Evaluation of Factors Contributing to Diagnosis of Crohn's Disease in the Face of Increasing Trend in Pakistan.

Background: Crohn's disease (CD) is characterized by granulomatous inflammation of the digestive tract. Diagnosing CD involves assessing clinical symptoms, radiological and endoscopic findings, and histopathological evidence. Although previously considered a disease in developed countries, CD is increasing in developing nations, but challenges exist in diagnosing CD promptly. This study aims to report diagnostic parameters for early and correct CD diagnosis in Pakistan. Methodology: A retrospective analysis from June 2016 to August 2023 of 22 CD patients was done, by data from medical records, questionnaires completed at diagnosis, and telephonic interviews. Baseline demographic and clinical characteristics were assessed, and patients were categorized using the Montreal classification. Results: CD was diagnosed in 22 patients, with a 1:1 male-to-female ratio with a mean age of 33 years (range 15-55 years). Symptoms at presentation included abdominal pain (95.5%), watery diarrhea (86.4%), fever (31.8%), rectal bleeding (54.5%), and weight loss (81.8%) with 68% having symptoms for over 12 months before diagnosis. Disease characteristics were diverse, with various patterns of involvement and histopathological findings. Conclusions: In resource-limited countries like Pakistan, the timely diagnosis of CD presents a significant healthcare challenge. Therefore, it is necessary to tackle these complex problems by enhancing diagnostic capabilities, raising medical awareness, and improving access to healthcare resources.

Machine learning prediction for COVID-19 disease severity at hospital admission.

IMPORTANCE: Early prognostication of patients hospitalized with COVID-19 who may require mechanical ventilation and have worse outcomes within 30 days of admission is useful for delivering appropriate clinical care and optimizing resource allocation. OBJECTIVE: To develop machine learning models to predict COVID-19 severity at the time of the hospital admission based on a single institution data. DESIGN, SETTING, AND PARTICIPANTS: We established a retrospective cohort of patients with COVID-19 from University of Texas Southwestern Medical Center from May 2020 to March 2022. Easily accessible objective markers including basic laboratory variables and initial respiratory status were assessed using Random Forest's feature importance score to create a predictive risk score. Twenty-five significant variables were identified to be used in classification models. The best predictive models were selected with repeated tenfold cross-validation methods. MAIN OUTCOMES AND MEASURES: Among patients with COVID-19 admitted to the hospital, severity was defined by 30-day mortality (30DM) rates and need for mechanical ventilation. RESULTS: This was a large, single institution COVID-19 cohort including total of 1795 patients. The average age was 59.7 years old with diverse heterogeneity. 236 (13%) required mechanical ventilation and 156 patients (8.6%) died within 30 days of hospitalization. Predictive accuracy of each predictive model was validated with the 10-CV method. Random Forest classifier for 30DM model had 192 sub-trees, and obtained 0.72 sensitivity and 0.78 specificity, and 0.82 AUC. The model used to predict MV has 64 sub-trees and returned obtained 0.75 sensitivity and 0.75 specificity, and 0.81 AUC. Our scoring tool can be accessed at https://faculty.tamuc.edu/mmete/covid-risk.html . CONCLUSIONS AND RELEVANCE: In this study, we developed a risk score based on objective variables of COVID-19 patients within six hours of admission to the hospital, therefore helping predict a patient's risk of developing critical illness secondary to COVID-19.

Gastrointestinal Manifestations Are Associated with Severe COVID-19 in Children.

