Upper Limit Of Normal Research Articles

Treatments and outcomes of patients with localized extranodal NK/T-cell lymphoma (ENKL) diagnosed between 2014 and 2021: A cooperative study in Japan.

7565 Background: A previous cooperative study of patients (pts) with ENKL who were diagnosed between 2000 and 2013 in 31 institutes in Japan reported that the most common first-line treatment for localized ENKL was radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) (66%). The 2-year (yr) overall survival (OS) and progression-free survival (PFS) of pts with localized ENKL were 78% and 68%, respectively (JCO 2017). RT-DeVIC has been included as a preferred regimen of combined modality therapy in the NCCN guidelines. The treatments and outcomes of pts with localized ENKL in recent clinical practice are unknown. Methods: We conducted a cooperative study (NKEA-Next; UMIN000046300) by hemato-oncologists and radiation oncologists of pts with ENKL who were diagnosed between 2014 and 2021 in 45 institutes in Japan. The results were compared with those from the 2000-2013 cohort (JCO 2017). The primary endpoint was OS of pts with ENKL who received next-generation treatment in 2014-2021 at participating institutes. We analyzed the data of localized ENKL. Results: Of 351 pts in the 2014-2021 cohort, 235 (67%) had localized ENKL. First-line therapy was RT-DeVIC in 185 (79%) pts, sequential chemoradiotherapy in 17, RT alone in 15 pts, and chemotherapy alone in 12 pts. Six pts received no treatment due to poor performance status (PS). Only two pts (1%) received anthracycline-containing regimens. With a median follow-up of 3.4 yrs, the 2-yr OS and PFS of localized ENKL were 83% and 75%, respectively. Pts treated with RT-DeVIC showed the following clinical features: median age, 58 yrs (range, 13-82); age > 60 yrs, 45%; stage IIE, 34%; B symptoms present, 27%; elevated serum lactate dehydrogenase, 23%; ECOG PS 2, 4%; and soluble interleukin-2 receptor (sIL-2R) level > upper limit of normal (ULN), 31% (57/183). The complete response rate was 88% among the 179 pts who were evaluated for response. The 2-yr OS and PFS of RT-DeVIC were 87% and 79%, respectively. There was no treatment-related death due to RT-DeVIC. G3/4 mucositis was recorded in 32% (G3, n = 59; G4, n = 0). G3/4 febrile neutropenia occurred in 18% (G3, n = 32; G4, n = 2). sIL-2R > ULN was associated with worse OS ( P < 0.01). In comparison with pts with localized disease in the 2000-2013 cohort, pts in the 2014-2021 cohort received RT-DeVIC more frequently ( P < .001). There was no significant difference in OS ( P = 0.24) or PFS ( P = 0.10) between the two cohorts. Conclusions: RT-DeVIC was more frequently used for first-line treatment of localized ENKL, and its efficacy has been maintained, with 87% 2-yr OS in recent clinical practice in Japan, providing further evidence of RT-DeVIC as a preferred first-line regimen for localized ENKL. No obvious improvement in OS and a reduction in G3 mucositis were observed, suggesting that more efficacious and less toxic regimens need to be introduced.

Feasibility of treatment with another CDK4/6 inhibitor after severe ribociclib liver toxicity.

