Pseudofilariasis, a Presenting Sign of Alkaptonuria.

PURPOSE: To report the association of Pseudofilariasis as a presenting sign of Alkaptonuria. METHOD: Case Report. RESULTS: A 49-year-old Indian man was referred because of wormlike objects in his left conjunctiva. Ocular and family history was non-contributory. He had not been to India in 15 years. Past medical history revealed hypertension, hypercholesterolemia, arthritis, and a myocardial infarct. He had undergone two stents, bilateral Achilles tendon repairs and bilateral knee replacements. ROS showed longstanding back stiffness and pain. On ocular examination the vision was 20/25 in each eye and positive findings were in the left eye bulbar conjunctival which showed stationary black vermiform (filarial in appearance) foreign bodies along with 2 small corneal limbal pigmented deposits. Conjunctival biopsy showed dilated lymph channels with interstitial proteinaceous material of a light brown color consistent with Ochronotic pigment; hence diagnostic of Alkaptonuria. CONCLUSIONS: Pseudofilariasis may be a presenting sign of Alkaptonuria and occur years before a clinical diagnosis is made. Filariasis is always involves white worms and never black. Knowing the ophthalmic signs of this rare disease may lead to an accurate diagnosis earlier thusly avoiding unnecessary tests and examinations.

A quadriphasic mechanical model of the human dermis.

The present study investigates the multiphasic nature of the mechanical behavior of human dermis. Motivated by experimental observations and by consideration of its composition, a quadriphasic model of the dermis is proposed, distinguishing solid matrix components, interstitial fluid and charged constituents moving within the fluid, i.e., anions and cations. Compression and tensile experiments with and without change of osmolarity of the bath are performed to characterize the chemo-mechanical coupling in the dermis. Model parameters are determined through inverse analysis. The computations predict a dominant role of the permeability in the determination of the temporal evolution of the mechanical response of the tissue. In line with the previous studies on other tissues, the analysis shows that an ideal model based on Donnan's equilibrium overestimates the osmotic pressure in skin for the case of very dilute solutions. The quadriphasic model is applied to predict changes in dermal cell environment and therefore alterations in what is called the "mechanome," associated with skin stretch. The simulations indicate that skin deformation causes a variation in several local variables, including in particular the electric field associated with a deformation-induced non-homogeneous distribution of fixed charges.

A Bioinspired and Cost-Effective Device for Minimally Invasive Blood Sampling.

Conventional venipuncture is invasive and challenging in low and middle-income countries. Conversely, point-of-care devices paired with fingersticks, although less invasive, suffer from high variability and low blood volume collection. Recently approved microsampling devices address some of these issues but remain cost-prohibitive for resource-limited settings. In this work, a cost-effective microsampling device is described for the collection of liquid blood with minimal invasiveness and sufficient volume retrieval for laboratory analyses or immediate point-of-care testing. Inspired by the anatomy of sanguivorous leeches, the single-use device features a storage compartment for blood collection and a microneedle patch hidden within a suction cup. Finite Element Method simulations, corroborated by mechanical analyses, guide the material selection for device fabrication and design optimization. In piglets, the device successfully collects ≈195 µL of blood with minimal invasiveness. Additionally, a tailor-made lid and adapter enable safe fluid transportation and integration with commercially available point-of-care systems for on-site analyses, respectively. Taken together, the proposed platform holds significant promise for enhancing healthcare in the pediatric population by improving patient compliance and reducing the risk of needlestick injuries through concealed microneedles. Most importantly, given its cost-effective fabrication, the open-source microsampling device may have a meaningful impact in resource-limited healthcare settings.

Enhancing Kidney Transplantation and the Role of Xenografts: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Chronic kidney disease affects an estimated 37 million people in the United States; of these,>800,000 have end-stage renal disease requiring chronic dialysis or a kidney transplant to survive. Despite efforts to increase the donor kidney supply, approximately 100,000 people are registered on the kidney transplant wait-list with no measurable decrease over the past 2 decades. The outcomes of kidney transplantation are significantly better than for chronic dialysis: kidney transplant recipients have lower rates of mortality and cardiovascular events and better quality of life, but wait-list time matters. Time on dialysis waiting for a deceased-donor kidney is a strong independent risk factor for outcomes after a kidney transplant. Deceased-donor recipients with wait-list times on dialysis of<6 months have graft survival rates equivalent to living-donor recipients with waitlist times on dialysis of>2 years. In 2021,>12,000 people had been on the kidney transplant waitlist for ≥5 years. As the gap between the demand for and availability of donor kidneys for allotransplantation continues to widen, alternative strategies are needed to provide a stable, sufficient, and timely supply. A strategy that is gaining momentum toward clinical application is pig-to-human kidney xenotransplantation. This report summarizes the proceedings of a meeting convened on April 11-12, 2022, by the National Kidney Foundation to review and assess the state of pig-to-human kidney xenotransplantation as a potential cure for end-stage renal disease.

