McMaster University

Purpose: This study aimed to characterize contemporary management of Canadian patients with cardiovascular implantable electronic devices (CIEDs) undergoing radiation therapy (RT) in light of updated American Association of Physicists in Medicine guidelines. Methods and materials: A 22-question web-based survey was distributed to members of the Canadian Association of Radiation Oncology, Canadian Organization of Medical Physicists, and Canadian Association of Medical Radiation Technologists from January to February 2020. Respondent demographics, knowledge, and management practices were elicited. Statistical comparisons by respondent demographics were performed using χ2 and Fisher exact tests. Results: In total, 155 surveys were completed by 54 radiation oncologists, 26 medical physicists, and 75 radiation therapists in academic (51%) and community (49%) practices across all provinces. The majority of respondents (77%) had managed >10 patients with CIEDs in their career. Most respondents (70%) reported using risk-stratified institutional management protocols. Respondents used manufacturer recommendations, rather than American Association of Physicists in Medicine or institutionally recommended dose limits, when the manufacturer limit was 0 Gy (44%), 0 to 2 Gy (45%), or >2 Gy (34%). The majority of respondents (86%) reported institutional policies to refer to a cardiologist for CIED evaluation both before and after completion of RT. Cumulative dose to CIED, pacing dependence, and neutron production were considered during risk stratification by 86%, 74%, and 50% of participants, respectively. Dose and energy thresholds for high-risk management were not known by 45% and 52% of respondents, with radiation oncologists and radiation therapists significantly less likely to report thresholds than medical physicists (P < .001). Although 59% of respondents felt comfortable managing patients with CIEDs, community respondents were less likely to feel comfortable than academic respondents (P = .037). Conclusions: The management of Canadian patients with CIEDs undergoing RT is characterized by variability and uncertainty. National consensus guidelines may have a role in improving provider knowledge and confidence in caring for this growing population.

About two-thirds of Canadian COVID-19 related deaths occurred in long-term care homes (LTCHs). Multiple jobholding and excessive part-time work among staff have been discussed as vectors of transmission. Using an administrative census of registered nurses (RNs) and registered practical nurses (RPNs) in the Canadian province of Ontario, this paper contrasts the prevalence of multiple jobholding, part-time/casual work, and other job and worker characteristics across health sectors in 2019 and 2020 to establish whether the LTCH sector deviates from the norms in Ontario healthcare. Prior to COVID-19, about 19% of RNs and 21% of RPNs in LTCHs held multiple jobs. For RPNs, this was almost identical to the RPN provincial average, while for RNs this was 2.5 percentage points above the RN provincial average. In 2020, multiple jobholding fell significantly in LTCHs after the province passed a single site order to reduce COVD-19 transmission. Although there are many similarities across sectors, nurses, especially RNs, in LTCHs differ on some dimensions. They are more likely to be internationally educated and, together with nurses in hospitals, those who work part- time/casual are more likely to prefer full-time hours (involuntary part-time/casual). Overall, while multiple jobholding and part-time work among nurses are problematic for infection prevention and control, these employment practices in LTCHs did not substantially deviate from the norms in the rest of healthcare in Ontario.

Purpose Approximately 95% of patients undergoing radiotherapy (RT) experience radiation dermatitis (RD). Evidence has suggested that photobiomodulation therapy (PBMT) can stimulate skin renewal and minimize RD. The aim of the present paper was to investigate the efficacy of PBMT in RD prevention through a comprehensive literature review. Methods A literature search of Ovid MEDLINE, Embase, and Cochrane databases was conducted from 1980 to March 2021 to identify RCT on the use of PBMT for RD prevention. Forest plots were developed using RevMan software to quantitatively compare data between studies. Results Five papers were identified: four in breast and one in head and neck cancer patients. Patients receiving PBMT experienced less severe RD than the control groups after 40 Gray (Gy) of RT (grade 3 toxicity: Odds Ratio (OR): 0.57, 95% CI 0.14–2.22, p = 0.42) and at the end of RT (grade 0 + 1 vs. 2 + 3 toxicity: OR: 0.28, 95% CI 0.15–0.53, p < 0.0001). RT interruptions due to RD severity were more frequent in the control group (OR: 0.81, 95% CI 0.10–6.58, p = 0.85). Conclusion Preventive PBMT may be protective against the development of severe grades of RD and reduce the frequency of RT interruptions. Larger sample sizes and other cancer sites at-risk of RD should be evaluated in future studies to confirm the true efficacy of PBMT, also in preventing the onset of RD and to finalize a standardized protocol to optimize the technique. At present, starting PBMT when RT starts is recommendable, as well as performing 2 to 3 laser sessions weekly.

