Postnatal weight gain and retinopathy of prematurity in preterm infants: a population-based retrospective cohort study.

OBJECTIVE: Infants who meet the screening guidelines for retinopathy of prematurity (ROP) based on birth weight and gestational age undergo serial ophthalmological examinations for its detection and treatment. However, <10% of patients require treatment, and less than half develop ROP. Poor postnatal weight gain has been reported to be a strong indicator of ROP development; however, the information regarding this is unclear. Therefore, this study aimed to determine the relationship between postnatal weight gain and ROP development in preterm infants. METHODS: The data of 675 preterm infants with gestational age ≤32 weeks, who were hospitalized in our neonatal intensive care unit, were obtained retrospectively from file records. The infants' demographic characteristics, clinical findings, and weekly weight gain (g/kg/day) during the first 8 weeks were recorded. The univariate was used to examine the risk factors for ROP followed by multivariate regression. RESULTS: The incidence of ROP in the infants included in the study was 41% (n = 278) and 13.3% (n = 37) of them required treatment. In the infants of the group that developed ROP, the mean birth weight and gestational age were significantly lower than those in the group that did not develop ROP (973 ± 288 and 1301 ± 349 g, p = 0.001 and 28.48 ± 1.95 and 30.08 ± 1.60 weeks, p = 0.001, respectively). As the gestational week and birth weight decreased, ROP development and the risk of ROP-requiring treatment increased. In the infants of the group that developed ROP, the mean weight gain in the postnatal third week was detected as significantly lower compared to those in the group that did not develop ROP (13.9 ± 8.2 and 15.4 ± 6.8 g, p = 0.034). On multiple logistic regression analysis, birth weight (<750 g) (odds ratio [OR], 8.67; 95% confidence interval [CI], 3.99-18.82, p = 0.001), blood transfusion (OR, 2.39; 95% CI, 1.34-4.24, p = 0.003), necrotizing enterocolitis (OR, 4.79; 95% CI, 1.05-26.85, p = 0.045), bronchopulmonary dysplasia (OR, 2.03; 95% CI, 1.22-3.36, p = 0.006), antenatal steroid therapy (OR, 1.60; 95% CI, 1.05-2.43, p = 0.028), surfactant administration (OR, 2.06; 95% CI, 1.32-3.2, p = 0.001) were independent risk factors for ROP development. CONCLUSION: Postnatal weight gain may not be an accurate predictor of ROP development after adjusting for confounding factors. However, the analysis of independent risk factors that influenced the development of ROP revealed a statistically significant effect in cases of low birth weight, blood transfusion, necrotizing enterocolitis, bronchopulmonary dysplasia, and antenatal steroid and surfactant therapies. These findings may help ophthalmologists and neonatologists to pay special attention to this patient group during ROP scanning.

Exosomes derived from M2 macrophages prevent steroid-induced osteonecrosis of the femoral head by modulating inflammation, promoting bone formation and inhibiting bone resorption.

Inflammatory reactions are involved in the development of steroid-induced osteonecrosis of the femoral head(ONFH). Studies have explored the therapeutic efficacy of inhibiting inflammatory reactions in steroid-induced ONFH and revealed that inhibiting inflammation may be a new strategy for preventing the development of steroid-induced ONFH. Exosomes derived from M2 macrophages(M2-Exos) display anti-inflammatory properties. This study aimed to examine the preventive effect of M2-Exos on early-stage steroid-induced ONFH and explore the underlying mechanisms involved. In vitro, we explored the effect of M2-Exos on the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells(BMMSCs). In vivo, we investigated the role of M2-Exos on inflammation, osteoclastogenesis, osteogenesis and angiogenesis in an early-stage rat model of steroid-induced ONFH. We found that M2-Exos promoted the proliferation and osteogenic differentiation of BMMSCs. Additionally, M2-Exos effectively attenuated the osteonecrotic changes, inhibited the expression of proinflammatory mediators, promoted osteogenesis and angiogenesis, reduced osteoclastogenesis, and regulated the polarization of M1/M2 macrophages in steroid-induced ONFH. Taken together, our data suggest that M2-Exos are effective at preventing steroid-induced ONFH. These findings may be helpful for providing a potential strategy to prevent the development of steroid-induced ONFH.

