A rural doctor's telehealth training program during the COVID-19 pandemic.

INTRODUCTION: In Australia, remote consultations have been used as an adjunct to traditional healthcare delivery during the COVID-19 pandemic using telephone and video techniques with an increase in the use of telephone consultations, and to a lesser extent video consultations, for management of patient conditions, assessment, treatment, monitoring and diagnosis. METHODS: To establish the needs of rural doctors for training in the provision of remote consultations, an online survey of members of the Australian College of Rural and Remote Medicine was undertaken. Subsequently an online scenario-based training program was designed to improve the competencies of members in providing these consultations. The outcomes of this program were analysed using pre- and post-intervention surveys, and qualitative analysis of session recordings. RESULTS: The program improved trainee confidence and competence in providing safe, quality remote consultations, particularly when using video technologies. Competencies in communication, history taking, physical online examination, clinical management and professionalism improved. Trainees adapted their practice because they were then able to manage potential issues, were more aware of the capabilities of telehealth technologies and could assist a health professional, such as a nurse or Aboriginal Health Worker (with the patient) to do an examination. Concerns remained about set-up time, technical quality, privacy, interaction with and examination of patients, and how to assess the severity of conditions. CONCLUSION: The outcomes of the program showed significant improvement in the levels of confidence and competencies required for providing remote consultations using telehealth services. A need remains to improve virtual interactions with patients, and to acquire better technology and financial support for remote consultations. In an environment where government is asking whether remote consultations are appropriate and clinically effective, these findings provide guidance from a professional group of experienced rural practitioners.

Ursolic Acid Induces Beneficial Changes in Skeletal Muscle mRNA Expression and Increases Exercise Participation and Performance in Dogs with Age-Related Muscle Atrophy.

Muscle atrophy and weakness are prevalent and debilitating conditions in dogs that cannot be reliably prevented or treated by current approaches. In non-canine species, the natural dietary compound ursolic acid inhibits molecular mechanisms of muscle atrophy, leading to improvements in muscle health. To begin to translate ursolic acid to canine health, we developed a novel ursolic acid dietary supplement for dogs and confirmed its safety and tolerability in dogs. We then conducted a randomized, placebo-controlled, proof-of-concept efficacy study in older beagles with age-related muscle atrophy, also known as sarcopenia. Animals received placebo or ursolic acid dietary supplements once a day for 60 days. To assess the study's primary outcome, we biopsied the quadriceps muscle and quantified atrophy-associated mRNA expression. Additionally, to determine whether the molecular effects of ursolic acid might have functional correlates consistent with improvements in muscle health, we assessed secondary outcomes of exercise participation and T-maze performance. Importantly, in canine skeletal muscle, ursolic acid inhibited numerous mRNA expression changes that are known to promote muscle atrophy and weakness. Furthermore, ursolic acid significantly improved exercise participation and T-maze performance. These findings identify ursolic acid as a natural dietary compound that inhibits molecular mechanisms of muscle atrophy and improves functional performance in dogs.

Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients: a case series.

Studies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we clinically characterize a case series of patients with COVID-19, who were otherwise healthy, young adults (N = 55; mean age 34.1 ± SD 5.0 years) from 16 Asian, Middle Eastern, and North African countries. Using whole exome sequencing, we identify rare, likely deleterious variants affecting 16 immune-related genes in 17 out of 55 patients (31%), including 7 patients (41% of all carriers or 12.7% of all patients) who harbored multiple such variants mainly in interferon and toll-like receptor genes. Protein network analysis as well as transcriptomic analysis of nasopharyngeal swabs from an independent COVID-19 cohort (N = 50; 42% Asians and 22% Arabs) revealed that most of the altered genes, as identified by whole exome sequencing, and the associated molecular pathways were significantly altered in COVID-19 patients. Genetic variants tended to be associated with mortality, intensive care admission, and ventilation support. Our clinical cases series, genomic and transcriptomic findings suggest a possible role for interferon pathway genes in severe COVID-19 and highlight the importance of extending genetic studies to diverse populations to better understand the human genetics of disease.

Heterozygous gain of function variants in a critical region of RNF13 cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive.

