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ObjectiveInflammation may be present with chronic kidney disease CKD and diet composition high in protein intake and fats may affect inflammation thereby impacting kidney health. We investigated whether acid load estimated from urine measures is associated with kidney function decline and whether the effect of acid load on an inflammatory marker, serum albumin, is a pathway to this association.MethodsWe studied 188 postmenopausal women in a randomized clinical trial of potassium bicarbonate treatment for up to 36months. Twenty-four-hour urine and arterialized blood collections were done at baseline and at subsequent follow-up visits at 3months interval. Acid load was estimated from potential renal acid load calculated using urinary measures of chloride, phosphate, sodium, potassium, calcium, and magnesium (UPRAL). Mixed effects model with random-intercept and slope was used to estimate subjects' annual decline rate in creatinine clearance (CrCl), and the association between (i) UPRAL and serum albumin and (ii) serum albumin and CrCl, adjusting for age, body mass index, systolic BP, and glucose. A Cox proportional regression model was used to study the relative hazard (RH) for rapid progression of kidney function decline (defined as loss of ≥5mL/min CrCl/yr based on the last CrCl in the rolling window) with UPRAL, adjusting for the potential covariates and baseline CrCl.ResultsA 25 mEq/day increase in UPRAL was inversely associated with serum albumin (Adjusted β[95% CI]: -0.02[-0.09;-0.001). During a mean follow-up of 28months, 19 women (10%) had a rapid decline in kidney function. For each 25 mEq/day increase in UPRAL, the risk of a rapid decline in CrCl increased by 17% (95% CI: 1.06-1.28). On adjustment for potential confounders, the risk attenuated to 5% (1.02-1.14). Mediation analysis indicated that of the total effect of the association between UPRAL and CrCl, the proportion mediated by serum albumin increased to 0.346 (i.e. 34.6%).ConclusionHigher UPRAL was associated with lower serum albumin as well as greater kidney function decline in postmenopausal women. Our findings suggest inflammatory response may exert a modulatory effect on the association of UPRAL and kidney function and might be a potential pathway explaining the effects of systemic acid load on progression of kidney failure.

Any effective screening program must satisfy 2 criteria: 1) the test must identify clinically significant disease earlier than its clinical presentation, and 2) a treatment must be available that will alter the natural history of the disease. The controversy surrounding PSA testing that has raged since 1991 centers on these 2 points. Screening and treatment trials published during the past 3 decades have provided critical insights into our understanding of the natural history of PSA identified cancers and the impact of treatment. This in turn raises questions concerning the mechanism of prostate cancer mortality reduction. This essay reflects on the mechanisms of disease progression and the implications for future screening and treatment efforts.

Dementia of Alzheimer's Type (DAT) is a complex disorder influenced by numerous factors, and it is difficult to predict individual progression trajectory from normal or mildly impaired cognition to DAT. An in-depth examination of multiple modalities of data may yield an accurate estimate of time-to-conversion to DAT for preclinical subjects at various stages of disease development. We used a deep-learning model designed for survival analyses to predict subjects' time-to-conversion to DAT using the baseline data of 401 subjects with 63 features from MRI, genetic, and CDC (Cognitive tests, Demographic, and CSF) data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our study demonstrated that CDC data outperform genetic or MRI data in predicting DAT time-to-conversion for subjects with Mild Cognitive Impairment (MCI). On the other hand, genetic data provided the most predictive power for subjects with Normal Cognition (NC) at the time of the visit. Furthermore, combining MRI and genetic features improved the time-to-event prediction over using either modality alone. Finally, adding CDC to any combination of features only worked as well as using only the CDC features.

The amyloid beta, tau, neurodegenerative markers framework has been proposed to serve as a system to classify and combine biomarkers for Alzheimer's Disease (AD). Although cerebrospinal (CSF) fluid AT (amyloid beta and tau)-based biomarkers have a well-established track record to distinguish AD from control subjects and to predict conversion from mild cognitive impairment (MCI) to AD, there is not an established non-tau based neurodegenerative ("N") marker from CSF. Here, we examine the ability of several candidate peptides in the CSF to serve as "N" markers to both classify disease state and predict MCI to AD conversion. We observed that although many putative N markers involved in synaptic processing and neuroinflammation were able to, when examined in isolation, distinguish MCI converters from non-converters, a derivative from VGF, when combined with AT markers, most strongly enhanced prediction of MCI to AD conversion. Low CSF VGF levels were also predictive of MCI to dementia conversion in the setting of normal AT markers, suggesting that it may serve as a very early predictor of dementia conversion. Other markers derived from neuronal pentraxin 2, GAP-43 and a 14-3-3 protein were also able to enhance MCI to AD prediction when used as a marker of neurodegeneration, but VGF had the highest predictive capacity. Thus, we propose that low levels of VGF in CSF may serve as "N" in the amyloid beta, tau, neurodegenerative markers framework to enhance the prediction of MCI to AD conversion.

BackgroundThe COVID-19 pandemic profoundly impacted the delivery of care and timing of elective surgical procedures. Most endocrine-related operations were considered elective and safe to postpone, providing a unique opportunity to assess clinical outcomes under protracted treatment plans.MethodsAmerican Association of Endocrine Surgeon members were surveyed for participation. A Research Electronic Data Capture survey was developed and distributed to 27 institutions to assess the impact of COVID-19-related delays. The information collected included patient demographics, primary diagnosis, resumption of care, and assessment of disease progression by the surgeon.ResultsTwelve out of 27 institutions completed the survey (44.4%). Of 850 patients, 74.8% (636) were female; median age was 56 (interquartile range, 44-66) years. Forty percent (34) of patients had not been seen since their original surgical appointment was delayed; 86.2% (733) of patients had a delay in care with women more likely to have a delay (87.6% vs 82.2% of men, χ2= 3.84, P= .05). Median duration of delay was 70 (interquartile range, 42-118) days. Among patients with a delay in care, primary disease site included thyroid (54.2%), parathyroid (37.2%), adrenal (6.5%), and pancreatic/gastrointestinal neuroendocrine tumors (1.3%). In addition, 4.0% (26) of patients experienced disease progression and 4.1% (24) had a change from the initial operative plan. The duration of delay was not associated with disease progression (P= .96) or a change in operative plan (P= .66).ConclusionAlthough some patients experienced disease progression during COVID-19 delays to endocrine disease-related care, most patients with follow-up did not. Our analysis indicated that temporary delay may be an acceptable course of action in extreme circumstances for most endocrine-related surgical disease.

Acute exacerbations due to COVID-19 vaccination in patients with interstitial lung disease (ILD) have been reported, but their incidence is unknown. We investigated the incidence of exacerbations of ILD and respiratory symptoms due to the mRNA COVID-19 vaccines. A questionnaire survey was conducted on adverse reactions to the mRNA COVID-19 vaccination in 545 patients with ILD attending our hospital and retrospectively examined whether the eligible patients actually developed acute exacerbations of ILD induced by the vaccine. Of the 545 patients, 17 (3.1%) patients were aware of the exacerbation of respiratory symptoms, and four (0.7%) patients developed an acute ILD exacerbation after vaccination. Of the four patients who experienced exacerbations, two had collagen vascular disease-associated ILD, one had nonspecific interstitial pneumonia, another had unclassifiable idiopathic pneumonia, and none had idiopathic pulmonary fibrosis. Four patients were treated using steroid pulse therapy with a steroid taper, and two of the four also received intravenous cyclophosphamide pulse therapy. Tacrolimus was started in one patient with myositis-associated interstitial lung disease. Eventually, all patients exhibited improvement with immunosuppressive treatment and were discharged. COVID-19 vaccination for patients with ILD should be noted for developing acute exacerbations of ILD with low incidence, although manageable with early diagnosis and treatment.