Long-term outcomes of two-dose alemtuzumab induction in pediatric kidney transplantation.

BACKGROUND: Alemtuzumab is a lymphocyte depleting agent used for induction in kidney transplant, but long-term information on its use in pediatric recipients remains sparse. METHODS: We performed a single-center retrospective cohort study of 57 pediatric kidney transplant recipients receiving alemtuzumab 20 mg/m2/dose ×2 doses for induction immunosuppression. All patients underwent surveillance biopsies, and 91.3% underwent steroid withdrawal by day 4 post-transplant. Outcomes of interest included graft survival, development of donor specific antibodies (DSA), incidence of viremia and PTLD, and duration of lymphopenia. RESULTS: Median follow-up time was 7.9 years (IQR 5-13.6 years). Median graft survival was 16.5 years (95% CI 11.6-unknown). DSA developed in 36.5% at a median of 944 days (IQR 252-2113 days). Incidences of BK polyomavirus DNAemia (BKPyV-DNAemia), CMV DNAemia, and EBV DNAemia were 38.6%, 22.8%, and 14%, respectively; one patient developed PTLD at 13.3 years post-transplant. Median duration of lymphopenia was 365 days (IQR 168-713 days); 19.3% of patients remained lymphopenic at 3 years post-transplant. There was no association between duration of lymphopenia and graft survival, rejection, DSA detection, or viremia. CONCLUSIONS: A two-dose alemtuzumab induction protocol can have excellent outcomes with a steroid-free maintenance immunosuppression regimen. More comprehensive, multicenter, comparative studies of pediatric kidney transplant are needed to improve long-term outcomes.

Convolutional neural network algorithm trained on lumbar spine radiographs to predict outcomes of transforaminal epidural steroid injection for lumbosacral radicular pain from spinal stenosis.

Little is known about the therapeutic outcomes of transforaminal epidural steroid injection (TFESI) in patients with lumbosacral radicular pain due to lumbar spinal stenosis (LSS). Using lumbar spine radiographs as input data, we trained a convolutional neural network (CNN) to predict therapeutic outcomes after lumbar TFESI in patients with lumbosacral radicular pain caused by LSS. We retrospectively recruited 193 patients for this study. The lumbar spine radiographs included anteroposterior, lateral, and bilateral (left and right) oblique views. We cut each lumbar spine radiograph image into a square shape that included the vertebra corresponding to the level at which the TFESI was performed and the vertebrae juxta below and above that level. Output data were divided into "favorable outcome" (≥ 50% reduction in the numeric rating scale [NRS] score at 2 months post-TFESI) and "poor outcome" (< 50% reduction in the NRS score at 2 months post-TFESI). Using these input and output data, we developed a CNN model for predicting TFESI outcomes. The area under the curve of our model was 0.920. Its accuracy was 87.2%. Our CNN model has an excellent capacity for predicting therapeutic outcomes after lumbar TFESI in patients with lumbosacral radicular pain induced by LSS.

Osteonecrosis of the Knee: The Unintended Consequence of Steroid Abuse.

The anti-inflammatory and immunosuppressive properties of steroids allow their use in a wide variety of rheumatological diseases, asthma, inflammatory bowel disease, cancer therapy, and severe viral infections. Though life-saving or organ-saving, long-term clinical use leads to a vast array of complications. Osteoporosis is the most common orthopedic side effect of steroid abuse, while osteonecrosis is a rare occurrence. The risk of osteonecrosis appears to be dose and duration dependent, but several patient factors also play a major role and usually affect the femoral head followed by the knee joint. The long-term effects of steroids must be explained to all patients on therapy, but this risk is missed in individuals who abuse steroids for recreational or performance-enhancing purposes. We describe a male, aged 29 years, who presented with dull aching bilateral knee pain of 2-years' duration after a long-term steroid abuse for weight and muscle mass gain. Radiological and magnetic resonance imaging studies confirmed osteonecrosis of femoral and tibial condyles and secondary degenerative arthritis of the knee joint. Prompt suspicion, early diagnosis, and intervention in osteonecrosis of knee joints, and termination of steroids may reverse the pathology and prevent progression of disease.

