Case series of retinal vein occlusions showing early recovery using oral l-methylfolate.

This case series describes the aggregate rate of recovery in five consecutive subjects (six eyes) with retinal vein occlusion (RVO) who received l-methylfolate and other vitamins via Ocufolin®, a medical food. Subjects were followed for 10-33 months by a single ophthalmologist. Ocufolin® was prescribed at the time of diagnosis and subjects remained on the regimen throughout the time of observation. Examinations were performed in an un-masked fashion at 3-month intervals with recording of best corrected visual acuity (BCVA), average retinal nerve fiber layer (ARNFL) and central macular thickness (CMT), and fundus (examination of the retina, macula, optic nerve, and vessels) photography. Testing was done for vitamin deficiencies, vascular and coagulable risk factors, and methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Vitamin deficiencies and vascular risk factors were found in all subjects, and all four tested subjects carried at least one MTHFR polymorphism. By the end of the study period BCVA in all subjects was 20/25 or better. Cystoid macular edema was identified and measured by optical coherence tomography (OCT). The percent change was calculated and plotted at 3-month intervals using the percent change in thickness from the time of diagnosis and percent change toward normative values for ARNFL and CMT. The total reduction in thickness of ARNFL and CMT from time of diagnosis was 44.19% and 30.27%, respectively. The comparison to normative data shows a reduction of ARNFL from 164.2% to 94% and CMT from 154.4% to 112.7% of normal thickness (100%). Plots showed the aggregate recovery was most rapid over the first 3 months and slowed over the next 3 months with most of the recovery taking place within 6 months of treatment. The rate of improvement in BCVA and resolution of retinal thickening was found to be better than predicted on historical grounds. No subjects progressed from nonischemic to ischemic RVO. Vitamin deficiencies, vascular risk factors, and genetic predisposition to oxidative stress were common in this RVO series. It appears that addressing these factors with Ocufolin® had a salutary effect on recovery.

Transforming aged care with virtual reality: How organisational culture impacts technology adoption and sustained uptake.

OBJECTIVES: Virtual reality (VR) is not a common leisure activity in aged care, despite pilot studies demonstrating its value as a tool to combat inactivity and loneliness. This study investigated the organisational enablers and barriers to sustained uptake of VR among aged care staff and organisations, who may lack familiarity or confidence with the technology. METHODS: Creative methods were adopted to co-design and develop a VR implementation toolkit tailored specifically for aged care staff. Three aged care homes in South-East Queensland participated, with 15 residents and seven staff engaging in up to four VR sessions facilitated by the research team. Participant observation of the VR sessions was complemented by interviews with aged care staff and residents. RESULTS: Guided by Normalisation Process Theory, a reflexive thematic analysis identified four key themes: (1) Positively Appreciating the VR Experience, (2) Staff VR Champions and the Importance of Personal Use and Experimentation with VR, (3) Management Support and (4) Technical Challenges. CONCLUSIONS: Our results indicate benefits and challenges of VR use in aged care, offering valuable insights into the factors that can lead to the long-term success of VR-based leisure activities for aged care. Providing time and resources for a VR champion to experiment and learn about the technology is critical. The development of an online implementation toolkit, based on our learning from this project, also provides aged care stakeholders with the evidence-based resources needed to ensure the successful implementation of VR-based leisure programs.

Movement Asymmetries: From Their Molecular Origin to the Analysis of Movement Asymmetries in Athletes.

Asymmetry plays a major role in biology at all scales. This can be seen in the helix of DNA, the fact that the human heart is on the left side, or that most people use their right hand. A single protein such as Myosin 1D can induce helical motion in another molecule. This causes cells, organs, and even entire bodies to twist in a domino effect, causing left-right behaviour. More generally, athlete movements are often asymmetric and, during the physical rehabilitation after injury, the asymmetry is visually discernible. Herein, we review the molecular basis of the movement asymmetries and report on the available knowledge on the few therapeutics investigated so far such as meloxicam. From a more rehabilitative perspective, it is very important to use effective methods to control the process of resolving the injury-related movement asymmetry through the complex use of specialised exercises, measurements, and gait analysis, which can all provide useful information on the effectiveness of the rehabilitation plans. If for each athlete, the normal range of asymmetry is known, the asymmetry can be individually treated and the evolution can be monitored over time. Appropriate measures should be taken if the movement asymmetry is outside this range. In addition, genetic, physiological, and psychological factors relevant to athlete health should be considered in the process of assessing and improving exercise asymmetry, which we also discuss in this review. The main proposal of this work is that the movement asymmetries in athletes should be individually treated, while taking into account the athlete's genetics, physical condition, and previous injuries.

