Changes in environmental exposures over decades may influence the genetic architecture of severe spermatogenic failure.

STUDY QUESTION: Do the genetic determinants of idiopathic severe spermatogenic failure (SPGF) differ between generations? SUMMARY ANSWER: Our data support that the genetic component of idiopathic SPGF is impacted by dynamic changes in environmental exposures over decades. WHAT IS KNOWN ALREADY: The idiopathic form of SPGF has a multifactorial etiology wherein an interaction between genetic, epigenetic, and environmental factors leads to the disease onset and progression. At the genetic level, genome-wide association studies (GWASs) allow the analysis of millions of genetic variants across the genome in a hypothesis-free manner, as a valuable tool for identifying susceptibility risk loci. However, little is known about the specific role of non-genetic factors and their influence on the genetic determinants in this type of conditions. STUDY DESIGN, SIZE, DURATION: Case-control genetic association analyses were performed including a total of 912 SPGF cases and 1360 unaffected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants had European ancestry (Iberian and German). SPGF cases were diagnosed during the last decade either with idiopathic non-obstructive azoospermia (n = 547) or with idiopathic non-obstructive oligozoospermia (n = 365). Case-control genetic association analyses were performed by logistic regression models considering the generation as a covariate and by in silico functional characterization of the susceptibility genomic regions. MAIN RESULTS AND THE ROLE OF CHANCE: This analysis revealed 13 novel genetic association signals with SPGF, with eight of them being independent. The observed associations were mostly explained by the interaction between each lead variant and the age-group. Additionally, we established links between these loci and diverse non-genetic factors, such as toxic or dietary habits, respiratory disorders, and autoimmune diseases, which might potentially influence the genetic architecture of idiopathic SPGF. LARGE SCALE DATA: GWAS data are available from the authors upon reasonable request. LIMITATIONS, REASONS FOR CAUTION: Additional independent studies involving large cohorts in ethnically diverse populations are warranted to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: Overall, this study proposes an innovative strategy to achieve a more precise understanding of conditions such as SPGF by considering the interactions between a variable exposome through different generations and genetic predisposition to complex diseases. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the "Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020)" (ref. PY20_00212, P20_00583), the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. PID2020-120157RB-I00 funded by MCIN/ AEI/10.13039/501100011033), and the 'Proyectos I+D+i del Programa Operativo FEDER 2020' (ref. B-CTS-584-UGR20). ToxOmics-Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, is also partially supported by the Portuguese Foundation for Science and Technology (Projects: UIDB/00009/2020; UIDP/00009/2020). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Age-dependent associations between RSA reactivity, affective and cognitive regulation, and psychopathology risk in young children exposed to varying levels of socioeconomic disadvantage.

This study examined autonomic nervous system activity (respiratory sinus arrhythmia [RSA]) as a biomarker of psychopathology in an ethnically and socioeconomically diverse sample (N = 57) of young children ages 4-7 years. RSA was measured at baseline and across four standardized tasks designed to assess self-regulation in both affective (i.e., "hot") and cognitive (i.e., "cool") contexts during early childhood. Our findings reveal that age moderated RSA activity, such that reduced RSA suppression was associated with a heightened risk of externalizing problems among older children during "cool" and "hot" contexts; for younger children, only RSA suppression during "hot" contexts predicted externalizing risk. The influence of socioeconomic disadvantage did not moderate the relationship between RSA and the risk of psychopathology, and there were minimal associations between RSA suppression and internalizing symptoms at this age range. These results suggest that autonomic variability may be a more effective predictor of psychopathology risk in older children, perhaps as they transition into formal schooling and face increasingly complex cognitive and social demands. Findings have implications for the identification of psychopathology in early developmental periods when regulation over emotions becomes essential for academic and social success.

Immunotherapy for Cancer: Common Gastrointestinal, Liver, and Pancreatic Side Effects and Their Management.