e13067 Background: Ribociclib is, for now, the only CDK4/6 inhibitor having demonstrated a statistically significant increase of overall survival in first-line in hormone receptor-positive, HER2-negative advanced breast cancer. One of the limiting toxicities of ribociclib is the occurrence of grade III/IV hepatobiliary toxicity in approximately 5% of patients. It contraindicates the reintroduction of the drug. Therapeutic options after this type of adverse event are challenging because there are very limited data regarding cross reactivity in risk for hepatic injury between ribociclib, palbociclib or abemaciclib. Methods: We describe a cohort of 28 patients who presented with grade III and/or IV ribociclib-induced hepatitis and who subsequently received another CDK4/6 inhibitor. Cases were collected from the French pharmacovigilance database and additional cases were obtained through institutional databases. Data were retrospectively obtained from patients’ reports. Results: Twenty-eight patients, from 11 centers, presented a grade III (71%, 20 patients) or a grade IV (29%, 8 patients) transaminase elevation with ribociclib. Median transaminase elevation was 12.3 x ULN (upper limit normal) for AST and 15.2 x ULN for ALT. This toxicity occurred within the first 6 months of treatment for all patients except one. Ribociclib was associated with letrozole in 21 patients, fulvestrant in 5 patients and anastrozole or exemestane in 2 patients. No acute liver failure occurred. All patients switched to another CDK4/6 inhibitor (23 patients - 82% - palbociclib and 5 - 18% - abemaciclib) without significant reoccurrence of liver toxicities. Four patients (14%) presented a transient grade 1 or 2 hepatic toxicity (all of them with palbociclib), 20 patients (71%) received the second CDK4/6 inhibitor at full dose. The median follow-up was 16 months. Conclusions: Treatment with palbociclib or abemaciclib after grade III or IV transaminase elevation due to ribociclib is feasible and none of the patients in this cohort exhibited reoccurrence of significant liver toxicity afterwards. Ribociclib liver toxicity occurs mainly during the first 6 months of treatment and takes several months to recover. [Table: see text]

Frequency and predictive factors for spontaneous normalization of anti-tissue transglutaminase-IgA serology among Saudi children with type 1 diabetes mellitus: A cohort study.

Celiac serology can be transiently elevated in patients with type 1 diabetes mellitus (T1DM) and normalized despite gluten consumption. This study aimed to identify the frequency and predictive factors of spontaneous normalization of anti-tissue transglutaminase (anti-TTG-IgA) antibodies in these patients. The charts of all patients (≤18 years) with T1DM were retrospectively reviewed from 2012 to 2021 at a tertiary care center in Riyadh, Saudi Arabia. The following data were collected: clinical characteristics of the participants, anti-TTG-IgA-immunoglobulin (Ig) A antibody, and histological findings. The outcome of positive anti-TTG-IgA-IgA in patients with T1DM and the predictive factors for spontaneous normalization were investigated. Of the 1,006 patients with T1DM, 138 (13.7%) had elevated anti-TTG-IgA antibodies, celiac disease was diagnosed in 58/138 (42%) patients, spontaneous normalization of anti-TTG-IgA was observed in 65 (47.1%) patients, and fluctuating anti-TTG-IgA antibodies were seen in 15 (10.9%) patients. The patients with anti-TTG-IgA levels at 3-10 times the upper normal limits (UNL), and those with levels ≥10 times UNL were less likely to have spontaneous normalization of anti-TTG-IgA compared to patients with levels at 1-3 times UNL (hazard ratio [HR] = 0.28, 95% confidence interval [Cl] = 0.13-0.61, P = 0.001, and HR = 0.03, 95% Cl = 0.00-0.19, P < 0.001, respectively). Asymptomatic patients with T1DM with mild elevation of anti-TTG-IgA need not be rushed for invasive endoscopy or exposed to an un-needed gluten-free diet but should rather have a regular follow-up of their celiac serology.

Safety and tolerability of isoniazid preventive therapy for tuberculosis for persons with HIV with and without alcohol use: a single arm trial.

Isoniazid (INH) preventive therapy is recommended to prevent tuberculosis (TB) disease for persons with HIV (PWH), except for those with regular and heavy alcohol consumption, due to hepatotoxicity concerns. We aimed to quantify the incidence of severe INH-related toxicity among PWH with and without recent alcohol consumption. Prospective study of PWH receiving INH. We included PWH in southwest Uganda with recent (prior three months) (n = 200) or no (prior year) self-reported alcohol consumption (n = 101), on antiretroviral therapy, TB infected (≥5 mm on tuberculin skin test), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2x the upper limit of normal (ULN). Grade 3+ INH-related toxicity was ALT or AST ≥5x the ULN or severe symptoms; we stopped IPT upon detection. Grade 2 INH-related toxicity was ALT or AST 2-5x the ULN or moderate symptoms. The cumulative incidence of Grade 3+ INH-related toxicity was 8.3% (95% CI: 5.7-12.0); all resolved after INH cessation. Incidence was 6.0% (95% CI: 3.1-10.2) among those reporting recent alcohol use and 12.9% (95% CI: 7.0-21.0) of those reporting no prior year alcohol use. We found no differences by baseline phosphatidylethanol-confirmed alcohol severity. The cumulative incidence of Grade 2 toxicities (without Grade 3+) was 21.7% (95% CI: 17.2-27.0); 25.0% (95% CI: 19.0-31.8) among those with recent alcohol use and 14.8% (95% CI: 8.1-23.9) among those with no prior year alcohol use. Alcohol use does not appear to increase risk for serious INH-related toxicity among PWH without significant liver enzyme elevations at baseline (≤2x ULN).