In the KEYNOTE-355 (KN355) trial, pembrolizumab in combination with chemotherapy demonstrated superior efficacy and manageable safety compared with chemotherapy alone in patients with previously untreated locally recurrent inoperable and metastatic triple-negative breast cancer (mTNBC) with PD-L1 positive (Combined Positive Score [CPS]≥ 10) tumours. This study aimed to evaluate the clinical benefits and risks of pembrolizumab measured by quality-adjusted survival in the trial population.The study used data from the final analysis of KN355. The Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis was used to compare treatments of pembrolizumab plus chemotherapy versus chemotherapy alone. Patients' survival time was partitioned into three health states - toxicity before disease progression (TOX), time without symptoms or toxicity before disease progression (TWiST), and relapse (REL). Utilities for these health states were estimated using EuroQol-5 Dimensions, 3 Levels (EQ-5D-3L) data collected in KN355. Q-TWiST was derived as the utility-weighted sum of the mean health state durations.Patients randomised to pembrolizumab plus chemotherapy had 3.7 months greater Q-TWiST (relative gain of 18%; P = 0.003) compared to those randomised to chemotherapy at the median follow-up of 44 months, and 4.3 months greater Q-TWiST (relative gain of 20%; P = 0.004) at the maximum follow-up of 52 months. The Q-TWiST gain increased with longer follow-up time.Pembrolizumab plus chemotherapy was associated with statistically significant and clinically important improvement in Q-TWiST compared to chemotherapy in previously untreated PD-L1-positive mTNBC.

Turning in gait digital parameters may be useful in measuring disease progression in Parkinson's disease (PD), however challenges remain over algorithm validation in real-world settings. The influence of clinician observation on turning outcomes is poorly understood. Our objective is to describe a unique in-home video dataset and explore the use of turning parameters as biomarkers in PD.11 participants with PD, 11 control participants stayed in a home-like setting living freely for 5 days (with two sessions of clinical assessment), during which high-resolution video was captured. Clinicians watched the videos, identified turns and documented turning parameters.From 85 hours of video 3869 turns were evaluated, averaging at 22.7 turns per hour per person. 6 participants had significantly different numbers of turning steps and/or turn duration between "ON" and "OFF" medication states. Positive Spearman correlations were seen between the Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale III score with a) number of turning steps (rho = 0.893, p 0.001), and b) duration of turn (rho = 0.744, p = 0.009) "OFF" medications. A positive correlation was seen "ON" medications between number of turning steps and clinical rating scale score (rho = 0.618, p = 0.048). Both cohorts took more steps and shorter durations of turn during observed clinical assessments than when free-living.This study shows proof of concept that real-world free-living turn duration and number of turning steps recorded can distinguish between PD medication states and correlate with gold-standard clinical rating scale scores. It illustrates a methodology for ecological validation of real-world digital outcomes.

Cancer patients with SARS-CoV-2 infection can experience a broad range of clinical manifestations and outcomes. Previous studies have demonstrated an association between torque teno virus (TTV) load and deficiencies of the immune system. The impact of SARS-CoV-2 and TTV viral loads in cancer patients is unknown.In this retrospective study, 157 cancer patients and 191 noncancer controls were analysed for SARS-CoV-2 RNA and TTV DNA presence.SARS-CoV-2 RNA was detected in 66.2% of cancer patients and in 68.6% of noncancer control subjects. In SARS-CoV-2-positive patients, TTV was detectable in 79.8% of cancer patients, while in controls, TTV was detected in 71.7% of subjects. No statistically significant correlation was found between TTV and SARS-CoV-2 loads in cancer patients. However, the 100-day survival rate in cancer patients who died from COVID-19 was significantly lower in the TTV-positive group than in the TTV-negative group (P = 0.0475). In the cancer TTV-positive group, those who died also had a higher load of TTV than those who did not die (P = 0.0097).Our findings indicated that the presence of TTV in nasopharyngeal swabs from cancer patients was related to a higher number of deaths from COVID-19 and to a higher TTV DNA load.

Chronic kidney disease (CKD) is a widespread condition that predisposes patients to a myriad of complications, including cardiovascular disease, electrolyte and acid-base derangements, anemia, mineral-bone disease, and volume excess. The frequency of CKD complications increases with the stage of disease, becoming nearly ubiquitous in later stages. The complications of CKD have profound implications for patient management, laboratory monitoring, medication prescribing, and follow up. Management of CKD seeks to slow disease progression and mitigate the risks posed by these complications.

Immune checkpoint inhibitors (ICIs) have become a key therapeutic modality for advanced non-small cell lung cancer (NSCLC), but most patients experience primary or acquired resistance to these drugs. We here explored the mechanisms underlying both types of ICI resistance by analysis of the tumor immune microenvironment (TME).Four patients who experienced a long-term response to ICI treatment (progression-free survival [PFS] of ≥12 months) followed by disease progression, after which a rebiopsy was immediately performed (cohort-A), as well as four patients who experienced early tumor progression during ICI treatment (PFS of9 weeks, cohort-B) were enrolled in this retrospective study. The pretreatment TME was evaluated by 16- or 17-color multiplex immunohistochemistry (mIHC)-based spatial profiling at the single-cell level for both cohorts. In cohort-A, changes in the TME after disease progression during ICI treatment were also investigated by mIHC analysis and transcriptomic analysis.Pretreatment tumor tissue from cohort-B manifested poor infiltration of tumor-reactive CD8The presence of intratumoral tumor-reactive CD8

To identify patterns of visual field (VF) loss based on unsupervised machine learning and to identify patterns that are associated with rapid progression.Cross-sectional and longitudinal study.A total of 2231 abnormal VFs from 205 eyes of 176 Ocular Hypertension Treatment Study (OHTS) participants followed over approximately 16 years.Visual fields were assessed by an unsupervised deep archetypal analysis algorithm and an OHTS-certified VF reader to identify prevalent patterns of VF loss. Machine-identified patterns of glaucoma damage were compared against those patterns previously identified (expert-identified) in the OHTS in 2003. Based on the longitudinal VFs of each eye, VF loss patterns that were strongly associated with rapid glaucoma progression were identified.Machine-expert correspondence and type of patterns of VF loss associated with rapid progression.The average VF mean deviation (MD) at conversion to glaucoma was -2.7 decibels (dB) (standard deviation [SD] = 2.4 dB), whereas the average MD of the eyes at the last visit was -5.2 dB (SD = 5.5 dB). Fifty out of 205 eyes had MD rate of -1 dB/year or worse and were considered rapid progressors. Eighteen machine-identified patterns of VF loss were compared with expert-identified patterns, in which 13 patterns of VF loss were similar. The most prevalent expert-identified patterns included partial arcuate, paracentral, and nasal step defects, and the most prevalent machine-identified patterns included temporal wedge, partial arcuate, nasal step, and paracentral VF defects. One of the machine-identified patterns of VF loss predicted future rapid VF progression after adjustment for age, sex, and initial MD.An automated machine learning system can identify patterns of VF loss and could provide objective and reproducible nomenclature for characterizing early signs of visual defects and rapid progression in patients with glaucoma.

OBJECTIVE: To identify how pre-diagnosis employment, education, demographic statuses, and disease factors relate to job retention among people with multiple sclerosis (MS). DESIGN: Cross-sectional. Logit model. SETTING: Data were collected at an academic Medical University and a specialty hospital, both in the Southeastern USA. PARTICIPANTS: People with MS (n = 1,126) who were employed at the time of MS diagnosis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Job retention was measured by employment status at the time of follow-up assessment. RESULTS: Pre-diagnostic educational attainment was predictive of job retention. Among several pre-diagnostic employment characteristics, only working in production, transportation, and materials moving was significantly related to a lower odds of job retention compared with those working in professional/managerial occupations. Aging factors were strongly related to job retention, with declines in job retention observed with increasing age and years since diagnosis. Non-Hispanic Black and Hispanic participants reported lower odds of job retention compared with non-Hispanic whites, although there were no observed effects of sex. A significantly lower job retention rate was observed among those with progressive MS, compared with relapsing remitting. Job retention was also less likely among people with greater MS severity and fatigue. CONCLUSION: Job retention strategies and interventions should target people with greater MS complications and severity, as well as non-Hispanic Blacks and Hispanics, as these characteristics are more highly related to job retention than our pre-diagnostic employment and vocational history.