Video Calls as a Replacement for Family Visits During Lockdowns in Aged Care: Interview Study With Family Members.

BACKGROUND: Lockdowns have been used to prevent the spread of transmissible illnesses such as influenza, norovirus, and COVID-19 in care homes. However, lockdowns deny care home residents supplemental care and the socioemotional enrichment that comes from seeing family members. Video calling has the potential to enable ongoing contact between residents and family members during lockdowns. However, video calls can be considered by some as a poor substitute for in-person visits. It is important to understand family members' experiences with video calling during lockdowns to ensure the effective use of this technology in the future. OBJECTIVE: This study aimed to understand how family members use video calls to communicate with relatives living in aged care during lockdowns. We focused on experiences during the COVID-19 pandemic, which involved extensive lockdowns in aged care homes. METHODS: We conducted semistructured interviews with 18 adults who had been using video calls with relatives living in aged care during pandemic lockdowns. The interviews focused on how participants had been using video calls, what benefits they gained from video-based interactions, and what challenges they encountered when using the technology. We analyzed the data using the 6-phase reflexive approach to thematic analysis by Braun and Clarke. RESULTS: We developed 4 themes through our analysis. Theme 1 interprets video calling as a medium for the continuation of care during lockdowns. Using video calls, family members were able to provide social enrichment for residents and engaged in health monitoring to uphold residents' welfare. Theme 2 highlights how video calling extended care by supporting frequent contact, transmitting nonverbal cues that were essential for communication, and negating the need for face masks. Theme 3 interprets organizational issues such as the lack of technology and staff time as impediments to the continuation of familial care through video. Finally, theme 4 highlights the need for 2-way communication, interpreting residents' unfamiliarity with video calling and their health conditions as further barriers to the continuation of care. CONCLUSIONS: This study suggests that, during restrictions arising from the COVID-19 pandemic, video calls became a medium for enabling family members to continue participating in the care of their relatives. The use of video calls to continue care illustrates their value for families during times of mandatory lockdown and supports the use of video to complement face-to-face visits at other times. However, better support is needed for video calling in aged care homes. This study also revealed a need for video calling systems that are designed for the aged care context.

Evaluation of electronic measurement of capillary refill for Sepsis screening at ED triage.

OBJECTIVE: To evaluate the association between capillary refill time (CRT) measured by a medical device and sepsis among patients presenting to the Emergency Department (ED). METHODS: This prospective observational study enrolled adult and pediatric patients during ED triage when sepsis was considered a potential diagnosis by the triage nurse. Patients were enrolled at an academic medical center between December 2020 and June 2022. CRT was measured by a research assistant using an investigational medical device. The outcomes included sepsis and septic shock defined using sep-3 criteria, septic shock defined as IV antibiotics and a vasopressor requirement, ICU admission, and hospital mortality. Other measures included patient demographics and vital signs at ED triage. We evaluated univariate associations between CRT and sepsis outcomes. RESULTS: We enrolled 563 patients in the study, 48 met Sep-3 criteria, 5 met Sep-3 shock criteria, and 11 met prior septic shock criteria (IV antibiotics and vasopressors to maintain mean arterial pressure of 65). Sixteen patients were admitted to the ICU. The mean age was 49.1 years, and 51% of the cohort was female. The device measured CRT was significantly associated with the diagnosis of sepsis by sep-3 criteria (OR 1.23, 95% CI 1.06-1-43), septic shock by sep-3 criteria (OR 1.57, 95% CI 1.02-2.40), and septic shock defined as receipt of IV antibiotics and a vasopressor requirement (OR 1.37, 95% CI 1.03-1.82). Patients with CRT >3.5 s measured by the DCR device had an odds ratio of 4.67 (95%CI 1.31-16.1) of septic shock (prior definition), and an odds ratio of 3.97 (95% CI 1.99-7.92) of ICU admission, supporting the potential for the 3.5-s cutoff of the DCR measurement. CONCLUSIONS: CRT measured by a medical device at ED triage was associated with the diagnosis of sepsis. Objective CRT measurement using a medical device may be a relatively simple way to improve sepsis diagnosis during ED triage.

