Securing the Internet of Healthcare

Cybersecurity, including the security of information technology (IT), is a critical requirement in ensuring society trusts, and therefore can benefit from, modern technology. Problematically, though, rarely a day goes by without a news story related to how critical data has been exposed, exfiltrated, or otherwise inappropriately used or accessed as a result of supply chain vulnerabilities. From the Russian government\u27s campaign to influence the 2016 U.S. presidential election to the September 2017 Equifax breach of more than 140-million Americans\u27 credit reports, mitigating cyber risk has become a topic of conversation in boardrooms and the White House, on Wall Street and Main Street. But oftentimes these discussions miss the problems replete in the often-expansive supply chains on which many of these products and services we depend on are built; this is particularly true in the medical device context. The problem recently made national news with the FDA-mandated recall of more than 400,000 pacemakers that were found to be vulnerable to hackers necessitating a firmware update. This Article explores the myriad vulnerabilities in the supply chain for medical devices, investigates existing FDA cybersecurity and privacy regulations to identify any potential governance gaps, and suggests a path forward to boost cybersecurity due diligence for manufacturers by making use of new approaches and technologies, including blockchain

The pathogenesis of cingulate atrophy in behavioral variant frontotemporal dementia and Alzheimer’s disease

BACKGROUND: Early atrophy of the cingulate cortex is a feature of both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD), with degeneration of the anterior cingulate region increasingly recognized as a strong predictor of bvFTD. The total number of neurons in this region, rather than the density of neurons, is associated with mood disturbance in other dementias, although there are no data on the extent and magnitude of neuronal loss in patients with bvFTD. While the density of small populations of neurons in this region has been assessed, it is unlikely that the degree of atrophy of the cingulate cortex seen in bvFTD can be explained by the loss of these subpopulations. This suggests that there is more generalized degeneration of neurons in this region in bvFTD. The present study assesses total neuronal number, as well as characteristic pathologies, in the anterior and posterior cingulate cortices of pathologically confirmed bvFTD (N = 11) and AD (N = 9) patients compared with age-matched controls (N = 14). The bvFTD cohort comprised 5 cases with tau pathology (Pick’s disease), and 6 with TDP-43 pathology. RESULTS: At postmortem, atrophy was detected in the anterior and posterior cingulate cortices of bvFTD cases, but only in the posterior cingulate cortex of AD cases. As predicted, there was a significant reduction in both the density and total number of neurons in the anterior but not the posterior cingulate cortex of bvFTD cases with the opposite observed for the AD cases. Importantly, neuronal loss in the anterior cingulate cortex was only observed in cases with tau pathology. CONCLUSIONS: This study confirms significant neuronal loss in the posterior but not anterior cingulate cortex in AD, and demonstrates that significant neuron loss in bvFTD occurs only in the anterior cingulate cortex but only in cases with tau pathology compared with cases with TDP pathology. We propose that significant neurodegeneration in the anterior cingulate cortex may be useful in differentiating the pathological subtypes in vivo

Health Care Use and Costs Among Patients With Nonalcoholic Steatohepatitis With Advanced Fibrosis Using the Fibrosis-4 Score

Limited evidence exists on the clinical and economic burden of advanced fibrosis in patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) due to the invasiveness of liver biopsies for accurately staging liver disease. The fibrosis-4 (FIB-4) score allows for noninvasive assessment of liver fibrosis by using clinical and laboratory data alone. This study aimed to characterize the comorbidity burden, health care resource use (HCRU), and costs among patients with NAFLD/NASH with FIB-4-defined F3 (bridging fibrosis) and F4 (compensated cirrhosis) fibrosis. Using the Optum Research Database, a retrospective cohort study was conducted among 251,725 commercially insured adult patients with ≥1 NAFLD/NASH diagnosis from January 1, 2008, to August 31, 2016, and laboratory data required to calculate FIB-4 scores. Five criteria using varying FIB-4 score cutoffs were identified based on expert clinical opinion and published literature. Date of the first valid FIB-4 score marked the index date. Mean annual HCRU and costs were calculated during the pre-index and post-index periods. The prevalence of FIB-4-based F3 and F4 fibrosis was 0.40%-2.72% and 1.03%-1.61%, respectively. Almost 50% of patients identified with FIB-4-based F3 or F4 had type 2 diabetes, cardiovascular disease, or renal impairment. Total all-cause health care costs increased significantly from pre-index to post-index for patients with FIB-4-based F3 fibrosis across most criteria (17%-29% increase) and patients with FIB-4-based F4 fibrosis across all criteria (47%-48% increase). Inpatient costs were the primary drivers of this increment