Missense variants in the RNF13 gene have been previously known to cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive through a gain-of-function disease mechanism. Here, we identify a nonsense variant, expected to result in protein truncation, in a similarly affected patient. We show that this nonsense variant, residing in the terminal exon, is likely to escape nonsense-mediated decay while removing a critical region for protein function, thus resulting in a gain-of-function effect. We review the literature and disease databases and identify several other affected individuals with overlapping phenotypes carrying distinct truncating variants in the terminal exon upstream of the putative critical region. Furthermore, we analyze truncating variants from the general population, namely, the Genome Aggregation Database (gnomAD), and provide additional evidence supporting our hypothesis, and ruling out haploinsufficiency as an alternative disease mechanism. In summary, our case report, literature review, and analysis of disease and population databases strongly support the hypothesis that heterozygous gain-of-function variants in a critical region of RNF13 cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive.

Which environmental sample type and statistical approach provides most information about metal exposure in young children from an urban setting?

Identification of sources and pathways is critical in minimizing exposure of young children to toxic materials. We monitored 108 children <5 years old 6-monthly for up to 5 years in a major urban setting. Samples (ñ7000) included interior handwipes (W1) and after exterior playing (W2), interior house dust (PD1) and day care dust (PD2) using petri dishes, exterior dust-fall accumulation, exterior dust sweepings, garden soil, blood and urine. Here we describe multi-element results to determine which sampling method and analysis of the data provide the most reliable indicators of metal exposure to young children. Samples were analysed by ICPMS for Ca, Cd, Cr, Cu, Fe, Mg, Mn, Ni, Pb, Ti, V and Zn. Pearson Correlations showed the highest number of significant correlations are for: W1 and W2, dust sweepings and soil. Mixed model analyses (MMA) for the blood levels as the dependent variable and environmental predictor variables showed the most consistent results were for W1, PD1 and sweepings. MMA to investigate the association between each metal (e.g. Ca) and the other 11 metals showed the largest numbers of significant relationships are for W1 and sweepings. Cluster analyses showed that the 'best' clusters in W1 and W2 are for Fe-Zn-Mg and Mn-Pb-Ni. For PD1 and PD2 the 'best' clusters were Fe-Zn-Mg, Cr-Ni-Ti, and Cu-Mn-Pb. Clusters for dust sweepings and soil are generally similar. Principal component analysis (PCA) loadings for W1 and PD1 accounted for >50% of the variance. Metals comprising loading 1 component for both sample types included Ca, Fe, Mg, and Mn. Overall cluster analyses provided more information than PCA loadings. In summary: The most suitable methods and analyses are MMA of W1 and sweepings, and cluster analyses of W1and PD1. Resuspension from outdoor surfaces and soils and deposition in the residences is a likely pathway for most metals.

Recognition of Prodromal Hypoglossal Nerve Palsy Presenting with Neck Pain as Primary Complaint: Findings from a Rare Case Report in Direct Access Physiotherapy during the COVID-19 Pandemic.

Neck pain (NP) is the second most common musculoskeletal disorder. Spinal cysts (SCs) are cystic dilatations of the synovial sheaths in joints and tendons. SCs are extremely rare in the cervical spine. Typically, patients are unaware of having an SC due to its asymptomatic nature; however, when cervical SC extends, its volume could compress the surrounding structures, such as the hypoglossal nerve. Isolated hypoglossal nerve palsy (HNP) is very rare and typically presents with unilateral atrophy of the musculature of the tongue and contralateral tongue deviation. Often, patients with HNP also report occipital/neck pain. A 75-year-old man with occipital/neck pain as a primary complaint. Although difficult to observe because of the filtering facepiece two mask, difficulties in articulation and sialorrhea during the interview were noticed. These latter were cues to consider CN examination that revealed CN XII palsy. This prompted a referral for further examination that revealed an SC compressing the right hypoglossal canal. The patient was not considered a surgical candidate and was managed conservatively. This case report outlines the relevant findings relating to the triage of a rare isolated hypoglossal nerve palsy from the physiotherapist's perspective within a complex setting because of the COVID-19 pandemic. Although referred with a diagnosis of cervical radiculopathy, our case highlights that skilled physiotherapists may play a fundamental role in both the recognition and, when applicable, subsequent novel management of a non-musculoskeletal presentation.

