Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model.

Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson's disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria ("mitophagy") by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.

A Cancer Care Ontario Consensus-Based Organizational Guideline for the Planning and Delivery of Spine Stereotactic Body Radiation Therapy Treatment in Ontario.

The proposed recommendations are primarily based on the consensus opinion and in-field experience of the Ontario Health/Cancer Care Ontario stereotactic body radiation therapy (SBRT) for Spine Metastasis Guideline Development Group and published literature when available. Primary consideration was given to the perceived benefits for patients and the small likelihood of harm arising from recommendation implementation. Apart from the magnetic resonance imaging (MRI) follow-up strategy, all evidence was considered indirect and was provided by the working group in conjunction with their collective expertise in the field of SBRT. The application of an SBRT program requires a multidisciplinary team consisting of a radiation oncologist, spine surgeon, neuroradiologist, medical physicist, medical dosimetrist, and radiation therapist. In Canada, linear accelerators are the most used treatment delivery units and should follow technology-specific quality assurance procedures. Immobilization technique is location dependant. Treatment planning MRI sequences should be acquired no more than 14 days from the date of treatment. In the case of epidural disease, simulation MRI should be completed no more than 7 days from the date of treatment. After treatment, patients should be followed with routine clinical visits every 3 months for the first year, every 3 to 6 months during years 2 and 3, and every 4 to 6 months thereafter. The recommendations enclosed provide a framework for the minimum requirements for a cancer center in Ontario, Canada to offer SBRT for spine metastases.

Perceived Impact of Digital Health Maturity on Patient Experience, Population Health, Health Care Costs, and Provider Experience: Mixed Methods Case Study.

BACKGROUND: Health care organizations understand the importance of new technology implementations; however, the best strategy for implementing successful digital transformations is often unclear. Digital health maturity assessments allow providers to understand the progress made toward technology-enhanced health service delivery. Existing models have been criticized for their lack of depth and breadth because of their technology focus and neglect of meaningful outcomes. OBJECTIVE: We aimed to examine the perceived impacts of digital health reported by health care staff employed in health care organizations across a spectrum of digital health maturity. METHODS: A mixed methods case study was conducted. The digital health maturity of public health care systems (n=16) in Queensland, Australia, was examined using the quantitative Digital Health Indicator (DHI) self-assessment survey. The lower and upper quartiles of DHI scores were calculated and used to stratify sites into 3 groups. Using qualitative methods, health care staff (n=154) participated in interviews and focus groups. Transcripts were analyzed assisted by automated text-mining software. Impacts were grouped according to the digital maturity of the health care worker's facility and mapped to the quadruple aims of health care: improved patient experience, improved population health, reduced health care cost, and enhanced provider experience. RESULTS: DHI scores ranged between 78 and 193 for the 16 health care systems. Health care systems in the high-maturity category (n=4, 25%) had a DHI score of ≥166.75 (the upper quartile); low-maturity sites (n=4, 25%) had a DHI score of ≤116.75 (the lower quartile); and intermediate-maturity sites (n=8, 50%) had a DHI score ranging from 116.75 to 166.75 (IQR). Overall, 18 perceived impacts were identified. Generally, a greater number of positive impacts were reported in health care systems of higher digital health maturity. For patient experiences, higher maturity was associated with maintaining a patient health record and tracking patient experience data, while telehealth enabled access and flexibility across all digital health maturity categories. For population health, patient journey tracking and clinical risk mitigation were reported as positive impacts at higher-maturity sites, and telehealth enabled health care access and efficiencies across all maturity categories. Limited interoperability and organizational factors (eg, strategy, policy, and vision) were universally negative impacts affecting health service delivery. For health care costs, the resource burden of ongoing investments in digital health and a sustainable skilled workforce was reported. For provider experiences, the negative impacts of poor usability and change fatigue were universal, while network and infrastructure issues were negative impacts at low-maturity sites. CONCLUSIONS: This is one of the first studies to show differences in the perceived impacts of digital maturity of health care systems at scale. Higher digital health maturity was associated with more positive reported impacts, most notably in achieving outcomes for the population health aim.

Comparison of first-pass intubation success rates between two different videolaryngoscopes in an Australian prehospital and retrieval medicine service.

