Filaggrin-Associated Atopic Skin, Eye, Airways, and Gut Disease, Modifying the Presentation of X-Linked Reticular Pigmentary Disorder (XLPDR).

BACKGROUND: X-linked reticular pigmentary disorder (XLPDR) is a rare condition characterized by skin hyperpigmentation, ectodermal features, multiorgan inflammation, and recurrent infections. All probands identified to date share the same intronic hemizygous POLA1 hypomorphic variant (NM_001330360.2(POLA1):c.1393-354A > G) on the X chromosome. Previous studies have supported excessive type 1 interferon (IFN) inflammation and natural killer (NK) cell dysfunction in disease pathogenesis. Common null polymorphisms in filaggrin (FLG) gene underlie ichthyosis vulgaris and atopic predisposition. CASE: A 9-year-old boy born to non-consanguineous parents developed eczema with reticular skin hyperpigmentation in early infancy. He suffered recurrent chest infections with chronic cough, clubbing, and asthma, moderate allergic rhinoconjunctivitis with keratitis, multiple food allergies, and vomiting with growth failure. Imaging demonstrated bronchiectasis, while gastroscopy identified chronic eosinophilic gastroduodenitis. Interestingly, growth failure and bronchiectasis improved over time without specific treatment. METHODS: Whole-genome sequencing (WGS) using Illumina short-read sequencing was followed by both manual and orthogonal automated bioinformatic analyses for single-nucleotide variants, small insertions/deletions (indels), and larger copy number variations. NK cell cytotoxic function was assessed using 51Cr release and degranulation assays. The presence of an interferon signature was investigated using a panel of six interferon-stimulated genes (ISGs) by QPCR. RESULTS: WGS identified a de novo hemizygous intronic variant in POLA1 (NM_001330360.2(POLA1):c.1393-354A > G) giving a diagnosis of XLPDR, as well as a heterozygous nonsense FLG variant (NM_002016.2(FLG):c.441del, NP_0020.1:p.(Arg151Glyfs*43)). Compared to healthy controls, the IFN signature was elevated although the degree moderated over time with the improvement in his chest disease. NK cell functional studies showed normal cytotoxicity and degranulation. CONCLUSION: This patient had multiple atopic manifestations affecting eye, skin, chest, and gut, complicating the presentation of XLPDR. This highlights that common FLG polymorphisms should always be considered when assessing genotype-phenotype correlations of other genetic variation in patients with atopic symptoms. Additionally, while the patient exhibited an enhanced IFN signature, he does not have an NK cell defect, suggesting this may not be a constant feature of XLPDR.

Incentives and individualized coaching improves completion rates of supervised exercise therapy for claudication.

OBJECTIVE: Supervised exercise therapy (SET) provides clinical benefit for patients suffering from intermittent claudication and has been widely recommended as first-line therapy before endovascular or surgical intervention. However, published rates of SET program completion range from 5% to 55%, with historic completion of 54% at our own institution. As such, we sought to identify if targeted patient-supportive interventions improve SET completion rates while still maintaining efficacious SET programming. METHODS: Patients who were diagnosed with intermittent claudication, as defined by ankle-brachial index (ABI) <0.9 without rest pain, were offered enrollment in a prospective quality improvement protocol for our 12-week SET for peripheral artery disease program. Program completion was defined as ≥24 of 36 offered sessions over 12 weeks. A three-pronged approach was utilized to improve completion during the study, including financial incentives up to $180, scheduled coaching with our advanced practitioner staff, and informational materials on the importance of SET programming and lifestyle modification. Patient-reported improvements in walking symptoms were tracked via regularly administered questionnaires. Functional measures of SET programming including total walking duration and distance, metabolic equivalent of task, and ABIs; vascular intervention within 12-months after enrollment was also collected and compared using univariate paired analysis. RESULTS: In total, seventy-three patients were enrolled in SET for peripheral artery disease programming over the study period. Utilizing our three-pronged coaching approach, 56 patients completed SET programming, increasing our SET completion rate to 76.7% over a 2-year study period. Compared with pre-SET baseline, patients who completed SET noted less pain, aching, cramps in calves when walking (P = .004), and less difficulty walking 1 block (P = .038). Additionally, patients significantly increased their metabolic equivalent of task (3.1 vs 2.6; P < .001), total walking duration (30 mins vs 13.5 mins; P < .001), and total walking distance (0.7 vs 0.3 miles; P < .001) from their pre-SET baseline. There were no changes in participant ABIs from enrollment to completion in participants. Patients who completed SET programming also delayed vascular intervention compared with those who did not complete SET or declined participation (213.5 vs 122.5 days from enrollment; P = .041). CONCLUSIONS: Targeted incentives, including cost-coverage vouchers and personalized coaching with instructional materials, successfully improved patient completion of a prescribed SET program. Patients who completed SET programming reported subjective improvement in walking symptoms and objective walking benefits. In addition, these patients had delayed time to vascular intervention, supporting current vascular guidelines advocating for effective SET therapy prior to offering vascular intervention for intermittent claudication.