A guide to identify cervical autonomic dysfunctions (and associated conditions) in patients with musculoskeletal disorders in physical therapy practice.

BACKGROUND: Differential diagnosis is a hot topic in physical therapy, especially for those working in a direct access setting dealing with neck pain and its associated disorders. All international guidelines agree in recommending to first rule out non-musculoskeletal pathologies as the cause of signs and symptoms in the patient. Although the autonomic nervous system (ANS) has a crucial role and is also involved in pain conditions, coverage of it in neuroscience textbooks and educational programmes is limited and most healthcare professionals are unfamiliar with it. Although autonomic conditions are benign in nature, they are clinically of great importance as they may be a 'red flag' warning of an injury along the sympathetic pathway. Therefore, sound knowledge of the ANS system is essential for clinicians. OBJECTIVE: To develop physical therapists' knowledge of and confidence in understanding cervical ANS function and dysfunction, thus enhancing clinical reasoning skills and the pattern recognition process, and performing and interpreting objective examinations. METHODS: This master class provides an introductory guide and essential knowledge to facilitate clinicians to understand cervical autonomic dysfunctions and their clinical evaluation. The optimal referral method is also handled. CONCLUSIONS: Gaining knowledge and understanding of the ANS, its function, its dysfunction, and the related clinical manifestations is likely to lead to a decision-making process driven by 'science and conscience'. This will empower physical therapists to be aware of subtle clues that may be offered by patients during the interview and history intake leading to the appropriate physical examination and triage.

Vascular flow limitations affecting the cervico-cranial region: Understanding ischaemia.

BACKGROUND: Blood flow and brain ischaemia have been of interest to physical therapists for decades. Despite much debate, and multiple publications around risk assessment of the cervical spine, more work is required to achieve consensus on this vital, complex topic. In 2020, the International Federation of Orthopaedic Manipulative Physical Therapists (IFOMPT) Cervical Framework adopted the dubious terminology 'vascular pathologies of the neck', which is misleading, on the premise that 1) not all flow limitations leading to ischaemia, are associated with observable blood vessel pathology and 2) not all blood flow limitations leading to ischaemia, are in the anatomical region of the 'neck'. OBJECTIVE: This paper draws upon the full body of haemodynamic knowledge and science, to describe the variety of arterial flow limitations affecting the cervico-cranial region. DISCUSSION: It is the authors' contention that to apply clinical reasoning and appropriate risk assessment of the cervical spine, there is a requirement for clinicians to have a clear understanding of anatomy/anatomical relations, the haemodynamic science of vascular flow limitation, and related pathologies. This paper describes the wide range of presentations and haemodynamic mechanisms that clinicians may encounter in practice. In cases with a high index suspicion of vascular involvement or an adverse response to assessment/intervention, appropriate referral should be made for further investigations, using consistent terminology. The term 'vascular flow limitation' is proposed when considering the range of mechanisms at play. This fits the terminology used (in vascular literature) at other anatomical sites and is understood by medical colleagues.

Reduced fire severity offers near-term buffer to climate-driven declines in conifer resilience across the western United States.

Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration.

Evaluation of a biodegradable polyurethane patch for repair of diaphragmatic hernia in a rat model: A pilot study.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) repair is an area of active research. Large defects requiring patches have a hernia recurrence rate of up to 50%. We designed a biodegradable polyurethane (PU)-based elastic patch that matches the mechanical properties of native diaphragm muscle. We compared the PU patch to a non-biodegradable Gore-Tex™ (polytetrafluoroethylene) patch. METHODS: The biodegradable polyurethane was synthesized from polycaprolactone, hexadiisocyanate and putrescine, and then processed into fibrous PU patches by electrospinning. Rats underwent 4 mm diaphragmatic hernia (DH) creation via laparotomy followed by immediate repair with Gore-Tex™ (n = 6) or PU (n = 6) patches. Six rats underwent sham laparotomy without DH creation/repair. Diaphragm function was evaluated by fluoroscopy at 1 and 4 weeks. At 4 weeks, animals underwent gross inspection for recurrence and histologic evaluation for inflammatory reaction to the patch materials. RESULTS: There were no hernia recurrences in either cohort. Gore-Tex™ had limited diaphragm rise compared to sham at 4 weeks (1.3 mm vs 2.9 mm, p = 0.003), but no difference was found between PU and sham (1.7 mm vs 2.9 mm, p = 0.09). There were no differences between PU and Gore-Tex™ at any time point. Both patches formed an inflammatory capsule, with similar thicknesses between cohorts on the abdominal (Gore-Tex™ 0.07 mm vs. PU 0.13 mm, p = 0.39) and thoracic (Gore-Tex™ 0.3 mm vs. PU 0.6 mm, p = 0.09) sides. CONCLUSION: The biodegradable PU patch allowed for similar diaphragmatic excursion compared to control animals. There were similar inflammatory responses to both patches. Further work is needed to evaluate long-term functional outcomes and further optimize the properties of the novel PU patch in vitro and in vivo. LEVEL OF EVIDENCE: Level II, Prospective Comparative Study.