Sustained Physiological Stretch Induces Abdominal Skin Growth in Pregnancy.

Supraphysiological stretches are exploited in skin expanders to induce tissue growth for autologous implants. As pregnancy is associated with large levels of sustained stretch, we investigated whether skin growth occurs in pregnancy. Therefore, we combined a mechanical model of skin and the observations from suction experiments on several body locations of five pregnant women at different gestational ages. The measurements show a continuous increase in stiffness, with the largest change observed during the last trimester. A comparison with numerical simulations indicates that the measured increase in skin stiffness is far below the level expected for the corresponding deformation of abdominal skin. A new set of simulations accounting for growth could rationalize all observations. The predicted amount of tissue growth corresponds to approximately 40% area increase before delivery. The results of the simulations also offered the opportunity to investigate the biophysical cues present in abdominal skin along gestation and to compare them with those arising in skin expanders. Alterations of the skin mechanome were quantified, including tissue stiffness, hydrostatic and osmotic pressure of the interstitial fluid, its flow velocity and electrical potential. The comparison between pregnancy and skin expansion highlights similarities as well as differences possibly influencing growth and remodeling.

Radial matrix constraint influences tissue contraction and promotes maturation of bi-layered skin equivalents.

Human skin equivalents (HSEs) serve as important tools for mechanistic studies with human skin cells, drug discovery, pre-clinical applications in the field of tissue engineering and for skin transplantation on skin defects. Besides the cellular and extracellular matrix (ECM) components used for HSEs, physical constraints applied on the scaffold during HSEs maturation influence tissue organization, functionality, and homogeneity. In this study, we introduce a 3D-printed culture insert that exposes bi-layered HSEs to a static radial constraint through matrix adhesion. We examine the effect of various diameters of the ring-shaped culture insert on the HSE's characteristics and compare them to state-of-the-art unconstrained and planar constrained HSEs. We show that radial matrix constraint of HSEs regulates tissue contraction, promotes fibroblast and matrix organization that is similar to human skin in vivo and improves keratinocyte differentiation, epidermal stratification, and basement membrane formation depending on the culture insert diameter. Together, these data demonstrate that the degree of HSE's contraction is an important design consideration in skin tissue engineering. Therefore, this study can help to mimic various in vivo skin conditions and to increase the control of relevant tissue properties.

Xenotransplantation and exotransplantation: Strategies to expand the number of donor organs.

Cardiovascular disease is common and has a high mortality. Due to the limited number of organs available for orthotopic heart transplantation, alternative therapies have received intense interest. In this commentary we contrast xenotransplantation and blastocyst complementation to produce pigs that will serve as donors for organ transplantation. These strategies hold tremendous promise and have the potential to provide an unlimited number of organs for chronic, terminal diseases.

Experiences and Perceptions of Distinct Telehealth Delivery Models for Remote Patient Monitoring among Older Adults in the Community.

Three major telehealth delivery models-home-based, community-based, and telephone-based-have been adopted to enable remote patient monitoring of older adults to improve patient experience and reduce healthcare costs. Even though prior work has evaluated each of these delivery models, we know less about the perceptions and user experiences across these telehealth delivery models for older adults. In the present work, we addressed this research gap by interviewing 16 older adults who had experience using all these telehealth delivery models. We found that the community-based telehealth model with in-person interactions was perceived as the most preferred and useful program, followed by home-based and telephone-based models. Persistent needs reported by participants included ease of access to their historical physiological data, useful educational information for health self-management, and additional health status tracking. Our findings will inform the design and deployment of telehealth technology for vulnerable aging populations.

Progress in xenotransplantation: overcoming immune barriers.

A major limitation of organ allotransplantation is the insufficient supply of donor organs. Consequently, thousands of patients die every year while waiting for a transplant. Progress in xenotransplantation that has permitted pig organ graft survivals of years in non-human primates has led to renewed excitement about the potential of this approach to alleviate the organ shortage. In 2022, the first pig-to-human heart transplant was performed on a compassionate use basis, and xenotransplantation experiments using pig kidneys in deceased human recipients provided encouraging data. Many advances in xenotransplantation have resulted from improvements in the ability to genetically modify pigs using CRISPR-Cas9 and other methodologies. Gene editing has the capacity to generate pig organs that more closely resemble those of humans and are hence more physiologically compatible and less prone to rejection. Despite such modifications, immune responses to xenografts remain powerful and multi-faceted, involving innate immune components that do not attack allografts. Thus, the induction of innate and adaptive immune tolerance to prevent rejection while preserving the capacity of the immune system to protect the recipient and the graft from infection is desirable to enable clinical xenotransplantation.