Patient Reported Barriers for Participation in Supervised Exercise Therapy for Symptomatic Peripheral Artery Disease.

BACKGROUND: Supervised exercise therapy (SET) provides clinical benefit for patients suffering from intermittent claudication due to peripheral artery disease (PAD). However, enrollment in programs when offered remains low. We sought to identify patient-reported barriers to enrollment in SET as part of a prospective quality improvement program. METHODS: Patients who presented to clinic and were diagnosed with claudication were offered enrollment in a prospective quality improvement protocol, offered at 9 regional offices throughout our health system. Both patients who enrolled and declined enrollment were offered a 12-question questionnaire to identify potential barriers to enrollment. Additional data including gender, smoking status, ankle-brachial index (ABI), proximity to the nearest regional office, and disadvantage levels of neighborhoods (low: 1-3, medium: 4-7, and high: 8-10 area deprivation index [ADI]) was collected and compared by program participation using univariate analysis. RESULTS: Patients enrolled in the SET program (n = 66 patients) versus those who declined (n = 84 patients) were of similar age (medium age: 71.4 vs. 69.7 years, P = 0.694), baseline ABI (0.6 vs. 0.6, P = 0.944), smoking status (former 56.1% vs. 53.6%, P = 0.668), distance away from outpatient center (8.2 mi vs. 8.4 mi, P = 0.249), and had similar Connecticut state ADIs (2021 high-disadvantage: 35.4% vs. 33.3%, P = 0.549). Patients participating in the SET program were more likely to be male (78.8% vs. 56.0%, P = 0.003). Top self-reported barriers for patients who declined participation included transportation/distance (39.3%), preference for independent walking (56.0%), inability to commit to 3 sessions per week (52.4%), and lack of interest (20.2%). In addition, a higher proportion of patients who declined participation identified severe barriers of preference for independent walking (39.3% vs. 1.5%, P < 0.001), inability to commit to 3 sessions per week (26.2% vs. 3.0% P < 0.001), transportation/distance issues (23.8% vs. 7.6% P = 0.008), and cost (27.4% vs. 9.1%, P = 0.005) as significant barriers for participation in SET. CONCLUSIONS: Patients who declined participation in SET for PAD had similar disease status and access to care than participating counterparts. Top reported barriers to enrollment include a preference for independent walking, transportation/distance, commitment to 3x/week program, and cost, which highlight areas of focus for equitable access to these limb-saving services.

Findings From a National Survey of Older US Adults on Patient Willingness to Use Telehealth Services: Cross-Sectional Survey.

BACKGROUND: Telehealth (telemedicine and telepharmacy) services increase access to patient services and ensure continuity of care. However, few studies have assessed factors that influence patients' willingness to use telehealth services, and we sought to investigate this. OBJECTIVE: This study aims to examine respondents' (aged between 45 and 75 years) willingness to use telehealth services (telepharmacy and telemedicine) and the correlates of the willingness to use telehealth services. METHODS: We administered a cross-sectional national survey of 1045 noninstitutionalized US adults aged between 45 and 75 years in March and April 2021. Multiple logistic regression analyses were used to identify demographic and health service use correlates of self-reported willingness to use telehealth services. RESULTS: Overall willingness to use telemedicine was high (674/1045, 64.5%). Adults aged 55 years and older were less willing to use telemedicine (aged between 55 and 64 years: odds ratio [OR] 0.61, 95% CI 0.42-0.86; aged 65 years or older: OR 0.33, 95% CI 0.22-0.49) than those younger than 55 years. Those with a regular provider (OR 1.01, 95% CI 1-1.02) and long travel times (OR 1.75, 95% CI 1.03-2.98) were more willing to use telemedicine compared to those without a regular provider and had shorter travel times, respectively. Willingness to use telemedicine services increased from 64.5% (674/1045) to 83% (867/1045) if the service was low-cost or insurance-covered, was with their existing health care provider, or was easy-to-use. Overall willingness to use telepharmacy was 76.7% (801/1045). Adults aged older than 55 years were less willing to use telepharmacy (aged between 55 and 64 years: OR 0.57, 95% CI 0.38-0.86; aged 65 years or older: OR 0.24, 95% CI 0.15-0.37) than those younger than 55 years. Those who rated pharmacy service quality higher were more willing to use telepharmacy (OR 1.06, 95% CI 1.03-1.09) than those who did not. CONCLUSIONS: Respondents were generally willing to use telehealth (telemedicine and telepharmacy) services, but the likelihood of their being willing to use telehealth decreased as they were older. For those initially unwilling (aged 55 years or older) to use telemedicine services, inexpensive or insurance-covered services were acceptable.