Data on the effectiveness of oral antivirals in patients with mild-to-moderate COVID-19 are urgently needed. This retrospective cohort study aimed to evaluate the clinical and virological outcomes associated with molnupiravir or nirmatrelvir-ritonavir use in hospitalised patients with mild-to-moderate COVID-19 during a pandemic wave dominated by the omicron BA.2 subvariant.We analysed data from a territory-wide retrospective cohort of patients in Hong Kong who were hospitalised with a confirmed diagnosis of SARS-CoV-2 infection between Feb 26 and April 26, 2022. Data were extracted from the Hospital Authority, the Department of Health, and the Hong Kong Death Registry. Patients were eligible for inclusion if their admission date was within 3 days before or after confirmation of their COVID-19 diagnosis. Those who were admitted to hospital more than 5 days after symptom onset, were younger than 18 years, had a history of oral antiviral use before admission, required supplemental oxygen on admission, had drug-related contraindications to nirmatrelvir-ritonavir use, or had severe renal or severe liver impairment were excluded. Patients who received the oral antivirals molnupiravir or nirmatrelvir-ritonavir were matched with controls using propensity-score matching in a ratio of 1:1. The primary outcome was all-cause mortality and secondary outcomes included a composite outcome of disease progression (all-cause mortality, initiation of invasive mechanical ventilation [IMV], intensive care unit [ICU] admission, or the need for oxygen therapy) and each of these individual disease progression outcomes, and time to reaching a low viral burden (RT-PCR cycle threshold value ≥30). For each event outcome, crude incidence rates were calculated and hazard ratios (HRs) estimated using Cox regression models.We identified 40 776 patients hospitalised with SARS-CoV-2 infection during the study period, with a mean follow-up of 41·3 days (total 925 713 person-days). After exclusions and propensity-score matching, we included 1856 molnupiravir recipients and 1856 matched controls, and 890 nirmatrelvir-ritonavir recipients and 890 matched controls. A lower risk of all-cause mortality was observed in molnupiravir recipients (crude incidence rate per 10 000 person-days 19·98 events [95% CI 16·91-23·45]) versus matched controls (38·07 events [33·85-42·67]; HR 0·48 [95% CI 0·40-0·59], p0·0001) and in nirmatrelvir-ritonavir recipients (10·28 events [7·03-14·51]) versus matched controls (26·47 events [21·34-32·46]; HR 0·34 [0·23-0·50], p0·0001). Oral antiviral recipients also had lower risks of the composite disease progression outcome (molnupiravir HR 0·60 [95% CI 0·52-0·69], p0·0001; nirmatrelvir-ritonavir 0·57 [0·45-0·72], p0·0001) and need for oxygen therapy (molnupiravir 0·69 [0·57-0·83], p=0·0001; nirmatrelvir-ritonavir 0·73 [0·54-0·97], p=0·032) compared with controls. Time to achieving a low viral burden was significantly shorter among oral antiviral recipients than matched controls (molnupiravir HR 1·38 [95% CI 1·15-1·64], p=0·0005; nirmatrelvir-ritonavir 1·38 [1·07-1·79], p=0·013). Significant differences in initiation of IMV and ICU admission were not found.During a wave of SARS-CoV-2 omicron BA.2, initiation of novel oral antiviral treatments in hospitalised patients not requiring oxygen therapy on admission showed substantial clinical benefit. Our findings support the early use of oral antivirals in this population of patients.Health and Medical Research Fund (Health Bureau, Government of the Hong Kong Special Administrative Region).For the Chinese translation of the abstract see Supplementary Materials section.

To evaluate the value of the pulmonary ultrasound for the diagnosis of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in emergency departments (EDs).Between January 2018 and December 2019, patients admitted to the ED of Shanxi Provincial People's Hospital for suspected AECOPD were prospectively included in this study. Pulmonary ultrasound was performed using a linear transducer. The pulmonary ultrasound findings were evaluated for further discrimination for patients with AECOPD. Then, the diagnostic performance of pulmonary ultrasound was estimated and calculated. The clinical characteristics between groups with and without pneumonia were compared.A total of 53 patients with AECOPD were included in the final analysis. For diagnosis of AECOPD due to pneumonia, ultrasound findings, such as consolidation, slightly rough pleural line, or irregular and interrupted pleural line had a sensitivity of 92.3% and a specificity of 86.7%. For diagnosis of AECOPD complicating pulmonary fibrosis, fringed pleural line had a sensitivity of 100% and a specificity of 97.5%. In addition, patients with pleural effusion (n=19) or pneumothorax (n=1) were correctly identified and wavy or bulging pleural lines were common in patients with AECOPD (58.5%, 31/53).Ultrasound findings could offer further discrimination for AECOPD complications and other pathological conditions, such as pneumonia, pulmonary fibrosis, pleural effusion, and pneumothorax in EDs.

Neovascular age-related macular degeneration (nAMD) often requires intensive therapy with anti-VEGF injections. In prior post hoc studies, early residual fluid (ERF) after the loading phase was associated with poorer treatment outcomes. This retrospective study examined the impact of ERF on vision using machine learning (ML) methods in routine clinical practice.Retrospective cohort.This study included treatment-naïve patients with nAMD who were initiated on anti-VEGF between 2012 and 2018, with at least 1 year of follow-up.Overall, 286 patients with nAMD were included. An ML algorithm quantified intraretinal fluid (IRF), subretinal fluid (SRF), and total retinal fluid from OCTs. The ERF group included those with fluid at week 12 and was further stratified by fluid subtype. Paired t tests and analysis of variance compared best visual acuity (BVA) and fluid among subgroups, and a quartile analysis correlated fluid volumes to week 52 BVA. The risk of ERF was predicted from baseline factors using 3 ML methods: Ridge logistic regression, k nearest neighbors classification, and support vector classification.Mean change in BVA from baseline to week 52 according to week 12 fluid status.At week 12, 58.4% of patients had ERF. The breakdown of those in the ERF group included SRF-only (45.5%), IRF-only (21.6%), and IRF and SRF (32.9%). The ERF and ERF-free groups had similar BVA gains from baseline to week 52 (+5.7 ± 15.4 vs. +4.9 ± 18; P = 0.69). Examining specific ERF subgroups revealed no significant differences among the IRF-only (+4.6 ± 16.4), SRF-only (+5.6 ± 12.5), and IRF and SRF (+6.6 ± 18.5, P = 0.93) groups. Quartile analysis of week 12 fluid revealed no predictive pattern for BVA gains. Three ML methods were developed to predict those at risk for ERF achieved equivalent performance, with F1 score of 0.73 to 0.76.These results diverge from prior post hoc studies, in that there was no significant difference in long-term BVA gains between ERF and ERF-free cohorts, as well as between the week 12 fluid subgroups.

Systemic sclerosis (SSc), also referred to as systemic scleroderma or scleroderma, is a rare, complex immune-mediated connective tissue disease characterized by progressive skin fibrosis and other clinically heterogenous features. The etiopathogenesis of SSc involves vasculopathy and immune system dysregulation occurring on a permissive genetic and epigenetic background, ultimately leading to fibrosis. Recent developments in our understanding of disease-specific autoantibodies and bioinformatic analyses has led to a reconsideration of the purely clinical classification of diffuse and limited cutaneous SSc subgroups. Autoantibody profiles are predictive of skin and internal organ involvement and disease course. Early diagnosis of SSc, with commencement of disease-modifying treatment, has the potential to improve patient outcomes. In SSc, many of the clinical manifestations that present early signs of disease progression and activity are cutaneous, meaning dermatologists can and should play a key role in the diagnosis and management of this significant condition. The first article in this continuing medical education series discusses the epidemiology, clinical characteristics, and pathogenesis of SSc in adults, with an emphasis on skin manifestations, the important role of dermatologists in recognizing these, and their correlation with systemic features and disease course.