OBJECTIVE: To determine the effectiveness of the GlideScope Go videolaryngoscope (VL) in tracheal intubation in an Australian physician-staffed critical care prehospital and retrieval medicine service. METHODS: Our service has used VLs for several years, including the McGrath Mac, and from February 2019 the GlideScope Go. Clinicians may alternatively use direct laryngoscopy with a Macintosh laryngoscope. We conducted a non-inferiority trial comparing first-pass intubation success using the GlideScope Go VL with that using the McGrath Mac VL. We collected data on video intubation of all adult patients between February 2017 and December 2019, by our service. Comparison was also made with patients intubated using direct laryngoscopy with a Macintosh direct laryngoscope. RESULTS: One hundred and seventy-two patients were intubated with the aid of a VL. First-pass success rates (95% confidence interval [CI]) were 0.98 (0.92-0.99) and 0.92 (0.84-0.96), respectively, for the GlideScope Go and McGrath Mac, giving a difference (95% CI) in first-pass success rates of 0.06 (-0.01 to 0.13). First-pass success rate for the Macintosh laryngoscope was 0.88 (0.84-0.91). CONCLUSIONS: We demonstrated that first-pass success rates with the GlideScope Go are at least as good as our service had achieved with both the McGrath Mac and with direct laryngoscopy.

A Comparison Between the Rates of Radiation Oncologist and Urologist Consultations in Men Diagnosed With Prostate Cancer in Northern Ontario, Canada.

Purpose: Recommendations from Cancer Care Ontario stress the importance of multidisciplinary care from radiologists and urologists for prostate cancer treatment. The present study sought to examine what percentage of patients had a consultation with a radiation oncologist before undergoing a radical prostatectomy in Ontario, Canada, between 2010 and 2019. Methods and Materials: Administrative health care databases were used to analyze the number of consultations billed to the Ontario Health Insurance Plan from radiologists and urologists who treated men with a first prostate cancer diagnosis (n = 22,169). Results: In Ontario, 94.70% of Ontario Health Insurance Plan billings for patients with prostate cancer who had a prostatectomy within 1 year of a prostate cancer diagnosis were from urology, and 37.66% and 1.77% of billings were received from radiation oncology and medical oncology specialties, respectively. When sociodemographic variables were examined, having a lower neighborhood income (adjusted odds ratio [aOR], 0.69; confidence interval [CI], 0.62-0.76) and a rural residence (aOR, 0.72; CI, 0.65-0.79) were associated with lower odds of receiving a consultation from a radiation oncologist. When billings for consultations were examined geographically by region, Northeast Ontario (Local Health Integrated Network 13) had the lowest odds of receiving a radiation consultation compared with the rest of Ontario (aOR, 0.50; CI, 0.42-0.59). Conclusions: The results of this study show that differences in equitable access to multidisciplinary health care exist for men with a first prostate cancer diagnosis who reside in more northern and rural regions within Ontario, relative to the rest of the province. The reasons for these findings are likely multifactorial and may include factors such as patient treatment preference and distance/travel to receive treatment. However, as diagnosis year increased, so did the chances of receiving a radiation oncologist consultation, and this upward trend may reflect the implementation of Cancer Care Ontario guidelines.

Evaluating Digital Health Capability at Scale Using the Digital Health Indicator.

BACKGROUND: Health service providers must understand their digital health capability if they are to drive digital transformation in a strategic and informed manner. Little is known about the assessment and benchmarking of digital maturity or capability at scale across an entire jurisdiction. The public health care system across the state of Queensland, Australia has an ambitious 10-year digital transformation strategy. OBJECTIVE: The aim of this research was to evaluate the digital health capability in Queensland to inform digital health strategy and investment. METHODS: The Healthcare Information and Management Systems Society Digital Health Indicator (DHI) was used via a cross-sectional survey design to assess four core dimensions of digital health transformation: governance and workforce; interoperability; person-enabled health; and predictive analytics across an entire jurisdiction simultaneously. The DHI questionnaire was completed by each health care system (n = 16) within Queensland in February to July 2021. DHI is scored 0 to 400 and dimension score is 0 to 100. RESULTS: The results reveal a variation in DHI scores reflecting the diverse stages of health care digitization across the state. The average DHI score across sites was 143 (range 78-193; SD35.3) which is similar to other systems in the Oceania region and global public systems but below the global private average. Governance and workforce was on average the highest scoring dimension (x̅= 54), followed by interoperability (x̅ = 46), person-enabled health (x̅ = 36), and predictive analytics (x̅ = 30). CONCLUSION: The findings were incorporated into the new digital health strategy for the jurisdiction. As one of the largest single simultaneous assessments of digital health capability globally, the findings and lessons learnt offer insights for policy makers and organizational managers.