Respiratory viruses: New frontiers-a Keystone Symposia report.

Respiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS-CoV-2 can rapidly spread through a population, causing acute infection and, in vulnerable populations, severe or chronic disease. Developing effective treatment and prevention strategies often becomes a race against ever-evolving viruses that develop resistance, leaving therapy efficacy either short-lived or relevant for specific viral strains. On June 29 to July 2, 2022, researchers met for the Keystone symposium "Respiratory Viruses: New Frontiers." Researchers presented new insights into viral biology and virus-host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.

All differential on the splicing front: Host alternative splicing alters the landscape of virus-host conflict.

Alternative RNA splicing is a co-transcriptional process that richly increases proteome diversity, and is dynamically regulated based on cell species, lineage, and activation state. Virus infection in vertebrate hosts results in rapid host transcriptome-wide changes, and regulation of alternative splicing can direct a combinatorial effect on the host transcriptome. There has been a recent increase in genome-wide studies evaluating host alternative splicing during viral infection, which integrates well with prior knowledge on viral interactions with host splicing proteins. A critical challenge remains in linking how these individual events direct global changes, and whether alternative splicing is an overall favorable pathway for fending off or supporting viral infection. Here, we introduce the process of alternative splicing, discuss how to analyze splice regulation, and detail studies on genome-wide and splice factor changes during viral infection. We seek to highlight where the field can focus on moving forward, and how incorporation of a virus-host co-evolutionary perspective can benefit this burgeoning subject.

Metabolites as signalling molecules.

Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation.

An Unusual Case of Hyperhemolysis Syndrome and Delayed Hemolytic Transfusion Reaction due to Anti-Jk(a) and Anti-P1 Antibodies.

Background: Hyperhemolysis syndrome (HS) is a severe hemolytic transfusion reaction that can cause hemoglobin and hematocrit levels to drop below pretransfusion levels, leading to severe anemia. HS most commonly occurs in patients with a pre-existing hemoglobinopathy such as sickle cell disease (SCD) or beta-thalassemia. Methods: We report a case of HS, occurring in the absence of hemoglobinopathy, making the diagnosis challenging. The patient reported was also affected by a CIC-rearranged sarcoma. As part of the workup, the patient received a bone marrow biopsy for suspected hemophagocytic lymphohistiocytosis. Results: This provided a rare biopsy specimen to correlate reticulocytopenia with marked erythroid hyperplasia in the marrow, supporting the hypothesis of reticulocyte destruction as a contributing cause of anemia in these patients. This patient had demonstrable alloantibodies to the Jk(a) and P1 antigens as potential triggers for HS. Conclusions: It is vital that a diagnosis of HS be correctly made in these patients with severe anemia, as blood transfusions generally lead to worsening of their conditions.

Alternative splicing liberates a cryptic cytoplasmic isoform of mitochondrial MECR that antagonizes influenza virus.

Viruses must balance their reliance on host cell machinery for replication while avoiding host defense. Influenza A viruses are zoonotic agents that frequently switch hosts, causing localized outbreaks with the potential for larger pandemics. The host range of influenza virus is limited by the need for successful interactions between the virus and cellular partners. Here we used immunocompetitive capture-mass spectrometry to identify cellular proteins that interact with human- and avian-style viral polymerases. We focused on the proviral activity of heterogenous nuclear ribonuclear protein U-like 1 (hnRNP UL1) and the antiviral activity of mitochondrial enoyl CoA-reductase (MECR). MECR is localized to mitochondria where it functions in mitochondrial fatty acid synthesis (mtFAS). While a small fraction of the polymerase subunit PB2 localizes to the mitochondria, PB2 did not interact with full-length MECR. By contrast, a minor splice variant produces cytoplasmic MECR (cMECR). Ectopic expression of cMECR shows that it binds the viral polymerase and suppresses viral replication by blocking assembly of viral ribonucleoprotein complexes (RNPs). MECR ablation through genome editing or drug treatment is detrimental for cell health, creating a generic block to virus replication. Using the yeast homolog Etr1 to supply the metabolic functions of MECR in MECR-null cells, we showed that specific antiviral activity is independent of mtFAS and is reconstituted by expressing cMECR. Thus, we propose a strategy where alternative splicing produces a cryptic antiviral protein that is embedded within a key metabolic enzyme.

Validated transport conditions maintain the quality of washed red blood cells.