Purpose: Although less severe than in adults, children can experience a range of COVID-19 symptoms, from asymptomatic to life-threatening, including respiratory and gastrointestinal symptoms. Medical conditions may also increase the severity of the disease in infected children. Methods: This study was performed at a single center, comparing cases and controls, and involving 253 pediatric patients who had been diagnosed with COVID-19. Two different outcomes were assessed. The first categorized symptomatic individuals who were hospitalized with COVID-19 (hospital) from those who were not (nonhospital). The second categorized admitted individuals who spent at least one day in the intensive care unit (ICU) from those who did not require intensive care (floor). Results: Ninety individuals (36%) had at least one underlying medical condition, the most common being pulmonary disorders, such as asthma (12%), followed by neurodevelopmental disorders (8%), gastrointestinal disorders (6%), and seizure disorders (6%). The hospital group was more likely to have a comorbidity, such as obstructive sleep apnea (OSA), diabetes mellitus, seizure disorder, hypertension, sickle cell disease, neurodevelopmental disorder, and immunocompromising conditions, including cancer, bone marrow transplant, and other immunodeficiencies, compared to the non-hospital group. Abdominal pain was more common in the hospital group. Shortness of breath (SOB) and diarrhea were significantly more common in the ICU group than in the floor group. Conclusions: Early identification of pediatric patients with severe COVID-19 is important to improve outcomes. In our single-center case-control study, we found that the presence of gastrointestinal symptoms on presentation was more commonly associated with severe COVID-19 in children.

Subtractive genomics profiling for potential drug targets identification against Moraxella catarrhalis.

Moraxella catarrhalis (M. catarrhalis) is a gram-negative bacterium, responsible for major respiratory tract and middle ear infection in infants and adults. The recent emergence of the antibiotic resistance M. catarrhalis demands the prioritization of an effective drug target as a top priority. Fortunately, the failure of new drugs and host toxicity associated with traditional drug development approaches can be avoided by using an in silico subtractive genomics approach. In the current study, the advanced in silico genome subtraction approach was applied to identify potential and pathogen-specific drug targets against M. catarrhalis. We applied a series of subtraction methods from the whole genome of pathogen based on certain steps i.e. paralogous protein that have extensive homology with humans, essential, drug like, non-virulent, and resistant proteins. Only 38 potent drug targets were identified in this study. Eventually, one protein was identified as a potential new drug target and forwarded to the structure-based studies i.e. histidine kinase (UniProt ID: D5VAF6). Furthermore, virtual screening of 2000 compounds from the ZINC database was performed against the histidine kinase that resulted in the shortlisting of three compounds as the potential therapeutic candidates based on their binding energies and the properties exhibited using ADMET analysis. The identified protein gives a platform for the discovery of a lead drug candidate that may inhibit it and may help to eradicate the otitis media caused by drug-resistant M. catarrhalis. Nevertheless, the current study helped in creating a pipeline for drug target identification that may assist wet-lab research in the future.

Immature Platelet Fraction as a Biomarker for Disease Severity in Pediatric Respiratory Coronavirus Disease 2019.

In this retrospective single-institution cohort study of 113 hospitalized pediatric patients with respiratory coronavirus disease 2019, those admitted to the intensive care unit or requiring mechanical ventilation had significantly higher immature platelet fractions than those who did not require intensive care unit-level care or ventilation. Immature platelet fraction may be an accessible biomarker for disease severity in pediatric respiratory coronavirus disease 2019.

A Rare Case of Pancreatic Schwannoma.

Pancreatic schwannoma is a neuroendocrine cell tumor that arises in the pancreas. It is very rare, and, to date, only fewer than 70 similar cases have been reported in the literature. Here, we present another case of this type of tumor in a 68-year-old female. In addition to describing the pancreatic schwannoma, we discuss the major challenges associated with its diagnosis and management. As such, clinically and on imaging, pancreatic schwannomas are almost indistinguishable from other cancerous or benign pancreatic tumors. Therefore, only a biopsy can definitively diagnose pancreatic schwannomas by demonstrating spindle-shaped cells with immunohistochemistry positive for S-100. Because pancreatic schwannomas are very rare, it is important to increase awareness among clinicians about this condition and inform them regarding the challenges associated with its diagnosis and management.

"Ideal" parathyroid hormone in erythropoietin-stimulating agents-resistant anemia.