Effects of aflatoxin B1 on metabolism- and immunity-related gene expression in Hermetia illucens L. (Diptera: Stratiomyidae).

Contamination of food products with mycotoxins such as aflatoxin B1 (AFB1) poses a severe risk to human health. Larvae of the black soldier fly (BSFL), Hermetia illucens (Diptera: Stratiomyidae), can successfully metabolize AFB1 without any negative consequences on their survival or growth. Organic waste streams contaminated with mycotoxins can be upcycled into protein-rich BSFL as an alternative feed for livestock and the left-over feed residue into nutrient-rich crop fertilizers. However, the underlying mechanisms that allow BSFL to metabolize AFB1 are unknown. In this study, five-day-old BSFL were fed with either a control or an AFB1-spiked (20 µg/kg) diet to elucidate the underlying mechanisms. Larval samples were collected at three timepoints (6 h, 24 h and 72 h) and subjected to RNA-Seq analysis to determine gene expression patterns. Provision of an AFB1-spiked diet resulted in an up-regulation of 357 and a down-regulation of 929 unique genes. Upregulated genes include multiple genes involved in AFB1 metabolism in other (insect) species. Downregulated genes were generally involved in the insects' growth, development, and immunity. BSFL possesses a diverse genetic arsenal that encodes for enzymes capable of metabolizing AFB1 without trade-offs on larval survival. In conclusion, the adverse impact of AFB1 exposure on immunity-related processes is observed in the transcriptomic response, and is indicative of a trade-off between detoxification and immune responses.

Colorectal cancer screening knowledge among community pharmacists: A national survey.

BACKGROUND: Colorectal cancer (CRC) screening can reduce CRC morbidity and mortality. Community pharmacies could be a viable option for delivering home-based CRC screening tests such as fecal immunochemical tests (FITs). However, little is known about community pharmacists' knowledge about CRC screening guidelines. OBJECTIVE: We assessed community pharmacists' knowledge about CRC screening to identify education and training needs for a pharmacy-based CRC screening program. METHODS: Between September 2022 and January 2023, we conducted an online national survey of community pharmacists practicing in the United States. Responders were eligible if they were currently-licensed community pharmacists and currently practiced in the United States. The survey assessed knowledge of national CRC screening guidelines, including recommended starting age, frequency of screening, different screening modalities, and follow-up care. Using multiple linear regression, we evaluated correlates of community pharmacists' level of CRC screening knowledge, defined as the total number of knowledge questions answered correctly from "0" (no questions correct) to "5" (all questions correct). RESULTS: A total of 578 eligible community pharmacists completed the survey, with a response rate of 59%. Most community pharmacists correctly answered the question about the next steps following a positive FIT (87%) and the question about where a FIT can be done (84%). A minority of community pharmacists responded correctly to questions about the age to start screening with FIT (34%) and how often a FIT should be repeated (28%). Only 5% of pharmacists answered all knowledge questions correctly. Community pharmacists answered more CRC screening knowledge questions correctly as their years in practice increased. Board-certified community pharmacists answered more CRC screening knowledge questions correctly compared to those who were not board-certified. CONCLUSION: To ensure the successful implementation of a pharmacy-based CRC screening program, community pharmacists need to be educated about CRC screening and trained to ensure comprehensive patient counseling and preventive service delivery.

Genomic sequencing for newborn screening: current perspectives and challenges.

Traditional newborn screening (NBS) serves as a critical tool in identifying conditions that may impact a child's health from an early stage. Newborn sequencing (NBSeq), the comprehensive analysis of an infant's genome, holds immense promise for revolutionizing health care throughout the lifespan. NBSeq allows for early detection of genetic disease risk and precision personalized medicine. The rapid evolution of DNA sequencing technologies and increasing affordability have spurred numerous endeavors to explore the potential of whole-genome sequencing in newborn screening. However, this transformative potential cannot be realized without challenges. Ethical aspects must be carefully navigated to safeguard individual rights and maintain public trust. Moreover, genomic data interpretation poses complex challenges due to its amount, the presence of variants of uncertain significance, and the dynamic nature of our understanding of genetics. Implementation hurdles, including cost, infrastructure, and specialized expertise, also present barriers to the widespread adoption of NBSeq. Addressing these challenges requires collaboration among clinicians, researchers, policymakers, ethicists, and stakeholders across various sectors. Robust frameworks for informed consent, data protection, and governance are essential. Advances in bioinformatics, machine learning, and genomic interpretation are crucial for translation into actionable clinical insights. Scalability and improving downstream health care access are vital for equitability, particularly in underserved communities. By fostering interdisciplinary collaboration, advancing technology and infrastructure, and upholding ethical principles, we can unlock the full potential of NBSeq as a tool for precision medicine and pave the way toward a future where every child has the opportunity for a healthier, genomics-informed start to life.