Cancer cells can block the activation of T lymphocytes by deploying inhibitory signals to cell surface receptors that downregulate the immune response. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that regulate the immune response by acting on these receptors. The use of ICI has been successful for cancer types that do not respond well to conventional chemotherapy, showing clinical benefit in various advanced and metastatic cancers and supporting the promise of cancer immunotherapy. However, in some cases, these treatments are associated with immune-related adverse events, many of which affect the digestive system. The treatment of immune-related adverse events depends on the affected organ and the severity of symptoms. Here, we review the commonly used US FDA-approved ICI and briefly outline their mechanism of action. We also describe the resulting collateral effects on the gastrointestinal tract, liver, and pancreas and discuss their management and prognosis.

Targeting renal cell carcinoma with a HIF-2 antagonist.

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.

3D Bioprinting: from Benches to Translational Applications.

Over the last decades, the fabrication of 3D tissues has become commonplace in tissue engineering and regenerative medicine. However, conventional 3D biofabrication techniques such as scaffolding, microengineering, and fiber and cell sheet engineering are limited in their capacity to fabricate complex tissue constructs with the required precision and controllability that is needed to replicate biologically relevant tissues. To this end, 3D bioprinting offers great versatility to fabricate biomimetic, volumetric tissues that are structurally and functionally relevant. It enables precise control of the composition, spatial distribution, and architecture of resulting constructs facilitating the recapitulation of the delicate shapes and structures of targeted organs and tissues. This Review systematically covers the history of bioprinting and the most recent advances in instrumentation and methods. It then focuses on the requirements for bioinks and cells to achieve optimal fabrication of biomimetic constructs. Next, emerging evolutions and future directions of bioprinting are discussed, such as freeform, high-resolution, multimaterial, and 4D bioprinting. Finally, the translational potential of bioprinting and bioprinted tissues of various categories are presented and the Review is concluded by exemplifying commercially available bioprinting platforms.

LECT2 Amyloidosis in Kidney Transplantation: A Report of 5 Cases.

Leukocyte chemotactic factor 2 (LECT2) amyloidosis is a recently recognized entity that often affects the kidneys. Little information is available regarding kidney transplant outcomes in patients with LECT2 amyloidosis or who received kidney allografts containing LECT2 amyloid. We present clinical findings and allograft outcomes of 5 patients who received kidneys with donor-derived LECT2 amyloidosis. In all 5, LECT2 amyloidosis was discovered during protocol biopsies or in evaluation of suspected rejection. Less than 10% of kidney parenchyma was involved, with mostly interstitial and vascular deposits. Allograft function was not impaired and the amyloid deposits persisted for up to 8 years of follow-up. We conclude that kidneys with limited and localized LECT2 amyloid deposits that are otherwise suitable for transplantation need not be automatically discarded.

Pregnancy outcomes and chronic kidney disease: Ecuadorian single center experience
.

BACKGROUND: Pregnancy is uncommon in women with chronic kidney disease (CKD), even more so in end-stage renal diseases (ESRD), and it is associated with high risks and complications that could lead to fetal and maternal morbidity or mortality and adverse outcomes. MATERIAL AND METHODS: This was a descriptive observational study with 14 pregnant women with CKD. Comparison of clinical and biochemical variables between CKD-5D and non-dialysis dependent CKD patients was performed.Categorical variables were summarized as frequencies and percentages. For continuous variables, mean and standard deviation were reported. The significance of differences between groups was assessed by Student's t-test, and p-value ≤ 0.05 was considered statistically significant. RESULTS: 57% of patients (n = 8/14) were on chronic hemodialysis (HD). Mean time on dialysis was 11 ± 4 months. All HD patients were on intensified therapy (24 hours weekly) since 12 weeks of pregnancy. The presence of severe hypertension, valvular heart disease, diastolic dysfunction, activity of systemic lupus erythematosus, and abortions were more frequent in the HD-CKD group. Patients with CKD but no HD had decreased renal function. The mean gestational age at delivery and birth weight in the HD-CKD group was lower than in the non-HD-CKD group but without statistically significant differences. There were no neonatal or maternal deaths in either group. DISCUSSION: Pregnancy in women with ESRD is complicated by increased adverse maternal and fetal outcomes, these remain high in women with kidney disease notwithstanding advances in obstetric and neonatal care. A HD condition seems to be related to worse outcomes. Preconception counseling and tight control after conception, including multidisciplinary evaluation and individualized therapy should be done.