Erythropoietin-stimulating agents (ESAs) have revolutionized anemia treatment in end-stage renal disease (ESRD), but ESA resistance is increasingly identified. Secondary hyperparathyroidism (SHP) is one cause of ESA resistance. We describe a patient with ESA-resistant, transfusion-dependent anemia and mild SHP with remodeling and reticulin fibrosis on bone marrow biopsy, all of which resolved with stricter SHP management. We identified 64 patients with anemia, ESRD, and bone marrow biopsy. The parathyroid hormone (PTH) range for bony remodeling was 183-16,161.9 pg/ml versus 90.8-3283 pg/ml. The PTH range for fibrotic changes was 183-2487 pg/ml versus 90.8-16,161.9 pg/ml. We found no clear PTH range predictive for bone marrow changes.

Fix the Heart, Damage the Gut: A Case Report and Literature Review of Ablation-Induced Gastroparesis.

Catheter ablation is a common procedure performed in patients with atrial fibrillation. While some commonly known complications include perforation, thromboembolism, pericardial effusion, and cardiac tamponade, gastroparesis is a less reported post-procedural complication. We present a case of a 66-year-old female admitted with intractable nausea and vomiting six weeks post-ablation. After ruling out the common causes of gastroparesis, a gastric emptying study was done, which confirmed the diagnosis of gastroparesis. Physicians should have a high degree of suspicion for vagus nerve damage in post-ablation patients that presents with unexplained persistent gastrointestinal (GI) symptoms to facilitate a better outcome.

Genomic prediction in the wild: A case study in Soay sheep.

Genomic prediction, the technique whereby an individual's genetic component of their phenotype is estimated from its genome, has revolutionised animal and plant breeding and medical genetics. However, despite being first introduced nearly two decades ago, it has hardly been adopted by the evolutionary genetics community studying wild organisms. Here, genomic prediction is performed on eight traits in a wild population of Soay sheep. The population has been the focus of a >30 year evolutionary ecology study and there is already considerable understanding of the genetic architecture of the focal Mendelian and quantitative traits. We show that the accuracy of genomic prediction is high for all traits, but especially those with loci of large effect segregating. Five different methods are compared, and the two methods that can accommodate zero-effect and large-effect loci in the same model tend to perform best. If the accuracy of genomic prediction is similar in other wild populations, then there is a real opportunity for pedigree-free molecular quantitative genetics research to be enabled in many more wild populations; currently the literature is dominated by studies that have required decades of field data collection to generate sufficiently deep pedigrees. Finally, some of the potential applications of genomic prediction in wild populations are discussed.

Southern Tick-Associated Rash Illness: Florida's Lyme Disease Variant.

Southern tick-associated rash illness (STARI) is an emerging zoonotic disease causing an annular rash with central clearing that is almost identical to erythema migrans seen in Lyme disease. It is spread by Amblyomma americanum tick bite. Although it is still debatable, this zoonotic disease is thought to be caused by Borrelia lonestari spirochete. At this time, there is no approved diagnostic modality nor approved treatment for such an illness. Here we describe a rare case of STARI in a 63-year-old female and shed light on the differences between STARI and Lyme disease.

Immature platelets as a biomarker for disease severity and mortality in COVID-19 patients.

COVID-19, caused by SARS-CoV-2, is a contagious life-threatening viral disease that has killed more than three million people worldwide to date. Attempts have been made to identify biomarker(s) to stratify disease severity and improve treatment and resource allocation. Patients with SARS-COV-2 infection manifest with a higher inflammatory response and platelet hyperreactivity; this raises the question of the role of thrombopoiesis in COVID-19 infection. Immature platelet fraction (IPF, %) and immature platelet counts (IPC, ×109 /l) can be used to assess thrombopoiesis. This study investigates whether the level of thrombopoiesis correlates with COVID-19 severity. A large cohort of 678 well-characterized COVID-19 patients was analyzed, including 658 (97%) hospitalized and 139 (21%) admitted to the intensive care unit (ICU). Elevated percentage IPF at presentation was predictive of length of hospitalization (P < 0·01) and ICU admission (P < 0·05). Additionally, percentage IPF at the peak was significantly higher among ICU patients than non-ICU patients (6·9 ± 5·1 vs 5·3 ± 8·4, P < 0·01) and among deceased patients than recovered patients (7·9 ± 6·3 vs 5·4 ± 7·8, P < 0·01). Furthermore, IPC at the peak was significantly higher among ICU patients than non-ICU patients (18·5 ± 16·2 vs. 13·2 ± 8·3, P < 0·05) and among patients on a ventilator than those not (22·1 ± 20·1 vs.13·4 ± 8·4, P < 0·05). Our study demonstrated that elevated initial and peak values of percentage IPF and IPC might serve as prognostic biomarkers for COVID-19 progression to severe conditions.