Patient preferences for the design of a pharmacy-based colorectal cancer screening program.

PURPOSE: To assess preferences for design of a pharmacy-based colorectal cancer (CRC) screening program (PharmFIT™) among screening-eligible adults in the United States (US) and explore the impact of rurality on pharmacy use patterns (e.g., pharmacy type, prescription pick-up preference, service quality rating). METHODS: We conducted a national online survey of non-institutionalized US adults through panels managed by Qualtrics, a survey research company. A total of 1,045 adults (response rate 62%) completed the survey between March and April 2021. Sampling quotas matched respondents to the 2010 US Census and oversampled rural residents. We assessed pharmacy use patterns by rurality and design preferences for learning about PharmFIT™; receiving a FIT kit from a pharmacy; and completing and returning the FIT kit. RESULTS: Pharmacy use patterns varied, with some notable differences across rurality. Rural respondents used local, independently owned pharmacies more than non-rural respondents (20.4%, 6.3%, p < 0.001) and rated pharmacy service quality higher than non-rural respondents. Non-rural respondents preferred digital communication to learn about PharmFIT™ (36% vs 47%; p < 0.001) as well as digital FIT counseling (41% vs 49%; p = 0.02) more frequently than rural participants. Preferences for receiving and returning FITs were associated with pharmacy use patterns: respondents who pick up prescriptions in-person preferred to get their FIT (OR 7.7; 5.3-11.2) and return it in-person at the pharmacy (OR 1.7; 1.1-2.4). CONCLUSION: Pharmacies are highly accessible and could be useful for expanding access to CRC screening services. Local context and pharmacy use patterns should be considered in the design and implementation of PharmFIT™.

Unsupervised segmentation and quantification of COVID-19 lesions on computed Tomography scans using CycleGAN.

BACKGROUND: Lesion segmentation is a critical step in medical image analysis, and methods to identify pathology without time-intensive manual labeling of data are of utmost importance during a pandemic and in resource-constrained healthcare settings. Here, we describe a method for fully automated segmentation and quantification of pathological COVID-19 lung tissue on chest Computed Tomography (CT) scans without the need for manually segmented training data. METHODS: We trained a cycle-consistent generative adversarial network (CycleGAN) to convert images of COVID-19 scans into their generated healthy equivalents. Subtraction of the generated healthy images from their corresponding original CT scans yielded maps of pathological tissue, without background lung parenchyma, fissures, airways, or vessels. We then used these maps to construct three-dimensional lesion segmentations. Using a validation dataset, Dice scores were computed for our lesion segmentations and other published segmentation networks using ground truth segmentations reviewed by radiologists. RESULTS: The COVID-to-Healthy generator eliminated high Hounsfield unit (HU) voxels within pulmonary lesions and replaced them with lower HU voxels. The generator did not distort normal anatomy such as vessels, airways, or fissures. The generated healthy images had higher gas content (2.45 ± 0.93 vs 3.01 ± 0.84 L, P < 0.001) and lower tissue density (1.27 ± 0.40 vs 0.73 ± 0.29 Kg, P < 0.001) than their corresponding original COVID-19 images, and they were not significantly different from those of the healthy images (P < 0.001). Using the validation dataset, lesion segmentations scored an average Dice score of 55.9, comparable to other weakly supervised networks that do require manual segmentations. CONCLUSION: Our CycleGAN model successfully segmented pulmonary lesions in mild and severe COVID-19 cases. Our model's performance was comparable to other published models; however, our model is unique in its ability to segment lesions without the need for manual segmentations.

Rectus Sheath Block Improves Patient Recovery Following Open Aortic Surgery.