COPD is a leading cause of death and disability. COPD therapy goals include reducing exacerbations and improving symptom control. Single-inhaler triple therapy (SITT) or multiple-inhaler triple therapy (MITT) is indicated for patients with frequent exacerbations despite bronchodilator therapy. No available evidence compares SITT vs MITT in Spain in terms of treatment persistence, exacerbations, and other outcomes. Do COPD patients in Spain initiating SITT vs MITT have improved persistence, exacerbations, and health care resource utilization? This real-world, observational, retrospective cohort study analyzed electronic health records in the Spanish National Healthcare System BIG-PAC database to identify COPD patients aged ≥ 40 years initiating SITT or MITT (using two or three inhalers) between June 1, 2018 and December 31, 2019. Comparative data on persistence (allowing up to 60 days without prescription refill), exacerbation rates, and health care resource utilization and costs during 12-month follow-up were analyzed. Multivariate adjusted analyses were performed. Eligible patients (N = 4,625) initiating SITT (n = 1,011) or MITT (n = 3,614) had a mean age of 70.9 years; most were male (73.9%) with mainly moderate (62.0%) or severe (26.5%) airflow limitation. Between-cohort baseline characteristics were similar. At 12-month follow-up, SITT patients had higher persistence (hazard ratio [HR] = 1.37; 95% CI = 1.22-1.53; P Patients initiating SITT had a clinically relevant improvement in persistence leading to reductions in mortality, incidence of exacerbations, and health care resource use with consequent mean cost savings.

Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes.We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age ≥18 years), large (≥500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression (standardised to a definition of a sustained ≥50% decrease in estimated glomerular filtration rate [eGFR] from randomisation, a sustained low eGFR, end-stage kidney disease, or death from kidney failure), acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618.We identified 13 trials involving 90 413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90 409 participants (74 804 [82·7%] participants with diabetes [99% with type 2 diabetes] and 15 605 [17·3%] without diabetes; trial-level mean baseline eGFR range 37-85 mL/min per 1·73 mIn addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.UK Medical Research Council and Kidney Research UK.

Patients with amyotrophic lateral sclerosis (ALS) show substantial differences in disease progression and survival. However, the genetic contribution to the extremes of this spectrum remains poorly characterized. We unbiasedly selected and genotyped 102 ALS patients with very short (100 months) from the ALS registry of Ulm University using whole-exome sequencing and C9orf72 repeat expansion testing followed by a clinicogenetic correlation analysis. Clinically, groups significantly differed regarding site of disease onset, age at onset, BMI at diagnosis, disease progression rates, and diagnostic latency. We found a monogenic disease cause in 31 patients (16%) without significant differences in patients with short and long survival (19% vs. 13%; p = 0.41), but differences in the genotypic architecture. C9orf72 expansions and FUS mutations were only found in fast progressors, whereas SOD1 variants were frequent in both groups contributing 52% of all monogenic cases-33% among fast and 75% among slow variants. Our genotype-phenotype correlation may be relevant for genetic counseling, estimation of prognosis, and therapeutic decisions.

For persons with proteinuria, angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) are treatment mainstays for reducing kidney disease progression. Guidelines for managing hypertension and chronic kidney disease recommend titrating to the maximum ACEi/ARB dose tolerated. Using deidentified national electronic health record data from the Optum Labs Data Warehouse, we examined ACEi/ARB dosing among adults with proteinuria-defined as either a urine albumin to creatinine ratio of 30 mg/g or greater or a protein to creatinine ratio of 150 mg/g or greater-who were prescribed an ACEi/ARB medication between January 1, 2017, and December 31, 2018. Among 100,238 included patients (mean age, 65.1 years; 49,523 [49.4%] female), 29,883 (29.8%) were taking maximal ACEi/ARB doses. Among 74,287 patients without potential contraindications to dose escalation (systolic blood pressure120 mm Hg, estimated glomerular filtration rate15 mL/min per 1.73 m

Red blood cells (RBC) are the most abundant circulating cell of the human body. RBC are constantly exposed to multiple stresses in the circulation, leading to molecular and structural impairments and death. The physiological process of RBC senescence or ageing is referred to as eryptosis. At the end of their lifespan, aged RBC are recognized and removed from the blood by professional phagocytes via a phenomenon called erythrophagocytosis (EP); the phagocytosis of RBC. Some genetic and acquired diseases can influence eryptosis, thereby affecting RBC lifespan and leading to hemolytic anemia. In some diseases, such as diabetes and atherosclerosis, eryptosis and EP can participate in disease progression with both professional and non-professional phagocytes. Therefore, investigating the process of EP in vivo and in vitro, as well as in different cell types, will not only contribute to the understanding of the physiological steps of EP, but also to the deciphering of the specific mechanisms involving RBC and EP that underlie certain pathologies. In this review, the process of EP is introduced and the different methods for studying EP are discussed together with examples of the experimental procedures and materials required.

In a prospective multicenter study, gemcitabine monotherapy followed by stereotactic body radiation therapy (SBRT) was well tolerated with outcomes comparable to chemoradiation for locally advanced pancreatic cancer (LAPC). Recent trials have reported improved survival with multiagent chemotherapy (MA-CTX) alone. This prospective trial explored whether SBRT could be safely delivered after MA-CTX. Herein, we report the long-term outcomes of adding SBRT after MA-CTX in LAPC patients and evaluate whether genetic profiles of specimens obtained before SBRT influence outcomes.This prospective nonrandomized controlled phase 2 trial enrolled 44 LAPC and 4 locally recurrent patients after multidisciplinary evaluation between 2012 and 2015 at a high-volume pancreatic cancer center. For induction CTX, most received modified FOLFIRINOX (mFFX), or gemcitabine and nab-paclitaxel (GnP) followed by 5-fraction SBRT for all. During fiducial placement, biopsies were obtained with DNA extracted for targeted sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform.Median induction CTX duration was ≥4 months, and 31 patients received mFFX (65%). Among 44 LAPC patients, 17 (39%) were surgically explored, and 12 of 16 (75%) achieved a R0 resection. Median overall survival (mOS) was 20.2 and 14.6 months from diagnosis and SBRT, respectively. One- and 2-year OS from SBRT was 58% and 28%. The mOS after resection was 28.6 and 22.4 months from diagnosis and SBRT, respectively. Median local progression-free survival was 23.9 and 15.8 months from diagnosis and SBRT, respectively. The mOS for pre-SBRT CA 19-9 ≤180 U/mL versus180 was 23.1 and 11.3 months, respectively (hazard ratio, 0.53; P = .04). Only 1 patient (2.1%) had late grade ≥2 gastrointestinal toxic effects attributable to SBRT. Despite significant pretreatment with chemotherapy, 88% of tumor specimens were effectively sequenced; survival outcomes were not significantly associated with specific mutational patterns. Quality of life was prospectively collected pre- and post-SBRT with the EORTC QLQ-C30 and PAN26 questionnaires showing no significant change.SBRT was safely administered with MA-CTX with minimal toxicity. A high proportion of LAPC patients underwent R0 resection with favorable survival outcomes.

