Miracle-dz/UniFAR-FTUs huggingface dataset:
Organizational learning from near misses in health care.

How clinicians detect and differentiate near misses from adverse events in health care is poorly understood. This study adopted a constructivist grounded theory approach and utilized document analysis and semi-structured interviews with 24 managers (middle and senior) and clinicians to examine the processes and factors associated with recognizing and recovering and learning from near misses in daily clinical practice. While safety science suggests that near misses are sources of learning to guide improvement efforts, the study identified how clinicians and managers cognitively downgrade and accept near misses as a routine part of daily practice. Such downgrading reduces the visibility of near misses and creates a paradoxical effect of promoting collective vigilance and increased safety while also encouraging violations in clinical practice. Three approaches to correcting and/or learning from near misses emerged: ―doing a quick fix,‖ ―going into the black hole,‖ and ―closing off the swiss-cheese holes‖; however, minimal organizational learning occurs. From these findings, two key paradoxes that undermine organization-level learning require further attention: (a) near misses are pervasive in everyday practice but many remain undetected and are missed learning opportunities, and (b) collective vigilance serves as both safety net and safety threat. Study findings suggest that organizational efforts are required to determine which near misses need to be reported. Organizations need to iii shift the culture from one of ―doing a quick fix‖ to one that learns from near misses in daily practice; they should reinforce the benefits and reduce the risks of collective vigilance, and further encourage learning at the clinical microsystem level. Future research is required to provide insight into how individual, social, and organizational factors influence the recognition, recovery, and instructional value of near misses and safety threats in health care organizations‘
Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease

Objective Monitoring of patients with Cushing’s disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing’s disease. Design Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing’s disease (clinicaltrials.gov: NCT01374906). Methods Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time. Results At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman’s correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN. Conclusion mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing’s disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.
Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma

Background: Folate intake increases plasma folate and reduces total homocysteine (tHcy) concentrations, which may lower coronary artery disease (CAD) and cancer risks. Folate metabolism may be altered by alcohol intake and 2 common polymorphisms in the methylenetetrahydrofolatereductase(MTHFR)gene,677C3Tand 1298A3C. Objective: We examined whether the associations between folate intake and plasma folate and tHcy concentrations were modified by alcohol intake or variations in the MTHFR gene. Design:Weconductedacross-sectionalanalysisamong988women by using multivariate linear regression models to estimate mean plasmatHcyandfolateconcentrations.Folateintakewasthesumof food and supplemental sources. Results: We observed an inverse association between folate intake andtHcy,whichwasmodifiedbyalcoholintake(Pforinteraction 0.04)andMTHFR677genotype(Pforinteraction0.05)butnotby MTHFR1298 genotype (P for interaction 0.97). In the lowest quintile of folate intake, moderate drinkers (15 g alcohol/d) had significantlyhighertHcyconcentrations(15.22.9nmol/mL)than didlightdrinkers(11.30.7nmol/mL)andnondrinkers(11.00.8 nmol/mL). However, the reduction in tHcy between the highest and lowestquintilesoffolateintakewassignificantlygreaterinmoderate drinkers(6.6nmol/mL)thaninlightdrinkers(2.3nmol/mL)and nondrinkers(2.1nmol/mL). TheelevatedtHcyinwomenwithlow folate intake who also consumed moderate amounts of alcohol was even higher (22.4 4.8 nmol/mL) in the presence of the variant MTHFR677 allele. The positive association between folate intake and plasma folate was somewhat modified by alcohol intake (P for interaction 0.08) but not by either MTHFR genotype. Conclusions: Moderate alcohol intake and low MTHFR activity have adverse effects on tHcy, but those effects may be overcome by sufficient folate intake. Am J Clin Nutr 2005;82:155–62.
Local, nonlinear effects of cGMP and Ca2+ reduce single photon response variability in retinal rods

The single photon response (SPR) in vertebrate photoreceptors is inherently variable due to several stochastic events in the phototransduction cascade, the main one being the shutoff of photoactivated rhodopsin. Deactivation is driven by a random number of steps, each of random duration with final quenching occurring after a random delay. Nevertheless, variability of the SPR is relatively low, making the signal highly reliable. Several biophysical and mathematical mechanisms contributing to variability suppression have been examined by the authors. Here we investigate the contribution of local depletion of cGMP by PDE*, the non linear dependence of the photocurrent on cGMP, Ca2+ feedback by making use of a fully space resolved (FSR) mathematical model, applied to two species (mouse and salamander), by varying the cGMP diffusion rate severalfold and rod outer segment diameter by an order of magnitude, and by introducing new, more refined, and time dependent variability functionals. Globally well stirred (GWS) models, and to a lesser extent transversally well stirred models (TWS), underestimate the role of nonlinearities and local cGMP depletion in quenching the variability of the circulating current with respect to fully space resolved models (FSR). These distortions minimize the true extent to which SPR is stabilized by locality in cGMP depletion, nonlinear effects linking cGMP to current, and Ca2+ feedback arising from the physical separation of E* from the ion channels located on the outer shell, and the diffusion of these second messengers in the cytoplasm.
Effects of perioperative pelvic floor muscle training on early recovery of urinary continence and erectile function in men undergoing radical prostatectomy: a randomized clinical trial