BACKGROUND: Postoperative pain management remains a barrier to recovery following aortic surgery. Although epidural catheters help in adjunctive pain management, less is known about the use of rectus sheath blocks. We compared patient recovery following open abdominal aortic surgery (OAS) with and without adjunctive rectus block. METHODS: Adult patients undergoing open abdominal aortic aneurysm repair and aortobifemoral or aortoiliac bypass for occlusive disease were identified and stratified by use of general anesthesia alone (GA) versus adjunctive use of a rectus sheath block (GA + RB). A small number of patients with GA and concomitant epidural analgesia, along with patients that had retroperitoneal repairs, were not included in further analysis. Outcomes included time to extubation, intraoperative and postoperative morphine milligram equivalents (MME) utilization, length of stay, discharge MME, and postoperative complications. Categorial data were compared with Person Chi-Square tests or Fisher's exact tests. Continuous data were tested with independent t-tests or Mann-Whitney U-tests. RESULTS: From January 2017 to April 2022, there were 106 patients who underwent open aortic surgery, 55 patients with GA alone, 39 with GA + RB, and 12 patients who had a GA with concomitant epidural analgesia. Between GA and GA + RB, patients were comparable in both groups in terms of age, BMI (body mass index), smoking history, hypertension, diabetes, CAD (coronary artery disease), COPD (chronic obstructive pulmonary disease), and ASA (American Society of Anesthesiologists) class and prior opioid use. Patients with GA + RB were more likely to have scheduled elective procedures (80% GA cohort vs. 94.9% RB, P = 0.040), and a lower incidence of retroperitoneal exposure (14.5% GA cohort vs. 0% RB, P = 0.019). Patients with GA + RB had shorter time to extubation than GA (84.6% < 12 hr vs. 44.4%, P < 0.001), greater rate of procedural ketamine usage (GA + RB: 61.5% vs. GA: 40.0%, P = 0.049), lower MME at first postoperative day (median MME GA + RB: 25.0 vs. GA: 67.5, P = 0.002), lower discharge MME (median MME GA + RB: 142.5 vs. GA: 225.0, P = 0.036), and overall shorter length of stay (median stay GA + RB: 5 vs. GA: 6 days, P = 0.006). Postoperative complications were similar between groups. Similar findings were found in the comparison between elective-only GA and GA + RB patients and after exclusion of patients who only had a single shot of regional anesthesia. CONCLUSIONS: Patients that receive adjunctive rectus sheath blocks for pain control following OAS utilize fewer opioid medications during hospital stay and at discharge. Rectus sheath blocks represent an alternative option to other periprocedural analgesia following open aortic surgery.

Integration of hospital and community care for paediatric ophthalmology: A mixed-methods study.

BACKGROUND: To explore collaborative care models for paediatric eye care that integrate hospital and community-based care to address access blocks. METHODS: Sequential referrals to a tertiary paediatric ophthalmology clinic between April and October 2019 and subsequent encounters up until July 2020 at a major metropolitan public children's hospital in Sydney, Australia, were reviewed to identify those cases suitable for community care. Semi-structured phone interviews were conducted with eye health service providers, including ophthalmologists, orthoptists and optometrists, as well as service users to explore their perspectives on potential changes to service delivery. Qualitative data were analysed deductively using the Levesque model for access to healthcare and Consolidated Framework for Implementation Research (CFIR) to inform implementation strategies for future models of care. RESULTS: One-third of the 439 audited referrals (30.5%; 134/439) were identified as suitable for community management. Interviews revealed five themes relating to potential models of care, which would support and promote access: integrated health systems, standardised quality of care, interprofessional trust, multidisciplinary governance and patient-centred care. Key recommendations for future implementation included: (i) identifying and preparing clinical champions, (ii) conducting educational meetings, (iii) conducting local needs assessments and (iv) informing local opinion leaders. CONCLUSIONS: This audit highlights access blocks and poor targeting of referrals to tertiary paediatric ophthalmology services in a metropolitan hospital. Integration with community practitioners was identified as an acceptable way to streamline services, and strategies that may support successful implementation in this setting were identified.

Temperature-modulated host-pathogen interactions between Hermetia illucens L. (Diptera: Stratiomyidae) and Pseudomonas protegens Pf-5.

Temperature is an important abiotic factor influencing the survival and fitness of pathogens as well as their hosts. We investigated the effect of three temperatures (18 °C, 27 °C and 37 °C) on survival and performance of black soldier fly larvae (BSFL), Hermetia illucens L., upon infection by an entomopathogenic Gram-negative bacterium, Pseudomonas protegens Pf-5. The effect of different temperatures on pathogen fitness was investigated both in vivo and in vitro. Pathogen performance under exposure to the insect antimicrobial peptide cecropin was investigated at the three temperatures using radial-diffusion plate assays. Higher rearing temperatures resulted in higher larval survival, increased larval weight, and higher inhibitory activity of cecropin against P. protegens Pf-5. At higher temperature, bacterial growth, both in vivo and in vitro, was reduced, resulting in increased BSFL survival. These observations collectively indicate the important effect of rearing temperature on host-pathogen interactions and the possibility to apply temperature treatment in reducing entomopathogen effects in BSFL.