Non-traumatic osteonecrosis of the femoral head induced by steroid and alcohol exposure is associated with intestinal flora alterations and metabolomic profiles.

OBJECTIVE: Osteonecrosis of the femoral head (ONFH) is a severe disease that primarily affects the middle-aged population, imposing a significant economic and social burden. Recent research has linked the progression of non-traumatic osteonecrosis of the femoral head (NONFH) to the composition of the gut microbiota. Steroids and alcohol are considered major contributing factors. However, the relationship between NONFH caused by two etiologies and the microbiota remains unclear. In this study, we examined the gut microbiota and fecal metabolic phenotypes of two groups of patients, and analyzed potential differences in the pathogenic mechanisms from both the microbial and metabolic perspectives. METHODS: Utilizing fecal samples from 68 NONFH patients (32 steroid-induced, 36 alcohol-induced), high-throughput 16 S rDNA sequencing and liquid chromatography with tandem mass spectrometry (LC-MS/MS) metabolomics analyses were conducted. Univariate and multivariate analyses were applied to the omics data, employing linear discriminant analysis effect size to identify potential biomarkers. Additionally, functional annotation of differential metabolites and associated pathways was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Subsequently, Spearman correlation analysis was employed to assess the potential correlations between differential gut microbiota and metabolites. RESULTS: High-throughput 16 S rDNA sequencing revealed significant gut microbial differences. At the genus level, the alcohol group had higher Lactobacillus and Roseburia, while the steroid group had more Megasphaera and Akkermansia. LC-MS/MS metabolomic analysis indicates significant differences in fecal metabolites between steroid- and alcohol-induced ONFH patients. Alcohol-induced ONFH (AONFH) showed elevated levels of L-Lysine and Oxoglutaric acid, while steroid-induced ONFH(SONFH) had increased Gluconic acid and Phosphoric acid. KEGG annotation revealed 10 pathways with metabolite differences between AONFH and SONFH patients. Correlation analysis revealed the association between differential gut flora and differential metabolites. CONCLUSIONS: Our results suggest that hormones and alcohol can induce changes in the gut microbiota, leading to alterations in fecal metabolites. These changes, driven by different pathways, contribute to the progression of the disease. The study opens new research directions for understanding the pathogenic mechanisms of hormone- or alcohol-induced NONFH, suggesting that differentiated preventive and therapeutic approaches may be needed for NONFH caused by different triggers.

Management after cataract surgery for patients with diabetic retinopathy: a systematic review and meta-analysis.

PURPOSE: To evaluate the safety and effectiveness of various treatment modalities in patients with diabetic retinopathy (DR) who underwent cataract surgery. METHODS: A comprehensive search for randomized controlled trials (RCTs) was conducted using the PubMed, Embase, Cochrane Library, and CNKI databases up to December 22, 2021. The safety and efficacy of treatment modalities were assessed using the risk ratio (RR) to compare the progression of DR and the mean difference to evaluate the best corrected visual acuity (BCVA) and macular thickness (MT). RESULTS: The meta-analysis of the RCTs revealed that anti-VEGF (anti-vascular endothelial growth factor) drugs significantly reduced the progression of DR [RR: 0.37 (95%CI 0.19, 0.70), P = 0.002] and improved BCVA [mean difference = - 0.06 (- 0.12, - 0.01), P = 0.03] in patients with pre-existing DR who underwent cataract surgery. Steroid drugs also showed a significant reduction in macular thickness [mean difference = - 55.63 (- 90.73, - 20.53), I2 = 56%, P = 0.002] in DR patients two weeks after cataract surgery compared to the control group. The safety profiles of different management options did not differ significantly. CONCLUSION: The present meta-analysis suggests that anti-VEGF drugs can effectively slow down the progression of diabetic retinopathy, improve BCVA, and reduce MT in DR patients who underwent cataract surgery. Steroid drugs also show promise in reducing MT. However, further studies with larger sample sizes are required to compare the efficacy and safety of different management options in a multi-center clinical setting.