Formulation of hydrophobic peptides for skin delivery via coated microneedles

Microneedles (MNs) have been investigated as a minimally-invasive delivery technology for a range of active pharmaceutical ingredients (APIs). Various formulations and methods for coating the surface of MNs with therapeutics have been proposed and exemplified, predominantly for hydrophilic drugs and particulates. The development of effective MN delivery formulations for hydrophobic drugs is more challenging with dosing restrictions and the use of organic solvents impacting on both the bioactivity and the kinetics of drug release. In this study we propose a novel formulation that is suitable for MN coating of hydrophobic auto-antigen peptides currently being investigated for antigen specific immunotherapy (ASI) of type 1 diabetes. The formulation, comprising three co-solvents (water, 2-methyl-2-butanol and acetic acid) and polyvinylalcohol 2000 (PVA2000) can dissolve both hydrophilic and hydrophobic peptide auto-antigens at relatively high, and clinically relevant, concentrations (25 mg/ml or 12.5 mg/ml). The drug:excipient ratio is restricted to 10:1 w/w to maximise dose whilst ensuring that the dry-coated payload does not significantly impact on MN skin penetration performance. The coating formulation and process does not adversely affect the biological activity of the peptide. The delivery efficiency of the coated peptide into skin is influenced by a number of parameters. Electropolishing the metal MN surface increases delivery efficiency from 2.0 ± 1.0% to 59.9 ± 6.7%. An increased mass of peptide formulation per needle, from 0.37 μg to 2 μg peptide dose, resulted in a thicker coating and a 20% reduction in the efficiency of skin delivery. Other important performance parameters for coated MNs include the role of excipients in assisting dissolution from the MNs, the intrinsic hydrophobicity of the peptide and the species of skin model used in laboratory studies. This study therefore both exemplifies the potential of a novel formulation for coating hydrophobic and hydrophilic peptides onto MN devices and provides new insight into the factors that influence delivery efficiency from coated MNs. Importantly, the results provide guidance for identifying critical attributes of the formulation, coating process and delivery device, that confer reproducible and effective delivery from coated MNs, and thus contribute to the requirements of the regulators appraising these devices

Community-Based OT Program Planning: A Virtual Level II Fieldwork Program Developed in Response to the Global Pandemic

The purpose of this article is to explain how an occupational therapy (OT) program in a university setting developed a virtual Level II community-based fieldwork program in response to the COVID-19 global pandemic. This virtual fieldwork program, guided by the PRECEDE-PROCEED Planning Model (PPM), was designed to help keep students on track with their academic goals while providing them with experiential learning that would increase their confidence in OT program planning and promote their professional development. Outcome measures for this study consisted of a pre-and post-fieldwork survey that asked participants to rank their self-perceived confidence in five distinct areas of community-based OT program development. Some portions of Section III in the Student’s Evaluation of the Fieldwork Experience (SEFWE) form were also used to examine students’ feedback after participating in this virtual fieldwork program. Retrospective data analysis of pre-post survey results showed improvements in students’ perceived confidence with certain aspects of OT program development in community settings. Within the core function of program development, occupation-based approaches to community-based programs can be used to inform, educate, and empower people and populations about important health issues while simultaneously offering students rich opportunities for professional development and identity. Dissemination of this information can be helpful to other OT professionals who are developing alternate fieldwork programs in response to the pandemic and beyond

Capacity for the management of kidney failure in the International Society of Nephrology North America and the Caribbean region:Report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)