Multiple myeloma (MM) is a malignancy of plasma cells that arises from premalignant Monoclonal Gammopathy of Undetermined Significance (MGUS) and often progresses through an asymptomatic Smoldering (SMM) phase. Understanding the interactions between abnormal clonal plasma cells and the tumor microenvironment (TME) in the early disease states (MGUS, SMM) may inform risk assessment and therapy.We performed high dimensional immunologic analysis of bone marrow specimens from 73 subjects with SMM by mass cytometry and T cell receptor sequencing of CD138-depleted bone marrow (BM) mononuclear cells, and proteomics and seromic profiling of BM plasma. Analysis of individual assay data identified self-organizing subgroups of SMM patients. We then applied novel bioinformatic methods to integrate data from pairs, trios, and quartets of assays.Mass cytometry, TCRSeq and proteomics identified three taxa (sing. taxon) of subjects that shared common characteristics across all three assays. Differential levels of BM plasma pleiotropin (PTN) and BM T cells and their productive clonality emerged as strong distinguishing factors among these taxa.These results suggest that the continuum from MGUS to MM does not consist of a single pathway in the TME, and that complex interactions between myeloma cells and the TME may ultimately determine progression and inform clinical management.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of arylsulfatase A (ARSA). Subsequent accumulation of sulfatides leads to demyelination and neurodegeneration in the central and peripheral nervous system. To date MLD is classified based on the age at onset, however, especially for late onset forms this classification provides only limited projection regarding the clinical disease course. Moreover, evolving newborn screening approaches raise the need to predict the disease onset and course in pre-symptomatic individuals. Here, we correlate the ARSA activity and the ARSA-genotype with clinical parameters in a large cohort of 96 affected individuals.Clinical data of 96 affected individuals with genetically and/or biochemically confirmed MLD were collected from a national database. Leukocyte samples from 69 affected individuals were re-analyzed for the ARSA activity using p-nitrocatecholsulfate as substrate with a refined ARSA assay towards the lower limit of detection. For 84 individuals genetic sequencing was conducted by Sanger or next generation sequencing (NGS).The adapted ARSA assay revealed the discriminatory power to differentiate MLD subtypes as the residual enzyme activity was low in late infantile and early juvenile forms, and clearly higher in late juvenile and adult MLD (plt; 0.001). A residual enzyme activity below 1% compared to controls predicted an early onset (late-infantile or early-juvenile) and rapid disease progression. A firm genotype-phenotype correlation was proven as reliable for bi-allelic protein-truncating variants in the ARSA gene resulting in minimal residual ARSA activity, an early onset of the disease and initial decline of motor functions. Although the impact of missense variants was equivocal, few variants with a recognizable clinical spectrum were identified.ARSA activity in leukocytes as well as the ARSA genotype can predict the age of disease onset and the dynamic of disease progression for most of the early onset forms. This knowledge is relevant for patient counseling and to guide treatment decisions, especially when identifying pre-symptomatic individuals, e.g., in newborn screening. However, due to the high cumulative frequency of rare disease-causing missense variants in the ARSA gene that lead to highly variable residual enzyme activity, reiterated biochemical and genetic studies are needed to improve disease course prediction.

The role of digoxin in clinical practice has narrowed over time. Data on digoxin toxicity trends and outcomes are variable and lacking in granularity for treatment outcomes. This study aimed to address data gaps in digoxin toxicity trends and outcomes in patients treated with or without digoxin immune fab (DIF). This single-center analysis examined patients with signs/symptoms concerning for digoxin toxicity, defined as hospital admission or emergency department visit with elevated digoxin serum concentrations (>2 ng/mL) and/or primary diagnosis code of digoxin toxicity and/or DIF order. Between 2000–2020, 727 patients were identified with signs concerning for digoxin toxicity with mortality rates of 12.7% during admission and 42.7% at 1 year. DIF was ordered in 9% of cases. Incidence of digoxin toxicity per 1000 patients with a digoxin prescription and frequency of DIF treatment fluctuated over time without a clear trend toward increase or reduction. DIF-treated patients demonstrated a heavier co-morbidity burden and lower presenting heart rates (median 53 [39.5–69.5] vs 77 [64.0–91.5] bpm, p

Mechanistic target of rapamycin (mTOR)-signaling is one key driver of glioblastoma (GBM), facilitating tumor growth by promoting the shift to an anti-inflammatory, pro-cancerogenic microenvironment. Even though mTOR inhibitors such as rapamycin (RAPA) have been shown to interfere with GBM disease progression, frequently chaperoned toxic drug side effects urge the need for developing alternative or supportive treatment strategies. Importantly, previous work document that taste-immune associative learning with RAPA may be utilized to induce learned pharmacological placebo responses in the immune system. Against this background, the current study aimed at investigating the potential efficacy of a taste-immune associative learning protocol with RAPA in a syngeneic GBM rat model. Following repeated pairings of a novel gustatory stimulus with injections of RAPA, learned immune-pharmacological effects could be retrieved in GBM-bearing animals when re-exposed to the gustatory stimulus together with administering 10 % amount of the initial drug dose (0.5 mg/kg). These inhibitory effects on tumor growth were accompanied by an up-regulation of central and peripheral pro-inflammatory markers, suggesting that taste-immune associative learning with RAPA promoted the development of a pro-inflammatory anti-tumor microenvironment that attenuated GBM tumor growth to an almost identical outcome as obtained after 100 % (5 mg/kg) RAPA treatment. Together, our results confirm the applicability of taste-immune associative learning with RAPA in animal disease models where mTOR overactivation is one key driver. This proof-of-concept study may also be taken as a role model for implementing learning protocols as alternative or supportive treatment strategy in clinical settings, allowing the reduction of required drug doses and side effects without losing treatment efficacy.

Esophageal adenocarcinoma (EAC) is increasing in prevalence. Barrett's esophagus (BE) has long been recognized as the putative precursor lesion for EAC, but much is still unknown regarding its cell of origin and what molecular factors influence its neoplastic progression. Accurate pathologic assessment of BE biopsies is important for identifying patients most at risk of progressing to EAC, whereas pathologic assessment of EAC specimens plays a major role in influencing therapeutic decision-making.

Sarcoidosis is a multiorgan granulomatous disease with a variable course.The purpose of this study is to identify the patients that are more likely to experience disease progression.A retrospective study in patients ≥18 years. Pulmonary function and radiological stage (Scadding criteria) were assessed at diagnosis, and at 1, 3 and 5 years. Sarcoidosis progression was established based on deterioration of radiological or pulmonary function (decrease ≥10% of FVC and/or ≥15% of diffusing capacity of the lung (DLCO).The sample included 277 caucasian patients [mean age, 50±13.6; 69.7% between 31-60 years; 56.3% men]. In total, 65% had stage II sarcoidosis, whereas only 8.3% had stage III/IV disease. Mean pulmonary function (FVC, FEVAt 3 years, a third of patients experienced sarcoidosis progression. Age was the only factor associated with disease prognosis.

Evolution of aortic intramural hematoma (IMH) over time may range from resolution to degeneration and is difficult to predict. We sought to measure differences in contrast attenuation between arterial and delayed phase computed tomography angiography (CTA) images within the IMH as a surrogate of hematoma blood flow to predict resolution versus aortic growth and/or adverse outcomes.IMH institutional data were gathered from 2005-2020. Hounsfield unit ratio (HUR) was measured as hematoma Hounsfield unit (HU), on delayed phase images divided by HU on arterial phase images on CTA. Aortic growth and effect of HUR was determined using a linear mixed effects model. Freedom from adverse aortic event, defined as the composite of intervention, recurrence of symptoms, radiographic progression, and rupture, was determined using Kaplan-Meier analysis.IMH occurred in 73 patients, of which 27 met the inclusion criteria. HUR ranged from 0.38-1.92 (mean: 0.98). Baseline aortic diameter growth independent of HUR measurement was 0.49 mm/year (95% confidence interval CI: -1.23 to 2.2). With the HUR was introduced into the model, the beta coefficient for time was -5.83 mm/year (95% CI: -10.4 to -1.28 mm/year) and the beta coefficient for the HUR was 5.05 mm/year per one-unit HUR (95% CI: 0.56 to 9.56 mm/year). Thus, an HUR1.15 would correspond to aortic growth while an HUR1.15 would correspond to reduction in aortic diameter, consistent with IMH resolution. Aortic adverse events occurred in 13 (48%) patients, 7 (26%) patients had recurrence of symptoms, 8 (30%) required intervention, 5 (18%) progressed to dissection, and 1(4%) had aortic rupture. There was a trend towards an association between higher HUR and composite adverse aortic events (HR 3.2 per 1-unit HUR; 95% CI: 0.6-17.3; P = 0.18).Increased HUR is associated with increased aortic growth and a trend toward adverse aortic events. Diminished delayed phase enhancement may predict partial or complete IMH resolution. HUR can be used to guide IMH surveillance and treatment.