The genomic landscape of rare disorders in the Middle East.

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant. RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

What to Look Out for, What to Do, and When: 3 Key Messages for Safely Treating Neck Pain, Headache, and/or Orofacial Symptoms in Musculoskeletal Rehabilitation Settings.

SYNOPSIS: Neck pain, headache, and/or orofacial symptoms are potentially the first (nonischemic) symptoms of an underlying vascular pathology or blood flow limitation. If an underlying vascular pathology or blood flow limitation is not recognized by the musculoskeletal rehabilitation clinician, it can subsequently be aggravated by treatment, raising the risk of serious adverse events. We argue that clinicians can make an important, and potentially lifesaving, difference by providing specific information and advice. This is especially the case in patients with an intermediate level of concern, for example, in patients who only show a few concerning features regarding a possible underlying serious condition and for whom an initial vasculogenic hypothesis was rejected during the clinical reasoning process. We present background information to help the reader understand the context of the problem and suggestions for how clinicians can provide appropriate information and advice to patients who present with neck pain, headache, and/or orofacial symptoms. J Orthop Sports Phys Ther 2023;53(2):59-63. Epub: 28 October 2022. doi:10.2519/jospt.2022.11568.

Health professionals' views of medical teleconsultation uptake in the Brazilian Unified Health System: A description using the NASSS framework.

BACKGROUND: The COVID-19 pandemic accelerated efforts to deploy and regulate medical teleconsultation in Brazil. Studying the Brazilian Unified Public Health System (SUS) experiences in implementing teleconsultations can help to inform their sustainability. This study identifies the changes required to integrate specialized teleconsultation in local workflows in SUS. METHODS: A case study of teleconsultation performed by a University Hospital and a Municipal Specialty Outpatient Clinic in the south of Brazil collected information from two focus groups with specialised doctors, two key informant interviews and associated documents. The Non-adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework domains of condition, technology, proposal value, users and organization informed a qualitative thematic analysis of this data. RESULTS: Several forms of teleconsultation were used to manage paediatrics and endocrine conditions including instant messaging, WhatsApp, telephone calls and video consultations which were also used for dermatology. In Brazil, telephone interactions are not considered teleconsultation. In contrast, video consultations were longer than face-to-face appointments, facilitate the understanding and evaluation of conditions, and offered continuity of care, comfort, and safety, without the need for patients to travel, reducing the risk of infection. Patients accepted video consultations to varying degrees but some found it difficult to use the technology. The willingness of doctors to provide any form of teleconsultation was important. Management support was key to defining workflows, coordinating care pathways, and providing technical support. CONCLUSIONS: This study highlights particularities of teleconsultation uptake for the included specialities. The NASSS framework provides a useful means of identifying the changes to enable teleconsultation continuity for specialised care in SUS.

Public and manager perceptions about prescribed fire in the Mid-Atlantic, United States.