The Impact of a Cyberattack at a Radiation Oncology Department: Immediate Response and Future Preparedness.

Cyberattacks are increasing year after year and many organizations, including hospitals, are becoming targets. Radiation oncology is especially vulnerable because of the reliance on computer and network capabilities to transfer relevant patient information for safe and effective patient treatment. In early 2019, our institution was hit by a ransomware attack that brought down our oncology information system (OIS). Although we were not fully prepared for such an attack, a total of 69 treatment fractions occurred without our OIS thanks to the quick development of a contingency plan and the ability to restore the patients' records. The OIS was recovered by the manufacturer 4 days after the attack. We also have developed a contingency plan and outline important considerations for institutions trying to prepare for unexpected downtime such as a cyberattack.

GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.

B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 µg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.

The Operation of Canada's Only Virtually Operated Radiation Oncology Service During the COVID-19 Pandemic.

PURPOSE: Our institution operates a remote radiation oncology service in Northern Ontario, Canada. Since the start of the coronavirus disease 2019 pandemic, this center has operated without radiation oncologists on site owing to safety precautions, and this study seeks to understand the effect of this shift. METHODS AND MATERIALS: Departmental level data reports were used to investigate differences in metrics between April to May of 2019 and April to May 2020. These metrics include the total number of referrals received, average wait time from referral to consult, the number of cases that underwent peer review before beginning treatment, the total number of fractions given over each period, patient-reported outcomes, and patient satisfaction. We also examined the importance of physical examinations and the use of SABR treatment. RESULTS: There was an observed decrease in the number of referrals received, total number of fractions administered, and number of patients providing patient-reported outcomes. We observed no change in patient wait times, cases undergoing peer review before commencing treatment, or overall patient satisfaction. Challenges were identified in the collection of patient- reported outcomes and the conduction of physical examinations. CONCLUSIONS: This paper provides proof of concept that a radiation clinic can function entirely virtually in the short term without sacrificing patient satisfaction, efficiency, or safety.

A Potent and Selective Kallikrein-5 Inhibitor Delivers High Pharmacological Activity in Skin from Patients with Netherton Syndrome.

Regulation of proteolytic activity in the skin plays a pivotal role in epidermal homeostasis. This is best exemplified in Netherton syndrome, a severe genetic skin condition caused by loss-of-function mutations in the gene serine protease inhibitor Kazal-type 5 encoding lympho-epithelial Kazal-type-related inhibitor, a serine protease inhibitor that regulates kallikrein (KLK)-related peptidase 5, 7, and 14 activities. KLK5 plays a central role in stratum corneum shedding and inflammatory cell signaling, activates KLK7 and KLK14, and is therefore an optimal therapeutic target. We aimed to identify a potent and selective small-molecule inhibitor of KLK5 amenable to epidermal delivery. GSK951 was identified using a structure-based design strategy and showed a half maximal inhibitory concentration of 250 pM for KLK5 and greater than 100-fold selectivity over KLK7 and KLK14. Cocrystal structure analysis identified the critical catalytic site interactions to a surrogate for KLK5. Topical application of GSK951-containing cream inhibited KLK5 activity in TgKLK5 mouse skin, reduced transepidermal water loss, and decreased proinflammatory cytokine expression. GSK951 achieved high concentrations in healthy human epidermis following topical application in a cream formulation. Finally, KLK5 protease activity was increased in stratum corneum of patients with Netherton syndrome and significantly inhibited by GSK951. These findings unveil a KLK5-specific small-molecule inhibitor with a high therapeutic potential for patients with Netherton syndrome.

The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding.

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.

Responding to the COVID-19 pandemic: The experiences of South Australia's Rescue, Retrieval and Aviation Services.

COVID-19 poses significant challenges to pre-hospital and retrieval medicine (PHRM) clinicians - and many are unique to this area of clinical practice. We share the experiences of the South Australian Ambulance Service (SAAS) MedSTAR Emergency Medical Retrieval Service in preparing for the COVID-19 pandemic in the pre-hospital and retrieval setting - including the role of a multidisciplinary leadership team; challenges and potential approaches to screening for COVID-19; personal protective equipment for pre-hospital and aeromedical taskings; issues arising with interstate retrievals; and the role of telehealth. Although novel solutions allowed SAAS MedSTAR to continue to deliver high-quality care, considering the resource implications involved in undertaking the transfer of patients with COVID-19, it is clear that significant community disease transmission threatens to overwhelm any PHRM service. Should Australia face a significant future outbreak, it is conceivable that some PHRM operations may need to be reduced or suspended entirely.

Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin.

Severe α1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z α1 -antitrypsin. The lead compound blocks Z α1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency.

The molecular species responsible for α1 -antitrypsin deficiency are suppressed by a small molecule chaperone.

The formation of ordered Z (Glu342Lys) α1 -antitrypsin polymers in hepatocytes is central to liver disease in α1 -antitrypsin deficiency. In vitro experiments have identified an intermediate conformational state (M*) that precedes polymer formation, but this has yet to be identified in vivo. Moreover, the mechanism of polymer formation and their fate in cells have been incompletely characterised. We have used cell models of disease in conjunction with conformation-selective monoclonal antibodies and a small molecule inhibitor of polymerisation to define the dynamics of polymer formation, accumulation and secretion. Pulse-chase experiments demonstrate that Z α1 -antitrypsin accumulates as short-chain polymers that partition with soluble cellular components and are partially secreted by cells. These precede the formation of larger, insoluble polymers with a longer half-life (10.9 ± 1.7 h and 20.9 ± 7.4 h for soluble and insoluble polymers, respectively). The M* intermediate (or a by-product thereof) was identified in the cells by a conformation-specific monoclonal antibody. This was completely abrogated by treatment with the small molecule, which also blocked the formation of intracellular polymers. These data allow us to conclude that the M* conformation is central to polymerisation of Z α1 -antitrypsin in vivo; preventing its accumulation represents a tractable approach for pharmacological treatment of this condition; polymers are partially secreted; and polymers exist as two distinct populations in cells whose different dynamics have likely consequences for the aetiology of the disease.

Apolipoprotein E Genotype Moderation of the Association Between Physical Activity and Brain Health. A Systematic Review and Meta-Analysis.

INTRODUCTION: Possession of one or two e4 alleles of the apolipoprotein E (APOE) gene is associated with cognitive decline and dementia risk. Some evidence suggests that physical activity may benefit carriers of the e4 allele differently. METHOD: We conducted a systematic review and meta-analysis of studies which assessed APOE differences in the association between physical activity and: lipid profile, Alzheimer's disease pathology, brain structure and brain function in healthy adults. Searches were carried out in PubMed, SCOPUS, Web of Science and PsycInfo. RESULTS: Thirty studies were included from 4,896 papers screened. Carriers of the e4 allele gained the same benefit from physical activity as non-carriers on most outcomes. For brain activation, e4 carriers appeared to gain a greater benefit from physical activity on task-related and resting-state activation and resting-state functional connectivity compared to non-carriers. Post-hoc analysis identified possible compensatory mechanisms allowing e4 carriers to maintain cognitive function. DISCUSSION: Though there is evidence suggesting physical activity may benefit e4 carriers differently compared to non-carriers, this may vary by the specific brain health outcome, perhaps limited to brain activation. Further research is required to confirm these findings and elucidate the mechanisms.

Decision support tool and suggestions for the development of guidelines for the helicopter transport of patients with COVID-19.

The novel coronavirus SARS-CoV2 emerged in December 2019 and is now pandemic. Initial analysis suggests that 5% of infected patients will require critical care, and that respiratory failure requiring intubation is associated with high mortality.Sick patients are geographically dispersed: most patients will remain in situ until they are in need of critical care. Additionally, there are likely to be patients who require retrieval for other reasons but who are co-incidentally infected with SARS-CoV-2 or shedding virus.The COVID-19 pandemic therefore poses a challenge to critical care retrieval systems, which often depend on small teams of specialists who live and work together closely. The infection or quarantining of a small absolute number of these staff could catastrophically compromise service delivery.Avoiding occupational exposure to COVID-19, and thereby ensuring service continuity, is the primary objective of aeromedical retrieval services during the pandemic. In this discussion paper we collaborated with helicopter emergency medical services(HEMS) worldwide to identify risks in retrieving COVID-19 patients, and develop strategies to mitigate these.Simulation involving the whole aeromedical retrieval team ensures that safety concerns can be addressed during the development of a standard operating procedure. Some services tested personal protective equipment and protocols in the aeromedical environment with simulation. We also incorporated experiences, standard operating procedures and approaches across several HEMS services internationally.As a result of this collaboration, we outline an approach to the safe aeromedical retrieval of a COVID-19 patient, and describe how this framework can be used to develop a local standard operating procedure.

Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors.

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.