Negative-pressure therapy in the postoperative treatment of incisional hernioplasty wounds: a pilot study.

Negative pressure therapy has proven useful in the treatment of the complex complications of surgical wounds. In this pilot study, the authors found that the negative pressure system can be used safely in the postoperative period of incisional hernia surgery and reduces the number of days of drainage.

[Preoperative blood ordering in elective colon surgery: requirement or routine?]. / Solicitud de sangre preoperatoria en cirugía programada de colon: ¿necesidad o rutina?

BACKGROUND: Preoperative blood ordering is frequently in elective colon surgery, even for procedures that rarely require blood transfusion. Most often this procedure is performed without proper analysis of the real needs. The aim of this study was to evaluate the patients who receive transfusion and determining their associated factors. METHODS: Retrospective study of all consecutive patients scheduled for elective colon surgery was carried out at 2007-2012. Several clinico-pathological and surgical variables were analyzed and predictive blood transfusion indices such as the cross-matched/transfusion ratio (C/T ratio), transfusion index and transfusion probability were calculated. Patients were divided in 2 groups according have received perioperative surgical transfusion or not. RESULTS: There were 457 surgery patients. A total of 171 blood units, in a 74 patients were perioperative transfused. Overall cross-matched transfused ratio was 5.34, the transfusion probability 162%, and the transfusion index 0.18. Variables that were significantly associated with receiving blood transfusion in a multivariable analysis were a preoperative haemoglobin level less than 10 g/dl (OR: 309.8; 95% CI: 52.7-985.2), chronic pulmonary obstructive disease (OR: 3.7; 95% CI: 1.3-10.7), oral anticoagulant therapy (OR: 5.7; 95% CI: 1.7-19.4) and surgical time over 120 min (OR: 10.7; 95% CI: 4.7-24.1). CONCLUSIONS: Likelihood of receiving perioperative transfusion in elective colon surgery is very low. Among their associated factors, the haemoglobin level less than 10 g/dl is the one with strongest association. Those patients with such low preoperative haemoglobin level should not be scheduled for elective colon surgery until they received specific treatment.

Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.

BACKGROUND: Clear-cell renal-cell carcinomas display divergent clinical behaviours. However, the molecular genetic events driving these behaviours are unknown. We discovered that BAP1 is mutated in about 15% of clear-cell renal-cell carcinoma, and that BAP1 and PBRM1 mutations are largely mutually exclusive. The aim of this study was to investigate the clinicopathological significance of these molecular subtypes and to determine whether patients with BAP1-mutant and PBRM1-mutant tumours had different overall survival. METHODS: In this retrospective analysis, we assessed 145 patients with primary clear-cell renal-cell carcinoma and defined PBRM1 and BAP1 mutation status from the University of Texas Southwestern Medical Center (UTSW), TX, USA, between 1998 and 2011. We classified patients into those with BAP1-mutant tumours and those with tumours exclusively mutated for PBRM1 (PBRM1-mutant). We used a second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) for validation. In both cohorts, more than 80% of patients had localised or locoregional disease at presentation. Overall both cohorts were similar, although the TCGA had more patients with metastatic and higher-grade disease, and more TCGA patients presented before molecularly targeted therapies became available. FINDINGS: The median overall survival in the UTSW cohort was significantly shorter for patients with BAP1-mutant tumours (4·6 years; 95% CI 2·1-7·2), than for patients with PBRM1-mutant tumours (10·6 years; 9·8-11·5), corresponding to a HR of 2·7 (95% CI 0·99-7·6, p=0·044). Median overall survival in the TCGA cohort was 1·9 years (95% CI 0·6-3·3) for patients with BAP1-mutant tumours and 5·4 years (4·0-6·8) for those with PBRM1-mutant tumours. A HR similar to the UTSW cohort was noted in the TCGA cohort (2·8; 95% CI 1·4-5·9; p=0·004). Patients with mutations in both BAP1 and PBRM1, although a minority (three in UTSW cohort and four in TCGA cohort), had the worst overall survival (median 2·1 years, 95% CI 0·3-3·8, for the UTSW cohort, and 0·2 years, 0·0-1·2, for the TCGA cohort). INTERPRETATION: Our findings identify mutation-defined subtypes of clear-cell renal-cell carcinoma with distinct clinical outcomes, a high-risk BAP1-mutant group and a favourable PBRM1-mutant group. These data establish the basis for a molecular genetic classification of clear-cell renal-cell carcinoma that could influence treatment decisions in the future. The existence of different molecular subtypes with disparate outcomes should be considered in the design and assessment of clinical studies. FUNDING: Cancer Prevention and Research Institution of Texas and National Cancer Institute.