Pediatric recurrent abdominal pain is commonly associated with negative impacts on quality of life (QOL). Positive schemas (core beliefs about the self with subthemes of self-efficacy, optimism, trust, success, and worthiness) are a resilience factor that has not yet been examined within a pediatric recurrent pain context. This cross-sectional study examined (a) associations between positive schemas, pain coping, and youth QOL, and (b) exploratory analyses to investigate whether specific positive schema subthemes predicted QOL outcomes in youth with recurrent abdominal pain. Participants were 98 youth with recurrent abdominal pain (i.e., pain related to a disorder of gut–brain interaction [DGBI] or organic cause) who completed measures on positive schemas, QOL, and pain coping. Age and diagnostic status were controlled for in analyses. Positive schemas were significantly positively correlated with emotional, social, school, and overall QOL, as well as with approach and problem-focused avoidant coping, and significantly negatively correlated with emotion-focused coping. Worthiness was the strongest and only significant predictor of youth social functioning. Positive schemas may be an important cognitive resilience factor to consider within interventions for pediatric recurrent pain.

Background Late-onset infections (LOI) are a major cause of morbidity and mortality among patients in the neonatal intensive care unit (NICU). Gloving after hand hygiene may be a pragmatic approach to prevent infections that arise when healthcare workers’ hands transmit pathogens to neonates. Objective To determine the feasibility of conducting a multicenter, open-labeled randomized controlled trial (RCT) to determine whether a protocol that requires healthcare workers (HCWs) in a level 3 NICU to wear non-sterile gloves plus hand hygiene reduces the occurrence of a late-onset infection, compared to hand hygiene alone. Methods In this single-center pilot study, we recruited neonates admitted to the McMaster Children’s Hospital NICU from June 2017 to May 2018. The NICU was randomized to begin with the standard (control) arm for 6 months (June 2017 to Dec 2017), followed by the gloving (GloveCare) arm for 6 months (Jan 2018 to July 2018), with a 2-week washout period in-between to educate healthcare workers about gloving. We measured numerous feasibility outcomes including enrollment, event rate, and compliance with hand hygiene (Moment 1: before patient contact, Moment 2: before clean procedure, Moment 3: after body fluid contact, Moment 4: after patient contact) and gloving compliance. Results We enrolled 750 neonates (390 Standard care, 360 GloveCare) and achieved 100% enrollment. We found higher hand hygiene compliance during the standard care arm compared to the GloveCare for all four moments of hand hygiene (Moment 1: 87% vs 79%, OR=1.86 (1.34, 2.59); Moment 2: OR=1.73 (1.00, 3.01); Moment 3: OR=1.11 (0.62, 1.98); Moment 4: OR=1.65 (1.27, 2.14)). We developed and validated a method to calculate glove compliance, which ranged from 48 to 85%, and was highest for moment 3 (doffing after a procedure or body fluid exposure risk). No adverse events were documented for patients or staff. Discussion Reduction in hand hygiene compliance in the GloveCare arm presents a pragmatic challenge in ascertaining the effectiveness of gloving to prevent LOI. Most LOIs were non-sterile-site infections, which is considered a less patient-important or clinically relevant outcome compared to sterile-site LOI. Ensuring efficient collection and validation of hand hygiene and gloving data is imperative. Conclusion The pilot study demonstrated the feasibility of this intervention though modifications to improve hand hygiene compliance during GloveCare will be important prior to a multicenter cluster RCT to assess the efficacy of non-sterile glove-based care in preventing LOI in the NICU. Trial registration Clinicaltrials.gov, NCT03078335

