigating off-target effects, mitigating risks associated with long-term duration of CGT interventions, and mitigating risks of immune overreactions., Conclusion: Our study identified preliminary considerations for CGT-based HIV cure across three key stakeholder groups. Respondents identified an ideal cure strategy as one which would durably control HIV infection, protect the individual from re-acquisition, and eliminate transmission to others. Known and unknown risks should be anticipated and perceived as learning opportunities to preserve and honor the altruism of participants. Preclinical studies should support these considerations and be transparently reviewed by regulatory experts and peers prior to first-in-human studies. To protect the public trust in CGT HIV cure research, ethical and practical considerations should be periodically revisited and updated as the science continues to evolve. Additional ethics studies are required to expand stakeholder participation to include traditionally marginalized groups and clinical care providers., (© 2022. The Author(s).)

Abstract: Tomazin, K, Strojnik, V, Feriche, B, Garcia Ramos, A, Štrumbelj, B, and Stirn, I. Neuromuscular adaptations in elite swimmers during concurrent strength and endurance training at low and moderate altitudes. J Strength Cond Res 36(4): 1111-1119, 2022-This study evaluated neuromuscular adaptations in elite swimmers during concurrent strength and endurance training (SET) at low (295 m) and moderate (2,320 m) altitudes. Sixteen elite swimmers took part in a 3-week SET during a general preparation phase. All neuromuscular tests were performed a week before and after a SET. In posttraining, maximal knee isometric torque (TMVC) and soleus H-reflex remained statistically unchanged for sea-level (SL) and for altitude (AL) training. Rate of torque development (RTD) decreased post-SL (-14.5%; p < 0.01) but not post-AL (-4.7%; p > 0.05) training. Vastus lateralis electromyographic (EMG) activity during RTD decreased post-SL (-17.0%; P = 0.05) but not post-AL (4.8%; p > 0.05) training. Quadriceps twitch torque (TTW) significantly increased post-AL (12.1%; p < 0.01) but not post-SL (-1.0%; p > 0.05; training × altitude: F1,15 = 12.4; p < 0.01) training. Quadriceps twitch contraction time and M-wave amplitude remained statistically unchanged post-SL and post-AL training. After SL training, increment in TMVC was accompanied with increment in vastus lateralis EMG (R = 0.76; p < 0.01) and TTW (R = 0.48; p < 0.06). Posttraining in AL, increment in TMVC was accompanied with increment in TTW (R = 0.54; p < 0.05). Strength and endurance training at altitude seems to prompt adaptations in twitch contractile properties. In contrast, SET performed at SL may hamper the magnitude of neural adaptations to strength training, particularly during rapid voluntary contractions. In conclusion, SET at AL might benefit muscular adaptations in swimmers compared with training at SL., (Copyright © 2020 National Strength and Conditioning Association.)

Background: Co-existence of multiple chronic diseases is increasingly becoming a norm among ageing population. The study aims to investigate the prevalence of multimorbidity and the association between anthropometric measures of obesity and multimorbidity among men and women aged 60 years and above in India., Methods: The present study is based on the first wave of the Longitudinal Aging Study in India. The analytical sample size for the study was 28,050 older adults aged 60 years and above. Descriptive statistics and multivariable analysis using logistic regression models were conducted., Results: Body Mass Index (BMI) based-obesity is more prevalent among older women than men (26.3% vs. 17.6%). Similarly, higher proportion of older women was at high-risk waist circumference (37.1% vs 8.9%) and waist-hip ratio (78.5 vs 75.4%) than men respectively. In Model-I, after controlling for several covariates, older adults with overweight/obesity were 1.6 times more likely to have multi-morbidity than non-obese older adults (Adjusted OR = 1.61; 95% CI: 1.48-1.74). Similarly, older adults with high-risk waist circumference [Adjusted OR: 1.66; 95% CI: 1.52-1.80] and waist-hip ratio [Adjusted OR: 1.45; 95% CI: 1.33-1.59] also had higher odds of having multi-morbidity in reference to their counterparts. In model-3 it was found that females with high-risk waist-hip ratio had 14% lower odds of multimorbidity than males with high-risk waist-hip ratio [Adjusted OR: 0.86; 95%CI: 0.78-0.94]., Conclusion: The findings of the study show significant gender difference in the prevalence of multimorbidity, men being at increased risk in the multivariate analysis which is uncommon in the existing epidemiological research. Interactive effect of male gender with anthropometric measures on multimorbidity reported in our study probably due to increased unhealthy behaviours among men requires further research., (© 2022. The Author(s).)

