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Cognitive impairment of dementia patients affects their ability to communicate and cooperate with care. Dementia patients need a specialized communication to increase their cooperation during daily care and a scale to measure cooperation with care. To improve communication, we created and applied a digital communication platform (DCP) in an observational study. To measure cooperation with care, we created and tested psychometric properties of the Cooperation with Care Scale‐Revised (CWCS‐R) in an institutional review board–approved 6‐week prospective study. DCP intervention was associated with decreased agitation and use of psychotropic medications for nursing home (NH) dementia patients. CWCS‐R is both a reliable and valid tool to measure cooperation with care in NH dementia patients. Innovations in communication with dementia patients and a scale to measure cooperation with care could reduce burdens of care and improve quality of life for patients, their family members, and staff. It may potentially help decrease cost of dementia care. [ABSTRACT FROM AUTHOR]

Objectives: Information is lacking regarding how commonly unblinding of treatment assignment occurs in hypnotic randomized clinic trials (RCTs). We now report the "best guesses" of clinical trial participants, versus study coordinators, versus study physicians in the study Reducing Suicidal Ideation Through Insomnia Treatment (REST‐IT). Methods: REST‐IT, a, 8‐week double‐blind RCT, compared zolpidem extended‐release (ER) versus placebo at bedtime in 103 adults with major depressive disorder with insomnia and suicidal ideation, and who received open label selective serotonin reuptake inhibitors. At the conclusion of study participation, 89 of the participants in this study, the study coordinators, and the study physicians each independently recorded their "best guess" of the treatment assigned. Results: Patients guessed correctly 58.4% of the time, coordinators 53.9% of the time, and physicians 49.4% of the time, and none were different from chance alone. Agreement between patient/coordinator, patient/doctor, and coordinator/doctor dyads were 75%–78% with no significant differences in agreement between the dyads. Conclusions: "Best guesses" of all parties were not different from chance, suggesting that the blind was maintained and that assessment bias was minimized in this RCT of zolpidem ER versus placebo. Our results may not apply to other hypnotics or other RCT designs. [ABSTRACT FROM AUTHOR]

Objective: The authors sought to determine whether targeted treatment of insomnia with controlled-release zolpidem (zolpidem-CR) in suicidal adults with insomnia would provide a reduction in suicidal ideation superior to placebo.Methods: Reducing Suicidal Ideation Through Insomnia Treatment was an 8-week three-site double-blind placebo-controlled parallel-group randomized controlled trial of zolpidem-CR hypnotic therapy compared with placebo, in conjunction with an open-label selective serotonin reuptake inhibitor. Participants were medication-free 18- to 65-year-olds with major depressive disorder, insomnia, and suicidal ideation. Suicidal ideation was the main outcome, measured first by the Scale for Suicide Ideation and second by the Columbia-Suicide Severity Rating Scale (C-SSRS).Results: A total of 103 participants were randomly assigned to receive zolpidem-CR (N=51) or placebo (N=52) (64 women and 39 men; mean age=40.5 years). Zolpidem-CR had a robust anti-insomnia effect, especially in patients with the most severe insomnia symptoms. No significant treatment effect was observed on the Scale for Suicide Ideation (least squares mean estimate=-0.56, SE=0.83, 95% CI=-2.19, 1.08), but the reduction in scores was significantly positively related to improvement in insomnia after accounting for the effect of other depression symptoms. The C-SSRS indicated that zolpidem-CR had a significant treatment effect (least squares mean estimate=-0.26, SE=0.12, 95% CI=-0.50, -0.02). The advantage for zolpidem-CR in reducing suicidal ideation on the C-SSRS was greater in patients with more severe insomnia. No deaths or suicide attempts occurred.Conclusions: Although the results do not support the routine prescription of hypnotic medication for mitigating suicidal ideation in all depressed outpatients with insomnia, they suggest that coprescription of a hypnotic during initiation of an antidepressant may be beneficial in suicidal outpatients, especially in patients with severe insomnia. [ABSTRACT FROM AUTHOR]

