Endometrial compaction to predict pregnancy outcomes in patients undergoing assisted reproductive technologies: a systematic review and meta-analysis.

STUDY QUESTION: Does endometrial compaction (EC) help predict pregnancy outcomes in those undergoing ART? SUMMARY ANSWER: EC is associated with a significantly higher clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR), but this does not translate to live birth rate (LBR). WHAT IS KNOWN ALREADY: EC describes the progesterone-induced decrease in endometrial thickness, which may be observed following the end of the proliferative phase, prior to embryo transfer. EC is proposed as a non-invasive tool to help predict pregnancy outcome in those undergoing ART, however, published data is conflicting. STUDY DESIGN SIZE DURATION: A literature search was carried out by two independent authors using PubMed, Cochrane Library, MEDLINE, Embase, Science Direct, Scopus, and Web of Science from inception of databases to May 2023. All peer-reviewed studies reporting EC and pregnancy outcomes in patients undergoing IVF/ICSI treatment were included. PARTICIPANTS/MATERIALS SETTING METHODS: The primary outcome is LBR. Secondary outcomes included other pregnancy metrics (positive pregnancy test (PPT), CPR, OPR, miscarriage rate (MR)) and rate of EC. Comparative meta-analyses comparing EC and no EC were conducted for each outcome using a random-effects model if I 2 > 50%. The Mantel-Haenszel method was applied for pooling dichotomous data. Results are presented as odds ratios (OR) with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 4030 screened articles, 21 cohort studies were included in the final analysis (n = 27 857). No significant difference was found between LBR in the EC versus the no EC group (OR 0.95; 95% CI 0.87-1.04). OPR was significantly higher within the EC group (OR 1.61; 95% CI 1.09-2.38), particularly when EC ≥ 15% compared to no EC (OR 3.52; 95% CI 2.36-5.23). CPR was inconsistently defined across the studies, affecting the findings. When defined as a viable intrauterine pregnancy <12 weeks, the EC group had significantly higher CPR than no EC (OR 1.83; 95% CI 1.15-2.92). No significant differences were found between EC and no EC for PPT (OR 1.54; 95% CI 0.97-2.45) or MR (OR 1.06; 95% CI 0.92-1.56). The pooled weighted incidence of EC across all studies was 32% (95% CI 26-38%). LIMITATIONS REASONS FOR CAUTION: Heterogeneity due to differences between reported pregnancy outcomes, definition of EC, method of ultrasound, and cycle protocol may account for the lack of translation between CPR/OPR and LBR findings; thus, all pooled data should be viewed with an element of caution. WIDER IMPLICATIONS OF THE FINDINGS: In this dataset, the significantly higher CPR/OPR with EC does not translate to LBR. Although stratification of women according to EC cannot currently be recommended in clinical practice, a large and well-designed clinical trial to rigorously assess EC as a non-invasive predictor of a successful pregnancy is warranted. We urge for consistent outcome reporting to be mandated for ART trials so that data can be pooled, compared, and concluded on. STUDY FUNDING/COMPETING INTERESTS: H.A. was supported by the Hewitt Fertility Centre. S.G.P. and J.W. were supported by the Liverpool University Hospital NHS Foundation Trust. D.K.H. was supported by a Wellbeing of Women project grant (RG2137) and MRC clinical research training fellowship (MR/V007238/1). N.T. was supported by the National Institute for Health and Care Research. D.K.H. had received honoraria for consultancy for Theramex and has received payment for presentations from Theramex and Gideon Richter. The remaining authors have no conflicts of interest to report. REGISTRATION NUMBER: PROSPERO CRD42022378464.

Genitourinary syndrome of menopause: Evaluation of symptoms, using a questionnaire, in a research setting, before and after treatment.