To explore the clinical effect of allogeneic sclera transplantation combined with tarso-conjunctival flap in total excision of divided eyelid nevus.Eleven patients (three male and eight female patients) who experienced divided nevus of the eyelids between January 2014 and April 2020 were recruited to this retrospective study. All lesions were thick, darkly pigmented, presented with a wart-like appearance, and invaded the eyelid margin and tarsal conjunctiva. The surgical method involved a full-thickness lesion excision; then, the posterior defect was reconstructed by sliding the residual tarso-conjunctival flap forward and allogeneic sclera transplantation, and the anterior defect was reconstructed with sliding flaps, rotating flaps, and free skin grafts.Neither malignant transformations nor recurrences were observed after a follow-up of more than one year. The eyelid shape was normal, the rim of the eyelid was smooth, there was no dissolution or rejection of the allogeneic sclera, and the eyelid had good mobility. All the flaps used were viable, soft, and thin. The most frequent complication was the loss of eyelashes in the reconstructed area.For divided nevus of the eyelids invaded the eyelid margin and tarsal conjunctiva, total excision is a better decision, regardless of tumor recurrence or aesthetic considerations. The posterior defect reconstruction through sliding residual tarso-conjunctival flaps combined with allogeneic sclera transplantation is simple and effective.

A post hoc analysis of the Disease Recovery Evaluation and Modification (DREaM) study was conducted to evaluate time to first major treatment failure (ie, arrest/incarceration or psychiatric hospitalization) in participants with recent-onset schizophrenia or schizophreniform disorder treated with paliperidone palmitate (PP) versus oral antipsychotics (OAPs).DREaM was an open-label, delayed-start, randomized, multipart trial consisting of: Part I, 2-month oral run-in; Part II, 9-month disease progression phase (PP or OAP); and Part III, 9 months of additional treatment (PP/PP; OAP re-randomized: OAP/OAP or OAP/PP). PP/PP and OAP/OAP comprised the 18-month extended disease progression (EDP) analysis.In Part II (PP, n = 78; OAP, n = 157), similar proportions of participants experienced a major treatment failure across groups (PP: 12.8 %; OAP: 13.4 %); no difference in time to first major treatment failure was identified (P = 0.918). Significant differences favoring PP emerged after 9 months; in Part III, no participants in the PP/PP group, 3.5 % of participants in the OAP/PP group, and 15.9 % in the OAP/OAP group experienced a major treatment failure (P = 0.002). In the EDP analysis, 10.2 % (PP/PP) and 25.4 % (OAP/OAP) of participants experienced a major treatment failure (P = 0.045; number needed to treat = 6). Safety results were similar between groups and consistent with the known safety profile of PP in adults with schizophrenia.Initiation of PP during the early stages of schizophrenia spectrum disorders significantly delayed time to hospitalization and arrest/incarceration, outcomes with important personal and economic consequences, compared with OAP during this 18-month study.gov identifier: NCT02431702.

Although the gold standard in predicting future progression from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) consists in the McDonald criteria, efforts are being made to employ various advanced MRI techniques for predicting clinical progression. This study's main aim was to evaluate the predictive power of diffusion tensor imaging (DTI) of the brain and brain volumetry to distinguish between patients having CIS with future progression to CDMS from those without progression during the following 2 years and to compare those parameters with conventional MRI evaluation.All participants underwent an MRI scan of the brain. DTI and volumetric data were processed and various parameters were compared between the study groups.We found significant differences between the subgroups of patients differing by future progression to CDMS in most of those DTI and volumetric parameters measured. Fractional anisotropy of water diffusion proved to be the strongest predictor of clinical conversion among all parameters evaluated, demonstrating also higher specificity compared to evaluation of conventional MRI images according to McDonald criteria.Conclusion: Our results provide evidence that the evaluation of DTI parameters together with brain volumetry in patients with early-stage CIS may be useful in predicting conversion to CDMS within the following 2 years of the disease course.

Socioeconomic status (SES) is associated with cardiovascular disease. However, the relationship between SES and atherosclerosis is not well documented. This study aims to explore this relationship.This is a retrospective cohort study in London, Ontario Canada. It includes 6,907 subjects from a vascular prevention centre at baseline, with long term follow up from 1989 to 2021 (total ultrasound examinations 27,103). Using carotid ultrasound, the burden of atherosclerosis was measured as total plaque area (TPA). The Ontario Marginalization Index (OMI) was used to identify SES of participants' neighborhoods. We used a Bayesian hierarchical regression and mixed effects model to identify associations between SES, baseline TPA and plaque progression. In 2003, we implemented more intensive therapy of vascular risk factors after 2003 (called "Treating arteries instead of risk treating factors"); therefore, we compared our findings before and after 2003.SES was found to have a significant association with TPA, with lower SES associated with higher TPA (adjusted odds ratio [OR] = 2.22, 95% Credible interval [CrI]: 1.37, 3.66). While we observed a higher rate of plaque progression with lower SES in those treated before 2003 (OR = 1.46, 95% CrI:1.04, 2.06), there was no significant association between plaque progression and SES after implementation more intensive therapy (OR = 0.99, 95% CrI: 0.78, 1.27).SES has a strong association with atherosclerosis and should be considered an important risk factor in clinical practice and vascular disease research. Intensive preventive therapy can prevent plaque progression irrespective of baseline SES.

To compare the enlargement rates of geographic atrophy (GA) over 5 years of follow-up with those of macular atrophy (MA) associated with macular neovascularization (MNV).Retrospective, longitudinal, comparative case series.Consecutive series of patients with age-related macular degeneration and GA (dry) or with MA and MNV.Atrophic regions detected on serial registered fundus autofluorescence images were semiautomatically delineated, and the measurements of these areas were recorded every 6 ± 3 months for the first 2 years of follow-up and at yearly intervals for up to 5 years.Annual raw and square root-transformed rates of atrophy growth.The study included 117 eyes of 95 patients (61 in the GA cohort and 56 in the MA cohort); 100% and 38.5% of the eyes completed 2 and 5 years of follow-up, respectively. The mean size of lesions at baseline was similar between the 2 groups (raw: 1.74 vs. 1.53 mmThe presence of MNV was associated with a slower rate of expansion, resulting in overall smaller areas of atrophy over time. These findings support the hypothesis that MNV may protect against the progression of atrophy.

Frailty denotes the increased vulnerability to stressors/insults associated with aging or diseases, and has high incidence in patients with diabetes mellitus (DM). We hypothesized that chronic kidney disease (CKD) and non-kidney morbidities in patients with newly diagnosed DM might modulate their risk of developing incident frailty.From the Longitudinal Cohort of Diabetes Patients, we identified 322,109 patients with newly diagnosed DM, and classified them into those without CKD, with CKD before and after DM. We used Kaplan-Meier analyses and Cox proportional hazard regression to analyze associations between CKD or non-kidney morbidities and the risk of incident frailty. We further analyzed the year-to-year trend of frailty risk brought by CKD or non-kidney morbidities.Patients with DM but without CKD (n = 249,752; 77.5%), with CKD prior to (n = 23,829; 7.4%), and after DM (n = 48,528; 15.1%) were enrolled. Those with CKD, regardless of onset timing, had a significantly higher risk of developing frailty than those without (for onset prior to DM, hazard ratio (HR) 1.235, 95% confidence interval (CI) 1.11-1.38; for onset after DM, HR 1.386, 95% CI 1.21-1.59). The risk was more prominent early after the diagnosis of DM was made. Patients with chronic obstructive pulmonary disease, liver, and cardiovascular morbidities all had a significantly higher risk of frailty than those without, with cerebrovascular accident carrying the most prominent risk elevation (HR 4.059, 95% CI 3.73-4.42).CKD regardless of onset timing relative to DM predicted a higher risk of incident frailty, while non-kidney morbidities including cardiovascular morbidities, similarly increased frailty risk among incident diabetic patients.