Insomnia commonly occurs in schizophrenia, and insomnia is associated with suicide risk. Clozapine has anti-suicidal properties and beneficial effects on sleep. We performed a meta-analysis of insomnia in randomized controlled trials (RCTs) of patients with schizophrenia treated with clozapine. We hypothesized that compared to clozapine there is an increased odds of insomnia in patients treated with other antipsychotics. We systematically searched PubMed, PsycINFO, and Web of Science databases. We included RCTs, in English, with data on insomnia in patients with schizophrenia treated with clozapine versus other antipsychotics. Data were pooled using a random effects model. Eight RCTs (1952 patients: 922 on clozapine and 1030 on other antipsychotics) met inclusion criteria. Patients treated with other antipsychotics versus clozapine had a significant increased odds of insomnia (22.3 % versus 12.4 %, OR = 2.20, 95 % CI = 1.64–2.94, p < 0.01). Olanzapine, quetiapine, risperidone, and ziprasidone were each associated with significant increased odds of insomnia compared to clozapine. In meta-regression analyses, clozapine dose, publication year, sex, trial duration, and study quality score were unrelated to the association; however, there was a significant association with age. The observed ORs for insomnia from RCTs were almost perfectly correlated with reported ORs from pharmacovigilance data. Clozapine is associated with significantly less insomnia compared to other antipsychotics. Findings provide additional evidence for improvement in sleep as a potential pathway underlying clozapine's anti-suicidal properties. A greater mechanistic understanding of this association is needed. [ABSTRACT FROM AUTHOR]

We report a case of sleep-isolated trichotillomania admitted to the hospital for alcohol detoxification. It would be helpful for patients with sleep-isolated trichotillomania to have diagnostic polysomnography to identify any other sleep-related pathology and correlate sleep-isolated trichotillomania behaviors with the sleep cycle to identify specific treatment for sleep-isolated trichotillomania. [ABSTRACT FROM AUTHOR]

• Electrodermal activity is a powerful and simple tool that uniquely measures the activity of the sympathetic branch of the autonomic nervous system. • Electrodermal activity has potential as a physiologic outcome measure for the autonomic nervous system response to transcranial magnetic stimulation. • Inhibitory transcranial magnetic stimulation of the right dorsolateral prefrontal cortex is associated with decreased electrodermal activity. • A number of studies document changes in electrodermal activity coinciding with a decrease in reported symptoms across psychiatric conditions. There is a growing body of evidence indicative of changes in autonomic nervous system (ANS) activity in patients with disorders of the central nervous system (CNS). Non-invasive measures of the ANS, including heart rate variability (HRV), electrodermal activity (EDA), and pupillary light reflex (PLR) may have value as markers of symptom severity, subtype, risk profile, and/or treatment response. In this paper we provide an introduction into the anatomy and physiology of EDA and review the literature published after 2007 in which EDA was an outcome measure of cortical stimulation with transcranial magnetic stimulation (TMS). Eleven studies were included and considered regarding the potential of EDA as an outcome measure reflecting ANS activity in TMS research and treatment. These studies are summarized according to study population, experimental methodology, cortical region targeted, and correlation with other measures of ANS activity. Results indicate that EDA changes vary with the frequency and target of TMS. Inhibitory TMS to the dorsolateral prefrontal cortex (dlPFC) was the most common paradigm in these studies, consistently resulting in decreased EDA. [ABSTRACT FROM AUTHOR]

Sleep variability (e.g. intra-individual variabilities in sleep duration or sleep timing, social jetlag, and catch-up sleep) is an important factor impacting health and mortality. However, limited information is available on the distribution of these sleep parameters across the human life span. We aimed to provide distribution of sleep variability related parameters across lifespan by sex and race in a national representative sample from the U.S. population. The study included 9981 participants 6 years and older from the National Health and Nutrition Examination Survey (NHANES) 2011–2014, who had 4–7 days of valid 24-h accelerometer recording with at least one day obtained during weekend (Friday or Saturday night). Of the study participants, 43% showed ≥ 60 min sleep duration standard deviation (SD), 51% experienced ≥ 60 min catch-up sleep, 20% showed ≥ 60 min sleep midpoint SD, and 43% experienced ≥ 60 min social jetlag. American youth and young adults averaged greater sleep variability compared to other age groups. Non-Hispanic Blacks showed greater sleep variability in all parameters compared to other racial groups. There was a main effect of sex on sleep midpoint SD and social jetlag with males averaging slightly more than females. Our study provides important observations on sleep variability parameters of residents of the United States by using objectively measured sleep patterns and will provide unique insights for personalized advice on sleep hygiene. [ABSTRACT FROM AUTHOR]