People living with HIV (PLHIV) need lifelong medical care. However, retention in HIV care is not measured uniformly, making it challenging to compare or pool data. The objective of this study within a review (SWAR) is to describe the assortment of definitions used for retention in HIV care in randomized controlled trials (RCTs). We conducted a SWAR, drawing data from an overview of systematic reviews on interventions to improve the HIV care cascade. Ethics review was not required for this analysis of secondary data. We identified RCTs of interventions used to improve retention in care for PLHIV, including all age groups and extracted the definitions used and their characteristics. We identified 50 trials that measured retention published between 2007 and 2021 and provided 59 definitions for retention in care. The definitions consisted of nine different characteristics with follow-up time (n = 47), and clinical visits (n = 36) most used. The definitions of retention in HIV care are highly heterogeneous. In this study, we present the pros and cons of characteristics used to measure retention in HIV care.

Background: Religiosity has been suggested to be protective against substance use disorder (SUD) initiation but its impact of the progression of development is not known. Aims: This study investigated the impact of religiosity/spirituality on the development of heavy use and SUD following substance use initiation (alcohol, cannabis, and tobacco) utilizing data from the 2012 to 2013 National Epidemiologic Survey on Alcohol and Related Conditions-III. Method: Individuals with a known age at onset of substance initiation were included (n = 30,590, n = 11,126, and n = 14,083; for alcohol, cannabis, or tobacco users, respectively). Religiosity was measured by importance of religious/spiritual beliefs and frequency of religious service attendance. The percentage of individuals who progressed to an SUD after substance initiation in each substance was estimated. Discrete-time analysis and survival analysis were used to measure the impact of religiosity on the progression from substance initiation to heavy use and from heavy use to SUD. Results: After controlling for various variables, religious services attendance frequency was statistically associated with a slower progression from substance initiation to heavy use for all three substances: tobacco by 8% to 15%, cannabis by 5% to 26%, and alcohol 9% (p ⩽ .01). Religious importance was associated with slower progression to heavy use in cannabis users by 16% to 21% (p ⩽ .02). Religiosity (believes and attendance) was associated with slowed progression from heavy use to SUD development in alcohol users only. Conclusions: The findings illustrate strongest association between attending religious services and lower probabilities of progressing to heavy/daily use after substance use initiation for alcohol, tobacco, and cannabis users. This indicates the potential use of religious services as social support for individuals with risky substance use.

A Kondo lattice is often electrically insulating at low temperatures. However, several recent experiments have detected signatures of bulk metallicity within this Kondo insulating phase. In this study, we visualized the real-space charge landscape within a Kondo lattice with atomic resolution using a scanning tunneling microscope. We discovered nanometer-scale puddles of metallic conduction electrons centered around uranium-site substitutions in the heavy-fermion compound uranium ruthenium silicide (URu2Si2) and around samarium-site defects in the topological Kondo insulator samarium hexaboride (SmB6). These defects disturbed the Kondo screening cloud, leaving behind a fingerprint of the metallic parent state. Our results suggest that the three-dimensional quantum oscillations measured in SmB6 arise from Kondo-lattice defects, although we cannot exclude other explanations. Our imaging technique could enable the development of atomic-scale charge sensors using heavy-fermion probes.

Background The Life-Space Assessment (LSA) can compliment traditional physical performance measures of mobility by accounting for the interaction between individuals and their environment. However, there are no studies that have generated percentile curves showing sex-stratified reference values in a large population-based sample of community-dwelling adults, making its interpretation difficult. Therefore, this study aimed to establish sex-stratified reference values for the LSA in middle-aged and older Canadians. Methods Baseline data for participants aged 45–84 years old from the Canadian Longitudinal Study on Aging (CLSA) were used (n = 22,154). Quantile regression was used to estimate specific percentiles, with age as the independent variable and LSA scores as the dependent variable. Models were run for the whole sample, then separately for males and females. The models were cross-validated to assess their reliability. CLSA inflation and analytic weights were applied. Results On average, the sample was 62.5 ± 10.0 y.o. (51.1% males), with a weighted mean LSA score of 89.2 ± 17.0. There was also a decrease in LSA scores with age, where scores were lower for older age groups compared to younger groups, and LSA scores were lower for females relative to males. Discussion and conclusions Reference data will aid in interpreting, comparing, and making inferences related to LSA scores obtained in clinical and research settings for Canadian adults.