ABSTRACT Aims: Radical prostatectomy (RP) can result in urinary incontinence (UI) and erectile dysfunction (ED), which negatively impact quality of life (QoL). This study aimed to evaluate the effects of a perioperative pelvic floor muscle training (PFMT) program versus usual care on early recovery of urinary continence and erectile function after RP. Materials and Methods: Of 59 eligible men, 31 were randomly allocated into 2 groups: Group 1 (Control, N=15) received usual post-RP care; and Group 2 (Physical therapy, N=16) received two pre-RP physical therapist-guided PFMT sessions, including exercises and electromyographic biofeedback, and verbal and written instructions to continue PFMT until RP, which was then resumed after urethral catheter removal. The International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF) and the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire were used to evaluate UI and ED, respectively. Results: Demographic characteristics were similar in both groups. Three months after RP, the UI rate was 72.7% and 70.0% in Groups 1 and 2, respectively (P >0.05). The severity and frequency of UI and its impact on QoL were evaluated by the ICIQ-Short Form, with scores of 6.9±6.26 in Group 1 and 7.0±5.12 in Group 2 (P >0.05). The IIEF-5 scores were similar in Groups 1 and 2 (5.73±7.43 vs. 6.70±6.68, respectively) (P >0.05). Conclusion: Our pre-RP protocol of two physical therapist-assisted sessions of PFMT plus instructions did not significantly improve urinary continence or erectile function at 3 months after RP.
Imaging Triage of Patients with Late-Window (6–24 Hours) Acute Ischemic Stroke: A Comparative Study Using Multiphase CT Angiography versus CT Perfusion

BACKGROUND AND PURPOSE: The role of collateral imaging in selecting patients for endovascular thrombectomy beyond 6 hours from onset has not been established. To assess the comparative utility of collateral imaging using multiphase CTA in selecting late window patients for EVT. MATERIALS AND METHODS: We used data from a prospective multicenter observational study in which all patients underwent imaging with multiphase CT angiography as well as CTP. Two blinded reviewers evaluated patients’ eligibility for endovascular thrombectomy using published collateral imaging (multiphase CTA) criteria compared with CTP using the selection criteria of the Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention with Trevo (DAWN) and Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE-3) trials. CTP images were processed using automated commercial software. The outcomes of patients eligible for endovascular thrombectomy according to multiphase CTA, DAWN, or DEFUSE-3 criteria were compared using multivariable logistic regression modeling. Model characteristics were compared using the C-statistic for the receiver operating characteristic curve, the Akaike information criterion, and the Bayesian information criterion. RESULTS: Eighty-six patients presented beyond 6 hours from onset/last known well (median, 9.6 hours; interquartile range, 4.1 hours). Thirty-five patients (40.7%) received endovascular thrombectomy, of whom good functional outcome (90-day mRS, 0–2) was achieved in 16/35 (47%). Collateral-based imaging paradigms significantly modified the treatment effect of endovascular thrombectomy on 90-day mRS 0–2 (Pinteraction = .007). The multiphase CTA–based regression model best fit the data for the 90-day outcome (C-statistic, 0.86; 95% CI, 0.77–0.94) and was associated with the least information loss (Akaike information criterion, 95.7; Bayesian information criterion, 114.9) compared with CTP-based models. CONCLUSIONS: The collateral-based imaging paradigm using multiphase CTA compares well with CTP in selecting patients for endovascular thrombectomy in the late time window.
Optimization in Detection of Antigen‐Specific T Cells Through Differentially Labeled MHC Multimers

A large variety of fluorescent molecules are used on a regular basis to tag major histocompatibility complex (MHC) multimers for detection of antigen‐specific T cells. We have evaluated the way in which the choice of fluorescent label can impact the detection of MHC multimer binding T cells in an exploratory proficiency panel where detection of MHC multimer binding T cells was assessed across 16 different laboratories. We found that the staining index (SI) of the multimer reagent provided the best direct correlation with the value of a given fluorochrome for T cell detection studies. The SI is dependent on flow cytometer settings and chosen antibody panel; hence, the optimal fluorochrome selection may differ from lab to lab. Consequently, we describe a strategy to evaluate performance of the detection channels and optimize the SI for selected fluorescent molecules. This approach can easily be used to test and optimize fluorescence detection in relation to MHC multimer staining and in general, for antibody‐based identification of rare cell populations. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.
Development and validation of a nomogram to predict the prognosis of patients with squamous cell carcinoma of the bladder

