TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions  in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin's benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.

Benchmarking mismatch repair testing for patients with cancer receiving immunotherapy.

Immunohistochemistry (IHC) is currently the first-line test for mismatch repair deficiency (MMR-D). Bou Farhat et al. show that mismatch repair (MMR) mutation signature by next-generation sequencing is a highly sensitive assay capable of detecting MMR-D cases that are missed in 1% and 5% of patients with MMR-D colorectal cancer (CRC) and endometrial cancer (EC), respectively. Patients with MMR-D tumors missed by IHC have similar clinical outcomes to patients with MMR-D by both IHC and mutation signature.

Virtual reality for healthcare: A scoping review of commercially available applications for head-mounted displays.

Objective: This scoping review aimed to describe the scope of commercially available virtual reality (VR) healthcare applications for mainstream head-mounted displays (HMD)s. Methods: A search was conducted during late April and early May 2022 over five major VR app stores using "health," "healthcare," "medicine," and "medical" as keywords. Apps were screened based on their title and description sections. Metadata collected included: title, description, release date, price (free or paid), multilingual support, VR app store availability, and HMD support. Results: The search yielded 1995 apps, out of which 60 met the inclusion criteria. The analysis showed that the number of healthcare VR apps has been steadily increasing since 2016, but no developer has released more than two apps so far. Most of the reviewed apps can run on HTC Vive, Oculus Quest, and Valve Index. Thirty-four (56.7%) apps had a free version, and 12 (20%) apps were multilingual, i.e., supported languages other than English. The reviewed apps fell into eight major themes: life science education (3D anatomy, physiology and pathology, biochemistry, and genetics); rehabilitation (physical, mental, and phobia therapy); public health training (safety, life-saving skills, and management); medical training (surgical and patient simulators); role-playing as a patient; 3D medical imagery viewing; children's health; and online health communities. Conclusions: Although commercial healthcare VR is still in its early phases, end-users can already access a broad range of healthcare VR apps on mainstream HMDs. Further research is needed to assess the usefulness and usability of existing apps.

Cost of bladder cancer in Lebanon before and after the economic collapse: a probabilistic modeling study.

BACKGROUND AND OBJECTIVES: Lebanon has one of the highest incidence rates of bladder cancer (BC) in the world. In 2019, Lebanon's economy collapsed which majorly impacted healthcare costs and coverage. This study assesses the overall direct costs of urothelial BC in Lebanon, from the perspective of public and private third-party payers (TPP) and households, and evaluates the impact of the economic collapse on these costs. METHODS: This was a quantitative, incidence-based cost-of-illness study, conducted using a macro-costing approach. Costs of medical procedures were obtained from the records of various TPPs and the Ministry of Public Health. We modeled the clinical management processes for each stage of BC, and conducted probabilistic sensitivity analyses to estimate and compare the cost of each stage, pre-and post-collapse, and for each payer category. RESULTS: Before the collapse, the total annual cost of BC in Lebanon was estimated at LBP 19,676,494,000 (USD 13,117,662). Post-collapse, the total annual cost of BC in Lebanon increased by 768% and was estimated at LBP 170,727,187,000 (USD 7,422,921). TPP payments increased by 61% whereas out-of-pocket (OOP) payments increased by 2,745% resulting in a decrease in TPP coverage to only 17% of total costs. CONCLUSION: Our study shows that BC in Lebanon constitutes a significant economic burden costing 0.32% of total health expenditures. The economic collapse induced an increase of 768% in the total annual cost, and a catastrophic increase in OOP payments.

Analysis of ASS1 gene in ten unrelated middle eastern families with citrullinemia type 1 identifies rare and novel variants.

BACKGROUND: Citrullinemia type 1 (CTLN1) is a rare autosomal recessive disease caused by argininosuccinate synthetase (ASS) deficiency. Manifestations vary from the acute neonatal or "classic" form to a milder, late-onset, or "unconventional" form. To date, more than 93 variants in the ASS1 gene located on chromosome 9q43.11 (OMIM #215700) are reportedly responsible for CTLN1. Their incidence and distribution vary according to geographic origins and ethnicity, and a correlation, although not clearly delineated, has been established between the genotype and the phenotype of the disease. Though, in the Middle East, national descriptions of CTLN1 are still lacking. METHODS: A total of ten unrelated Middle Eastern families, five Lebanese, two Syrians, and three Iraqis with citrullinemia index cases, were included in this study. Upon informed consent, DNA was extracted from the whole blood of the index patients as well as their parents and siblings. Genetic analysis was carried out by Sanger sequencing of the ASS1 gene. RESULTS: Seven different variants were identified. Two novel variants, c.286C>A (p.(Pro96Thr), RNA not analyzed) in exon 5 and deletion c.685_688+6del(p.(Lys229Glyfs*4), RNA not analyzed) in exon 10, were found in one Lebanese and one Syrian family, respectively, and were correlated with early-onset and severe clinical presentation. Five other known variants: c.535T>C (p.(Trp179Arg), RNA not analyzed) in exon 8, c.787G>A (p.(Val263Met), RNA not analyzed) in exon 12, c.847G>A (p.(Glu283Lys), RNA not analyzed) in exon 13, c.910C>T (p.(Arg304Trp), RNA not analyzed) in exon 13, and c.1168G>A (p.(Gly390Arg), RNA not analyzed) in exon 15, were found in Lebanese, Syrian, and Iraqi families, and were associated with diverse clinical presentations. CONCLUSION: Two novel variants and five known variants were found in a total of ten unrelated Middle Eastern families.

Ensuring Care Continuity in Extreme Crises: A Participatory Action Research Approach.

The Lebanese healthcare system has been facing major challenges due to an unprecedented financial crisis, socio-political instability, and the COVID-19 pandemic. This study aims to examine the impact of overlapping major crises on care continuity and to propose IT-based solutions to address current challenges and build future resilience. To this end, we adopted a participatory action research approach and conducted a two-phase qualitative study - six semi-structured interviews followed by three future workshops with local stakeholders including physicians and interns practicing in Lebanon. Through the interviews, we identified the primary consequences of the crises and the ways they impacted the continuity of care. We also identified adaptation mechanisms used by physicians and patients to ensure continuity of care. Through the future workshops, we identified various IT-based solutions that could be implemented to tackle existing challenges and support local adaptation attempts.

Telehealth in rheumatology: the 2021 Arab League of Rheumatology Best Practice Guidelines.

To develop Best Practice Guidelines (BPG) for the use of Telehealth in Rheumatology in the Arab region, to identify the main barriers and facilitators of telehealth, and to provide rheumatologists with a practical toolkit for the implementation of telehealth. Guidelines were drafted by a core steering committee from the Arab League of Associations for Rheumatology (ArLAR) after performing a literature search. A multidisciplinary task force (TF), including 18 rheumatologists, 2 patients, and 2 regulators from 15 Arab countries, assessed the BPG using 3 rounds of anonymous online voting by modified Delphi process. The statements were included in the final BPG without further voting if ≥ 80% of TF members indicated high agreement. The voting on barriers and facilitators was performed through one voting round. The toolkit was developed based on available literature and discussions during the Delphi rounds. Four General Principles and twelve Statements were formulated. A teleconsultation was specifically defined for the purpose of these guidelines. The concept of choice in telehealth was highlighted, emphasizing patient confidentiality, medical information security, rheumatologist's clinical judgment, and local jurisdictional regulations. The top barrier for telehealth was the concern about the quality of care. The toolkit emphasized technical aspects of teleconsultation and proposed a triage system. The ArLAR BPG provide rheumatologists with a series of strategies about the most reliable, productive, and rational approaches to apply telehealth.