BACKGROUND: Genitourinary syndrome of menopause (GSM) is a common condition, yet there is no defined, objective, and reproducible intervention with which to make a diagnosis. There are many different treatment options available, but without the correct diagnosis, affected women are unable to access the right therapy. This paper reports on the questionnaire arm of the VAN study (VAginal Health - What's Normal?) which aimed to evaluate the performance and acceptability of the methods of assessment of GSM, described below. OBJECTIVES: To determine the value of the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire: a multidimensional measure of the impact of vaginal symptoms on functioning and well-being in postmenopausal women, in a prospective, observational, feasibility study. METHODS: 60 women were recruited to the study (20 premenopausal, asymptomatic women (control group) and 40 peri- and postmenopausal, symptomatic women). All women had a baseline assessment, using three different interventions, in addition to the DIVA questionnaire and symptomatic women were offered treatment, followed by a second assessment undertaken at 16 weeks, using the same interventions. This paper focusses on the outcomes for the questionnaire and specifically on the paired data sets, before and after treatment. RESULTS: An improvement in the score for all four sections of DIVA (Activities of daily living, Emotions, Sexual Activity, and Feelings about yourself and your body (female embodiment)) was observed, following any treatment. Additional questions were added to DIVA, to assess patient preference in relation to the different diagnostic interventions. These included a speculum examination as part of the clinical assessment, a smear taken from the lateral vaginal wall to assess the vaginal maturation index, both undertaken by a clinician and a self-administered tampon to collect vaginal secretions, to determine the small molecule metabolite profile, using NMR spectroscopy, and to enable analysis of the vaginal microbiome. The medical standard tampon was the preferred intervention, before and after treatment, for women eligible for treatment. CONCLUSION: The VAN study demonstrates that DIVA, a previously tested questionnaire, is an easily accessible intervention, to assess the impact of urogenital symptoms on quality-of-life indicators in women in the United Kingdom with GSM and that women prefer to use a tampon themselves, rather than have a clinician performed vaginal speculum examination or a vaginal smear.

Surgical Treatment for Endometrial Cancer, Hysterectomy Performed via Minimally Invasive Routes Compared with Open Surgery: A Systematic Review and Network Meta-Analysis.

Background: Total hysterectomy with bilateral salpingo-oophorectomy via minimally invasive surgery (MIS) has emerged as the standard of care for early-stage endometrial cancer (EC). Prior systematic reviews and meta-analyses have focused on outcomes reported solely from randomised controlled trials (RCTs), overlooking valuable data from non-randomised studies. This inaugural systematic review and network meta-analysis comprehensively compares clinical and oncological outcomes between MIS and open surgery for early-stage EC, incorporating evidence from randomised and non-randomised studies. Methods: This study was prospectively registered on PROSPERO (CRD42020186959). All original research of any experimental design reporting clinical and oncological outcomes of surgical treatment for endometrial cancer was included. Study selection was restricted to English-language peer-reviewed journal articles published 1 January 1995-31 December 2021. A Bayesian network meta-analysis was conducted. Results: A total of 99 studies were included in the network meta-analysis, comprising 181,716 women and 14 outcomes. Compared with open surgery, laparoscopic and robotic-assisted surgery demonstrated reduced blood loss and length of hospital stay but increased operating time. Compared with laparoscopic surgery, robotic-assisted surgery was associated with a significant reduction in ileus (OR = 0.40, 95% CrI: 0.17-0.87) and total intra-operative complications (OR = 0.38, 95% CrI: 0.17-0.75) as well as a higher disease-free survival (OR = 2.45, 95% CrI: 1.04-6.34). Conclusions: For treating early endometrial cancer, minimal-access surgery via robotic-assisted or laparoscopic techniques appears safer and more efficacious than open surgery. Robotic-assisted surgery is associated with fewer complications and favourable oncological outcomes.

Prevalence of chronic pain after severe lower limb injury (SLLI): A systematic review and meta-analysis.

BACKGROUND: Globally, severe lower limb injuries (SLLIs) are the predominant cause of long-term injury related disability and poor functional outcomes. Chronic pain is a major source of this morbidity, but the magnitude of the contribution is not clearly understood. The aim of this systematic review and meta-analysis was to determine the prevalence of chronic pain following SLLIs in civilian and military patients. METHOD: This systematic review was prospectively registered with The International Prospective Register of Systematic Reviews (PROSPERO) with study ID CRD42022313615. A systematic literature search (Medline, Embase, Ovid, and Web of Science) was performed to identify original studies that reported chronic pain outcomes for adults who underwent surgical treatment for SLLIs in a civilian or military setting. Risk of bias in included studies was assessed using the ROBINS-E tool, and quality assessment was reported at study level using the Newcastle-Ottawa Scale, and at outcome-level using the GRADE framework. Absolute (proportional) and relative (odds ratio) outcome measures were calculated and pooled using a random effects model. RESULTS: Forty-three studies reporting the outcomes of 5601 patients were included. Estimated overall prevalence of pain was 63 % (CI 55-70 %). The prevalence of chronic pain in amputees (64 % (CI 55-73 %)) was similar to those who underwent limb salvage (56 % (CI 44-67 %)). The prevalence of chronic pain in civilian populations was 70 % (CI 63-77 %) compared to military populations (51 % (CI 35-66 %)). In amputees, the prevalence of residual limb pain was similar to phantom limb pain (OR 1.06 [0.64-1.78], p = 0.81, I2 = 92 %). CONCLUSION: Most people who sustain a SLLI will suffer from chronic pain. Healthcare systems must continue to research interventions that can reduce the incidence and severity of long-term pain and ensure adequate resources are allocated for this common and debilitating complication.