Background Diabetic neuropathy is the most common microvascular complication of diabetes mellitus and a major risk factor for diabetes-related lower-extremity complications. Diffuse neuropathy is the most frequently encountered pattern of neurological dysfunction and presents clinically as distal symmetrical sensorimotor polyneuropathy. Due to the increasing public health significance of diabetes mellitus and its complications, screening for diabetic peripheral neuropathy is essential. Consequently, a review of the principles that guide screening practices, especially in resource-limited clinical settings, is urgently needed. Main body Numerous evidence-based assessments are used to detect diabetic peripheral neuropathy. In accordance with current guideline recommendations from the American Diabetes Association, International Diabetes Federation, International Working Group on the Diabetic Foot, and National Institute for Health and Care Excellence, a screening algorithm for diabetic peripheral neuropathy based on multiphasic clinical assessment, stratification according to risk of developing diabetic foot syndrome, individualized treatment, and scheduled follow-up is suggested for use in resource-limited settings. Conclusions Screening for diabetic peripheral neuropathy in resource-limited settings requires a practical and comprehensive approach in order to promptly identify affected individuals. The principles of screening for diabetic peripheral neuropathy are: multiphasic approach, risk stratification, individualized treatment, and scheduled follow-up. Regular screening for diabetes-related foot disease using simple clinical assessments may improve patient outcomes.

Vibration-induced fluidization (ViF) is a phenomenon where a granular medium completely loses shear resistance or flows continuously under vibration and thus behaves like a fluid without invoking remarkable excess pore pressure. This paper attempts to investigate ViF through a series of modified triaxial tests and using an extended shear-transformation-zone (STZ) model that correlates macroscopic plastic deformation to the motion of internal mesoscopic weak spots (i.e., STZs) within granular materials. The test results revealed that the ViF may take place when the vibration is applied at either critical or non-critical states. Theoretical analyses using the extended STZ model show that the vibration intensity required to cause fluidization increases linearly with the initial quasi-static shear stress level at which vibration is imposed. The model results are generally consistent with experimental data, indicating that the extended STZ model has a desirable performance in simulating the fluidization of granular soil subjected to quasi-static shearing and vibration simultaneously.

Background COVID-19 has negatively impacted the mental health and well-being of both Canadians and the world as a whole, with Veterans, in particular, showing increased rates of depression, anxiety, and PTSD. Spouses and common-law partners often serve as primary caregivers and sources of support for Veterans, which may have a deleterious effect on mental health and increase risk of burnout. Pandemic related stressors may increase burden and further exacerbate distress; yet the effect of the pandemic on the mental health and well-being of Veterans’ spouses is currently unknown. This study explores the self-reported mental health and well-being of a group of spouses of Canadian Armed Forces Veterans and their adoption of new ways to access healthcare remotely (telehealth), using baseline data from an ongoing longitudinal survey. Methods Between July 2020 and February 2021, 365 spouses of Veterans completed an online survey regarding their general mental health, lifestyle changes, and experiences relating to the COVID-19 pandemic. Also completed were questions relating to their use of and satisfaction with health-care treatment services during the pandemic. Results Reported rates of probable major depressive disorder (MDD), generalized anxiety disorder (GAD), alcohol use disorder (AUD), and PTSD were higher than the general public, with 50–61% believing their symptoms either directly related to or were made worse by the pandemic. Those reporting being exposed to COVID-19 were found to have significantly higher absolute scores on mental health measures than those reporting no exposure. Over 56% reported using telehealth during the pandemic, with over 70% stating they would continue its use post-pandemic. Conclusions This is the first Canadian study to examine the impact of the COVID-19 pandemic specifically on the mental health and well-being of Veterans’ spouses. Subjectively, the pandemic negatively affected the mental health of this group, however, the pre-pandemic rate for mental health issues in this population is unknown. These results have important implications pertaining to future avenues of research and clinical/programme development postpandemic, particularly relating to the potential need for increased support for spouses of Veterans, both as individuals and in their role as supports for Veterans.