Cost-effectiveness of Transforaminal epidural steroid injections for patients with ACUTE sciatica: a randomized controlled trial.

BACKGROUND: Transforaminal epidural injections with steroids (TESI) are increasingly being used in patients sciatica. The STAR (steroids against radiculopathy)-trial aimed to evaluate the (cost-) effectiveness of TESI in patients with acute sciatica (< 8 weeks). This article contains the economic evaluation of the STAR-trial. METHODS: Participants were randomized to one of three study arms: Usual Care (UC), that is oral pain medication with or without physiotherapy, n = 45); intervention group 1: UC and transforaminal epidural steroid injection (TESI) 1 ml of 0.5% Levobupivacaine and 1 ml of 40 mg/ml Methylprednisolone and intervention group 2: UC and transforaminal epidural injection (TEI) with 1 ml of 0,5% Levobupivacaine and 1 ml of 0.9% NaCl (n = 50). The primary effect measure was health-related quality of life. Secondary outcomes were pain, functioning, and recovery. Costs were measured from a societal perspective, meaning that all costs were included, irrespective of who paid or benefited. Missing data were imputed using multiple imputation, and bootstrapping was used to estimate statistical uncertainty. RESULTS: None of the between-group differences in effects were statistically significant for any of the outcomes (QALY, back pain, leg pain, functioning, and global perceived effect) at the 26-weeks follow-up. The adjusted mean difference in total societal costs was €1718 (95% confidence interval [CI]: - 3020 to 6052) for comparison 1 (intervention group 1 versus usual care), €1640 (95%CI: - 3354 to 6106) for comparison 2 (intervention group 1 versus intervention group 2), and €770 (95%CI: - 3758 to 5702) for comparison 3 (intervention group 2 versus usual care). Except for the intervention costs, none of the aggregate and disaggregate cost differences were statistically significant. The maximum probability of all interventions being cost-effective compared to the control was low (< 0.7) for all effect measures. CONCLUSION: These results suggest that adding TESI (or TEI) to usual care is not cost-effective compared to usual care in patients with acute sciatica (< 8 weeks) from a societal perspective in a Dutch healthcare setting. TRIAL REGISTRATION: Dutch National trial register: NTR4457 (March, 6th, 2014).

Let's get physical: Aerobic capacity, muscle strength, and muscle endurance after pediatric heart transplantation.

BACKGROUND: Pediatric heart (HTx) and kidney transplant (KTx) recipients may have lower physical fitness than healthy children. This study sought to quantify fitness levels in transplant recipients, investigate associations to clinical factors and quality of life, and identify whether a quick, simple wall-sit test is feasible as a surrogate for overall fitness for longitudinal assessment. METHODS: Aerobic capacity (6-min walk test, 6MWT), normalized muscle strength, muscle endurance, physical activity questionnaire (PAQ), and quality of life (PedsQL™) were prospectively assessed in transplanted children and matched healthy controls. RESULTS: Twenty-two HTx were compared to 20 controls and 6 KTx. 6MWT %predicted was shorter in HTx (87.2 [69.9-118.6] %) than controls (99.9 [80.4-120] %), but similar to KTx (90.3 [78.6-115] %). Muscle strength was lower in HTx deltoids (6.15 [4.35-11.3] kg/m2) and KTx quadriceps (9.27 [8.65-19.1] kg/m2) versus controls. Similarly, muscle endurance was lower in HTx push-ups (28.6 [0-250] %predicted), KTx push-ups (8.35 [0-150] %predicted), HTx curl-ups (115 [0-450] %predicted), and KTx wall-sit time (18.5 [10.0-54.0] s) than controls. In contrast to HTx with only 9%, all KTx were receiving steroid therapy. The wall-sit test significantly correlated with other fitness parameters (normalized quadriceps strength R = .31, #push-ups R = .39, and #curl-ups R = .43) and PedsQL™ (R = .36). CONCLUSIONS: Compared to controls, pediatric HTx and KTx have similarly lower aerobic capacity, but different deficits in muscle strength, likely related to steroid therapy in KTx. The convenient wall-sit test correlates with fitness and reported quality of life, and thus could be a useful easy routine for longitudinal assessment.