What is the optimal timing of surgery after short-course radiotherapy for rectal cancer?

BACKGROUND: Short-course neoadjuvant radiotherapy is a valuable tool in managing rectal cancers and has improved local recurrence rates. However, limited and conflicting data has resulted in variable usage and a lack of consensus on the optimal timing of surgery following short-course radiotherapy. This review aims to provide a contemporary summation of the available evidence regarding the optimal time interval between short-course neoadjuvant radiotherapy and surgery. METHODS: A focused literature search was undertaken using the PubMed and Embase databases from January 1980 until January 2023. Randomised control trials, large observational studies and systematic reviews focusing on the use of short-course preoperative radiotherapy for localised rectal cancers, with a focus on the timing of surgery, were included. Primary outcomes were overall survival, disease-free survival and perioperative complications. RESULTS: Five randomised control trials, two meta-analyses, and two large, population-based studies were included for their eligibility and relevance. Increased downstaging and fewer postoperative complications are demonstrated in patients receiving delayed surgery (> four weeks), but more recent data raise concerns regarding increased rates of local recurrence in this cohort. Studies directly comparing different time intervals to surgery following short-course radiotherapy have failed to demonstrate an effect on overall survival. CONCLUSIONS: This review highlights the complexities and relative shortcomings of the available data with few high-quality studies and randomised control trials directly comparing different time intervals to surgery following short-course radiotherapy. Continuing research is needed to confirm existing findings and explore gaps in the current literature.

The role of iron in the pathogenesis of endometriosis: a systematic review.

STUDY QUESTION: What is the role of iron in the pathophysiology of endometriosis? SUMMARY ANSWER: Iron excess is demonstrated wherever endometriotic tissues are found and is associated with oxidative stress, an inflammatory micro-environment, and cell damage; the iron-mediated oxidative stress is independently linked to subfertility, symptom severity, and malignant transformation. WHAT IS KNOWN ALREADY: Iron is found in excess in endometriotic tissues, and multiple mechanisms have been studied and posited to explain this. It is clear that iron excess plays a vital role in promoting oxidative stress and cell damage. The evidence base is large, but no comprehensive reviews exist to summarize our understanding and highlight the overarching themes to further our understanding and suggest future directions of study for the field. STUDY DESIGN SIZE DURATION: This systematic review with a thematic analysis retrieved studies from the PubMed, Embase, Web of Science, and Cochrane Library databases and searches were conducted from inception through to August 2022. Human and animal studies published in the English language were included and identified using a combination of exploded MeSH terms ('Iron' and 'Endometriosis') and free-text search terms ('Iron', 'Ferric', 'Ferrous', 'Endometriosis', 'Endometrioma'). PARTICIPANTS/MATERIALS SETTING METHODS: This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning the role of iron or iron complexes in the pathophysiology of endometriosis were included. Studies that did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included study by using the Newcastle-Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE: There were 776 records identified and these were screened down to 53 studies which met the eligibility criteria, including 6 animal and 47 human studies, with 3556 individual participants. Iron excess is demonstrated in various tissues and fluids, including ovarian endometriomas, ovarian follicles, ectopic endometriotic lesions, and peritoneal fluid. Markers of oxidative stress are strongly associated with high iron levels, and aberrant expression of iron-transport proteins has been demonstrated. Abnormal resistance to ferroptosis is likely. Iron-mediated oxidative stress is responsible for a pro-inflammatory micro-environment and is linked to subfertility, symptom severity, and, possibly, malignant transformation. LIMITATIONS REASONS FOR CAUTION: A minority of the included studies were of objectively low quality with a high risk of bias and may lead to misleading conclusions. Additionally, multiple studies failed to appropriately characterize the included patients by known confounding variables, such as menstrual cycle phase, which may introduce bias to the findings. WIDER IMPLICATIONS OF THE FINDINGS: Current literature depicts a central role of aberrant iron mechanics and subsequent oxidative stress in endometriosis. It is likely that iron excess is at least partly responsible for the persistence and proliferation of ectopic endometriotic lesions. As such, iron mechanics represent an attractive target for novel therapeutics, including iron chelators or effectors of the iron-oxidative stress pathway. There are significant gaps in our current understanding, and this review highlights and recommends several topics for further research. These include the role of iron chelation, resistance to ferroptosis, the relationship between iron excess and localized hypoxia, systemic iron pathophysiology in endometriosis, and the role of oxidative stress in malignant transformation. STUDY FUNDING/COMPETING INTERESTS: J.W. and S.G.P. are supported by clinical fellowships at Liverpool University Hospital NHS Foundation trust. No additional funding was requested or required for the completion of this work. C.J.H. is supported by a Wellbeing of Women project grant (RG2137). D.K.H. is supported by a Wellbeing of Women project grant (RG2137) and an MRC clinical research training fellowship (MR/V007238/1). The authors have no conflicts of interest to declare. REGISTRATION NUMBER: A protocol was prospectively registered with the PROSPERO database in August 2021 (CRD42021272818).