Evaluation of the Relationship Between Diabetic Macular Edema and Renal Function in a Latino Population.

INTRODUCTION: Diabetic macular edema (DME) is one of the leading causes of vision impairment. The relationship between DME and estimated glomerular filtration rate (eGFR) has not been clearly evaluated in Hispanic or Latino populations. The objective of this study was to evaluate the eGFR in a Latino population with DME. METHODS: A cross-sectional, observational, and descriptive study was carried out on the basis of a multicenter phase III clinical trial. RESULTS: A total of 82 subjects diagnosed with DME (36 women and 46 men) were included in the study. The mean age was 61.93 ± 6.71 years. Mean values of the blood chemistry parameters glycated hemoglobin and eGFR were 7.20 ± 0.95% and 74.42 ± 26.82 mL/min/1.73 m2, respectively. The time elapsed since diagnosis of diabetes mellitus was 15.30 ± 7.35 years, while the duration of DME was 1.41 ± 1.75 years. Mean values for central macular thickness (CMT) and total macular volume (TMV) were 440.99 ± 132.22 µm and 11.97 ± 2.11 mm3, respectively. DME duration had a negative correlation with TMV (Rho - 0.26, p < 0.05) and a positive correlation with mean arterial pressure (Rho 0.26, p < 0.05). CMT was correlated with TMV (Rho 0.43, p < 0.0001) and visual acuity (Rho 0.26, p < 0.05). No significant correlations were observed between eGFR and CMT, TMV, or any demographic variable (p > 0.05). Chronic kidney disease (CKD) was associated with hypertension (OR 9.32, p = 0.035), elevated intraocular pressure (IOP) (OR 0.03, p = 0.011), and advanced age (OR 0.45, p = 0.011). CMT was significantly associated with TMV (ß = 27.69, p < 0.0001). CONCLUSIONS: We did not find a correlation between eGFR and DME. Our findings suggest that the presence of hypertension is associated with a decrease in the GFR < 60 mL/min/1.73 m2, and CKD may be associated with advanced age and elevated IOP which may increase the risk for the development of glaucoma. TRIAL REGISTRATION: NCT05217680 (clinicaltrials.gov).

Delivering on sustainable development goals in wastewater reuse for agriculture: Initial prioritization of emerging pollutants in the Tula Valley, Mexico.

Wastewater reuse for agricultural irrigation is a widespread beneficial practice, in line with the sustainable development goals. However, contaminants of emerging concern (CECs) present in wastewater, such as pharmaceuticals, pose an environmental risk. The Tula Valley in Mexico is one of the world's largest agricultural areas reusing wastewater for agriculture. However, no untargeted CEC monitoring has been undertaken there, limiting the information available to prioritise local environmental risk assessment. Furthermore, CEC environmental presence in the Global South remains understudied, compared to the Global North. There is a risk that current research efforts focus on CECs predominantly found in the Global North, leading to strategies that may not be appropriate for the Global South where the pollution profile may be different. To address these knowledge gaps, a sampling campaign at five key sites in the Tula Valley was undertaken and samples analysed using multi-residue targeted and untargeted liquid chromatography mass spectrometry methods. Using the targeted data, ten CECs were found to be of environmental risk for at least one sampling site: 4­tert-octylphenol, acetaminophen, bezafibrate, diclofenac, erythromycin, levonorgestrel, simvastatin, sulfamethoxazole, trimethoprim and tramadol as well as total estrogenicity (combination of three steroid hormones). Six of these have not been previously quantified in the Tula Valley. Over one hundred pollutants never previously measured in the area were identified through untargeted analysis supported by library spectrum match. Examples include diclofenac and carbamazepine metabolites and area-specific pollutants such as the herbicide fomesafen. This research contributes to characterising the presence of CECs in the Global South, as well as providing site-specific data for the Tula Valley.