Clinicopathological features and outcome of secondary steroid resistant nephrotic syndrome: A retrospective analysis.

Objective: To determine the clinico-pathological features and long-term outcome of secondary steroid-resistant nephrotic syndrome treated with steroids and calcineurin inhibitors. METHODS: The retrospective cohort study was conducted at the Sindh Institute of Urology and Transplant, Karachi, in June and July 2023, and comprised data from January 1, 2008, to December 31, 2020, of children aged 1-18 years who developed steroid resistance after initial sensitivity to steroids with at least 1-year of follow-up. Demographics as well as time taken to secondary steroid response were documented. Renal biopsy of all patients with secondary steroid resistance had been performed. Eventual outcomes after treatment with calcineurin inhibitors based on the degree of proteinuria and serum albumin levels were used to categorise complete remission, partial remission and no response. Kidney function, as determined by estimated glomerular filtration rate, was recorded. Data was analysed using SPSS 22. RESULTS: Of the 1,000 patients who underwent renal biopsy for steroid resistance, 48(4.8%) had idiopathic steroid-resistant nephrotic syndrome; 32(66.7%) males, 16(33.3%) females and median age of 5 years (interquartile range: 4-7.3 years). Median age at diagnosis of nephrotic syndrome was 5 years (interquartile range: 3.6-7.3 years). The median time from nephrotic syndrome to secondary steroid-resistant nephrotic syndrome was 23 months (interquartile range: 8.75-44.5 months). Biopsy results at diagnosis showed that 27(56.3%) had minimal change disease. The mean follow-up time was 6.1±3.2 years. Of the 43(89.5%) patients who received cyclosporin for 1 year, 29(67%) obtained complete remission, 5(12%) attained partial remission and no response was seen in 9(21%) patients. Conclusion: Majority of the children had minimal change disease at the time of diagnosis of secondary steroid-resistant nephrotic syndrome. The long-term response with calcineurin inhibitors was favourable at 1 year.

Association of adrenal steroids with metabolomic profiles in patients with primary and endocrine hypertension.

Introduction: Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing's syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT. Methods: Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus. Results: After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites - 18 in PPGL, 15 in CS, and 23 in PA - were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites. Discussions: Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL's metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.

A distal enhancer guides the negative selection of toxic glycoalkaloids during tomato domestication.

Steroidal glycoalkaloids (SGAs) are major plant defense metabolites against pests, while they are considered poisonous in food. The genetic basis that guides negative selection of SGAs production during tomato domestication remains poorly understood. Here, we identify a distal enhancer, GAME Enhancer 1 (GE1), as the key regulator of SGAs metabolism in tomato. GE1 recruits MYC2-GAME9 transcriptional complex to regulate the expression of GAME cluster genes via the formation of chromatin loops located in the neighboring DNA region. A naturally occurring GE176 allelic variant is found to be more active in stimulating GAME expression. We show that the weaker GE1 allele has been the main driver for selecting reduced SGAs levels during tomato domestication. Unravelling the "TFs-Enhancer-Promoter" regulatory mechanism operating in SGAs metabolism opens unprecedented prospects for SGAs manipulation in Solanaceae via precision breeding strategies.

Anabolic-androgenic steroids are linked to depression and anxiety in male bodybuilders: the hidden psychogenic side of anabolic androgenic steroids.