Inguinal lymph node metastases from rectal adenocarcinoma: a systematic review.

PURPOSE: Inguinal lymph nodes are a rare but recognised site of metastasis in rectal adenocarcinoma. No guideline or consensus exists for the management of such cases. This review aims to provide a contemporary and comprehensive analysis of the published literature to aid clinical decision-making. METHODS: Systematic searches were performed using the PubMed, Embase, MEDLINE and Scopus and Cochrane CENTRAL Library databases from inception till December 2022. All studies reporting on the presentation, prognosis or management of patients with inguinal lymph node metastases (ILNM) were included. Pooled proportion meta-analyses were completed when possible and descriptive synthesis was utilised for the remaining outcomes. The Joanna Briggs Institute tool for case series was used to assess the risk of bias. RESULTS: Nineteen studies were eligible for inclusion, encompassing 18 case series and one population-based study using national registry data. A total of 487 patients were included in the primary studies. The prevalence of ILNM in rectal cancer is 0.36%. ILNM are associated with very low rectal tumours with a mean distance from the anal verge of 1.1 cm (95% CI 0.92-1.27). Invasion of the dentate line was found in 76% of cases (95% CI 59-93). In patients with isolated inguinal lymph node metastases, modern chemoradiotherapy regimens in combination with surgical excision of inguinal nodes are associated with 5-year overall survival rates of 53-78%. CONCLUSION: In specific subsets of patients with ILNM, curative-intent treatment regimens are feasible, with oncological outcomes akin to those demonstrated in locally advanced rectal cancers.

Vascularisation in Deep Endometriosis: A Systematic Review with Narrative Outcomes.

Deep endometriosis (DE) is the most severe subtype of endometriosis, with the hallmark of lesions infiltrating adjacent tissue. Abnormal vascularisation has been implicated in contributing to endometriosis lesion development in general, and how vascularisation influences the pathogenesis of DE, in particular, is of interest. This systematic review followed the PRISMA guidelines to elucidate and examine the evidence for DE-specific vascularisation. A literature search was performed using MEDLINE, Embase, PubMed, Scopus, Cochrane CENTRAL Library and Europe PubMed Central databases. The databases were searched from inception to the 13 March 2023. A total of 15 studies with 1125 patients were included in the review. The DE lesions were highly vascularised, with a higher microvessel density (MVD) than other types of endometriotic lesions, eutopic endometrium from women with endometriosis and control tissue. Vascular endothelial growth factor, its major subtype (VEGF-A) and associated receptor (VEGFR-2) were significantly increased in the DE lesions compared to superficial endometriosis, eutopic endometrium and control tissue. Progestin therapy was associated with a significant decrease in the MVD of the DE lesions, explaining their therapeutic effect. This review comprehensively summarises the available literature, reporting abnormal vascularisation to be intimately related to the pathogenesis of DE and presents potentially preferential therapeutic targets for the medical management of DE.

A Micro-Longitudinal Study of Naps, Sleep Disturbance, and Headache Severity in Women with Chronic Migraine.

OBJECTIVE: To examine the relationship between headaches, naps, and nocturnal sleep in women with chronic migraine (CM) using micro-longitudinal data from diaries and actigraphy. METHODS: 20 women with CM and 20 age and sex-matched healthy controls (HC) completed self-report questionnaires, electronic diaries, and wrist actigraphy over a 4-week period. Between-group comparisons were conducted with naps (frequency and duration) as the primary variable of interest. Within-group analyses were conducted on the CM group using hierarchical linear mixed models to examine the temporal relationships between headache severity, sleep behaviors, and sleep parameters. The primary variables of interest were naps (number and duration) and nocturnal sleep efficiency (diary and actigraphy). RESULTS: The CM group reported significantly more days with naps (25.85%) compared to the HC group (9.03%) during the study period (p = .0025). Within-group analyses in CM revealed that greater headache severity was associated with longer nap duration (p = .0037) and longer nap duration was associated with lower sleep efficiency measured using diaries (p = .0014) and actigraphy (p < .0001). CONCLUSIONS: Napping is more frequent in CM than HC and nap duration in CM is associated with headache severity and nocturnal sleep disturbance. These findings provide initial support for the hypothesis that daytime napping is a behavioral coping strategy used in CM that could contribute to insomnia.