Background: Insomnia disorder is a highly prevalent, significant public health concern associated with substantial and growing health burden. There are limited real-world data assessing the burden of insomnia disorder on daytime functioning and its association with comorbidities. The objective of this study was to leverage large-scale, real-world data to assess the burden of untreated insomnia disorder in terms of daytime impairment and clinical outcomes. Methods: This United States medical claims database study compares patients diagnosed with insomnia disorder but not receiving treatment ('untreated insomnia' cohort) to patients without an insomnia disorder diagnosis and without treatment ('non-insomnia' cohort). International Classification of Disease, Tenth Revision codes were used as a proxy to represent the three symptom domains (Sleepiness, Alert/Cognition, Mood) of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), a newly developed and validated tool used in clinical studies to assess daytime functioning in insomnia disorder. Chronic Fatigue (R53.83) and Other Fatigue (R53.83), Somnolence (R40.0) and Disorientation (R41.0) were selected as categories representing one or more IDSIQ domains. Clinical outcomes included cardiovascular events, psychiatric disorders, cognitive impairment and metabolic disorders. Results: Approximately 1 million patients were included (untreated insomnia: n = 139,959; non-insomnia: n = 836,975). Compared with the 'non-insomnia' cohort, the 'untreated insomnia' cohort was more likely to experience daytime impairments, with mean differences in occurrences per 100 patient-years for: (a) fatigue, at 27.35 (95% confidence interval [CI] 26.81, 27.77, p < 0.01); (b) dizziness, at 4.66 (95% CI 4.40, 4.90, p < 0.01); (c) somnolence, at 4.18 (95% CI 3.94, 4.43, p < 0.01); and (d) disorientation, at 0.92 (95% CI 0.77, 1.06, p < 0.01). During the 1-year look-back period, patients in the 'untreated insomnia' cohort were also more likely to have been diagnosed with arterial hypertension (40.9% vs. 26.3%), psychiatric comorbidities (40.1% vs. 13.2%), anxiety (29.2% vs. 8.5%), depression (26.1% vs. 8.1%) or obesity (21.3% vs. 11.1%) compared with those in the 'non-insomnia' cohort. Conclusions: This large-scale study confirms the substantial burden of insomnia disorder on patients in a real-world setting, with significant daytime impairment and numerous comorbidities. This reinforces the need for timely insomnia disorder diagnosis and treatments that improve both sleep, as well as daytime functioning. [ABSTRACT FROM AUTHOR]

Background: Attention-deficit hyperactivity disorder is a common disorder that affects both children and adults. However, for adults, little is known about ADHD-attributable medical expenditures. Objective: To estimate the medical expenditures associated with ADHD, stratified by age, in the US adult population. Design: Using a two-part model, we analyzed data from Medical Expenditure Panel Survey for 2015 to 2019. The first part of the model predicts the probability that individuals incurred any medical costs during the calendar year using a logit model. The second part of the model estimates the medical expenditures for individuals who incurred any medical expenses in the calendar year using a generalized linear model. Covariates included age, sex, race/ethnicity, geographic region, Charlson comorbidity index, insurance, asthma, anxiety, and mood disorders. Participants: Adults (18 +) who participated in the Medical Expenditure Panel Survey from 2015 to 2019 (N = 83,776). Main Measures: Overall and service specific direct ADHD-attributable medical expenditures. Key Results: A total of 1206 participants (1.44%) were classified as having ADHD. The estimated incremental costs of ADHD in adults were $2591.06 per person, amounting to $8.29 billion nationally. Significant adjusted incremental costs were prescription medication ($1347.06; 95% CI: $990.69–$1625.93), which accounted for the largest portion of total costs, and office-based visits ($724.86; 95% CI: $177.75–$1528.62). The adjusted incremental costs for outpatient visits, inpatient visits, emergency room visits, and home health visits were not significantly different. Among older adults (31 +), the incremental cost of ADHD was $2623.48, while in young adults (18–30), the incremental cost was $1856.66. Conclusions: The average medical expenditures for adults with ADHD in the US were substantially higher than those without ADHD and the incremental costs were higher in older adults (31 +) than younger adults (18–30). Future research is needed to understand the increasing trend in ADHD attributable cost. [ABSTRACT FROM AUTHOR]