Varenicline for Tobacco-Dependent Adults Who Are Not Ready to Discontinue Use: A Systematic Review and Meta-Analysis.

Rationale: Not all individuals with tobacco dependence are ready to give up smoking. Research reveals behavioral differences between adults ready to discontinue tobacco use and those who are not. Thus, the interventions applied to these populations might differ. However, the evidence of using varenicline in individuals who are not ready to discontinue tobacco use is uncertain. Objectives: To determine if, in tobacco-dependent adults who report not being ready to discontinue tobacco use, clinicians should begin treatment with varenicline or wait until subjects are ready to discontinue tobacco use. Methods: We conducted a systematic review to assess the effectiveness and safety of treatment with varenicline in tobacco-dependent adults who are not ready to discontinue tobacco use. We systematically searched the Cumulative Index to Nursing and Allied Health Literature, Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials comparing varenicline versus placebo for individuals who were not ready to discontinue tobacco use. Outcomes of interest include point prevalence abstinence during treatment or at six months or longer, smoking reduction, motivation to quit, adverse events, and withdrawal symptoms. Two authors independently extracted data and assessed eligibility and risk of bias using a standardized data collection form. We followed the Grading of Recommendations, Assessment, Development and Evaluations approach to assess the certainty of evidence. Results: Five trials met our inclusion criteria. All 2,616 participants were adults who were not ready to discontinue tobacco use at study entry. For 7-day point prevalence abstinence at six months or longer, high-certainty evidence suggested that varenicline increased abstinence compared with placebo (relative risk, 2.00 [95% confidence interval (CI), 1.70-2.35]; absolute risk reduction, 173 more per 1,000 [95% CI, 121 more to 234 more]). We identified moderate-certainty evidence suggesting that varenicline increased serious adverse events (relative risk, 1.75 [95% CI, 0.98-3.13]; absolute risk reduction, 12 more per 1,000 [95% CI, 0 fewer to 35 more]). For withdrawal, low-certainty evidence suggested that varenicline treatment was associated with a lower symptom score (mean difference, 1.54 points lower; 95% CI, 2.15-0.93 points lower; low certainty) assessed using the Brief Questionnaire of Smoking Urges. Conclusions: In tobacco-dependent adults who are not ready to discontinue tobacco use, initiating varenicline treatment results in a large increase in abstinence and likely results in a slight increase in serious adverse events.

Human muscle in gene edited pigs for treatment of volumetric muscle loss.

Focusing on complex extremity trauma and volumetric muscle loss (VML) injuries, this review highlights: 1) the current pathophysiologic limitations of the injury sequela; 2) the gene editing strategy of the pig as a model that provides a novel treatment approach; 3) the notion that human skeletal muscle derived from gene edited, humanized pigs provides a groundbreaking treatment option; and 4) the impact of this technologic platform and how it will advance to far more multifaceted applications. This review seeks to shed insights on a novel treatment option using gene edited pigs as a platform which is necessary to overcome the clinical challenges and limitations in the field.

Mechanisms and strategies to promote cardiac xenotransplantation.

End stage heart failure is a terminal disease, and the only curative therapy is orthotopic heart transplantation. Due to limited organ availability, alternative strategies have received intense interest for treatment of patients with advanced heart failure. Recent studies using gene-edited porcine organs suggest that cardiac xenotransplantation may provide a future source of organs. In this review, we highlight the historical milestones for cardiac xenotransplantation and the gene editing strategies designed to overcome immunological barriers, which have culminated in a recent cardiac pig-to-human xenotransplant. We also discuss recent results of studies on the engineering of human-porcine chimeric organs that may provide an alternative and complementary strategy to overcome some of the major immunological barriers to producing a new source of transplantable organs.

PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes.

Pluripotent stem-cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease, but they are functionally and structurally immature. Here, we induce efficient human PSC-CM (hPSC-CM) maturation through metabolic-pathway modulations. Specifically, we find that peroxisome-proliferator-associated receptor (PPAR) signaling regulates glycolysis and fatty acid oxidation (FAO) in an isoform-specific manner. While PPARalpha (PPARa) is the most active isoform in hPSC-CMs, PPARdelta (PPARd) activation efficiently upregulates the gene regulatory networks underlying FAO, increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation, and augments FAO flux. PPARd activation further increases binucleation, enhances myofibril organization, and improves contractility. Transient lactate exposure, which is frequently used for hPSC-CM purification, induces an independent cardiac maturation program but, when combined with PPARd activation, still enhances oxidative metabolism. In summary, we investigate multiple metabolic modifications in hPSC-CMs and identify a role for PPARd signaling in inducing the metabolic switch from glycolysis to FAO in hPSC-CMs.