CAR T-cell therapies targeting the B-cell maturation antigen eliminate tumors in relapsed/refractory multiple myeloma patients, however durable remissions remain difficult to attain. Transforming growth factor beta (TGF-β) is a multifunctional cytokine abundantly expressed in the multiple myeloma bone marrow niche, where it promotes an immunosuppressive tumor microenvironment. We hypothesized that BCMA CAR T-cells armored to resist the suppressive effects of TGF-β will provide an advantage in treating multiple myeloma. The armored B2ARM CAR T cells, co-expressing BCMA targeting CAR with TGF-β dominant-negative receptor II, were generated by lentiviral transduction of primary human CD4+ and CD8+ T cells. The B2ARM CAR T cells eliminated MM.1S multiple myeloma targets in long-term cytotoxicity assays, even under TGF-β-high conditions, whereas cytotoxic function of the non-armored B2 CAR -T cells was inhibited by TGF-β. Concordantly, after long-term exposure to targets in the presence of TGF-β, the B2ARM CAR T cells were enriched for Granzyme B, CD107a, Ki67 and polyfunctional cells T-cells (double or triple-positive for IFN-γ, IL-2 and/or TNF-α), as determined by flow cytometry. In addition, the B2ARM CAR T-cells, but not the conventional B2 CAR T-cells, resisted the TGF-β-mediated suppression of activation (CD25), exhaustion (PD-1, LAG3), and differentiation to T effectors (CD45RA+ CD45RO-CD62L-). In NSG mice bearing RPMI-8226 tumors overexpressing TGF-β, the B2ARM CAR mediated 100% tumor rejection and survival, superior infiltration of tumors on day 7 post CAR T treatment (%CD3+CAR+), and greater expression of IFN-γ, TNF-α, Ki67, Granzyme B, and PD-1, as compared to tumor-infiltrating non-armored B2 CAR T-cells. In NSG RPMI-8226 xenograft model in which tumors were additionally supplemented with TGF-β injections on days -1 through 11 of CAR T treatment, the B2ARM CAR T cells rejected tumors faster than the non-armored B2 CARs, and showed greater numbers of CD3+ and CD3+CAR+, central memory (CD45RO+CD62L+) and effector memory (CD45RO+CD62L-) T cells in the peripheral blood 18 days after treatment. In summary, the armored B2ARM CAR T cells mediate superior persistence, proliferation, multi-functionality, effector differentiation and anti-tumor function in pre-clinical models of multiple myeloma, while abrogating TGF-β-mediated suppression., Competing Interests: DS, LA, YX, ZZ, BV, DW, PH, PD are employees of Lentigen Technology, a Miltenyi Biotec Company. BW is an employee of Miltenyi Biotec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alabanza, Xiong, Vu, Webster, Wu, Hu, Zhu, Dropulic, Dash and Schneider.)

Although Olympic athletes are celebrated for their sports achievements, they often face serious difficulties in their post-sport career employment. Factors of development that are affecting the quality of post-sport career transition of Olympic athletes are important to acknowledge in the dual career (DC) development perspective. Due to the side lining of academic activities, athletes are often not well prepared for the labor market. If they do not gain sufficient financial background in their careers, it can lead to a lack of proper economic inclusion of athletes in their post-sport career employment and further impact their lives. Career transitions of athletes have been the subject of research in different aspects of DC support (e.g., athletic, psychological, psychosocial, academic/vocational, financial), but most research is linked to the student-athlete DC perspective. Therefore, the aim of our research was to examine the impact of factors directly contributing to the quality of the post-sport career transition in Slovenian elite and Olympic athletes and the social class position and employment of these athletes after the termination of their sports career. From DC support practice, we learned that although athletes often have a proper level of education, their post-sport career transitions were not successful. To fill this gap, 168 elite athletes (M age = 33.34, SD = 13.1) from Slovenia were asked to complete online questionnaires. The results showed a significant contribution of education and DC support-related finances (e.g., employment of athletes in public administration) to the quality of post-sport career transition. Regarding developing a national DC model and based on empirical research, this study identifies the social class position and employment status of former elite athletes from Slovenia. It also identifies opportunities for further research on the quality of the post-sport career transitions and perspectives on DC support. Understanding how different factors contribute to the integrated development of individual athletes to reach their potential in sports, education, and their post-sport career employment is important for theorists, DC practitioners, and stakeholders working with DC athletes. To develop a sufficient mechanism, DC support providers should consider supporting education along with the financial support of athletes during their sports careers and recognizing study-training ecosystems, based on good practices to successfully transition to their post-sport careers. These findings can also be useful for athletes and their athletic triangle support network (e.g., coaches and parents) as a support in the decision-making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Robnik, Kolar, Štrumbelj and Ferjan.)