Genetic drift from the out-of-Africa bottleneck leads to biased estimation of genetic architecture and selection.

Most complex traits evolved in the ancestors of all modern humans and have been under negative or balancing selection to maintain the distribution of phenotypes observed today. Yet all large studies mapping genomes to complex traits occur in populations that have experienced the Out-of-Africa bottleneck. Does this bottleneck affect the way we characterise complex traits? We demonstrate using the 1000 Genomes dataset and hypothetical complex traits that genetic drift can strongly affect the joint distribution of effect size and SNP frequency, and that the bias can be positive or negative depending on subtle details. Characterisations that rely on this distribution therefore conflate genetic drift and selection. We provide a model to identify the underlying selection parameter in the presence of drift, and demonstrate that a simple sensitivity analysis may be enough to validate existing characterisations. We conclude that biobanks characterising more worldwide diversity would benefit studies of complex traits.

Health Care Utilization Patterns for Patients With a History of Substance Use Requiring OPAT.

Background: Uninsured people who use drugs (PWUD) require extended parenteral antibiotic therapy when diagnosed with complex infections such as osteomyelitis. They are ineligible to enroll in our self-administered outpatient antimicrobial therapy (S-OPAT) program and instead sent to a skilled nursing facility (SNF). We aim to retrospectively assess clinical outcomes of PWUD discharged from our safety net hospital to complete OPAT in an SNF. Methods: Using our hospital electronic medical record, PWUD discharged to an SNF for extended antibiotic therapy were identified for the study period, 1/1/17-4/30/18. Demographics, drug use, discharge diagnosis, antibiotic therapy, discharge disposition from SNF (AMA, early non-AMA, completed), 30-day emergency department (ED) utilization, and 30-day readmission were collected for the study cohort. ED utilization and 30-day readmission rates were analyzed by disposition group. Results: While the majority of patients completed treatment (83), a sizeable number left AMA (26) or early non-AMA (20). Patients who left early, AMA or non-AMA, had increased rates of 30-day readmission or ED utilization (P=.01) and increased rates of 30-day readmission alone (P=.01), but not ED utilization alone (P=.43), compared with patients who completed treatment. Conclusions: In our cohort, many PWUD discharged to an SNF to receive parenteral antibiotics did not complete treatment. These patients were observed to have increased health care utilization compared with patients completing therapy.

Correction to: Is population structure in the genetic biobank era irrelevant, a challenge, or an opportunity?

In the original article publication, there is an incorrect impression that Fig. 1 formed a formal Directed Acyclic Graph (DAG) by describing it as a causal model. However, it was not correct if interpreted in this way.

Is population structure in the genetic biobank era irrelevant, a challenge, or an opportunity?

Replicable genetic association signals have consistently been found through genome-wide association studies in recent years. The recent dramatic expansion of study sizes improves power of estimation of effect sizes, genomic prediction, causal inference, and polygenic selection, but it simultaneously increases susceptibility of these methods to bias due to subtle population structure. Standard methods using genetic principal components to correct for structure might not always be appropriate and we use a simulation study to illustrate when correction might be ineffective for avoiding biases. New methods such as trans-ethnic modeling and chromosome painting allow for a richer understanding of the relationship between traits and population structure. We illustrate the arguments using real examples (stroke and educational attainment) and provide a more nuanced understanding of population structure, which is set to be revisited as a critical aspect of future analyses in genetic epidemiology. We also make simple recommendations for how problems can be avoided in the future. Our results have particular importance for the implementation of GWAS meta-analysis, for prediction of traits, and for causal inference.