Desynchronizing the sleep---wake cycle from circadian timing to assess their separate contributions to physiology and behaviour and to estimate intrinsic circadian period.

Circadian clocks drive cyclic variations in many aspects of physiology, but some daily variations are evoked by periodic changes in the environment or sleep-wake state and associated behaviors, such as changes in posture, light levels, fasting or eating, rest or activity and social interactions; thus, it is often important to quantify the relative contributions of these factors. Yet, circadian rhythms and these evoked effects cannot be separated under typical 24-h day conditions, because circadian phase and the length of time awake or asleep co-vary. Nathaniel Kleitman's forced desynchrony (FD) protocol was designed to assess endogenous circadian rhythmicity and to separate circadian from evoked components of daily rhythms in multiple parameters. Under FD protocol conditions, light intensity is kept low to minimize its impact on the circadian pacemaker, and participants have sleep-wake state and associated behaviors scheduled to an imposed non-24-h cycle. The period of this imposed cycle, Τ, is chosen so that the circadian pacemaker cannot entrain to it and therefore continues to oscillate at its intrinsic period (τ, ~24.15 h), ensuring circadian components are separated from evoked components of daily rhythms. Here we provide detailed instructions and troubleshooting techniques on how to design, implement and analyze the data from an FD protocol. We provide two procedures: one with general guidance for designing an FD study and another with more precise instructions for replicating one of our previous FD studies. We discuss estimating circadian parameters and quantifying the separate contributions of circadian rhythmicity and the sleep-wake cycle, including statistical analysis procedures and an R package for conducting the non-orthogonal spectral analysis method that enables an accurate estimation of period, amplitude and phase.

The immune cell profile of human fallopian tubes in health and benign pathology: a systematic review.

The fallopian tubes (FT) play a key role in fertility by facilitating the movement of gametes to promote fertilisation and, subsequently, passage of the zygote for implantation. Histologically, the FT mucosa consists of three main cell types: secretory, ciliated and peg cells. In addition, several studies have reported the presence of immune cells. This systematic review aims to present a comprehensive analysis of the immune cell populations in the human FT, both in health and benign pathology, to promote a better understanding of tubal pathologies and their influence on infertility. A comprehensive literature search was conducted across five databases and augmented with manual citation chaining. Forty-two eligible studies were selected in accordance with PRISMA guidelines. Following screening, risk of bias assessments were conducted, data extracted and the findings presented thematically. T lymphocytes, predominantly CD8+ T cells, represent the most abundant immune cell population within the healthy FT, with B lymphocytes, macrophages, NK cells and dendritic cells also localised to the tubal mucosa. There is evidence to suggest that lymphocyte and macrophage populations are susceptible to changes in the concentration of reproductive hormones. Tubal ectopic pregnancy, salpingitis, hydrosalpinx and endometriosis are all characterised by an increased population of macrophages in comparison to healthy FT. However, given the inconsistent evidence presented between studies, and the lack of studies examining all immune cell subtypes in tubal pathologies, only limited conclusions can be formulated on pathology-specific immune cell populations, and further research is required for validation.

Playing the harmonica with chronic obstructive pulmonary disease. A qualitative study.

Objectives: To investigate the experience of playing the harmonica for individuals with COPD.Methods: A qualitative, phenomenological study using semi-structured interviews and reflexive thematic analysis.Results: Eight people living with COPD (six females, two males) were recruited, who had attended at least six weeks of harmonica group sessions, either face-to-face prior to the COVID-19 pandemic or remotely. Five themes were generated. Themes included 'hard in the beginning', 'holding the condition', 'breathing control', 'gives you a high' and 'needing the Zoom class'.Discussion: Playing the harmonica with COPD is difficult at first, particularly drawing a breath through the harmonica. With practice, experience in a fun activity and quality teaching, individuals were able to become more attuned and embodied with their breathing, and playing the harmonica offered a breathing control strategy. Songs, rather than breathing, became the focus, and participants were able to escape living with respiratory disease when playing. Participants reported the harmonica helped mucous expectoration. The group was a priority in the weekly lives of participants, even though the 'buzz' of being part of a group was lost when participating online. Further mechanistic studies and randomised controlled trials are needed to investigate the biopsychosocial benefits of playing the harmonica with COPD.