Determining the most effective insomnia medication for patients may require therapeutic trials of different medications. In addition, medication side effects, interactions with co-administered medications, and declining therapeutic efficacy can necessitate switching between different insomnia medications or deprescribing altogether. Currently, little guidance exists regarding the safest and most effective way to transition from one medication to another. Thus, we developed evidence-based guidelines to inform clinicians regarding best practices when deprescribing or transitioning between insomnia medications. Five U.S.-based sleep experts reviewed the literature involving insomnia medication deprescribing, tapering, and switching and rated the quality of evidence. They used this evidence to generate recommendations through discussion and consensus. When switching or discontinuing insomnia medications, we recommend benzodiazepine hypnotic drugs be tapered while additional CBT-I is provided. For Z-drugs zolpidem and eszopiclone (and not zaleplon), especially when prescribed at supratherapeutic doses, tapering is recommended with a 1–2-day delay in administration of the next insomnia therapy when applicable. There is no need to taper DORAs, doxepin, and ramelteon. Lastly, off-label antidepressants and antipsychotics used to treat insomnia should be gradually reduced when discontinuing. In general, offering individuals a rationale for deprescribing or switching and involving them in the decision-making process can facilitate the change and enhance treatment success. [ABSTRACT FROM AUTHOR]

Background and Objective: The dual orexin receptor antagonist daridorexant, studied in two phase III trials, dose-dependently improved objective and subjective sleep variables and daytime functioning in adults with insomnia. Because treatment of insomnia in older adults is challenging and has limited options, the purpose of the current analysis was to further analyse the phase III trial studying the higher doses of daridorexant, those that showed efficacy (daridorexant 50 mg, daridorexant 25 mg and placebo, nightly for 3 months), and compare the safety and efficacy of daridorexant in patients aged ≥ 65 ('older adults') to those aged < 65 years ('younger adults'). Methods: Analyses by age (≥ 65 years, n = 364; < 65 years, n = 566) were performed on data from the randomised, double-blind, placebo-controlled Trial 1 in adult patients with insomnia (NCT03545191). Efficacy endpoints included a change from baseline at month 1 and month 3 in polysomnography-measured wake after sleep onset (WASO) and latency to persistent sleep (LPS), self-reported total sleep time (sTST) and daytime functioning assessed using the validated Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Safety endpoints included adverse events and the Visual Analog Scale for morning sleepiness. Results: At baseline, mean [standard deviation] WASO was numerically greater (110 [39] vs 92 [38] min) in older than younger adults, while LPS was comparable (~ 65 min). Mean baseline IDSIQ total and all domain scores were numerically lower (i.e. better) in older adults. Daridorexant caused similar reductions in WASO and LPS, and similar increases in sTST, from baseline, in both age groups; improvements were numerically greater with daridorexant 50 mg than 25 mg. At month 3, daridorexant 50 mg, compared with placebo, decreased WASO by a least-squares mean of 19.6 (95% confidence interval 9.7, 29.5) in older patients versus 17.4 min (10.7, 24.0) in younger patients and decreased LPS by a least-squares mean of 14.9 (7.5, 22.3) in older patients versus 9.7 min (3.7, 15.7) in younger patients. Daridorexant 50 mg increased sTST from baseline to month 3 by a least-squares mean of 59.9 (49.6, 70.3) in older patients versus 57.1 min (48.9, 65.3) in younger patients. Daridorexant 50 mg progressively improved IDSIQ total and domain scores from week 1 onwards similarly in both groups; daridorexant 25 mg improved IDSIQ scores, but only in younger adults. In both age groups, in comparison with placebo, the overall incidence of adverse events was comparable, and there were fewer falls on daridorexant. Daridorexant improved Visual Analog Scale morning sleepiness in both groups; daridorexant 50 mg increased the mean (standard deviation) Visual Analog Scale morning sleepiness score by 15.9 (20.7) in older adults and by 14.9 (18.7) in younger adults from baseline to month 3. In older adults, there was one case of sleep paralysis, and no cases of narcolepsy, cataplexy, or complex sleep behaviour. Conclusions: In older patients with insomnia, as in younger patients, the efficacy of daridorexant is maximal on night-time and daytime variables at the higher dose of 50 mg. Older patients particularly require this dose to improve daytime functioning. Older patients are not at an increased risk of adverse events or residual effects the next morning after night-time administration of daridorexant, even at 50 mg. The dose of daridorexant does not need to be decreased for older patients. Clinical Trial Registration: ClinicalTrials.gov (NCT03545191) [first posted: 4 June, 4 2018], https://clinicaltrials.gov/ct2/show/NCT03545191. Plain Language Summary: The burden of chronic insomnia (difficulty in falling/staying asleep or not getting enough sleep) increases with age yet treatment options in older patients are limited. In older patients, because of a risk of side effects, guidelines suggest caution when prescribing sleep medications and, for some drugs, recommend starting at a lower dose. Daridorexant was approved in 2022 for the treatment of insomnia in adults following positive results in two trials that showed daridorexant significantly improved night-time sleep and daytime functioning over 3 months of treatment in adults with insomnia. Approximately 40% of patients taking part in these trials were aged 65 years or older. This current analysis compared the safety and benefits of daridorexant in older adults (aged at least 65 years) and younger adults (aged less than 65 years) in the trial that administered the highest two doses of daridorexant, 25 and 50 mg. The results showed that the benefits of daridorexant were comparable in both age groups over 3 months; compared with placebo, daridorexant improved night-time sleep (reduced time awake during the night, reduced time to fall asleep and increased total sleep time) and daytime functioning—patients had less daytime sleepiness and a better mood and feeling of alertness. In older patients, the benefits, particularly for daytime functioning, were greatest at the higher 50-mg dose, without any increase in side effects. Both doses of daridorexant were equally well tolerated in the two age groups, indicating that treatment with daridorexant at 50 mg can be safely started in older patients. [ABSTRACT FROM AUTHOR]