Prevalence and Cost Analysis of Chronic Pain After Hernia Repair: A Potential Alternative Approach With Neurostimulation.

OBJECTIVES: Chronic pain (CP) affects a significant number of patients following hernia repair, ranging from 11 to 54% in the literature. The aim of this study was to assess the prevalence, overall costs, and health care utilization associated with CP after hernia repair. MATERIALS AND METHODS: A retrospective longitudinal study was performed using the Truven MarketScan® data base to identify patients who develop chronic neuropathic posthernia repair pain from 2001 to 2012. Patients were grouped into CP and No Chronic Pain (No CP) cohorts. Patients were excluded if they 1) were under 18 years of age; 2) had a previous pain diagnosis; 3) had CP diagnosed <90 days after the index hernia repair; 4) had less than one year of follow-up; or 5) had less than one-year baseline record before hernia repair. Patients were grouped into the CP cohort if their CP diagnosis was made within the two years following index hernia repair. Total, outpatient, and pain prescription costs were collected in the period of five years prehernia to nine years posthernia repair. A longitudinal multivariate analysis was used to model the effects of chronic neuropathic posthernia repair pain on total inpatient/outpatient and pain prescription costs. RESULTS: We identified 76,173 patients who underwent hernia repair and met inclusion criteria (CP: n = 14,919, No CP: n = 61,254). There was a trend for increased total inpatient/outpatient and pain prescription costs one-year posthernia repair, when compared to baseline costs for both cohorts. In both cohorts, total inpatient/outpatient costs remained elevated from baseline through nine years posthernia repair, with the CP cohort experiencing significantly higher cumulative median costs (CP: $51,334, No CP: $37,388). The CP diagnosis year was associated with a 1.75-fold increase (p < 0.001) in total inpatient/outpatient costs and a 2.26-fold increase (p < 0.001) in pain prescription costs versus all other years. In the longitudinal analysis, the CP cohort had a 1.14-fold increase (p < 0.001) in total inpatient/outpatient costs and 2.00-fold increase (p < 0.001) in pain prescription costs. CONCLUSIONS: Our study demonstrates the prevalence of CP after hernia surgery to be nearly 20%, with significantly increased costs and healthcare resource utilization. While current treatment paradigms are effective for many, there remains a large number of patients that could benefit from an overall approach that includes nonopioid treatments, such as potentially incorporating neurostimulation, for CP that presents posthernia repair.

Prevalence and Cost Analysis of Complex Regional Pain Syndrome (CRPS): A Role for Neuromodulation.

OBJECTIVE: The diagnosis and treatment of complex regional pain syndrome (CRPS) is challenging and there is a paucity of data describing its overall cost burden and quantifying its impact on the US healthcare system. The aim of this study was to assess the prevalence and healthcare utilization costs associated with CRPS. MATERIALS AND METHODS: A retrospective longitudinal study was performed using the Truven MarketScan® database to identify patients with a new indexed diagnosis of CRPS (Type I, II, or both) from 2001 to 2012. We collected total, outpatient, and pain prescription costs three years prior to CRPS diagnosis (baseline), at year of CRPS diagnosis, and eight-year post-CRPS diagnosis. A longitudinal multivariate analysis was used to model the estimated total and pain prescription cost ratios comparing patients diagnosed before and after CRPS. RESULTS: We included 35,316 patients with a newly indexed diagnosis of CRPS (Type I: n = 18,703, Type II: n = 14,599, Unspecified: n = 2014). Baseline characteristics were similar between the CRPS cohorts. Compared to two- and three-year baseline costs, one-year prior to diagnosis for all CRPS patients yielded the highest interquartile median [IQR] costs: total costs $7904[$3469, $16,084]; outpatient costs $6706[$3119, $12,715]; and pain prescription costs $1862[$147, $7649]. At the year of CRPS diagnosis, the median [IQR] costs were significantly higher than baseline costs: total costs $8508[$3943, $16,666]; outpatient costs $7251[$3527, $13,568]; and pain prescription costs $2077[$140, $8856]. Over the eight-year period after CRPS diagnosis, costs between all the years were similar, ranging from the highest (one-year) to lowest (seven-years), $4845 to $3888. The median total cumulative cost 8-years after CRPS diagnosis was $43,026 and $12,037 for pain prescription costs. [Correction added on 06 November 2017 after first online publication: the preceding sentence has been updated to demonstrate the median cumulative cost in replacement of the additive cumulative mean costs.]. During the CRPS diagnosis period, patients are expected to have a total cost 2.17-fold and prescription cost 2.56-fold of their baseline cost annually. CONCLUSIONS: Our study demonstrates that there is a significant increase in cost and healthcare resource utilization one-year prior to and around the time of CRPS diagnosis. Furthermore, there is an increased annual cost post-diagnosis compared to baseline costs prior to CRPS diagnosis.