Firescapes of the Mid-Atlantic are understudied compared to other ecosystems in the United States, and little is known about the acceptance of prescribed fire as a forest management tool. Yet, this region harbors high levels of wildland-urban interface (WUI), has a close intermingling of land ownerships, and reflects substantial regional heterogeneity in burning histories and fire hazards. As prescribed fire is increasingly applied in the Mid-Atlantic as a critical tool to meet various land management objectives, research is needed to help managers understand community perceptions of prescribed fire implementation. Through intercept surveys of forest recreationists and online surveys of fire managers, this study investigates perceptions about prescribed fire use in the Mid-Atlantic, in addition to the critical contributing factors of public support toward prescribed fires. Two states, Pennsylvania and New Jersey, were selected as case studies to explore regional differences in social perception due to their contrasts in fire history, policy, management objectives, and social exposure. Our results show moderate social awareness of local prescribed fires, moderate to high familiarity with prescribed burning, high agency trust, and strong community support toward prescribed fires. However, the perceived concerns and benefits differed between managers and forest recreationists and between recreationists from Pennsylvania and New Jersey. The factors influencing the support of prescribed burning practices included forest management beliefs, concern about prescribed fire effects, familiarity with prescribed fires as a forest management tool, and awareness of local prescribed fires. Collectively, these results highlighted needs in public outreach to strengthen education, build broader community awareness, engage critical stakeholder groups such as forest recreationists, and re-align public outreach messages based on community-level concerns and perceived benefits. Additionally, it will be vital for the scientific community to help monitor critical shifts in forest value orientations and fill in significant research gaps regarding prescribed fire benefits.

Knowledge, beliefs, and attitudes of spinal manipulation: a cross-sectional survey of Italian physiotherapists.

BACKGROUND AND OBJECTIVE: High-velocity low-amplitude thrust spinal manipulation (SM) is a recommended and commonly used manual therapy intervention in physiotherapy. Beliefs surrounding the safety and effectiveness of SM have challenged its use, and even advocated for its abandonment. Our study aimed to investigate the knowledge and beliefs surrounding SM by Italian physiotherapists compared with similar practitioners in other countries. METHODS: An online survey with 41 questions was adapted from previous surveys and was distributed via a mailing list of the Italian Physiotherapists Association (March 22-26, 2020). The questionnaire was divided into 4 sections to capture information on participant demographics, utilization, potential barriers, and knowledge about SM. Questions were differentiated between spinal regions. Attitudes towards different spinal regions, attributes associated with beliefs, and the influence of previous educational background were each evaluated. RESULTS: Of the 7398 registered physiotherapists, 575 (7.8%) completed the survey and were included for analysis. The majority of respondents perceived SM as safe and effective when applied to the thoracic (74.1%) and lumbar (72.2%) spines; whereas, a smaller proportion viewed SM to the upper cervical spine (56.8%) as safe and effective. Respondents reported they were less likely to provide and feel comfortable with upper cervical SM (respectively, 27.5% and 48.5%) compared to the thoracic (respectively, 52.2% and 74.8%) and lumbar spines (respectively, 46.3% and 74.3%). Most physiotherapists (70.4%) agreed they would perform additional screening prior to upper cervical SM compared to other spinal regions. Respondents who were aware of clinical prediction rules were more likely to report being comfortable with SM (OR 2.38-3.69) and to perceive it as safe (OR 1.75-3.12). Finally, physiotherapists without musculoskeletal specialization, especially those with a traditional manual therapy background, were more likely to perform additional screening prior to SM, use SM less frequently, report being less comfortable performing SM, and report upper cervical SM as less safe (p < 0.001). DISCUSSION: The beliefs and attitudes of physiotherapists surrounding the use of SM are significantly different when comparing the upper cervical spine to other spinal regions. An educational background in traditional manual therapy significantly influences beliefs and attitudes. We propose an updated framework on evidence-based SM.

Implementation of the International IFOMPT Cervical Framework: A survey among educational programmes.