Psychologists in faculty affairs/faculty development (FAFD) roles can contribute to faculty vitality in academic health centers (AHCs) and mitigate barriers to advancement and retention. We describe a novel psychologist-led consultation service within an Office for Faculty Success (OFS) to support faculty across their career trajectories. We used 5 years of consultation data including faculty demographics, presenting concerns, and post-consultation evaluation data on consultation satisfaction and perceived benefits to examine trends and demographic group differences in consultation frequency, presenting concerns, and perceived benefits. From 2018 to 2023, 434 individuals presented for 683 consultations. Promotion in rank was the most frequent presenting concern. Women and racially/ethically minoritized faculty were found to present more frequently for repeat consultations, for concerns related to careers negotiation and advancement, and for intersectionality issues specific to gender and/or racial minority identities. From years one to five, there was a 93% increase in number of annual consultations performed and users were highly satisfied with the service (3.86/4). The consultation service is a unique, highly acceptable addition to interventions focused on career satisfaction and retention for AHC faculty, especially for women, early career, and minoritized faculty, and can serve as a model for other institutions. [ABSTRACT FROM AUTHOR]

BACKGROUND: Currently, 5 million seniors who reside in the community or assisted living or nursing facilities are affected by Alzheimer's disease and other neurocognitive disorders. They experience various psychiatric symptoms. Also, their family members are stressed from caregiving, and may feel guilty for not doing more. METHODS: We created an innovative nonpharmacological intervention, AlzhaTV, to decrease behavioral and psychological symptoms associated with neurocognitive disorders. We offered AlzhaTV to 9 nursing home patients. RESULTS: In our retrospective examination of this case series, we found AlzhaTV was effective in reducing behavioral and psychological symptoms in patients with neurocognitive disorders. We achieved either dose reductions, discontinuation, or avoided initiating the use of antipsychotic medications and benzodiazepines in nearly all patients. CONCLUSIONS: AlzhaTV may help decrease behavioral and psychological symptoms of dementia and decrease or avoid the use of antipsychotic medications or benzodiazepines. It may help in reducing the overall cost of health care in patients with dementia or neurocognitive disorders. AlzhaTV helps patients stay connected to their families, friends, and their past while bringing them joy in the present. It also helps families and caregivers feel more connected and less helpless. [ABSTRACT FROM AUTHOR]