Accuracy of Genomic Prediction in a Commercial Perennial Ryegrass Breeding Program.

The implementation of genomic selection (GS) in plant breeding, so far, has been mainly evaluated in crops farmed as homogeneous varieties, and the results have been generally positive. Fewer results are available for species, such as forage grasses, that are grown as heterogenous families (developed from multiparent crosses) in which the control of the genetic variation is far more complex. Here we test the potential for implementing GS in the breeding of perennial ryegrass ( L.) using empirical data from a commercial forage breeding program. Biparental F and multiparental synthetic (SYN) families of diploid perennial ryegrass were genotyped using genotyping-by-sequencing, and phenotypes for five different traits were analyzed. Genotypes were expressed as family allele frequencies, and phenotypes were recorded as family means. Different models for genomic prediction were compared by using practically relevant cross-validation strategies. All traits showed a highly significant level of genetic variance, which could be traced using the genotyping assay. While there was significant genotype × environment (G × E) interaction for some traits, accuracies were high among F families and between biparental F and multiparental SYN families. We have demonstrated that the implementation of GS in grass breeding is now possible and presents an opportunity to make significant gains for various traits.

Estimating genomic heritabilities at the level of family-pool samples of perennial ryegrass using genotyping-by-sequencing.

KEYMESSAGE: By using the genotyping-by-sequencing method, it is feasible to characterize genomic relationships directly at the level of family pools and to estimate genomic heritabilities from phenotypes scored on family-pools in outbreeding species. Genotyping-by-sequencing (GBS) has recently become a promising approach for characterizing plant genetic diversity on a genome-wide scale. We use GBS to extend the concept of heritability beyond individuals by genotyping family-pool samples by GBS and computing genomic relationship matrices (GRMs) and genomic heritabilities directly at the level of family-pools from pool-frequencies obtained by sequencing. The concept is of interest for species where breeding and phenotyping is not done at the individual level but operates uniquely at the level of (multi-parent) families. As an example we demonstrate the approach using a set of 990 two-parent F2 families of perennial ryegrass (Lolium Perenne). The families were phenotyped as a family-unit in field plots for heading date and crown rust resistance. A total of 728 K single nucleotide polymorphism (SNP) variants were available and were divided in groups of different sequencing depths. GRMs based on GBS data showed diagonal values biased upwards at low sequencing depth, while off-diagonals were little affected by the sequencing depth. Using variants with high sequencing depth, genomic heritability for crown rust resistance was 0.33, and for heading date 0.22, and these genomic heritabilities were biased downwards when using variants with lower sequencing depth. Broad sense heritabilities were 0.61 and 0.66, respectively. Underestimation of genomic heritability at lower sequencing depth was confirmed with simulated data. We conclude that it is feasible to use GBS to describe relationships between family-pools and to estimate genomic heritability directly at the level of F2 family-pool samples, but estimates are biased at low sequencing depth.