Acute Attack of Glaucoma after Scleral Melting and Iris Blockage of the Surgical Ostium: A Case Report of a Complication Derived from a Mitomycin C Supplemented Trabeculectomy.

Aim: To describe a case of an acute attack of glaucoma due to scleral melting in the area where a trabeculectomy was previously done. This condition resulted from the blockage of the surgical opening due to an iris prolapse in an eye that was previously supplemented with mitomycin C (MMC) during a filtering surgery and bleb needling revision. Case description: A 74-year-old Mexican female with a prior glaucoma diagnosis who assisted to an appointment presenting an acute ocular hypertensive crisis after several months of adequately controlled intraocular pressure (IOP). Ocular hypertension had been regulated after undergoing a trabeculectomy and bleb needling revision; both supplemented with MMC. The severe IOP increase occurred due to uveal tissue blockage in the filtering site, related to melting of the sclera in the same area. The patient was successfully treated through the use of a scleral patch graft and the implantation of an Ahmed valve. Conclusion: An acute attack of glaucoma associated with scleromalacia after trabeculectomy and needling has not been previously reported and is currently attributed to MMC supplementation. Nevertheless, the use of a scleral patch graft and further glaucoma surgery seems to be an efficient way to treat this condition. Clinical significance: Even though this complication was appropriately managed with this patient, we want to prevent further cases like this through the judicious and careful use of MMC. How to cite this article: Paczka JA, Ponce-Horta AM, Tornero-Jimenez A. Acute Attack of Glaucoma after Scleral Melting and Iris Blockage of the Surgical Ostium: A Case Report of a Complication derived from a Mitomycin C Supplemented Trabeculectomy. J Curr Glaucoma Pract 2022;16(3):199-204.

Meta-analysis and machine learning to explore soil-water partitioning of common pharmaceuticals.

The first meta-analysis and modelling from batch-sorption literature studies of the soil/water partitioning of pharmaceuticals is presented. Analysis of the experimental conditions reported in the literature demonstrated that though batch-sorption studies have value, they are limited in evaluating partitioning under environmentally-relevant conditions. Recommendations are made to utilise environmental relevant pharmaceutical concentrations, perform batch-sorption studies at temperatures other than 4, 20 and 25 °C to better reflect climate diversity, and utilise the Guideline 106 methodology as a benchmark to enable comparison between future studies (and support modelling and prediction). The meta-dataset comprised 82 data points, which were modelled using multivariate analysis; where Kd (soil/water partitioning coefficient) was the independent variable. The dependent variables fit into three categories: 1) pharmaceutical studied (including physical-chemical properties), 2) soil characteristics and 3) experimental conditions. The pharmaceutical solubility, the soil/liquid equilibration time (prior to adding the pharmaceutical), the soil organic carbon, the soil sterilisation method and the liquid phase were found to be significantly important variables for predicting Kd.

Translating wastewater reuse for irrigation from OECD Guidelines: Tramadol sorption and desorption in soil-water matrices.