Completion Total Mesorectal Excision After Transanal Local Excision of Early Rectal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Completion total mesorectal excision is recommended when local excision of early rectal cancers demonstrates high-risk histopathological features. Concerns regarding the quality of completion resections and the impact on oncological safety remain unanswered. OBJECTIVE: This study aims to summarize and analyze the outcomes associated with completion surgery and undertake a comparative analysis with primary rectal resections. DATA SOURCES: Data sources included PubMed, Cochrane library, MEDLINE, and Embase databases up to April 2021. STUDY SELECTION: All studies reporting any outcome of completion surgery after transanal local excision of an early rectal cancer were selected. Case reports, studies of benign lesions, and studies using flexible endoscopic techniques were not included. INTERVENTION: The intervention was completion total mesorectal excision after transanal local excision of early rectal cancers. MAIN OUTCOME MEASURES: Primary outcome measures included histopathological and long-term oncological outcomes of completion total mesorectal excision. Secondary outcome measures included short-term perioperative outcomes. RESULTS: Twenty-three studies including 646 patients met the eligibility criteria, and 8 studies were included in the meta-analyses. Patients undergoing completion surgery have longer operative times (standardized mean difference, 0.49; 95% CI, 0.23-0.75; p = 0.0002) and higher intraoperative blood loss (standardized mean difference, 0.25; 95% CI, 0.01-0.5; p = 0.04) compared with primary resections, but perioperative morbidity is comparable (risk ratio, 1.26; 95% CI, 0.98-1.62; p = 0.08). Completion surgery is associated with higher rates of incomplete mesorectal specimens (risk ratio, 3.06; 95% CI, 1.41-6.62; p = 0.005) and lower lymph node yields (standardized mean difference, -0.26; 95% CI, -0.47 to 0.06; p = 0.01). Comparative analysis on long-term outcomes is limited, but no evidence of inferior recurrence or survival rates is found. LIMITATIONS: Only small retrospective cohort and case-control studies are published on this topic, with considerable heterogeneity limiting the effectiveness of meta-analysis. CONCLUSIONS: This review provides the strongest evidence to date that completion surgery is associated with an inferior histopathological grade of the mesorectum and finds insufficient long-term results to satisfy concerns regarding oncological safety. International collaborative research is required to demonstrate noninferiority. REGISTRATION NO: CRD42021245101.

A randomized controlled trial of cognitive behavioral therapy for insomnia and PAP for obstructive sleep apnea and comorbid insomnia: effects on nocturnal sleep and daytime performance.

STUDY OBJECTIVES: This study examines the impact of cognitive behavioral therapy for insomnia (CBT-I) and positive airway pressure (PAP) therapy for comorbid insomnia and sleep apnea on nocturnal sleep and daytime functioning. METHODS: A partial factorial design was used to examine treatment pathways with CBT-I and PAP and the relative benefits of each treatment. One hundred eighteen individuals with comorbid insomnia and sleep apnea were randomized to receive CBT-I followed by PAP, self-monitoring followed by CBT-I concurrent with PAP, or self-monitoring followed by PAP only. Participants were assessed at baseline, PAP titration, and 30 and 90 days after PAP initiation. Outcome measures included sleep diary- and actigraphy-measured sleep, Flinders Fatigue Scale, Epworth Sleepiness Scale, Functional Outcome of Sleep Questionnaire, and cognitive emotional measures. RESULTS: A main effect of time was found on diary-measured sleep parameters (decreased sleep onset latency and wake after sleep onset; increased total sleep time and sleep efficiency) and actigraphy-measured sleep parameters (decreased wake after sleep onset; increased sleep efficiency) and daytime functioning (reduced Epworth Sleepiness Scale, Flinders Fatigue Scale; increased Functional Outcome of Sleep Questionnaire) across all arms (all P < .05). Significant interactions and planned contrast comparisons revealed that CBT-I was superior to PAP and self-monitoring on reducing diary-measured sleep onset latency and wake after sleep onset and increasing sleep efficiency, as well as improving Functional Outcome of Sleep Questionnaire and Flinders Fatigue Scale compared to self-monitoring. CONCLUSIONS: Improvements in sleep and daytime functioning were found with PAP alone or concomitant with CBT-I. However, more rapid effects were observed on self-reported sleep and daytime performance when receiving CBT-I regardless of when it was initiated. Therefore, concomitant treatment appears to be a favorable approach to accelerate treatment outcomes. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Multidisciplinary Approach to the Treatment of Insomnia and Comorbid Sleep Apnea (MATRICS); URL: https://clinicaltrials.gov/ct2/show/NCT01785303; Identifier: NCT01785303. CITATION: Tu AY, Crawford MR, Dawson SC, et al. A randomized controlled trial of cognitive behavioral therapy for insomnia and PAP for obstructive sleep apnea and comorbid insomnia: effects on nocturnal sleep and daytime performance. J Clin Sleep Med. 2022;18(3):789-800.