Objective: Daridorexant is approved for the treatment of insomnia at two dose levels (25 and 50 mg). Dose-efficacy and -safety response relationships were evaluated using Phase 2 and 3 data., Methods: Data (N = 2153) from one Phase 2 (daridorexant 5, 10, 25, 50 mg, placebo once daily for 1 month) and two Phase 3 studies (daridorexant 10 and 25 or 25 and 50 mg, placebo once daily for 3 months) were pooled. Dose-response analyses at 1 month of double-blind treatment were performed using a linear regression and a two-stage meta-analysis approach. Efficacy endpoints were polysomnography-derived wake after sleep onset, latency to persistent sleep (LPS), self-reported total sleep time and the Insomnia Daytime Symptoms and Impacts Questionnaire total score (only Phase 3 data for the latter). Safety endpoints were the incidence of total adverse events (AEs) and AEs corresponding to somnolence/fatigue., Results: Dose-responses for all efficacy endpoints were significant in the observed dose range (both statistical approaches, p < 0.01). All dose-response relationships were linear except for LPS (two-stage meta-analysis) which showed a change in slope above 10 mg without reaching a plateau. No significant dose-response was observed for any AE (both approaches, p > 0.05). The incidence of AEs corresponding to somnolence/fatigue was low at all doses and, without linear assumption (two-stage meta-analysis) there was no dose-dependency (p = 0.369)., Conclusions: The data support the use of 50 mg as the preferred daridorexant dose in patients with insomnia disorder to provide the greatest opportunity for efficacy with no increased risk for AEs, including somnolence/fatigue, compared to lower doses., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report article publishing charges, statistical analysis, and writing assistance were provided by Idorsia Pharmaceuticals Ltd. Antonio Olivieri reports a relationship with Idorsia Pharmaceuticals Ltd that includes: employment and equity or stocks. Guy Braunstein reports a relationship with Idorsia Pharmaceuticals Ltd that includes: employment and equity or stocks. Pierre-Philippe Luyet reports a relationship with Idorsia Pharmaceuticals Ltd that includes: employment. Johann Laurent reports a relationship with Idorsia Pharmaceuticals Ltd that includes: employment. William V McCall reports a relationship with Idorsia Pharmaceuticals Ltd that includes: consulting or advisory. William V McCall reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. William V McCall reports a relationship with Carelon that includes: consulting or advisory. Claudio Bassetti reports a relationship with Bioproject that includes: consulting or advisory. Claudio Bassetti reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory. Claudio Bassetti reports a relationship with Jazz Pharmaceuticals Inc that includes: consulting or advisory. Claudio Bassetti reports a relationship with Idorsia Pharmaceuticals Ltd that includes: consulting or advisory. Jan Hedner reports a relationship with Somnomed that includes: funding grants. Jan Hedner reports a relationship with Desitin GmbH that includes: funding grants., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: This trial involves no commercial input: the findings from this trial will not benefit any commercial manufacturers/suppliers of clinical ECT devices. GLS has collaborated with MagVenture and MECTA as part of investigator-initiated trials, consults for and has equity in the company Trial Catalyst, and has provided consultation to Indivior. Dr Harold A. Sackeim serves as a scientific adviser and receives consulting fees from Cerebral Therapeutics Inc, Holmusk Technologies Inc, LivaNova PLC, MECTA Corporation, Neurolief Ltd, Neuronetics Inc, Parow Entheobiosciences LLC, and SigmaStim LLC. He receives honoraria and royalties from Elsevier Inc and Oxford University Press. He is the inventor on nonremunerative US patents for Focal Electrically Administered Seizure Therapy (FEAST), titration in the current domain in ECT, and the adjustment of current in ECT devices, each held by Balance Point LLC. He is also the originator of magnetic seizure therapy (MST). In the last 3 years PBF has received equipment for research from Neurosoft, Nexstim, and Brainsway Ltd. He has served on scientific advisory boards for Magstim and LivaNova and received speaker fees from Otsuka. He has also acted as a founder and board member for TMS Clinics Australia and Resonance Therapeutics. PBF is supported by a National Health and Medical Research Council of Australia Investigator grant (1193596). The other authors have no conflicts of interest or financial disclosures to report.