Treated and untreated wastewater is often used for agricultural irrigation and, despite the many benefits of this practice, it poses the risk of biologically active chemical pollutants (such as pharmaceuticals, like tramadol) entering the environment. The partitioning of tramadol between soil/water at environmentally relevant concentrations is important to understand its environmental toxicity. Kinetics and isotherm sorption studies based on the Organisation for Economic Cooperation and Development (OECD) 106 Guideline were undertaken, ensuring comparability to previous studies. Studies were undertaken in three soils of different characteristics using aqueous concentrations of tramadol from 500 ng L-1 (environmentally relevant) to 100 µg L-1 (comparable to previous studies). Two of the soils presented a significantly (p < 0.05) higher sorption at a lower initial tramadol concentration (5000 ng L-1), compared to 20,000 ng L-1. Hysteresis was observed in all studied soils, indicating the accumulation of tramadol. Higher sorption to soils correlated with higher clay content, with soil/water partitioning coefficients (Kd) of 5.5 ± 13.3, 2.5 ± 3.8 and 0.9 ± 3.0 L kg1 for soils with clay contents of 41.9%, 24.5% and 7.4%, respectively. Cation exchange was proposed as the main sorption mechanism for tramadol to soils when the pH was below tramadol's pKa values (9.41 and 13.08). A comparative kinetics study between tramadol in soil/calcium chloride buffer and soil/wastewater effluent demonstrated significantly higher (p < 0.05) tramadol sorption to soil from wastewater effluent. This has the environmental implication that clay soils will be able to retain tramadol from irrigation water, despite the organic content of the irrigation water. Therefore, our studies show that tramadol soil sorption is likely to be higher in agricultural environments reusing wastewater than that predicted from experiments using the OECD 106 Guideline calcium chloride buffer.

Intensity of care and perceived burden among informal caregivers to persons with chronic medical conditions: a systematic review and meta-analysis.

PURPOSE: Informal caregivers provide ongoing assistance to a loved one with a health condition. No studies have compared caregiving intensity and perception of burden across chronic medical conditions. MATERIALS AND METHODS: Databases were searched from inception through 11 September 2020 to identify studies that included the Level of Care Index or the Zarit Burden Inventory (ZBI) among caregivers for people with chronic diseases. Pooled mean ZBI scores and 95% confidence intervals by medical condition were calculated using a random effects model and heterogeneity with I2. RESULTS: Ninety-seven included articles reported on 98 unique samples across 21 chronic diseases. No study used the Level of Care Index. Among 12 disease groups with more than one study, heterogeneity was too high (I2 range: 0-99.6%, ≥76.5% in 11 groups) to confidently estimate burden. The percent of studies rated high risk of bias ranged from 0% to 98%, but all external validity items were rated as high-risk in >50% of studies. CONCLUSIONS: Findings highlight the need for studies on caregiver burden to improve sampling techniques; better report sampling procedures and caregiver and care recipient characteristics; and develop a standard set of outcomes, including a measure of caregiving intensity. Systematic Review Registration: CRD42017080962IMPLICATIONS FOR REHABILITATIONThe amount of burden reported by caregivers to loved ones is associated with reduced physical and mental health.We found considerable heterogeneity in perceived burden reported by informal caregivers across different studies within disease groups, which is likely related to methodological issues, including sampling techniques.Health care providers who use research on caregiver burden should assess how representative study samples may be and exercise caution in drawing conclusions.

Effect of Low-Dose Radiotherapy on the Circulating Levels of Paraoxonase-1-Related Variables and Markers of Inflammation in Patients with COVID-19 Pneumonia.

The aim of our study was to investigate the changes produced by low-dose radiotherapy (LDRT) in the circulating levels of the antioxidant enzyme paraoxonase-1 (PON1) and inflammatory markers in patients with COVID-19 pneumonia treated with LDRT and their interactions with clinical and radiological changes. Data were collected from the IPACOVID prospective clinical trial (NCT04380818). The study included 30 patients treated with a whole-lung dose of 0.5 Gy. Clinical follow-up, as well as PON1-related variables, cytokines, and radiological parameters were analyzed before LDRT, at 24 h, and 1 week after treatment. Twenty-five patients (83.3%) survived 1 week after LDRT. Respiratory function and radiological images improved in survivors. Twenty-four hours after LDRT, PON1 concentration significantly decreased, while transforming growth factor beta 1 (TGF-ß1) increased with respect to baseline. One week after LDRT, patients had increased PON1 activities and lower PON1 and TGF-ß1 concentrations compared with 24 h after LDRT, PON1 specific activity increased, lactate dehydrogenase (LDH), and C-reactive protein (CRP) decreased, and CD4+ and CD8+ cells increased after one week. Our results highlight the benefit of LDRT in patients with COVID-19 pneumonia and it might be mediated, at least in part, by an increase in serum PON1 activity at one week and an increase in TGF-ß1 concentrations at 24 h.