The International Society of Nephrology Global Kidney Health Atlas charts the availability and capacity of kidney care globally. In the North America and the Caribbean region, the Atlas can identify opportunities for kidney care improvement particularly in Caribbean countries where structures for systematic data collection are lacking. In this third iteration, respondents from 12 of 18 countries from the region reported a 2-fold higher than global median prevalence of dialysis and transplant, and a 3-fold higher than global median prevalence of dialysis centers. Peritoneal dialysis prevalence was lower than global median, and transplantation data was missing from 6 of the 10 Caribbean countries. Government-funded payments predominated for dialysis modalities, with greater heterogeneity in transplantation payor mix. Services for chronic kidney disease (CKD), such as monitoring of anemia and blood pressure, and diagnostic capability relying on serum creatinine and urinalyses were universally available. Notable exceptions in Caribbean countries included non-calcium-based phosphate binders and kidney biopsy services. Personnel shortages were reported across the region. Kidney failure was more commonly identified as a governmental priority than was CKD or acute kidney injury. In this generally affluent region, there is better access to kidney replacement therapy and CKD-related services than in much of the world. Yet clear heterogeneity exists, especially among the Caribbean countries struggling with dialysis and personnel capacity. Important steps to improve kidney care in the region include increased emphasis on preventive care, a focus on home-based modalities and transplantation, and solutions to train and retain specialized allied health professionals

IMI – industry guidelines and ethical considerations for myopia control report

PURPOSE. To discuss guidelines and ethical considerations associated with the development and prescription of treatments intended for myopia control (MC). METHODS. Critical review of published papers and guidance documents was undertaken, with a view to carefully considering the ethical standards associated with the investigation, development, registration, marketing, prescription, and use of MC treatments. RESULTS. The roles and responsibilities of regulatory bodies, manufacturers, academics, eye care practitioners, and patients in the use of MC treatments are explored. Particular attention is given to the ethical considerations for deciding whether to implement a MC strategy and how to implement this within a clinical trial or practice setting. Finally, the responsibilities in marketing, support, and education required to transfer required knowledge and skills to eye care practitioners and academics are discussed. CONCLUSIONS. Undertaking MC treatment in minors creates an ethical challenge for a wide variety of stakeholders. Regulatory bodies, manufacturers, academics, and clinicians all share an ethical responsibility to ensure that the products used for MC are safe and efficacious and that patients understand the benefits and potential risks of such products. This International Myopia Institute report highlights these ethical challenges and provides stakeholders with recommendations and guidelines in the development, financial support, prescribing, and advertising of such treatments.</p

IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity.

Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell-intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell-specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell-intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell-dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen-driven, GC and Tfh cell responses. Together, our data define a novel B cell-intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus

Increased Epithelial Gaps in the Small Intestine Are Predictive of Hospitalization and Surgery in Patients With Inflammatory Bowel Disease

Objectives: Epithelial gaps resulting from intestinal cell extrusions can be visualized with confocal laser endomicroscopy (CLE) during colonoscopy and increased in normal-appearing terminal ileum of inflammatory bowel disease (IBD) patients. Cell-shedding events on CLE were found to be predictive of disease relapse. The aim of this study was to assess the prognostic value of epithelial gap densities for major clinical events (hospitalization or surgery) in follow-up. Methods: We prospectively followed IBD patients undergoing colonoscopy with probe-based CLE (pCLE) for clinical events including symptom flares, medication changes, hospitalization, or surgery. Survival analysis methods were used to compare event times for the composite outcome of hospitalization or surgery using log-rank tests and Cox proportional hazards models. We also examined the relationship of gap density with IBD flares, need for anti-tumor necrosis factor therapy, disease duration, gender and endoscopic disease severity, and location. Results: A total of 21 Crohn's disease and 20 ulcerative colitis patients with a median follow-up of 14 (11–31) months were studied. Patients with elevated gap density were at significantly higher risk for hospitalization or surgery (log-rank test P=0.02). Gap density was a significant predictor for risk of major events, with a hazard ratio of 1.10 (95% confidence interval=1.01, 1.20) associated with each increase of 1% in gap density. Gap density was also correlated with IBD disease duration (Spearman's correlation coefficient rho=0.44, P=0.004), and was higher in male patients (9.0 vs. 3.6 gaps per 100 cells, P=0.038). Conclusions: Increased epithelial gaps in the small intestine as determined by pCLE are a predictor for future hospitalization or surgery in IBD patients