The emergence of the COVID-19 pandemic imposed fundamental changes in the field of surgery. Reorganization was made in order to adequately treat the patients during the pandemic. WALANT (Wide Awake Local Anesthesia No Tourniquet) approach was found to be a very convenient method in facilitating continuity in hand surgery with limited staff. A retrospective comparative study was performed between period of April 2020 till September 2021 at our clinic to evaluate advantages of WALANT approach. This study included 136 patients, from which 72 (53%) were operated with WALANT, compared to the control group of 64 (47%) patients without WALANT. Average hospital stay for the WALANT group was 2.2 days vs. 4.7 days for the control group. Average operating room personnel were 3.8 for WALANT and 6.2 for the control non-WALANT group. Intraoperative and postoperative VAS (visual analogue scale) score was evaluated. Due to its diversity, low cost and low complication rate, we recommend WALANT approach in acute and elective hand surgery.

Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies., (© 2021. The Author(s).)

Gene expression signatures have proven their potential to characterize important cancer phenomena like oncogenic signaling pathway activities, cellular origins of tumors, or immune cell infiltration into tumor tissues. Large collections of expression signatures provide the basis for their application to data sets, but the applicability of each signature in a new experimental context must be reassessed. We apply a methodology that utilizes the previously developed concept of coherent expression of genes in signatures to identify translatable signatures before scoring their activity in single tumors. We present a web interface (www.rosettasx.com) that applies our methodology to expression data from the Cancer Cell Line Encyclopaedia and The Cancer Genome Atlas. Configurable heat maps visualize per-cancer signature scores for 293 hand-curated literature-derived gene sets representing a wide range of cancer-relevant transcriptional modules and phenomena. The platform allows users to complement heatmaps of signature scores with molecular information on SNVs, CNVs, gene expression, gene dependency, and protein abundance or to analyze own signatures. Clustered heatmaps and further plots to drill-down results support users in studying oncological processes in cancer subtypes, thereby providing a rich resource to explore how mechanisms of cancer interact with each other as demonstrated by exemplary analyses of 2 cancer types., (Copyright © 2021. Published by Elsevier Inc.)

Anti-CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated activity against relapsed/refractory lymphomas. Cytokine release syndrome (CRS) and immune effector cell - associated neurotoxicity syndrome (ICANS) are well-known complications. Tocilizumab, a monoclonal antibody targeting the interleukin-6 (IL-6) receptor was administered 1 hour prior to infusion of anti-CD19 CAR-T cells with CD3ζ/4-1BB costimulatory signaling used to treat non-Hodgkin lymphoma patients. Relapsed/refractory lymphoma patients treated with anti-CD19 CAR-T cells were included in this analysis. Cytokine plasma levels were measured by electrochemiluminescence before lymphodepleting chemotherapy, prior to infusion and then on days 2, 4,6, and 14 days after treatment. Twenty patients were treated. Cell products included locally manufactured anti-CD19 CAR-T (n=18) and tisagenlecleucel (n=2). There were no adverse events attributed to tocilizumab. Ten patients had grade 1-2 CRS at a median of 4 (range 3-7) days. There were no cases of grade ≥3 CRS. Five patients had ICANS, grade 1 (n=4) and grade 4 (n=1). Laboratory studies obtained prior to lymphodepleting chemotherapy were comparable between patients with and without CRS, except for interleukin (IL)-15 plasma concentrations. patients with CRS had higher post-infusion ferritin and C reactive protein, with more marked increases in inflammatory cytokines, including IL-6, IL-15, IFN-γ, fractalkine and MCP-1. Fifteen patients (75%) achieved CR and 2 (10%), PR. One-year OS and PFS estimates were 83% and 73%. Prophylactic tocilizumab was associated with low CRS incidence and severity. There were no adverse events associated with tocilizumab, no increase in frequency or severity of ICANS and excellent disease control and overall survival., Competing Interests: BD is a previous employee of Lentigen, a Miltenyi Biotec Company, and has Patents and Royalties related to CAR-T immunotherapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Caimi, Pacheco Sanchez, Sharma, Otegbeye, Ahmed, Rojas, Patel, Kleinsorge Block, Schiavone, Zamborsky, Boughan, Hillian, Reese-Koc, Maschan, Dropulic, Sekaly and de Lima.)