BACKGROUND: Washing red blood cell (RBC) units prior to transfusion is indicated for certain patients. In the United States, units stored at 1°C-6°C or transported at 1°C-10°C are available for issue up to 24 h, if not used immediately. The washing procedure commonly utilizes room temperature saline resulting in units starting out above the allowed temperature range. This leads to wastage if units are issued and returned too quickly before having a chance to equilibrate in a transport cooler. STUDY DESIGN AND METHODS: Here we performed an experimental study of washed RBC quality comparing "ideal" storage conditions in a blood bank refrigerator to a "real-world" simulation of unit transport, including holding in a transport cooler. Twelve RBC units were washed and allocated evenly into either condition. RESULTS: Measurements at 0, 1, 3, 6, 12, and 24 h post-washing revealed that placement in a transport cooler was associated with higher unit temperature prior to 12 h (p = .013) with a maximum difference of 9.3°C. Despite this difference, several measures of unit quality including extracellular potassium, pH, lactate, and free hemoglobin were indistinguishable between conditions (p = .382, .224, .286, .691, respectively). We selected half of the tested units from our irradiated inventory and confirmed increased potassium leak (p < .001) and accumulation of free hemoglobin (p = .012) in irradiated units. DISCUSSION: Washed units stored under approved transport conditions are acceptable to return to inventory up to 24 h after washing and we provide a prediction interval-based temperature threshold for rejecting these units, permitting reduced waste.

Outcomes of a Hybrid Ophthalmology Telemedicine Model for Outpatient Eye Care During COVID-19.

Importance: The hybrid ophthalmology telemedicine model asynchronously pairs an imaging appointment by a technician with a subsequent virtual appointment by a clinician. Although it has been mentioned in several studies as an alternative to standard in-person care during the COVID-19 pandemic, outcomes of this alternative clinical care model remain to be evaluated. Objective: To investigate the outcomes associated with the hybrid ophthalmology telemedicine model during the COVID-19 pandemic for nonurgent and nonprocedural ophthalmological care. Design, Setting, and Participants: Retrospective, cross-sectional study of all hybrid visits scheduled during the year 2020 in a single academic, hospital-based eye clinic in Boston, Massachusetts. All hybrid ophthalmology telemedicine visits completed in the year 2020 by opthalmologists and optometrists were included. Data were analyzed from January to December 2020. Exposures: Hybrid telemedicine clinical encounters. Main Outcomes and Measures: Four outcome metrics were calculated: (1) need for subsequent procedure visit, (2) medication change, (3) nonurgent, and (4) urgent consultation with another eye clinician. Adverse outcomes were defined as irreversible vision loss and the need for additional in-person evaluation to reach a management decision. Results: From April 9 to December 30, 2020, 889 patients (506 female patients [56.9%]; mean [SD] age, 62.1 [14.5] years; age range, 13-98 years) completed 940 hybrid visits. The most common visit indications were glaucoma (424 visits [45.1%]) and retinal diseases (499 visits [53.1%]). A total of 25 visits (2.7%) led to a procedure, 22 visits (2.3%) led to a change in medication, and 44 visits (4.7%) were referred for nonurgent consultation with another subspecialty with no instances of urgent referrals. Sixteen patients (1.7%) were referred to the on-call clinician for a same-day emergency in-person visit or recommended for a subsequent standard in-person visit to reach a management decision. There were no cases of irreversible vision loss following a hybrid visit. Conclusions and Relevance: These findings suggest that with the appropriate patient selection and clinical setting, the hybrid ophthalmology telemedicine model may be a good alternative to standard in-person visits, particularly for patients with glaucoma and retinal diseases.

Erratum to 'Left Profunda Femoral Artery Pseudoaneurysm After Revision Total Hip Arthroplasty' [Arthroplasty Today 6 (2020) 906-910].

[This corrects the article DOI: 10.1016/j.artd.2020.09.004.].

Capillary Refill Technology to Enhance the Accuracy of Peripheral Perfusion Evaluation in Sepsis.