Abstract Background: The present study aimed to develop and validate a nomogram based on expanded TNM staging to predict the prognosis for patients with squamous cell carcinoma of the bladder (SCCB). Methods: A total of 595 eligible patients with SCCB identified in the Surveillance, Epidemiology, and End Results (SEER) dataset were randomly divided into training set (n = 416) and validation set (n = 179). The likelihood ratio test was used to select potentially relevant factors for developing the nomogram. The performance of the nomogram was validated on the training and validation sets using a C-index with 95% confidence interval (95% CI) and calibration curve, and was further compared with TNM staging system. Results: The nomogram included six factors: age, T stage, N stage, M stage, the method of surgery and tumor size. The C-indexes of the nomogram were 0.768 (0.741–0.795) and 0.717 (0.671–0.763) in the training and validation sets, respectively, which were higher than the TNM staging system with C-indexes of 0.580 (0.543–0.617) and 0.540 (0.484–0.596) in the training and validation sets, respectively. Furthermore, the decision curve analysis (DCA) proved that the nomogram provided superior clinical effectiveness. Conclusions: We developed a nomogram that help predict individualized prognosis for patients with SCCB.
Multi-Level Multi-Modality Fusion Radiomics: Application to PET and CT Imaging for Prognostication of Head and Neck Cancer

To characterize intra-tumor heterogeneity comprehensively, we propose a multi-level fusion strategy to combine PET and CT information at the image-, matrix-and feature-levels towards improved prognosis. Specifically, we developed fusion radiomics in the context of 3 prognostic outcomes in a multi-center setting (4 centers) involving 296 head & neck cancer patients. Eight clinical parameters were first utilized to build a (1) clinical model. We also built models by extracting 127 radiomics features from (2) PET images alone; (3–8) PET and CT images fused via wavelet-based fusion (WF) using CT-weights of 0.2, 0.4, 0.6 and 0.8, gradient transfer fusion (GTF), and guided filtering-based fusion (GFF); (9) fused matrices (sumMat); (10–11) fused features constructed via feature averaging (avgFea) and feature concatenation (conFea); and finally, (12) CT images alone; above models were also expanded to include both clinical and radiomics features. Seven variations of training and testing partitions were investigated. Highest performance in 5, 6 and 5 partitions was achieved by image-level fusion strategies for RFS, MFS and OS prediction, respectively. Among all partitions, WF0.6 and WF0.8 showed significantly higher performance than CT model for RFS (C-index: 0.60 ± 0.04 vs. 0.56 ± 0.03, p-value: 0.015) and MFS (C-index: 0.71 ± 0.13 vs. 0.62 ± 0.08, p-value: 0.020) predictions, respectively. In partition CER 23 vs. 14, WF0.6 significantly outperformed Clinical model for RFS prediction (C-index: 0.67 vs. 0.53, p-value: 0.003); both avgFea and WF0.6 showed C-index of 0.64 and significantly higher than that of PET only (C-index: 0.51, p-value: 0.018 and 0.031, respectively) for OS prediction. Fusion radiomics modeling showed varying improvements compared to single modality models for different outcome predictions in different partitions, highlighting the importance of generalizing radiomics models. Image-level fusion holds potential to capture more useful characteristics.
A Novel Anti-PD-L1 Vaccine for Cancer Immunotherapy and Immunoprevention

Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in activating cellular and humoral immune responses. DC-based tumor vaccines targeting tumor-associated antigens (TAAs) have been extensively tested and demonstrated to be safe and potent in inducing anti-TAA immune responses in cancer patients. Sipuleucel-T (Provenge), a cancer vaccine of autologous DCs loaded with TAA, was approved by the United States Food and Drug Administration (FDA) for the treatment of castration-resistant prostate cancer. Sipuleucel-T prolongs patient survival, but has little or no effect on clinical disease progression or biomarker kinetics. Due to the overall limited clinical efficacy of tumor vaccines, there is a need to enhance their potency. PD-L1 is a key immune checkpoint molecule and is frequently overexpressed on tumor cells to evade antitumor immune destruction. Repeated administrations of PD-L1 or PD-1 antibodies have induced sustained tumor regression in a fraction of cancer patients. In this study, we tested whether vaccinations with DCs, loaded with a PD-L1 immunogen (PDL1-Vax), are able to induce anti-PD-L1 immune responses. We found that DCs loaded with PDL1-Vax induced anti-PD-L1 antibody and T cell responses in immunized mice and that PD-L1-specific CTLs had cytolytic activities against PD-L1+ tumor cells. We demonstrated that vaccination with PDL1-Vax DCs potently inhibited the growth of PD-L1+ tumor cells. In summary, this study demonstrates for the first time the principle and feasibility of DC vaccination (PDL1-Vax) to actively induce anti-PD-L1 antibody and T cell responses capable of inhibiting PD-L1+ tumor growth. This novel anti-PD-L1 vaccination strategy could be used for cancer treatment and prevention.
Hospital based serological evidence of rickettsial diseases and assessment diagnostic tests of pyrexia of unknown origin