Primary care provider perspectives on the role of community pharmacy in colorectal cancer screening: a qualitative study.

BACKGROUND: The United States Preventive Services Task Force (USPSTF) lists 32 grade A or B recommended preventive services for non-pregnant United States (US) adults, including colorectal cancer screening (CRC). Little guidance is given on how to implement these services with consistency and fidelity in primary care. Given limited patient visit time and competing demands, primary care providers (PCPs) tend to prioritize a small subset of these recommendations. Completion rates of some of these services, including CRC screening, are suboptimal. Expanding delivery of preventive services to other healthcare providers, where possible, can improve access and uptake, particularly in medically underserved areas or populations. Fecal immunochemical testing (FIT) (at-home, stool-based testing) for CRC screening can be distributed and resulted without PCP involvement. Pharmacists have long delivered preventive services (e.g., influenza vaccination) and may be a good option for expanding CRC screening delivery using FIT, but it is not clear how PCPs would perceive this expansion. METHODS: We used semi-structured interviews with PCPs in North Carolina and Washington state to assess perceptions and recommendations for a potential pharmacy-based FIT distribution program (PharmFIT™). Transcripts were coded and analyzed using a hybrid inductive-deductive content analysis guided by the Consolidated Framework for Implementation Research (CFIR) to elucidate potential multi-level facilitators of and barriers to implementation of PharmFIT™. RESULTS: We completed 30 interviews with PCPs in North Carolina (N = 12) and Washington state (N = 18). PCPs in both states were largely accepting of PharmFIT™, with several important considerations. First, PCPs felt that pharmacists should receive appropriate training for identifying patients eligible and due for FIT screening. Second, a clear understanding of responsibility for tracking tests, communication, and, particularly, follow-up of positive test results should be established and followed. Finally, clear electronic workflows should be established for relay of test result information between the pharmacy and the primary care clinic. CONCLUSION: If the conditions are met regarding pharmacist training, follow-up for positive FITs, and transfer of documentation, PCPs are likely to support PharmFIT™ as a way for their patients to obtain and complete CRC screening using FIT.

Genomic Editing and Diabetes.

The diabetes types and its complications have varying developmental and metabolic pathways. There is an interplay of nongenetic and genetic components in pathogenesis of diabetes and its complications. There are several established genes such as ABCC8, TCF7L2, SLC2A2, and CAPN10 which are known to influence blood insulin and glucose levels. Current management of diabetes types may include lifetime burdensome use of insulin, insulin sensitizers, insulin secretagogues, etc. There has been increasing interest in improving genetic editing tools such as CRISPR/Cas9 and using genetically edited stem cells to alter diabetes disease course or possibly cure it. Current research on microRNAs and long noncoding RNAs may provide insights into the pathways involved in development of diabetes and its complications. Consequently, developing further understanding of genetics and its messenger pathways in diabetes would enhance our ability to develop precise and accurate genetic editing tools which can translate into clinically useful therapeutics.

Acute on Chronic Liver Failure From Nonalcoholic Fatty Liver Disease: A Growing and Aging Cohort With Rising Mortality.

BACKGROUND AND AIMS: We assessed the burden of nonalcoholic fatty liver disease (NAFLD)-related acute on chronic liver failure (ACLF) among transplant candidates in the United States, along with waitlist outcomes for this population. APPROACH AND RESULTS: We analyzed the United Network for Organ Sharing registry from 2005 to 2017. Patients with ACLF were identified using the European Association for the Study of the Liver/Chronic Liver Failure criteria and categorized into NAFLD, alcohol-associated liver disease (ALD), and hepatitis C virus (HCV) infection. We used linear regression and Chow's test to determine significance in trends and evaluated waitlist outcomes using Fine and Gray's competing risks regression and Cox proportional hazards regression. Between 2005 and 2017, waitlist registrants for NAFLD-ACLF rose by 331.6% from 134 to 574 candidates (P < 0.001), representing the largest percentage increase in the study population. ALD-ACLF also increased by 206.3% (348-1,066 registrants; P < 0.001), whereas HCV-ACLF declined by 45.2% (P < 0.001). As of 2017, the NAFLD-ACLF population consisted primarily of persons aged ≥60 years (54.1%), and linear regression demonstrated a significant rise in the proportion of patients aged ≥65 in this group (ß = 0.90; P = 0.011). Since 2014, NAFLD-ACLF grade 1 was associated with a greater risk of waitlist mortality relative to ALD-ACLF (subhazard ratio [SHR] = 1.24; 95% confidence interval [CI], 1.05-1.44) and HCV-ACLF (SHR = 1.35; 95% CI, 1.08-1.71), among patients aged ≥60 years. Mortality was similar among the three groups for patients with ACLF grade 2 or 3. CONCLUSIONS: NAFLD is the fastest rising etiology of cirrhosis associated with ACLF among patients listed in the United States. As the NAFLD population continues to grow and age, patients with NAFLD-ACLF will likely have the highest risk of waitlist mortality.