Introduction Anderson–Hynes pyeloplasty is the technique of choice for the treatment of pyeloureteral junction obstruction (PUJO) with an excellent success rate. Minimally invasive surgery has become the standard of care for the management of PUJO in children. Although it has been comparable to the open approach at all levels, its diffusion or employment in younger children has not been widely adopted. Our aim is to evaluate laparoscopic pyeloplasty outcomes from international academic centers in children under 1 year of age, focusing on feasibility and outcomes including possible complications. Materials and methods This is review of consecutive infants under 1 year of age who underwent laparoscopic pyeloplasty between 2009 and 2018 with more than 12 months of follow-up. Seven different training centers with different backgrounds participated in this study. Evaluation was carried out with ultrasound and renogram before and after surgery. Demographic data, perioperative characteristics, complications, and results are described and analyzed. Results Over 9 years, 124 transperitoneal laparoscopic Anderson–Hynes pyeloplasties were performed on 123 children under 1 year of age; 88 males and 35 females, with 1 case of bilateral PUJO. Of the 124 renal units, 86 were left-sided. Mean age at surgery was 6.6 months (1 week–12 months), with 56% (n = 70) done before 6 months of age. Mean weight at surgery was 6.8 kg (3–12 kg), with 59% (n = 73) weighing less than 8 kg. Mean operative time (skin-to-skin) was 150 min (75–330 min). After a mean follow-up of 46 months (12–84 months), 12 (9%) patients developed complications, with only 1 needing a redo pyeloplasty also done laparoscopically. One child, with deterioration in renal function, underwent nephrectomy. Conclusion Laparoscopic pyeloplasty under 1 year of age and/or less than 12 kilos is feasible with lower complication rate. Furthermore, age younger than 6 months and weight less than 8 kg are no longer limiting factors for a successful pyeloplasty as shown by this multicentre study.

Though mental health and substance use concerns often co-occur, few studies have characterized patterns of co-occurrence among adolescents in clinical settings. The current investigation identifies and characterizes these patterns among adolescents presenting to an outpatient mental health service in Ontario, Canada. Data come from cross-sectional standardized patient intake assessments from 916 adolescents attending an outpatient mental health program (January 2019–March 2021). Latent profile analysis identified patterns of substance use (alcohol, cannabis, (e-) cigarettes) and emotional and behavioral disorder symptoms. Sociodemographic and clinical correlates of these patterns were examined using multinomial regression. Three profiles were identified including: 1) low substance use and lower frequency and/or severity (relative to other patients in the sample) emotional and behavioral disorder symptoms (26.2%), 2) low substance use with higher emotional and behavioral disorder symptoms (48.2%), and 3) high in both (25.6%). Profiles differed in sociodemographic and clinical indicators related to age, gender, trauma, harm to self, harm to others, and service use. Experiences of trauma, suicide attempts, and thoughts of hurting others increased the odds of adolescents being in the profile high in both substance use and symptoms compared to other profiles. These findings further document the high rates of substance use in adolescents in mental health treatment and the profiles generally map onto three out of four quadrants in the adapted four-quadrant model of concurrent disorders, indicating the importance of assessing and addressing substance use in these settings.