Case Report: Case report: An unusual presentation of granulomatosis with polyangiitis

Aim: We are reporting a case of an unusual presentation of granulomatosis with polyangiitis (GPA) with liver involvement. Case presentation: A 45-year-old male patient presented with erythematous plaques on the face and bilateral nasal obstruction. On physical examination, the patient had a ring-shaped squamous plaque on the face. The laboratory findings revealed an accelerated erythrocyte sedimentation rate at 100 mm/h, an elevated C-reactive protein at 66 mg/L, hyper gamma globulinemia 16 g/L and an elevated alkaline phosphatase (twice the upper normal limit). The craniofacial and thoracoabdominal computed tomography (CT) -scans showed ethmoid and maxillary sinusitis, low facial bone density, multiple mediastinal and hilar lymphadenopathy, diffuse small pulmonary nodules, and hepatomegaly. A cutaneous lesion biopsy, the nasal mucosa, and the liver showed a chronic inflammatory granulomatosis process with necrosis. Serum anti-neutrophil cytoplasmic antibody (ANCA) against PR3 was positive. The clinical, biological, radiological, and histological findings substantiated the diagnosis of GPA. The patient received systemic steroids combined with cyclophosphamide pulses on days 1, 14 and 28 and then he was lost to follow-up. Two-years later, he presented with a cardiac failure and skin ulcer in the right lower limb. A nasal endoscopic exam showed nasal septum cartilage perforation with resorption of the middle and inferior nasal concha. Two weeks later, he developed a diffuse alveolar hemorrhage and was therefore transferred to the intensive care unit but died of respiratory failure 3 days later. Conclusion: Clinicians should be aware of GPA atypical clinical manifestations.

The Impact of the Definitions of Clinical Phases on the Profiles of Grey-Zone Patients with Chronic Hepatitis B Virus Infection.

We aim to investigate the impact of different clinical phases' definitions of chronic hepatitis B (CHB) infection on the profiles of grey zone, based on HBV guidelines set by the Chinese Society of Hepatology and Chinese Society of Infectious Diseases (CSH/CSID, 2022 version) and guidelines set by the American Association for the Study of Liver Diseases (AASLD, 2018 version). We retrospectively examined untreated CHB patients enrolled in the China Registry of Hepatitis B database. Patients' clinical phases were determined as per CSH/CSID and AASLD. Liver fibrosis was estimated by FIB-4 and/or APRI. Among 3462 CHB patients, 56.9% and 41.7% fell into the grey zone based on AASLD and CSH/CSID. Compared with grey zone patients as per AASLD, those under CSH/CSID guidelines showed lower levels of median ALT (26.0 vs. 37.0 U/L, p < 0.001), AST (25.0 vs. 29.4 U/L, p < 0.001) and APRI (0.3 vs. 0.4, p < 0.001), and lower rates of advanced fibrosis estimated by APRI (7.9% vs. 11.4% p = 0.001), but comparable rates by FIB-4 (13.0% vs. 14.1%, p = 0.389). With the stepwise lowering of ALT upper limits of normal (ULN) values from 50/40 U/L for males/females to 40/40 U/L, 35/25 U/L and 30/19 U/L, the proportions of grey zone patients as per CSH/CSID declined from 46.7% to 41.7%, 34.3% and 28.8%, respectively, whereas they remained stable (55.7%, 56.2%, 56.9% and 57.0%) as per AASLD. Compared with the AASLD guidelines, CSH/CSID guidelines leave fewer and less severe patients in the grey zone. Lowering ALT ULN values reduces the number of grey zone patients as per CSH/CSID, but not under AASLD guidelines.