Efficacy of intermittent exposure to bright light for treating maladaptation to night work on a counterclockwise shift work rotation.

OBJECTIVES: Rotating shift work is associated with adverse outcomes due to circadian misalignment, sleep curtailment, work-family conflicts, and other factors. We tested a bright light countermeasure to enhance circadian adaptation on a counterclockwise rotation schedule. METHODS: Twenty-nine adults (aged 20-40 years; 15 women) participated in a 4-week laboratory simulation with weekly counterclockwise transitions from day, to night, to evening, to day shifts. Each week consisted of five 8-hour workdays including psychomotor vigilance tests, two days off, designated 8-hour sleep episodes every day, and an assessment of circadian melatonin secretion. Participants were randomized to a treatment group (N=14), receiving intermittent bright light during work designed to facilitate circadian adaptation, or a control group (N=15) working in indoor light. Adaptation was measured by how much of the melatonin secretion episode overlapped with scheduled sleep timing. RESULTS: On the last night shift, there was a greater overlap between melatonin secretion and scheduled sleep time in the treatment group [mean 4.90, standard deviation (SD) 2.8 hours] compared to the control group (2.62, SD 2.8 hours; P=0.002), with night shift adaptation strongly influenced by baseline melatonin timing (r2=-0.71, P=0.01). While the control group exhibited cognitive deficits on the last night shift, the treatment group's cognitive deficits on the last night and evening shifts were minimized. CONCLUSIONS: In this laboratory setting, intermittent bright light during work hours enhanced adaptation to night work and subsequent readaptation to evening and day work. Light regimens scheduled to shift circadian timing should be tested in actual shift workers on counterclockwise schedules as a workplace intervention.

Workshop report. Circadian rhythm sleep-wake disorders: gaps and opportunities.

This White Paper presents the results from a workshop cosponsored by the Sleep Research Society (SRS) and the Society for Research on Biological Rhythms (SRBR) whose goals were to bring together sleep clinicians and sleep and circadian rhythm researchers to identify existing gaps in diagnosis and treatment and areas of high-priority research in circadian rhythm sleep-wake disorders (CRSWD). CRSWD are a distinct class of sleep disorders caused by alterations of the circadian time-keeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm and the external environment. In these disorders, the timing of the primary sleep episode is either earlier or later than desired, irregular from day-to-day, and/or sleep occurs at the wrong circadian time. While there are incomplete and insufficient prevalence data, CRSWD likely affect at least 800,000 and perhaps as many as 3 million individuals in the United States, and if Shift Work Disorder and Jet Lag are included, then many millions more are impacted. The SRS Advocacy Taskforce has identified CRSWD as a class of sleep disorders for which additional high-quality research could have a significant impact to improve patient care. Participants were selected for their expertise and were assigned to one of three working groups: Phase Disorders, Entrainment Disorders, and Other. Each working group presented a summary of the current state of the science for their specific CRSWD area, followed by discussion from all participants. The outcome of those presentations and discussions are presented here.

A randomized controlled trial of CBT-I and PAP for obstructive sleep apnea and comorbid insomnia: main outcomes from the MATRICS study.