BACKGROUND: The prevalence of anabolic-androgenic steroids (AAS) use is on the rise among athletes and bodybuilders worldwide. In addition to the well-documented adverse effects on hepatic, renal, and reproductive functions, there is an increasing recognition of psychiatric complications associated with AAS use. This study aimed to investigate psychiatric morbidity among male bodybuilders who are AAS users. METHODS: In this cross-sectional study, 25 male bodybuilders using AAS (mean age 31.2 ± 8.9 years) were compared with a control group of 25 healthy male bodybuilders matched in age (31.3 ± 5.5 years). The demographic, hormonal, and biochemical parameters of the participants were recorded. The impact of AAS use on psychiatric morbidity was assessed using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) in both groups. RESULTS: The BDI and BAI scores were significantly higher in male bodybuilders using anabolic-androgenic steroids (p < 0.0001). While the control group showed no instances of anxiety, seven individuals in the AAS user group reported mild anxiety. No participants in the control group exhibited depression, whereas seven AAS users displayed depressive symptoms (4 mild, 3 moderate). Correlations were observed between lactate dehydrogenase (LDH) levels and BAI scores, creatinine levels and both BAI and BDI scores, as well as between estradiol levels and BDI. CONCLUSION: The study concluded that AAS use among male bodybuilders is associated with elevated levels of depression and anxiety. Our findings suggest a potential correlation between anxiety and depression levels and the levels of creatinine, LDH, and estradiol in AAS users.

Pregnenolone and progesterone production from natural sterols using recombinant strain of Mycolicibacterium smegmatis mc2 155 expressing mammalian steroidogenesis system.

BACKGROUND: Pregnenolone and progesterone are the life-important steroid hormones regulating essential vital functions in mammals, and widely used in different fields of medicine. Microbiological production of these compounds from sterols is based on the use of recombinant strains expressing the enzyme system cholesterol hydroxylase/C20-C22 lyase (CH/L) of mammalian steroidogenesis. However, the efficiency of the known recombinant strains is still low. New recombinant strains and combination approaches are now needed to produce these steroid hormones. RESULTS: Based on Mycolicibacterium smegmatis, a recombinant strain was created that expresses the steroidogenesis system (CYP11A1, adrenodoxin reductase, adrenodoxin) of the bovine adrenal cortex. The recombinant strain transformed cholesterol and phytosterol to form progesterone among the metabolites. When 3-methoxymethyl ethers of sterols were applied as bioconversion substrates, the corresponding 3-ethers of pregnenolone and dehydroepiandrosterone (DHEA) were identified as major metabolites. Under optimized conditions, the recombinant strain produced 85.2 ± 4.7 mol % 3-methoxymethyl-pregnenolone within 48 h, while production of 3-substituted DHEA was not detected. After the 3-methoxymethyl function was deprotected by acid hydrolysis, crystalline pregnenolone was isolated in high purity (over 98%, w/w). The structures of steroids were confirmed using TLC, HPLC, MS and 1H- and 13C-NMR analyses. CONCLUSION: The use of mycolicybacteria as a microbial platform for the expression of systems at the initial stage of mammalian steroidogenesis ensures the production of valuable steroid hormones-progesterone and pregnenolone from cholesterol. Selective production of pregnenolone from cholesterol is ensured by the use of 3-substituted cholesterol as a substrate and optimization of the conditions for its bioconversion. The results open the prospects for the generation of the new microbial biocatalysts capable of effectively producing value-added steroid hormones.

Anti-inflammatory therapies are associated with delayed onset of anemia and reduction in transfusion requirements in critically ill patients: results from two studies.

BACKGROUND: Anemia is a hallmark of critical illness, which is largely inflammatory driven. We hypothesized that the use of anti-inflammatory agents limits the development of anemia and reduces the need for red blood cell (RBC) transfusions in patients with a hyper-inflammatory condition due to COVID-19. METHODS: An observational cohort (n = 772) and a validation cohort (a subset of REMAP-CAP, n = 119) of critically ill patients with hypoxemic respiratory failure due to COVID-19 were analyzed, who either received no treatment, received steroids or received steroids plus IL-6 blocking agents. The trajectory of hemoglobin (Hb) decline and the need for RBC transfusions were compared using descriptive statistics as well as multivariate modeling. RESULTS: In both cohorts, Hb level was higher in the treated groups compared to the untreated group at all time points. In the observational cohort, incidence and number of transfused patients were lower in the group receiving the combination treatment compared to the untreated groups. In a multivariate analysis controlling for baseline Hb imbalance and mechanical ventilation, receipt of steroids remained associated with a slower decline in Hb level and the combination treatment remained associated with a slower decline of Hb and with less transfusions. Results remained the same in the validation cohort. CONCLUSION: Immunomodulatory treatment was associated with a slower decline in Hb level in critically ill patients with COVID-19 and with less transfusion. Findings point toward inflammation as an important cause for the occurrence of anemia in the critically ill.