Optimizing therapy in primary biliary cholangitis: Alkaline phosphatase at six months identifies one-year non-responders and predicts survival.

Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response. UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included. POISE criteria were used to assess response to treatment, defined as ALP <1.67 × upper limit of normal (ULN) and normal total bilirubin at one year. Various thresholds of ALP at six months were evaluated to predict insufficient response based on negative predictive value (NPV) and that with nearest to 90% NPV was selected. For the study, 1362 patients were included, 1232 (90.5%) female, mean age of 54 years. The POISE criteria were met by 56.4% (n = 768) of patients at one year. The median ALP (IQR) of those who met POISE criteria compared to those who did not was 1.05 × ULN (0.82-1.33) vs. 2.37 × ULN (1.72-3.69) at six months (p < .001). Of 235 patients with serum ALP >1.9 × ULN at six months, 89% did not achieve POISE criteria (NPV) after one year of UDCA. Of those with insufficient response by POISE criteria at one year, 210 (67%) had an ALP >1.9 × ULN at six months and thus would have been identified early. We can identify patients for second-line therapy at six months using an ALP threshold of 1.9 × ULN, given that approximately 90% of these patients are non-responders according to POISE criteria.

Predictive value of Th17 and Treg cells at baseline for HBsAg loss in chronic hepatitis B patients with low HBsAg quantification treated with pegylated interferon and nucleos(t)ide analogue

Background and aimsThe primary goal of chronic hepatitis B (CHB) treatment is to reduce hepatitis B surface antigen (HBsAg). T helper 17 (Th17) and regulatory T (Treg) cells are essential for the development of CHB. However, how Th17 and Treg cells contribute to HBsAg loss is still unknown. Therefore, this study aimed to search for the predictive value of Th17 and Treg cells for HBsAg loss in CHB patients with low HBsAg quantification. MethodsThe study included 99 hepatitis B e antigen (HBeAg)-negative CHB patients who had completed a year of nucleos(t)ide analogue (NA) monotherapy and had received both NA and pegylated interferon (PEG-IFN) treatment for less than 96 weeks (96 wk). In the cured group, 48 patients lost HBsAg within 48 wk, while 51 patients did not (uncured group). Blood samples and clinical data were collected for research. ResultsDuring PEG-IFN and NA combination therapy, the proportion of Th17 cells in the cured group increased significantly, while the proportion of Treg cells in the uncured group increased. From 0 to 24 wk, the proportion of Th17 cells in the cured group was significantly higher than in the uncured group, while the opposite was true for Treg cells. Patients with alanine aminotransferase (ALT) ≥ 2.5 upper limit of normal (ULN) at 12 wk had a higher proportion of Th17 cells and a lower proportion of Treg cells than those with ALT <2.5 ULN at 12 wk. Additionally, the proportion of Th17 cells is inversely associated with the level of HBsAg, whereas the level of Treg cells is positively related to HBsAg quantification. The clinical cure index, including age, HBsAg quantification, and the proportions of Th17 and Treg cells, had a higher area under the curve (0.957) for predicting HBsAg loss when compared to the proportions of Th17 and Treg cells and HBsAg quantification alone. ConclusionsCombined with quantification of HBsAg, the proportions of Th17 cells and Treg cells at baseline can be used as good predictors of HBsAg loss in patients with low HBsAg quantification treated with NA and PEG-IFN.

Biomarkers and factors in small cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis.