Delayed neurological sequelae (DNS) are a severe complication of carbon monoxide poisoning (COP) and high predisposing rates of disability and mortality, yet the relationship between exposure factors and DNS remains unknown. The aim was to investigate the association between domestic sources of COP and DNS.Patients diagnosed with COP between December 2016 and November 2021 were included and divided into two groups according to their sources of poisoning and the endpoint outcome was analyzed by logistic regression before and after propensity score matching (PSM).Overall, medical data from 314 patients were analyzed. In multivariate logistic regression, advanced age (adjusted odds ratio (AOR): 1.028, 95% CI: 1.008-1.049, P = 0.007), longer duration of exposure to the first treatment of hyperbaric oxygen (HBO) (AOR: 1.081, 95% CI: 1.036-1.127, P = 0.001), and intoxication by charcoal burning (AOR: 3.24, 95% CI: 1.208-8.69, P = 0.019) were associated with a higher risk of developing DNS. After 1:1 PSM, the outcomes also revealed that charcoal burning intoxication (odds ratio (OR): 8.396, 95% CI: 3.342-21.095, P0.001) was associated with greater odds of DNS.This study indicates that domestic COP caused by charcoal burning is more likely to trigger DNS than gas-emitting heaters.

CEND-1 is a novel cyclic peptide that targets αV integrins and neuropilin-1 and enhances tumour delivery of co-administered anticancer drugs. We investigated the safety, tolerability, and biological activity of CEND-1 in patients with metastatic pancreatic ductal adenocarcinoma in combination with nab-paclitaxel and gemcitabine.This open-label, multicentre, phase 1 study, conducted at three hospitals in Australia, enrolled participants aged 18 years or older with histologically confirmed metastatic pancreatic ductal adenocarcinoma who had one or more lesions measurable on MRI or CT, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a life expectancy of at least 3 months. Exclusion criteria included previous chemotherapy and brain metastases or other malignancy (unless receiving curative intent). There was no randomisation or masking. CEND-1 monotherapy was given as an intravenous fluid bolus on day 1 of a run-in phase of 7 days (0·2-3·2 mg/kg) followed by CEND-1 plus intravenous gemcitabine (1000 mg/mBetween Aug 13, 2018, and Nov 30, 2019, 31 patients were enrolled (eight in the dose-escalation phase [cohort 1a] and 23 in the expansion phase [cohort 1b]). Two patients were excluded from the efficacy population. No CEND-1 dose-limiting toxicities were observed in the safety population (n=31). The most common grade 3 or 4 events were neutropenia (17 [55%] patients), anaemia (eight [26%]), leukopenia (five [16%]), and pulmonary embolism (four [13%]). Serious adverse events occurred in 22 (71%) patients, mostly related to disease progression. Ten deaths occurred during the study due to progression of metastatic pancreatic cancer (n=9) and a left middle cerebral artery stroke (n=1). In the efficacy population (n=29), 17 (59%) patients had an objective response, including one complete response and 16 partial responses. After a median follow-up of 26 months (IQR 24-30), median overall survival was 13·2 months (95% CI 9·7-22·5).CEND-1 with nab-paclitaxel and gemcitabine has an acceptable safety profile, with no dose-limiting toxicities and encouraging activity. Adverse events were generally consistent with those seen with nab-paclitaxel and gemcitabine. Further randomised trials to determine the efficacy of CEND-1 are warranted.DrugCendR Australia Pty.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is associated with a clinical spectrum ranging from asymptomatic carriers to critically ill patients with complications including thromboembolic events, myocardial injury, multisystemic inflammatory syndromes and death. Since the beginning of the pandemic several therapeutic options emerged, with a multitude of randomized trials, changing the medical landscape of COVID-19. The effect of various monoclonal antibodies, antiviral, anti-inflammatory and anticoagulation drugs have been studied, and to some extent, implemented into clinical practice. In addition, a multitude of trials improved the understanding of the disease and emerging evidence points towards a significant role of the complement system, kallikrein-kinin, and contact activation system as drivers of disease in severe COVID-19. Despite their involvement in COVID-19, treatments targeting these plasmatic cascades have neither been systematically studied nor introduced into clinical practice, and randomized studies with regards to these treatments are scarce. Given the multiple-action, multiple-target nature of C1 inhibitor (C1-INH), the natural inhibitor of these cascades, this drug may be an interesting candidate to prevent disease progression and combat thromboinflammation in COVID-19. This narrative review will discuss the current evidence with regards to the involvement of these plasmatic cascades as well as endothelial cells in COVID-19. Furthermore, we summarize the evidence of C1-INH in COVID-19 and potential benefits and pitfalls of C1-INH treatment in COVID-19.

The prognosis of patients with severe cases of COVID-19 is poor; thus, biomarkers for earlier prediction of COVID-19 progression are vital. We measured levels of five lung injury-related biomarkers, SP-D, KL-6, presepsin, kallistatin and stratifin, in serum samples collected serially during hospitalization from 31 patients with mild/moderate or severe/critical COVID-19 pneumonia, and their predictive performances were compared. Like the previously reported presepsin, a new biomarker candidate, stratifin, was significantly elevated with the onset of severe or critical symptoms in COVID-19 patients and decreased with symptom improvement. Notably, changes in stratifin and presepsin levels were distinctly earlier than those in SP-D, KL-6 and even SpO

We aimed to evaluate the clinical and radiological results of total elbow arthroplasty (TEA) performed for trauma sequelae in patients45 years of age.This retrospective study included 63 patients aged45 years who underwent TEA between 2005 and 2017 for previous elbow injuries. The average follow-up period was 5.23 years (range, 2-13 years). The clinical analysis included limb function according to the Mayo Elbow Performance Score, Oxford Elbow Score, and range of motion. The degree of radiolucency was determined using plain radiographic images.The average amplitude of elbow flexion/extension increased from 49.1 ± 36.7 to 98.7 ± 28.2 (P .01), and the average amplitude of elbow pronation/supination increased from 87.2 ± 52.3 to 118.7 ± 26.3 (P = .02). Functional results improved from 21.4 ± 13.1 to 67.3 ± 14.5 (P .01) on the Mayo scale, and those measured according to the Oxford scale improved from 15.4% ± 7.0% to 28.0% ± 10.6% (P .01). Complications were observed in 16 (32.7%) patients. Among them, 10 patients (20.4%) required revision elbow arthroplasty with replacement of implant components. The overall 5-year implant survival rate was 79.4% (95% confidence interval: 63.4-91.2), and the 10-year survival rate was 77.5% (95% confidence interval: 59.3-88.2).TEA allows restoration of the full range of motion in the elbow joint and significantly improves limb function in most cases. However, the low survival rate of implants and high incidence of complications do not permit TEA to become a routine intervention for treating post-traumatic consequences in young patients.

OBJECTIVE: Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL). METHODS: The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of disease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28). RESULTS: This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were -2.1 (95% confidence interval -2.4, -1.7) for FOSI, -4.6 (-5.6, -3.5) for the EQ-5D-5L index, and -7.9 (-9.6, -6.3) for EQ-VAS. CONCLUSIONS: Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL. ispartof: GYNECOLOGIC ONCOLOGY vol:166 issue:3 pages:494-502 ispartof: location:United States status: published

Increasing adverse outcomes in patients with chronic kidney disease reflect growth of patients with early-stage chronic kidney disease and their increasing per population rates of these outcomes. Progression of chronic kidney disease, more than current level of kidney function, is the primary driver of adverse chronic kidney disease-related outcomes. Racial/ethnic minorities progress faster to end-stage kidney disease with greater risk for adverse outcomes. Diabetes and hypertension cause two-thirds of end-stage kidney disease, for which primary medical care integrated with healthy eating and increased physical activity (healthy moving) slows chronic kidney disease progression. Patients with early-stage chronic kidney disease are appropriately managed by primary care practices but most lack infrastructure to facilitate this integration that reduces adverse chronic kidney disease-related outcomes. Individuals of low socioeconomic status are at greater chronic kidney disease risk, and flexible regulatory options in Medicaid can fund infrastructure to facilitate healthy eating and healthy moving integration with primary medical care. This integration promises to reduce chronic kidney disease-related adverse outcomes, disproportionately in racial/ethnic minorities, and thereby reduce chronic kidney disease-related health disparities.