Background: COVID-19 is affecting the entire population of India. Understanding district level correlates of the COVID-19's infection ratio (IR) is essential for formulating policies and interventions., Objective: The present study aims to investigate the district level variation in COVID-19 during March-October 2020. The present study also examines the association between India's socioeconomic and demographic characteristics and the COVID-19 infection ratio at the district level., Data and Methods: We used publicly available crowdsourced district-level data on COVID-19 from March 14, 2020, to October 31, 2020. We identified hotspot and cold spot districts for COVID-19 cases and infection ratio. We have also carried out two sets of regression analysis to highlight the district level demographic, socioeconomic, household infrastructure facilities, and health-related correlates of the COVID-19 infection ratio., Results: The results showed on October 31, 2020, the IR in India was 42.85 per hundred thousand population, with the highest in Kerala (259.63) and the lowest in Bihar (6.58). About 80 percent infected cases and 61 percent deaths were observed in nine states (Delhi, Gujarat, West Bengal, Uttar Pradesh, Andhra Pradesh, Maharashtra, Karnataka, Tamil Nadu, and Telangana). Moran's- I showed a positive yet poor spatial clustering in the COVID-19 IR over neighboring districts. Our regression analysis demonstrated that percent of 15-59 aged population, district population density, percent of the urban population, district-level testing ratio, and percent of stunted children were significantly and positively associated with the COVID-19 infection ratio. We also found that, with an increasing percentage of literacy, there is a lower infection ratio in Indian districts., Conclusion: The COVID-19 infection ratio was found to be more rampant in districts with a higher working-age population, higher population density, a higher urban population, a higher testing ratio, and a higher level of stunted children. The study findings provide crucial information for policy discourse, emphasizing the vulnerability of the highly urbanized and densely populated areas., Competing Interests: The authors have declared that no competing interests exist.

Chimeric antigen receptor (CAR) T cells typically use a strong constitutive promoter to ensure maximal long-term CAR expression. However, recent evidence suggests that restricting the timing and magnitude of CAR expression is functionally beneficial, whereas constitutive CAR activation may lead to exhaustion and loss of function. We created a self-driving CD19-targeting CAR, which regulates its own function based on the presence of a CD19 antigen engaged by the CAR itself, by placing self-driving CAR19 constructs under transcriptional control of synthetic activator protein 1 (AP1)-nuclear factor κB (NF-κB) or signal transducer and activator of transcription (STAT)5 promoters. CD19 antigen-regulated expression was observed for self-driving AP1-NFκB-CAR19, with CAR19 upregulation within 18 h after exposure to target CD19, and corresponded to the level of tumor burden. Self-driving CAR-T cells showed enhanced tumor-dependent activation, expansion, and low exhaustion in vitro as compared to constitutively expressed EF1α and murine stem cell virus (MSCV) CARs and mediated tumor regression and survival in Raji-bearing NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice. Long-term CAR function correlated with upregulated CAR expression within 24 h of exposure to tumor antigen. The self-driving AP1-NFκB-CAR19 circuit was also used to inducibly express dominant-negative transforming growth factor β receptor II (TGFBRIIdn), which effectively countered the negative effects of TGF-β on CAR-T activation. Thus, a self-driving CAR approach may offer a new modality to express CAR and auxiliary proteins by enhancing CAR-T functional activity and limiting exhaustion., Competing Interests: Declaration of interests D.S., B.D., and B.W. have submitted a patent application regarding treating cancer with self-driving chimeric antigen receptors (PCT/US2020/021320) on the basis of this work. This study was funded by Lentigen Technology, a Miltenyi Biotec Company, and Miltenyi Biotec. Y.X., P.H., D.W., L.A., D.S., and B.D. are employees of Lentigen, a Miltenyi Biotec company, and B.W. is an employee of Miltenyi Biotec., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)