The aim of this meta-analysis was to summarize the available results of immunotherapy predictors for small cell lung cancer (SCLC) and to provide evidence-based information for their potential predictive value of efficacy. We searched PubMed, EMBASE, Web of Science, The Cochrane Library, and ClinicalTrials (from January 1, 1975 to November 1, 2021). The hazard ratios (HR) and its 95% confidence intervals (CIs) and tumor response rate of the included studies were extracted. Eleven studies were eventually included and the pooled results showed that programmed cell death ligand 1 (PD-L1) positive: objective response rate (ORR) (relative risk [RR]=1.39, 95% CI [0.48, 4.03], p=0.54), with high heterogeneity (p=0.05, I2 = 56%); disease control rate [DCR] (RR=1.31, 95% CI [0.04, 38.57], p=0.88), with high heterogeneity (p=0.04, I2 = 75%); overall survival (OS) (HR=0.89, 95% CI [0.74, 1.07], p=0.22); and progression-free survival (PFS) (HR=0.83, 95% CI [0.59, 1.16], p=0.27), with high heterogeneity (p=0.005, I2 = 73.1%). TMB-High (TMB-H): OS (HR=0.86, 95% CI [0.74, 1.00], p=0.05); PFS (HR=0.71, 95% CI [0.6, 0.85], p< 0.001). Lactate dehydrogenase (LDH) >upper limit of normal (ULN): OS (HR=0.95, 95% CI [0.81, 1.11], p=0.511). Asian patients: OS (HR=0.87, 95% CI [0.72, 1.04], p=0.135); White/Non-Asian patients: OS (HR=0.83, 95% CI [0.76, 0.90], p < 0.001). Liver metastasis patients: OS (HR=0.93, 95% CI [0.83, 1.05], p=0.229); PFS (HR=0.84, 95% CI [0.67, 1.06], p=0.141). Central nervous system (CNS) metastasis patients: OS (HR=0.91, 95% CI [0.71, 1.17], p=0.474); PFS (HR=1.03, 95% CI [0.66, 1.60], p=0.903). The available research results do not support the recommendation of PD-L1 positive and TMB-H as predictors for the application of immune checkpoint inhibitors (ICIs) in SCLC patients. LDH, baseline liver metastasis and CNS metastasis may be used as markers/influencing factors for predicting the efficacy of ICIs in SCLC patients. Non-Asian SCLC patients had better efficacy with ICIs in our results.

Safety and Tolerability of Rimegepant Every Other Day for Preventive Treatment of Migraine Plus As-Needed for Acute Treatment of Migraine: Results from A 52-Week, Open-Label Extension Phase (P12-12.006)

Safety and Tolerability of Rimegepant Every Other Day for Preventive Treatment of Migraine Plus As-Needed for Acute Treatment of Migraine: Results from A 52-Week, Open-Label Extension Phase (P12-12.006)

A Phase 2/3 Open-label, Long-term, Safety Trial of Zavegepant 10 mg Nasal Spray for the Acute Treatment of Migraine (P9-12.002)

A Phase 2/3 Open-label, Long-term, Safety Trial of Zavegepant 10 mg Nasal Spray for the Acute Treatment of Migraine (P9-12.002)

Case Report: An unusual presentation of granulomatosis with polyangiitis

Aim: We are reporting a case of an unusual presentation of granulomatosis with polyangiitis (GPA) with liver involvement. Case presentation: A 45-year-old male patient presented with erythematous plaques on the face and bilateral nasal obstruction. On physical examination, the patient had a ring-shaped squamous plaque on the face. The laboratory findings revealed an accelerated erythrocyte sedimentation rate at 100 mm/h, an elevated C-reactive protein at 66 mg/L, hyper gamma globulinemia 16 g/L and an elevated alkaline phosphatase (twice the upper normal limit). The craniofacial and thoracoabdominal computed tomography (CT) -scans showed ethmoid and maxillary sinusitis, low facial bone density, multiple mediastinal and hilar lymphadenopathy, diffuse small pulmonary nodules, and hepatomegaly. A cutaneous lesion biopsy, the nasal mucosa, and the liver showed a chronic inflammatory granulomatosis process with necrosis. Serum anti-neutrophil cytoplasmic antibody (ANCA) against PR3 was positive. The clinical, biological, radiological, and histological findings substantiated the diagnosis of GPA. The patient received systemic steroids combined with cyclophosphamide pulses on days 1, 14 and 28 and then he was lost to follow-up. Two-years later, he presented with a cardiac failure and skin ulcer in the right lower limb. A nasal endoscopic exam showed nasal septum cartilage perforation with resorption of the middle and inferior nasal concha. Two weeks later, he developed a diffuse alveolar hemorrhage and was therefore transferred to the intensive care unit but died of respiratory failure 3 days later. Conclusion: Clinicians should be aware of GPA atypical clinical manifestations.

Baseline Predictors of the Long-Term Insufficient Biochemical Response in Patients with Autoimmune Hepatitis: A Single Center Experience.