Background Continuous local infiltration analgesia (CLIA) can be administered via intraarticular or periarticular techniques in patients undergoing total knee arthroplasty (TKA). The purpose of this investigation was to retrospectively report a single-center experience of epidural analgesia with subcutaneous CLIA versus epidural analgesia without CLIA among patients undergoing TKA. Methods This single-center retrospective study was conducted in Saudi Arabia. From January 01, 2014, to December 30, 2020, medical records of all patients who underwent TKA were reviewed. Patients who received subcutaneous CLIA with epidural analgesia were assigned to the intervention group, whereas those who received epidural analgesia without subcutaneous CLIA were assigned to the control group. The efficacy endpoints included: (i) postoperative pain scores at 24 h, 48 h, 72 h, and 3 months; (ii) postoperative opioid consumption at 24 h, 48 h, 72 h, and 24–72 h (cumulative); (iii) length of hospital stay; and (iv) postoperative functional recovery of the knee 3 months post-operation, according to the Knee Injury and Osteoarthritis Outcome Score. Results At rest and during mobilization, the CLIA group (n = 28) achieved significantly lower postoperative pain scores 24 h, 48 h, 72 h, and 3 months post-operation than the non-CLIA group (n = 35). Subgroup analysis revealed that the CLIA group achieved significantly less opioid consumption 24 h and 48 h post-operation than the non-CLIA group. There was no difference between the groups regarding the length of hospital stay or functional scores 3 months post-operation. There was no significant difference between the groups regarding the rate of wound infection, other infections, and readmission within 30 days. Conclusion Subcutaneous CLIA is a technically feasible and safe procedure without major adverse events but with reduced postoperative pain scores (at rest and during mobilization) and opioid consumption. Additional larger studies are warranted to confirm our results. Moreover, a head-to-head comparison between subcutaneous CLIA and periarticular or intraarticular CLIA is an interesting prospective investigation.

Interprofessional learning improves students' clinical and interprofessional competencies. COVID-19 prevented delivering in-person education and motivated the development of a virtual interprofessional cadaveric dissection (ICD) course. This study reports on the effects of a virtual ICD course compared to a previously delivered in-person course, on students' readiness for, and perceptions about, interprofessional learning. Students attending the ICD course in-person (2019-2020) or virtually (2020-2021) completed the Readiness for Interprofessional Learning Scale (RIPLS) and the Interdisciplinary Education Perception Scale (IEPS). Students in the virtual course also provided written feedback. Thirty-two (24 women; Median: 24 [Q1-Q3: 22-25] yrs.) and twenty-three students (18 women; 22 [21-23] yrs.) attended the in-person and virtual courses, respectively. In the virtual cohort, the RIPLS total score (82 [76-87] vs. 85 [78-90]; p=0.034) and the roles and responsibilities sub-score (11 [9-12] vs. 12 [11-13]; p=0.001) improved significantly. In the in-person cohort, the roles and responsibilities sub-score improved significantly (12 [10-14] vs. 13 [11-14]; p=0.017). No significant differences were observed between cohorts (p<0.05). Themes identified in the qualitative analysis were advantages & positive experiences, competencies acquired, disadvantages & challenges, and preferences & suggestions. In-person and virtual ICD courses seem to have similar effects on students' interprofessional learning. However, students reported preferring the in-person setting for learning anatomy-dissection skills.

Deep brain stimulation devices can disrupt cardiac rhythm interpretation by causing electrocardiogram artifact. We report the case of a deep brain stimulating device initiating ventricular fibrillation simulated electrocardiogram artifact in the prehospital setting. Mimicked ventricular fibrillation due to a deep brain stimulator has not been documented, and if unrecognized could influence unwarranted or potentially harmful clinical decisions.