The association of malnutrition with chronic kidney disease (CKD) is well established. However, there is a paucity of studies of the effect of malnutrition risk (MR) on kidney function decline among older persons who do not have end-stage or dialyzable CKD. This study aimed to examine the association between MR status and kidney function, and future risks of kidney function decline and CKD progression in community-dwelling older adults.Nutrition Screening Initiative's DETERMINE Your Nutritional Health Checklist and estimated glomerular filtration rate (eGFR) were assessed at baseline among 5,122 participants free of end-stage renal failure or dialyzed CKD in the Singapore Longitudinal Aging Studies (SLAS-1 and SLAS-2). Follow-up eGFR was assessed in a subcohort of SLAS-2 participants without CKD (eGFR60 mL/min/1.73 mIn baseline cross-sectional analyses adjusting for other risk factors, low, moderate, and high MR was significantly associated with decreasing eGFR coefficients of -1.5, -3.3, and -5.0 mL/min/1.73 mAmong older adults without advanced kidney disease, MR is associated with poor kidney function and increased risk of kidney function decline and CKD. Preventive interventions to modify MR may help to reduce the deterioration of renal function in older people.

Arginase 1 Deficiency (ARG1-D) is a rare, progressive, metabolic disorder that is characterized by devastating manifestations driven by elevated plasma arginine levels. It typically presents in early childhood with spasticity (predominately affecting the lower limbs), mobility impairment, seizures, developmental delay, and intellectual disability. This systematic review aims to identify and describe the published evidence outlining the epidemiology, diagnosis methods, measures of disease progression, clinical management, and outcomes for ARG1-D patients.A comprehensive literature search across multiple databases such as MEDLINE, Embase, and a review of clinical studies in ClinicalTrials.gov (with results reported) was carried out per PRISMA guidelines on 20 April 2020 with no date restriction. Pre-defined eligibility criteria were used to identify studies with data specific to patients with ARG1-D. Two independent reviewers screened records and extracted data from included studies. Quality was assessed using the modified Newcastle-Ottawa Scale for non-comparative studies.Overall, 55 records reporting 40 completed studies and 3 ongoing studies were included. Ten studies reported the prevalence of ARG1-D in the general population, with a median of 1 in 1,000,000. Frequently reported diagnostic methods included genetic testing, plasma arginine levels, and red blood cell arginase activity. However, routine newborn screening is not universally available, and lack of disease awareness may prevent early diagnosis or lead to misdiagnosis, as the disease has overlapping symptomology with other diseases, such as cerebral palsy. Common manifestations reported at time of diagnosis and assessed for disease progression included spasticity (predominately affecting the lower limbs), mobility impairment, developmental delay, intellectual disability, and seizures. Severe dietary protein restriction, essential amino acid supplementation, and nitrogen scavenger administration were the most commonly reported treatments among patients with ARG1-D. Only a few studies reported meaningful clinical outcomes of these interventions on intellectual disability, motor function and adaptive behavior assessment, hospitalization, or death. The overall quality of included studies was assessed as good according to the Newcastle-Ottawa Scale.Although ARG1-D is a rare disease, published evidence demonstrates a high burden of disease for patients. The current standard of care is ineffective at preventing disease progression. There remains a clear need for new treatment options as well as improved access to diagnostics and disease awareness to detect and initiate treatment before the onset of clinical manifestations to potentially enable more normal development, improve symptomatology, or prevent disease progression.

Few data from randomized clinical trials (RCTs) investigating the efficacy of post-induction strategies after the first-line treatment with anti-Epidermal Growth Factor Receptor (EGFR) in patients with metastatic colorectal cancer (mCRC) are available. A systematic review and metanalysis might therefore be useful to highlight and even strengthen these data. A literature search in Pubmed, Embase, American Society of Clinical Oncology (ASCO) Annual Meetings, ASCO Gastrointestinal Symposia, and European Society for Medical Oncology (ESMO) Congresses was performed. The search included RCTs of patients with mCRC treated with an initial period of cytotoxic chemotherapy (CT) in association with anti-EGFR (ie, panitumumab or cetuximab) as first-line regimen, and then switched to one of the following strategies: observation; maintenance with anti-EGFR, fluoropyrimidine (FP), or both; or continuing the induction regimen until disease progression or unacceptable toxicity. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the Mantel-Haenszel method fixed-effect model or the DerSimonian-Laird method random-effect model according to heterogeneity (I

We aimed to identify features associated with different disease trajectories in Alzheimer's disease (AD)-related primary progressive aphasia (PPA). We considered 23 patients diagnosed with AD-related PPA. All patients underwent neuropsychological evaluation

The environmental role in disease progression has been appreciated for decades; however, understanding how airborne toxicant exposure can affect organs beyond the lungs is an underappreciated area of scientific inquiry. Particulate matter (PM) includes various gases, liquids, and particles in suspension and is produced by industrial activities such as fossil fuel combustion and natural events including wildfires and volcanic eruptions. Although agencies have attempted to reduce acceptable airborne particulate levels, with urbanization and population growth, these policies have been only moderately effective in mitigating disease progression. A growing area of research is focused on the role of PM exposure in the progression of Alzheimer's disease (AD). This review will summarize the knowns and unknowns of this expanding field.

Investigations for programmed cell death-1 (PD-1) blockade-induced hyperprogressive disease (HPD) have not been stringently conducted in patients with advanced gastric cancer (AGC). We explored the occurrence of HPD and its clinical implications in patients with AGC and treated with PD-1 inhibitors.We enrolled 169 patients with AGC and treated with either the PD-1 blockade (nivolumab or pembrolizumab; N = 112) or irinotecan monotherapy (N = 57) as a single agent. Tumour growth dynamics based on tumour growth kinetics and tumour growth rate (TGR) and time to treatment failure were analysed to define HPD. The incidence, clinical consequences and predictive markers of HPD were investigated.The optimal criteria for HPD were 4-fold increases in both tumour growth kinetics and TGR ratios and a 40% increase in TGR based on the analysis for patients treated with irinotecan. In total, 10.7% (12/112) of patients experienced HPD after PD-1 inhibitor treatment. Patients with HPD had both shorter progression-free survival (hazard ratio: 2.318; 95% confidence interval: 1.205-4.460) and overall survival (hazard ratio: 2.542; 95% confidence interval: 1.314-4.918) than patients with progressive disease without HPD, losing opportunities for subsequent systemic treatments. Although other variables including PD-L1 expression were not associated with the occurrence of HPD, hypoalbuminemia (lt;3.25 mg/dL) at baseline was significantly associated with the occurrence of HPD (P lt; 0.001) and inferior survival outcomes.HPD occurs in a proportion of patients with AGC and treated with PD-1 inhibitors. PD-1 inhibitor-induced HPD is associated with worse outcome, loss of eligibility for subsequent treatment and hypoalbuminemia, warranting further investigation.

Rationale and Objectives: The temporomandibular joint (TMJ) is commonly involved in children with juvenile idiopathic arthritis. The diagnosis and evaluation of the disease progression is dependent on medical imaging. The precision of this imaging is under debate. SeveralR scoring systems have been proposed but transparent testing of the precision of the constituents of the scoring systems is lacking. The present study aims to test the precision of 25 imaging features based on magnetic resonance imaging (MRI). Materials and Methods: Clinical data and imaging were obtained from the Norwegian juvenile idiopathic arthritis study, The NorJIA study. Twenty-five imaging features of the TMJ in MRI datasets from 86 study participants were evaluated by two experienced radiologists for inter- and intraobserver agreement. Agreement of ordinal variables was measured with Cohen s linear or weighted Kappa as appropriate. Agreement of continuous measurements was assessed with 95% limit of agreement according to Bland-Altman. Results: In the osteochondral domain, the ordinal imaging variables “loss of condylar volume,” “condylar shape,” “condylar irregularities,” “shape of the eminence/fossa,” “disk abnormalities,” and “condylar inclination” showed inter- and intraobserver agreement above Kappa 0.5. In the inflammatory domain, the ordinal imaging variables “joint fluid,” “overall impression of inflammation,” “synovial enhancement” and “bone marrow oedema” showed inter- and intraobserver agreement above Kappa 0.5. Continuous measurements performed poorly with wide limits of agreement. Conclusion: A precise MRI-based scoring system for assessment of TMJ in JIA is proposed consisting of seven variables in the osteochondral domain and four variables in the inflammatory domain. Further testing of the clinical validity of the variables is needed.