The treatment response criteria in autoimmune hepatitis (AIH) have been recently updated. This study aimed to assess treatment responses in 39 (16 males) patients with AIH confirmed by histology. Prednisone added to azathioprine or mycophenolate was the most frequent first-line treatment. Serum alanine aminotransferase (ALT) levels were periodically checked for a median of 45 months. Eight (20.5%) patients presented 4 weeks non-response (NR). Baseline lower multiples of ALT above the upper normal limit (UNL) (p = 0.005), Ishak liver fibrosis score > 3 (p = 0.029), and less frequent confluent necrosis > 2 (p < 0.001) were independent predictors of NR. 24 (61.5%) patients achieved complete biochemical response (CBR) at six months. Ishak liver fibrosis score ≤ 3 (p < 0.001), lobular eosinophilic infiltrate (p < 0.001), and ≥50% decrease in serum ALT levels at week 4 (p < 0.001) were independent predictors of CBR. In addition, the GLUCRE score, derived from the multiplication of serum creatinine (mg/dL) and glucose (mg/dL) levels, were identified. A baseline GLUCRE value > 100 strongly predicted CBR failure (p = 0.003) at a follow-up greater than 12 months. In conclusion, the absence of cirrhosis and a ≥50% UNL decrease in serum ALT levels were independent predictors for CBR. A baseline GLUCRE score may help identify patients maintaining longer CBR.

Characteristics and Risk Factors of Ultra-High-Risk Patients with Newly Diagnosed Multiple Myeloma.

To investigate the clinical characteristics and risk factors of ultra-high-risk (UHR) patients with newly diagnosed multiple myeloma (MM). We screened UHR patients with a survival of less than 24 months and we selected patients with a concurrent survival of more than 24 months as a control group. We retrospectively analyzed the clinical characteristics of UHR patients with newly diagnosed MM and screened related risk factors. In total we analyzed 477 patients, which included 121 (25.4%) UHR patients and 356 (74.6%) control patients. Median overall survival (OS) and progression-free survival (PFS) of UHR patients was 10.5 months (7.5-13.5 months) and 6.3 months (5.4-7.2 months), respectively. Univariate logistic regression analysis showed that age > 65 years, hemoglobin (HGB) < 100 g/L, lactate dehydrogenase (LDH) > 250 U/L, serum creatinine (SCr) > 2 mg/dL, corrected serum calcium (CsCa) > 2.75 mmol/L, B-type natriuretic peptide (BNP) or N-terminal prohormone BNP (NT-proBNP) > 2 upper limit of normal (ULN), high-risk cytogenetics, Barthel index score, and International Staging System (ISS) stage III were associated with UHR MM. In a multivariate analysis, age > 65 years, LDH > 250 U/L, CsCa > 2.75 mmol/L, BNP or NT-proBNP > 2 ULN, high-risk cytogenetics, and Barthel index score were independent risk factors for UHR MM. Moreover, UHR patients had a worse response rate than control patients. Our study highlighted the characteristics of UHR MM patients and suggested that the combination of organ insufficiency and highly malignant myeloma cells resulted in poor outcomes of patients with UHR MM.

129Xe MRI Ventilation Defects in Asthma: What is the Upper Limit of Normal and Minimal Clinically Important Difference?

The minimal clinically important difference (MCID) and upper limit of normal (ULN) for MRI ventilation defect percent (VDP) were previously reported for hyperpolarized 3He gas MRI. Hyperpolarized 129Xe VDP is more sensitive to airway dysfunction than 3He, therefore the objective of this study was to determine the ULN and MCID for 129Xe MRI VDP in healthy and asthma participants. We retrospectively evaluated healthy and asthma participants who underwent spirometry and 129XeMRI on a single visit; participants with asthma completed the asthma control questionnaire (ACQ-7). The MCID was estimated using distribution- (smallest detectable difference [SDD]) and anchor-based (ACQ-7) methods. Two observers measured VDP (semiautomated k-means-cluster segmentation algorithm) in 10 participants with asthma, five-times each in random order, to determine SDD. The ULN was estimated based on the 95% confidence interval of the relationships between VDP and age. Mean VDP was 1.6 ± 1.2% for healthy (n=27) and 13.7 ± 12.9% for asthma participants (n=55). ACQ-7 and VDP were correlated (r=.37, p=.006; VDP=3.5·ACQ+4.9). The anchor-based MCID was 1.75% while the mean SDD and distribution-based MCID was 2.25%. VDP was correlated with age for healthy participants (p=.56, p =.003; VDP=.04·Age-.01). The ULN for all healthy participants was 2.0%. By age tertiles, the ULN was 1.3% ages 18-39 years, 2.5% for 40-59 years and 3.8% for 60-79 years. The 129Xe MRI VDP MCID was estimated in participants with asthma; the ULN was estimated in healthy participants across a range of ages, both of which provide a way to interpret VDP measurements in clinical investigations.

Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19

COVID-19 pneumonia is often associated with hyperinflammation. The efficacy and safety of anakinra in treating patients with severe COVID-19 pneumonia and hyperinflammation are still unclear. To assess the efficacy and safety of anakinra vs standard of care alone for patients with severe COVID-19 pneumonia and hyperinflammation. The Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to COVID-19 (ANA-COVID-GEAS) was a multicenter, randomized, open-label, 2-group, phase 2/3 clinical trial conducted at 12 hospitals in Spain between May 8, 2020, and March 1, 2021, with a follow-up of 1 month. Participants were adult patients with severe COVID-19 pneumonia and hyperinflammation. Hyperinflammation was defined as interleukin-6 greater than 40 pg/mL, ferritin greater than 500 ng/mL, C-reactive protein greater than 3 mg/dL (rationale, ≥5 upper normal limit), and/or lactate dehydrogenase greater than 300 U/L. Severe pneumonia was considered if at least 1 of the following conditions was met: ambient air oxygen saturation 94% or less measured with a pulse oximeter, ratio of partial pressure O2 to fraction of inspired O2 of 300 or less, and/or a ratio of O2 saturation measured with pulse oximeter to fraction of inspired O2 of 350 or less. Data analysis was performed from April to October 2021. Usual standard of care plus anakinra (anakinra group) or usual standard of care alone (SoC group). Anakinra was given at a dose of 100 mg 4 times a day intravenously. The primary outcome was the proportion of patients not requiring mechanical ventilation up to 15 days after treatment initiation, assessed on an intention-to-treat basis. A total of 179 patients (123 men [69.9%]; mean [SD] age, 60.5 [11.5] years) were randomly assigned to the anakinra group (92 patients) or to the SoC group (87 patients). The proportion of patients not requiring mechanical ventilation up to day 15 was not significantly different between groups (64 of 83 patients [77.1%] in the anakinra group vs 67 of 78 patients [85.9%] in the SoC group; risk ratio [RR], 0.90; 95% CI, 0.77-1.04; P = .16). Anakinra did not result in any difference in time to mechanical ventilation (hazard ratio, 1.72; 95% CI, 0.82-3.62; P = .14). There was no significant difference between groups in the proportion of patients not requiring invasive mechanical ventilation up to day 15 (RR, 0.99; 95% CI, 0.88-1.11; P > .99). In this randomized clinical trial, anakinra did not prevent the need for mechanical ventilation or reduce mortality risk compared with standard of care alone among hospitalized patients with severe COVID-19 pneumonia. ClinicalTrials.gov Identifier: NCT04443881.

Visual Outcomes, Contrast Sensitivity, and Satisfaction with Multifocal Intraocular Lens Blended Technique: Late Mid-term Results

To describe clinical visual outcomes, spectacle independence, and patient satisfaction after cataract surgery with blending implantation of ReSTOR (Alcon laboratories) multifocal intraocular lenses. A single-arm, non-randomized prospective study assessed patients undergoing cataract surgery with ReSTOR® +2.50 intraocular lens in the dominant eye and +3.00 add in the fellow eye between January 2015 to January 2020. In total, 47 patients (94 eyes) were enrolled, 28 women and 19 men. The average age at surgery time was 64 ±8 years, average postoperative follow-up was 45.4 ±7.0 months, with a minimum of 18.9 months. Postoperative binocular uncorrected distance visual acuity (UDVA) was on average 0.07 logMar (Snellen 20/24), uncorrected binocular intermediate visual acuity at 65 cm was 0.07 logMar (20/24), uncorrected binocular near visual acuity at 40 cm was 0.06 logMar (20/23). Contrast sensitivity under photopic and scotopic conditions, with and without glare, remained at the upper limit of normality. 98% of patients were quite satisfied or very satisfied. 87% did not require glasses for any activities, either at distant vision, nor at near vision. Cataract surgery with ReSTOR® IOL blended vision showed medium-term satisfactory visual results, achieving spectacle independence and a high level of satisfaction.