[Pouchitis showed complete response to ustekinumab].

Pouchitis is the most common long-term complication following ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis. Although several agents, including probiotics, steroids, and immunomodulators, have been used, the treatment of pouchitis remains challenging. Owing to the proven efficacy of biological therapy in inflammatory bowel disease, there is now growing evidence suggesting the potential benefits of biological therapy in refractory pouchitis. Here, we report the case of a 64-year-old woman with pouchitis due to ulcerative colitis who was successfully treated with ustekinumab (UST). The patient developed ulcerative pancolitis at the age of 35. Total colectomy and IPAA with J-pouch anastomosis were performed when the patient was 47 years old. Ileotomy closure was performed 6 months later. Postoperatively, the patient developed steroid-dependent pouchitis. Three years later, she developed steroid-induced diabetes. The patient has been taking 3mg of steroid for 20 years;therefore, her lifetime total steroid dose was 21g. The patient had over 20 episodes of bloody diarrhea a day. The last pouchoscopy in 20XX-9 revealed inflammatory stenosis with deep ulcerations of the afferent limb just before the ileoanal pouch junction. In July 20XX, when we took over her treatment, the policy of treatment was to withdraw her from steroids. Pouchoscopy revealed a widened but still tight afferent limb through which the scope could easily pass, and the ileoanal pouch still showed erosive ileitis without ulcers. Thiopurine administration and steroid tapering were initiated. Steroid tapering increased the erythrocyte sedimentation rate (ESR). As ESR increased, her arthritis exacerbated. Six months after the end of steroid administration, the patient consented to UST treatment. On April 20XX+1, the patient received her first 260-mg UST infusion. At this point, she experienced 14-15 episodes of muddy bloody stools. She had no abdominal pain;however, she experienced shoulder pain. Gradually, UST affected both pouchitis and arthritis. UST treatment was continued at 90mg subcutaneously every 12 weeks without abdominal pain recurrence. Eight months after the first UST infusion, nonsteroidal anti-inflammatory drugs were no longer necessary for shoulder pain. Follow-up pouchoscopy performed 14 months after UST optimization revealed a normal afferent limb without ulcerations in either segment. Pouchitis remission was maintained for over 2 years.

Dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis.

BACKGROUND: Colitis caused by checkpoint inhibitors (CPI) is frequent and is treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear. METHODS: Using colon biopsies and blood from predominantly steroid-experienced CPI colitis patients, we performed multiplexed single-cell transcriptomics and proteomics to nominate contributing populations. RESULTS: CPI colitis biopsies showed enrichment of CD4+resident memory (RM) T cells in addition to CD8+ RM and cytotoxic CD8+ T cells. Matching T cell receptor (TCR) clonotypes suggested that both RMs are progenitors that yield cytotoxic effectors. Activated, CD38+ HLA-DR+ CD4+ RM and cytotoxic CD8+ T cells were enriched in steroid-experienced and a validation data set of steroid-naïve CPI colitis, underscoring their pathogenic potential across steroid exposure. Distinct from ulcerative colitis, CPI colitis exhibited perturbed stromal metabolism (NAD+, tryptophan) impacting epithelial survival and inflammation. Endothelial cells in CPI colitis after anti-TNF and anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) upregulated the integrin α4ß7 ligand molecular vascular addressin cell adhesion molecule 1 (MAdCAM-1), which may preferentially respond to vedolizumab (anti-α4ß7). CONCLUSIONS: These findings nominate CD4+ RM and MAdCAM-1+ endothelial cells for targeting in specific subsets of CPI colitis patients.