Real world data on cardiometabolic diseases in U.S. adults during the SARS-CoV-2 pandemic: a decentralized registry study.

BACKGROUND: Pre-existing cardiometabolic comorbidities place SARS-CoV-2 positive patients at a greater risk for poorer clinical course and mortality than those without it. We aimed to analyze real-world registry data focused primarily on participants with cardiometabolic diseases (CMD), which were remotely obtained via a digital platform. METHODS: Participants were divided into two groups: CMD or no cardiometabolic disease (non-CMD). They were evaluated based on their medical history, current medications/supplements, COVID-19 status, demographics, and baseline characteristics. The frequency of medications/supplements for CMD were compared using relative risks and 95% confidence intervals. The WHO (Five) Well-Being Index (WHO-5) were collected monthly for 6 months to assess psychological well-being which included cheerfulness, calmness, vigor, rest, and engagement with daily activities of interest. RESULTS: The 791 enrollees represented 49 U.S. states. The CMD group had significantly higher (p < 0.0001) BMI (mean + 3.04 kg/m2) and age (mean + 9.15 years) compared to non-CMD group. In the CMD group, participants who tested positive for COVID-19 had lower (p < 0.0001) well-being scores than those without COVID-19. For the 274 participants on CMD medications/supplements, there was no statistical difference in risk of COVID-19 contracture based on medication/supplement type; however, all six participants who were not being treated for CMD were COVID-19 positive (RR ~ 104). For 89 participants who were on treatment for diabetes or insulin resistance, there was a 90% reduced risk of COVID-19 incidence (p = 0.0187). CONCLUSION: The well-being score of the CMD group was dependent on whether they tested positive for COVID-19. Type of CMD treatment did not impact COVID-19 status, but absence of treatment significantly increased COVID-19 incidence. With respect to SARS-CoV-2, our analysis supports continued use of the statins, ACE-I, ARBs, and diabetes medications in CMD patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04348942.

The diagnostic utility of exome-based carrier screening in families with a positive family history.

Identification of disease-causing variants in families with a history of a suspected recessive disorder is essential for appropriate counseling and reproductive decision making. The present case series depicts the utility of whole exome-based phenotypes-driven carrier analysis in 14 families with a positive family history. A phenotype-based analysis revealed a putative diagnostic yield of 71.4%. Proband sample, though insufficient, was available in only one family, which allowed the diagnosis to be confirmed. In the remaining nine families, despite the detection of heterozygous pathogenic/likely pathogenic variants, only a putative diagnosis was possible due to incomplete proband phenotyping as well as nonavailability of proband samples. We describe the youngest known patient homozygous for a likely pathogenic variant in PPP1R21. He is currently asymptomatic at 7 days of life and has a simplified gyral pattern on neuroimaging. The case series, though small, captures the challenges in the diagnosis of genetic disorders in low to middle income countries with in-equitable health care access. It reinforces the significance of detailed phenotyping in the proband as well as the importance of DNA storage for a conclusive diagnosis. A recurring post-test counseling challenge was risk ascertainment and reproductive decision making in subsequent pregnancies if the detected pathogenic/likely pathogenic variants are co-inherited, in families with a putative diagnosis. When opted for, prenatal testing in such a scenario would be limited in its ability to comment on the fetal status with respect to the disorder in the proband.

Association between asthma and severe tooth loss in the adult population of the United States.