The present study examined hospital-based serological tests of rickettsial infections and assessment for diagnosis of pyrexia of unknown origin (PUO). Blood samples were tested for Weil Felix antigens, ELISA for scrub typhus group and polymerase chain reaction (PCR) to detect the presence of DNA of spotted and scrub typhus group with the help of specific oligonucleotide. We tested 450 patient samples and found 101 Weil Felix-positive with 15 having ≥320 titres. IgM ELISA identified 32 (7.1%) positive cases. Positive PCR was seen in 13 (2.9%) samples, being only 40.1% of those testing positive for ELISA. Rickettsial infection is predominantly diagnosed through serological evidence in combination with molecular techniques. The Weil Felix test has a number of disadvantages and tends to provide false-positive results in a number of scenarios, especially where scrub typhus and spotted fever are widely distributed.
Same fold, different properties: polarizable molecular dynamics simulations of telomeric and TERRA G-quadruplexes

Abstract DNA and RNA sequences rich in guanine can fold into noncanonical structures called G-quadruplexes (GQs), which exhibit a common stem structure of Hoogsteen hydrogen-bonded guanine tetrads and diverse loop structures. GQ sequence motifs are overrepresented in promoters, origins of replication, telomeres, and untranslated regions in mRNA, suggesting roles in modulating gene expression and preserving genomic integrity. Given these roles and unique aspects of different structures, GQs are attractive targets for drug design, but greater insight into GQ folding pathways and the interactions stabilizing them is required. Here, we performed molecular dynamics simulations to study two bimolecular GQs, a telomeric DNA GQ and the analogous telomeric repeat-containing RNA (TERRA) GQ. We applied the Drude polarizable force field, which we show outperforms the additive CHARMM36 force field in both ion retention and maintenance of the GQ folds. The polarizable simulations reveal that the GQs bind bulk K+ ions differently, and that the TERRA GQ accumulates more K+ ions, suggesting different ion interactions stabilize these structures. Nucleobase dipole moments vary as a function of position and also contribute to ion binding. Finally, we show that the TERRA GQ is more sensitive than the telomeric DNA GQ to water-mediated modulation of ion-induced dipole-dipole interactions.
Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency

Biallelic ENPP1 deficiency in humans induces generalized arterial calcification of infancy (GACI) and/or autosomal recessive hypophosphatemic rickets type 2 (ARHR2). The latter is characterized by markedly increased circulating FGF23 levels and renal phosphate wasting, but aberrant skeletal manifestations associated with heterozygous ENPP1 deficiency are unknown. Here, we report three adult men with early onset osteoporosis who presented with fractures in the thoracic spine and/or left radius, mildly elevated circulating FGF23, and hypophosphatemia. Total hip bone mineral density scans demonstrated osteoporosis (Z‐score < −2.5) and HRpQCT demonstrated microarchitectural defects in trabecular and cortical bone. Next‐generation sequencing revealed heterozygous loss‐of‐function mutations in ENPP1 previously observed as biallelic mutations in infants with GACI. In addition, we present bone mass and structure data as well as plasma pyrophosphate (PPi) data of two siblings suffering from ARHR2 in comparison to their heterozygous and wild‐type family members indicative of an ENPP1 gene dose effect. The skeletal phenotype in murine Enpp1 deficiency yielded nearly identical findings. Ten‐week‐old male Enpp1 asj/asj mice exhibited mild elevations in plasma FGF23 and hypophosphatemia, and micro‐CT analysis revealed microarchitectural defects in trabecular and cortical bone of similar magnitude to HRpQCT defects observed in humans. Histomorphometry revealed mild osteomalacia and osteopenia at both 10 and 23 weeks. The biomechanical relevance of these findings was demonstrated by increased bone fragility and ductility in Enpp1 asj/asj mice. In summary, ENPP1 exerts a gene dose effect such that humans with heterozygous ENPP1 deficiency exhibit intermediate levels of plasma analytes associated with bone mineralization disturbance resulting in early onset osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.