BACKGROUND: Orthopaedic Manual Therapy (OMT) is a specialized area of physiotherapy for the management of neuromusculoskeletal conditions. Although rare, adverse events after OMT are reported in literature. In 2020, the International Framework for Examination of the Cervical Region for potential of vascular pathologies of the neck prior to OMT Intervention was presented. OBJECTIVE: To evaluate the knowledge and implementation status of OMT educational programmes regarding the 2020 International IFOMPT Cervical Framework. METHODS: An international survey with closed- and open-ended questions was conducted among all IFOMPT educational programmes using an online survey. Formal informed consent was requested at the beginning of the survey and all data were collected anonymously. RESULTS: Thirty-nine educational programmes filled in the survey. Twenty-four programmes (61.5%) had already implemented the new Framework. Four programmes (10.3%) answered that they will not implement the new Framework in their educational programme. Positional testing will be kept in about 54% of the programmes. Craniovertebral ligament testing will be kept in about 90% of the programmes. A considerable number of educational programmes still teach end range manipulations in the middle and lower cervical spine (33.3%) and upper cervical spine (25.5%). CONCLUSIONS: The dissemination and implementation of the International IFOMPT Cervical Framework among educational programmes has been successful. However, although positional testing and craniovertebral ligament testing are excluded from the Framework, most educational programmes will keep these tests in their curriculum, which raises some concern regarding the success and impact of international consensus frameworks.

ISO/IEC-Standards on Quality and Safety of Telehealth Services and Mobile Medical Apps.

This paper investigates consistency of ISO/IEC-standards on quality and safety of telehealth services and mobile medical apps. Since mobile medical apps are 'software as a medical device', requirements for these apps are in software standards, in particular health software standards, as well as in medical device standards. These requirements were analyzed within an analysis model that has three domains: quality and safety management, core healthcare processes and resources. Telehealth services are healthcare processes and mobile medical apps are resources. There is good alignment of the standards that pertain to quality and safety management, the healthcare processes and medical devices. However, there is a lack of alignment, consistency and transparency of the ISO/IEC-standards on quality and safety of telehealth services and mobile medical apps. An international effort to address these issues is recommended.

Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy.

Genome editing holds great potential for cancer treatment due to the ability to precisely inactivate or repair cancer-related genes. However, delivery of CRISPR/Cas to solid tumours for efficient cancer therapy remains challenging. Here we targeted tumour tissue mechanics via a multiplexed dendrimer lipid nanoparticle (LNP) approach involving co-delivery of focal adhesion kinase (FAK) siRNA, Cas9 mRNA and sgRNA (siFAK + CRISPR-LNPs) to enable tumour delivery and enhance gene-editing efficacy. We show that gene editing was enhanced >10-fold in tumour spheroids due to increased cellular uptake and tumour penetration of nanoparticles mediated by FAK-knockdown. siFAK + CRISPR-PD-L1-LNPs reduced extracellular matrix stiffness and efficiently disrupted PD-L1 expression by CRISPR/Cas gene editing, which significantly inhibited tumour growth and metastasis in four mouse models of cancer. Overall, we provide evidence that modulating the stiffness of tumour tissue can enhance gene editing in tumours, which offers a new strategy for synergistic LNPs and other nanoparticle systems to treat cancer using gene editing.

Rapid whole genome sequencing of critically ill pediatric patients from genetically underrepresented populations.

We describe a case series of five infants (age range: 1-90 days; 4 females and 1 male) who presented to Al Jalila Children's intensive care units (ICU) with complex multisystem disorders. Patients were Emirati, Kenyan, Jordanian, Filipino, or Pakistani. Trio rapid whole genome sequencing (rWGS) was performed on all five patients and their parents within the hospital's genomics facility. Results were returned within ~37 h from blood sample draws and were diagnostic in 3 out of 5 patients. Positive findings were a homozygous pathogenic variant in POMT1 gene causing muscular dystrophydystroglycanopathy, a mosaic tetrasomy of the short arm of chromosome 12 (12p13.33p11.1) causing Pallister-Killian syndrome, and compound heterozygous pathogenic variants in the LIPA gene causing lysosomal acid lipase deficiency and Wolman disease. The rWGS analysis provided fast and precise diagnostic findings in those 3 patients and also aided in devising better management plans for them in the intensive care setting. For example, the 3-month-old infant with pathogenic variants in the LIPA gene is now a candidate for an FDA-approved, potentially lifesaving enzyme replacement therapy (sebelipase alfa). Our case series emphasize the feasibility and utility of rWGS in pediatric intensive care setting, in a diverse population that has long been underserved in genomic services. Significant investments in local healthcare infrastructure are needed, globally, for more equitable access of genomic medicine among vulnerable patients.