OBJECTIVE: This study aimed to investigate the association between asthma and severe tooth loss in the U.S. (United States) adult population. METHODS: Data were analyzed from the national health and nutritional examination survey (NHANES), 2009-2014. Study-participants were classified into current, former, and never asthmatics based on their asthma status. Former-asthmatics were excluded. The case definition of severe tooth loss (outcome variable) was having 9 or fewer remaining permanent teeth. Characteristics of our study-sample were identified based on the descriptive statistical analyses. Logistic regression analyses were performed to examine the association between asthma and severe tooth. Multivariable models were constructed to control for the known common clinical, demographic, and lifestyle factors. Each analysis accounted for the examination sample weights and the complex clustered design of the continuous NHANES. RESULTS: Total study-participants were 14,184 representing ≈185.77 million U.S. adults. Prevalence of asthma was 8.99% in our study-sample, and 8.78% had severe tooth loss. Current-asthmatic adults had 34% higher odds of severe tooth loss as compared to their reference group of never-asthmatics adults in the U.S. after controlling for age, race or ethnicity, gender, diabetes, smoking, body mass index, education, and family income-to-poverty ratio. CONCLUSION: In the United States, as compared to never-asthmatic adults, current-asthmatic adults were more likely to have severe tooth-loss. Oral health promotion is therefore recommended through medical-dental integration to ensure overall health for asthmatic adults.

Association between asthma and periodontitis in the US adult population: A population-based observational epidemiological study.

AIM: To examine the association between asthma and periodontitis in a nationally representative sample of adults in the United States. MATERIALS AND METHODS: Data obtained from 10,710 adult men and women who participated in National Health and Nutritional Examination Survey from 2009 to 2014 were analysed. Asthma was measured based on self-reported physician diagnosis. Periodontitis was the outcome of interest. It was classified into mild, moderate, and severe periodontitis according to the updated CDC/AAP case definitions. Multivariable models were developed to examine the association of asthma with periodontitis while controlling for age, race/ethnicity, gender, education, income, body mass index, diabetes, and smoking. Odds ratio (OR) and respective 95% confidence interval (CI) were calculated. Replication was performed by differently classifying the outcome using another system called periodontal profile class (PPC). RESULTS: Current asthmatics, in reference to never asthmatics, had lower odds of severe periodontitis [(adjusted OR = 0.51, 95% CI = 0.30-0.87) and (adjusted OR = 0.58, 95% CI = 0.35-0.97) as classified using CDC/AAP case definitions and PPC system, respectively]. However, there was no statistically significant association between asthma and any other forms of periodontitis (p value >.05). CONCLUSIONS: In the United States, current-asthmatic adults were less likely to have severe periodontitis as compared with never-asthmatic adults. Further research is required to fully understand this association.

Female Sex is Associated with Worse Outcomes following Complex Fenestrated or Branched Endovascular Aortic Repair.

BACKGROUND: Sex-related discrepancies after standard endovascular aneurysm repair (EVAR) are noted to disproportionally affect females. A growing body of literature suggests similar disparities may extend to complex fenestrated or branched endovascular aneurysm repair (FBEVAR). However, recent examination of complex FBEVAR by a consortium of high-volume centers noted equivalent mortality among sexes. Whether similar results extend to non-trial data is unknown. METHODS: We examined all juxta-renal through type IV thoraco-abdominal aneurysms (sealing zones 6-8) which underwent elective FBEVAR within the Vascular Quality Initiative (VQI) database from January 2012 to December 2020. Urgent, symptomatic, ruptured, and staged cases were excluded, as were parallel stent grafts. Demographics, comorbid conditions, and technical factors were compared between sexes. Univariate analysis with Wilcoxon ranked sum tests and Chi-square tests of proportion were performed, followed by multivariate logistic regression for failure of target vessel technical success, reintervention, complications, and in-hospital mortality. RESULTS: Our analysis included 1,521 patients, 1,180 males (77.6%) and 341 females (22.4%). There were noted differences in pre-operative demographics, medical optimization, and technical aspects of the procedure. However, no difference was noted in proximal or distal sealing stents, number of fenestrations, or immediate endoleaks. On a multi variate logistic regression, female sex was an independent predictor of failure of target vessel technical success (odds ratio (OR) 3.339, 95% confidence interval (CI): 2.173-5.132, P < 0.001), reintervention (OR 2.192, 95% CI: 1.304-3.683, P = 0.003), complications (OR 1.747, 95% CI: 1.282-2.381, P < 0.001), and in-hospital mortality (OR 2.836, 95% CI: 1.510-5.328, P = 0.001). CONCLUSIONS: Females suffer worse outcomes after FBEVAR despite similar extent of disease, number of fenestrations, and incidence of immediate endoleak. Notable discrepancies were higher rates of chronic obstructive pulmonary disease (COPD) and lower rates of pre-operative aspirin, statin, and beta blocker therapy in females. Controlling for pre-operative demographics, female sex remained an independent predictor of worse outcomes. These discrepancies warrant further examination and should impact case planning for female patients undergoing complex aortic aneurysm repair.