Background: Current critical care pharmacist (CCP) practices and perceptions related to neuromuscular infusion (NMBI) use for acute respiratory distress syndrome (ARDS) maybe different with the COVID-19 pandemic and the publication of 2020 NMBI practice guidelines. Objective: To evaluate CCP practices and perceptions regarding NMBI use for patients with moderate-severe ARDS. Methods: We developed, tested, and electronically administered a questionnaire (7 parent-, 42 sub-questions) to 409 American College of Clinical Pharmacy (ACCP) Critical Care Practice and Research Network members in 12 geographically diverse states. The questionnaire focused on adults with moderate-severe ARDS (PaO2:FiO2<150) whose causes of dyssynchrony were addressed. Two reminders were sent at 10-day intervals. Results: Respondents [131/409 (32%)] primarily worked in a medical intensive care unit (ICU) 102 (78%). Compared to COVID-negative(-) ARDS patients, COVID positive(+) ARDS patients were twice as likely to receive a NMBI (34 ± 18 vs.16 ± 17%; P < 0.01). Respondents somewhat/strongly agreed a NMBI should be reserved until after trials of deep sedation (112, 86%) or proning (92, 81%) and that NMBI reduced barotrauma (88, 67%), dyssynchrony (87, 66%), and plateau pressure (79, 60%). Few respondents somewhat/strongly agreed that a NMBI should be initiated at ARDS onset (23, 18%) or that NMBI reduced 90-day mortality (12, 10%). Only 2/14 potential NMBI risks [paralysis awareness (101, 82%) and prolonged muscle weakness (84, 68%)] were frequently reported to be of high/very high concern. Multiple NMBI titration targets were assessed as very/extremely important including arterial pH (109, 88%), dyssynchrony (107, 86%), and PaO2: FiO2 ratio (82, 66%). Train-of-four (55, 44%) and BIS monitoring (36, 29%) were deemed less important. Preferred NMBI discontinuation criteria included absence of dysschrony (84, 69%) and use ≥48 hour (72, 59%). Conclusions and relevance: Current critical care pharmacists believe NMBI for ARDS patients are best reserved until after trials of deep sedation or proning; unique considerations exist in COVID+ patients. Our results should be considered when ICU NMBI protocols are being developed and bedside decisions regarding NMBI use in ARDS are being formulated.

Background: Pharmacological treatment is common in practice and widely used for the management of insomnia. However, evidence comparing the relative effectiveness, safety, and certainty of evidence among drug classes and individual drugs for insomnia are still lacking. This study aimed to determine the relative effectiveness, safety, and tolerability of drugs for insomnia. Methods: In this systematic review and network meta-analysis we systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and ClinicalTrials.gov, from inception to January 10, 2022 to identify randomized controlled trials that compared insomnia drugs with placebo or an active comparator in adults with insomnia. We conducted random-effects frequentist network meta-analyses to summarize the evidence, and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty, categorize interventionsand present the findings. Results: A total of 148 articles met our eligibility criteria; these included 153 trials which enrolled 46,412 participants and assessed 36 individual drugs from eight drug classes. Compared with placebo, both subjectively and objectively measured total sleep time were significantly improved with non-benzodiazepine (subjective: mean difference [MD] 25.07, 95% confidence interval [CI] 15.49-34.64, low certainty; objective: MD 22.34, 95% CI 7.64-37.05, high certainty), antidepressants (subjective: MD 54.40, 95% CI 34.96-75.83, low certainty; objective: MD 35.64, 95% CI 13.05-58.24, high certainty), and orexin receptor antagonists (subjective: MD 21.62, 95% CI 0.84-42.40, high certainty; objective: MD 31.81, 95% CI 2.66-60.95, high certainty); of which doxepin, almorexant, suvorexant, and lemborexant were among the relatively effective drugs with relatively good tolerability and lower risks of any adverse events (AEs). Both subjectively and objectively measured sleep onset latency were significantly shortened with non-benzodiazepines (subjective: MD - 10.12, 95% CI - 13.84 to - 6.40, moderate certainty; objective: MD - 12.11, 95% CI - 19.31 to - 4.90, moderate certainty) and melatonin receptor agonists (subjective: MD - 7.73, 95% CI - 15.21 to - 0.26, high certainty; objective: MD - 7.04, 95% CI - 12.12 to - 1.95, moderate certainty); in particular, zopiclone was among the most effective drugs with a lower risk of any AEs but worse tolerability. Non-benzodiazepines could significantly decrease both subjective and objective measured wake time after sleep onset (subjective: MD - 16.67, 95% CI - 21.79 to - 11.56, moderate certainty; objective: MD - 13.92, 95% CI - 22.71 to - 5.14, moderate certainty). Conclusions: Non-benzodiazepines probably improve total sleep time, sleep onset latency, and wake time after sleep onset. Other insomnia drug classes and individual drugs also showed potential benefits in improving insomnia symptoms. However, the choice of insomnia drugs should be based on the phenotype of insomnia presented, as well as each drug's safety and tolerability. Protocol registration PROSPERO (CRD42019138790).