The MHC-characterized Miniature Swine: Lessons Learned From a 40-Year Experience in Transplantation.

Over the last 40 y, a specialized herd of miniature swine has been intentionally bred to develop lines of animals homozygous for the swine major histocompatibility complex (MHC), which have facilitated transplantation studies across reproducible MHC and minor antigen mismatch barriers. These MHC-characterized miniature swine (Mc-MS) have been used for the study of novel surgical techniques, various approaches to tolerance induction of solid organ and vascularized composite allografts, as well as studies of the immunobiology of allografts and xenografts. Mc-MS possess characteristics that are highly advantageous to these studies, and their continued use will likely continue to play an important role in bridging "bench-to-cage-to bedside" therapies in the field of transplantation. In this review, we highlight the seminal contributions of the Mc-MS model to the field and analyze their role in the broader context of large animal models in transplantation research.

Older adults' perceptions of community-based telehealth wellness programs: a qualitative study.

As older adult populations rise in the United States, community-based telehealth programs are gaining momentum because of their ability to provide telehealth services for community-dwelling older adults at a lower cost compared to home-based telehealth services. The success of such community-based telehealth programs heavily depends on end-user engagement and acceptance; however, few studies to date have explored these issues. We conducted an interview study with 14 active and 3 inactive participants of a community-based Telehealth Intervention Program for Seniors (TIPS) to examine older individuals' perceived benefits and barriers to participating in community-based telehealth programs as well as strategies to improve those programs. We found that older adults had a positive experience toward the use of telehealth services in a community setting, including benefits like monitoring health status and enabling socialization. There were no perceived barriers about the telehealth program. Aspects that can be improved include facilitating the management and sharing of historical physiological data, providing additional assessments of cognitive and/or mental status, supporting self-education, and enabling more comprehensive health status tracking. We conclude this paper by discussing the implications of our results to the improvement of community-based telehealth programs for low-income, vulnerable aging populations.

Expression of human CD47 in pig glomeruli prevents proteinuria and prolongs graft survival following pig-to-baboon xenotransplantation.

BACKGROUND: Nephrotic syndrome is a common complication of pig-to-baboon kidney xenotransplantation (KXTx) that adversely affects outcomes. We have reported that upregulation of CD80 and down-regulation of SMPDL-3b in glomeruli have an important role in the development of proteinuria following pig-to-baboon KXTx. Recently we found induced expression of human CD47 (hCD47) on endothelial cells and podocytes isolated from hCD47 transgenic (Tg) swine markedly reduced phagocytosis by baboon and human macrophages. These observations led us to hypothesize that transplanting hCD47 Tg porcine kidneys could overcome the incompatibility of the porcine CD47-baboon SIRPα interspecies ligand-receptor interaction and prevent the development of proteinuria following KXTx. METHODS: Ten baboons received pig kidneys with vascularized thymic grafts (n = 8) or intra-bone bone marrow transplants (n = 2). Baboons were divided into three groups (A, B, and C) based on the transgenic expression of hCD47 in GalT-KO pigs. Baboons in Group A received kidney grafts with expression of hCD47 restricted to glomerular cells (n = 2). Baboons in Group B received kidney grafts with high expression of hCD47 on both glomerular and tubular cells of the kidneys (n = 4). Baboons in Group C received kidney grafts with low/no glomerular expression of hCD47, and high expression of hCD47 on renal tubular cells (n = 4). RESULTS: Consistent with this hypothesis, GalT-KO/hCD47 kidney grafts with high expression of hCD47 on glomerular cells developed minimal proteinuria. However, high hCD47 expression in all renal cells including renal tubular cells induced an apparent destructive inflammatory response associated with upregulated thrombospondin-1. This response could be avoided by a short course of weekly anti-IL6R antibody administration, resulting in prolonged survival without proteinuria (mean 170.5 days from 47.8 days). CONCLUSION: Data showed that transgenic expression of hCD47 on glomerular cells in the GalT-KO donor kidneys can prevent xenograft nephropathy, a significant barrier for therapeutic applications of xenotransplantation. The ability to prevent nephrotic syndrome following KXTx overcomes a critical barrier for future clinical applications of KXTx.