STUDY OBJECTIVES: To investigate treatment models using cognitive behavioral therapy for insomnia (CBT-I) and positive airway pressure (PAP) for people with obstructive sleep apnea (OSA) and comorbid insomnia. METHODS: 121 adults with OSA and comorbid insomnia were randomized to receive CBT-I followed by PAP, CBT-I concurrent with PAP, or PAP only. PAP was delivered following standard clinical procedures for in-lab titration and home setup and CBT-I was delivered in four individual sessions. The primary outcome measure was PAP adherence across the first 90 days, with regular PAP use (≥4 h on ≥70% of nights during a 30-day period) serving as the clinical endpoint. The secondary outcome measures were the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) with good sleeper (PSQI <5), remission (ISI <8), and response (ISI reduction from baseline >7) serving as the clinical endpoints. RESULTS: No significant differences were found between the concomitant treatment arms and PAP only on PAP adherence measures, including the percentage of participants who met the clinical endpoint. Compared to PAP alone, the concomitant treatment arms reported a significantly greater reduction from baseline on the ISI (p = .0009) and had a greater percentage of participants who were good sleepers (p = .044) and remitters (p = .008). No significant differences were found between the sequential and concurrent treatment models on any outcome measure. CONCLUSIONS: The findings from this study indicate that combining CBT-I with PAP is superior to PAP alone on insomnia outcomes but does not significantly improve adherence to PAP.

Circadian Rhythm Sleep-Wake Phase Disorders.

This article reviews delayed and advanced sleep-wake phase disorders. Diagnostic procedures include a clinical interview to verify the misalignment of the major nocturnal sleep episode relative to the desired and social-normed timing of sleep, a 3-month or greater duration of the sleep-wake disturbance, and at least a week of sleep diary data consistent with the sleep timing complaint. Treatment options include gradual, daily shifting of the sleep schedule (chronotherapy); shifting circadian phase with properly timed light exposure (phototherapy); or melatonin administration. Future directions are discussed to conclude the article.

Increased high-frequency NREM EEG power associated with mindfulness-based interventions for chronic insomnia: Preliminary findings from spectral analysis.

OBJECTIVE: Mindfulness-based interventions (MBI) have been shown to reduce subjective symptoms of insomnia but the effects on objective measures remain unclear. The purpose of this study was to examine sleep EEG microarchitecture patterns from a randomized controlled trial of Mindfulness-Based Stress Reduction (MBSR) and Mindfulness-Based Therapy for Insomnia (MBTI). METHODS: Sleep EEG spectral analysis was conducted on 36 participants with chronic insomnia (>6 months) randomized to 8-week MBSR, MBTI, or self-monitoring control (SM). Overnight polysomnography with 6-channel EEG was conducted at baseline, post-treatment, and 6-month follow-up. Spectral power averaged from channels C3/C4 across NREM epochs (excluding N1) was examined for within-group changes and relationships with self-report measures. RESULTS: Increases in absolute NREM beta (16-25 Hz) power were observed from baseline to post-treatment (p = .02, d = 0.53) and maintained at 6-month follow-up (p = .01, d = 0.57) in the combined MBI groups, and additionally in the gamma (25-40 Hz) range at follow-up for the MBTI group only. No significant changes in these frequency bands were observed for SM. Following mindfulness intervention, NREM beta was positively associated with Five-Facet Mindfulness (FFM) score (rho = 0.37, p = .091) and negatively associated with Insomnia Severity Index (rho = -0.43, p = .047). CONCLUSION: These results in people with insomnia corroborate prior reports of increased high-frequency sleep EEG power associated with mindfulness training. This change in beta EEG pattern merits further evaluation as a potential marker of the effects of mindfulness meditation on sleep, especially given the paradoxical findings in the context of insomnia. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, NCT00768781.

Sleep, Circadian Rhythms, and Risk Across Health Domains in Adolescents With an Evening Circadian Preference.

Sleep and circadian rhythm changes during adolescence contribute to increased risk across emotional, behavioral, cognitive, social, and physical health domains. This study examines if sleep and dim light melatonin onset (DLMO) are related to greater risk in these 5 health domains. Participants were 163 (93 female, age = 14.7 years) adolescents with an evening circadian preference from a study funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Sleep and circadian measures included weekday total sleep time (TST), bedtime, and shut-eye time assessed via sleep diary, the Children's Morningness-Eveningness Preferences scale, and DLMO. Health domains included self-reported emotional, cognitive, behavioral, social, and physical health. Later DLMO was significantly associated with shorter weekday TST, later weekday bedtime, and later weekday shut-eye time, as well as lower risk in the behavioral domain. At the trend level, later DLMO was related to fewer physical health problems. Earlier DLMO combined with a later bedtime, later shut-eye time, or shorter TST predicted greater risk in the cognitive domain. Later DLMO and shorter TST or a later bedtime predicted worse physical health. DLMO timing was not related to the emotional or social domain. There is evidence that a discrepancy between sleep behaviors and the endogenous circadian rhythm may be related to risk in the cognitive domain for adolescents with an evening circadian preference. Preliminary evidence also indicated that a delayed DLMO and shorter TST or a later bedtime may be related to vulnerability to physical health risk.