Background: Monitoring of capillary refill time (CRT) is a common bedside assessment used to ascertain peripheral perfusion in a patient for a vast array of conditions. The literature has shown that a change in CRT can be used to recognize life-threatening conditions that cause decreased perfusion, such as sepsis, and aid in resuscitation. The current practice for calculating CRT invites subjectivity and produces a highly variable result. Innovative technology may be able to standardize this process and provide a reliable and accurate value for use in diagnostics and treatment. This study aimed to assess a new technology (DCR by ProMedix Inc.) for rapid, bedside, and noninvasive detection of CRT. Methods: This was a secondary analysis of a prospective observational study evaluating the accuracy of new technology towards CRT-guided diagnosis of sepsis. It was carried out in the adult emergency departments (ED) of an academic tertiary care medical center. Patients seeking care in the ED were determined eligible if they were > 18 years in age and exhibited chief complaints suggestive of possible sepsis. The CRT produced by the technology was compared to the gold standard manual waveform assessment. Results: 218 consecutive subject enrollments were included and multiple measurements were made on each patient. Data with irregular waveforms were excluded. A total of 692 waveforms were evaluated for CRT values by a pair of trained PhD biomedical engineers. The average age of the cohort was 50.62 and 51.4% female. Results showed a Pearson correlation coefficient of 0.91 for the device CRT compared to the CRT gold standard. The Pearson correlation coefficient for the two independent engineering review of the waveform data was 0.98. This device produces accurate, consistent results and eliminates the subjectivity of CRT measurements that is in practice currently.

Clinical practice guideline for the management of paediatric Charcot-Marie-Tooth disease.

BACKGROUND AND OBJECTIVES: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally. METHODS: Development of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations. RESULTS: The final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research. CONCLUSIONS: This clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings.

The Role of Nutrition and Forest-Bathing in the Physical Rehabilitation of Physically Inactive Patients: From the Molecular Aspects to New Nature-Inspired Techniques.

Physical rehabilitation plays a fundamental role in the management of individuals with disabilities associated with age-related muscle loss or affected by catastrophic conditions such as trauma, surgery, cancer or other severe pathologies. These events have in common an extended period of physical inactivity. Patients who undergo prolonged bed rest often present with a number of complications; for example, muscle loss that can exacerbate existing conditions determined by sarcopenia, which in turn greatly limits physical functions. The main scope of this work is to summarize certain key strategies for the physiotherapeutic management of physically inactive patients, regardless of the reason behind their prolonged bed rest, with a particular focus on physical rehabilitation, nutrition and forest-bathing. The importance of correct nutrition in counter-acting the loss of muscle mass and consequent function is explored alongside a description of the main nutrients that are needed for muscle regeneration. From a biomolecular perspective, some specific molecular mechanisms associated with physical rehabilitation are also reported not only in the context of physical therapy, but also within nature-inspired techniques, such as forest-bathing as well as body self-healing. Combining a targeted physiotherapeutic approach with an appropriate diet as well as nature-based therapy could thus help with the recovery of bed ridden patients.

Canadian Guidelines for Hereditary Transthyretin Amyloidosis Polyneuropathy Management.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.

Lignes directrices sur la prise en charge de l'amylose héréditaire à transthyrétine, accompagnée de polyneuropathie, au Canada.L'amylose héréditaire à transthyrétine (ATTRh) est une maladie évolutive, causée par des mutations du gène de la transthyrétine (TTR), qui entraînent un dysfonctionnement plurisystémique. L'agrégation, le mauvais repliement et la fibrillisation pathogènes de la TTR aboutissent au dépôt de protéines amyloïdes dans plusieurs organes, et affectent souvent le système nerveux périphérique et le cœur. Les troubles neurologiques fréquents comprennent une polyneuropathie sensorimotrice (PN), une neuropathie autonome, une polyneuropathie des petites fibres et le syndrome du canal carpien. Chez bon nombre de patients, la maladie a connu une évolution importante en raison de la pose tardive du diagnostic, la PN-ATTRh ne faisant pas l'objet d'un diagnostic différentiel. Santé Canada a approuvé, depuis peu, deux nouveaux médicaments modificateurs de la PN-ATTRh et efficaces contre l'affection, soit l'inotersen et le patisiran. La pose précoce du diagnostic revêt une importance cruciale dans l'instauration, en temps opportun, de ces tout nouveaux traitements qui atténuent les troubles, améliorent la qualité de vie et prolongent la survie. Les auteurs, par l'élaboration de la nouvelle ligne directrice, espèrent sensibiliser la communauté médicale à la PN-ATTRh, et améliorer les résultats cliniques qui y sont associés, en formulant des recommandations sur le diagnostic et le traitement de la maladie au Canada ainsi que sur la surveillance de son évolution.