Role of age in dynamics of autoantibodies in pediatric Celiac disease

BackgroundCeliac disease (CD) is characterized by elevated serum titers of autoantibodies IgA anti-tissue transglutaminase 2 (TGA-IgA) and IgA anti-endomysial (EMA), with small bowel mucosa atrophy. We evaluated age differences between CD children exhibiting variable antibody titers at diagnosis.MethodsCD children diagnosed between January 2014 and June 2019, according to 2012 ESPGHAN guidelines were studied. All had EMA and TGA-IgA measurements, while a proportion of them underwent esophagogastroduodenoscopy (EGD). Patients were grouped based on serum TGA-IgA titers normalized to the upper limit of normal (ULN) and differences in median age (years) assessed by analysis of variance (ANOVA) and creation of orthogonal contrasts.ResultsCD was diagnosed in 295 subjects (median age: 4.4 [IQR: 2.60–8.52]) with a biopsy sparing protocol (high titer: ≥ 10xULN) and in 204 by EGD biopsy. Of the latter, 142 (median age: 8.5 [IQR: 5.81–11.06]) and 62 (median age: 9.5 [IQR: 6.26–12.76]) had a low (< 5xULN) and a moderate (≥ 5 < 10xULN) TGA-IgA titer, respectively. Potential CD was diagnosed in 20 patients (median age: 3.6 [IQR: 2.47–6.91]). The median age was significantly lower in the no-biopsy group (ANOVA: F(3, 516) = 25.98, p < .001) than in low- and moderate titer groups (p < 0.0001), while there was no statistical difference between biopsy-sparing and potential CD groups.ConclusionCD patients with greatly elevated antibody titers (≥ 10xULN) were diagnosed at an earlier age than those with lower titers. This may indicate that an increase in TGA-IgA is independent of age and suggests a polarization of autoimmunity in younger individuals with higher serum antibody levels.

Factors and cytokine signatures associated with the response to therapy in patients with primary biliary cholangitis-autoimmune hepatitis overlap syndrome: a real-world study.

Factors and cytokine signatures associated with the response to therapy in patients with primary biliary cholangitis-autoimmune hepatitis overlap syndrome: a real-world study.

Retrospective analyses of antibody titers in the diagnosis of pediatric Celiac Disease

Objective: We aimed to evaluate the relationship between Tissue Transglutaminase IgA titer (tTGIgA) and Endomisium antibody (EMA) positivity and the stage of duodenal mucosal damage at Celiac disease (CD). Material and Methods: The study group consisted of 233 children (2-18 years old) who were diagnosed with CD and admitted to our XXX Hospital, Pediatric Gastroenterology Outpatient Clinic, between September 2017 and November 2022. All patients underwent an endoscopy, and a histopathological diagnosis was made. In upper gastrointestinal endoscopy, one biopsy sample were taken from the duodenum bulb and four samples from the second part of the duodenum. Histological patterns were evaluated according to the Marsh-Oberhuber classification. Results: A total 233 patients with CD were included in the study. The mean age of the patients at the time of diagnosis was 97.0 ± 57.1 months. The patients' mean tissue transglutaminase (tTG) IgA value was 172 ± 133. The most common Marsh-Oberhuber classification was found to be Marsh 3b (47.6%) in CD patients. According to the Marsh-Oberhuber classification, the mean tTGIgA values were significantly different compared to the groups. Conclusion: We recommend starting a diet with a diagnosis of CD without endoscopy for patients with a tTGIgA value of 10 X ULN (upper limit of normal) or more recommended by ESPGAN, and we even support randomized prospective studies to reduce this value to 7-10 times or less.