Prevalence and Association of Sarcopenia with Mortality in Patients with Head and Neck Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: The objective of this meta-analysis was to assess the association of sarcopenia defined on computed tomography (CT) head and neck with survival in head and neck cancer patients. METHODS: Following a PROSPERO-registered protocol, two blinded reviewers extracted data and evaluated the quality of the included studies using the Quality In Prognostic Studies (QUIPS) tool, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. A meta-analysis was conducted using maximally adjusted hazard ratios (HRs) with the random-effects model. Heterogeneity was measured using the I2 statistic and was investigated using meta-regression and subgroup analyses where appropriate. RESULTS: From 37 studies (11,181 participants), sarcopenia was associated with poorer overall survival (HR 2.11, 95% confidence interval [CI] 1.81-2.45; p < 0.01), disease-free survival (HR 1.76, 95% CI 1.38-2.24; p < 0.01), disease-specific survival (HR 2.65, 95% CI 1.80-3.90; p < 0.01), progression-free survival (HR 2.24, 95% CI 1.21-4.13; p < 0.01) and increased chemotherapy or radiotherapy toxicity (risk ratio 2.28, 95% CI 1.31-3.95; p < 0.01). The observed association between sarcopenia and overall survival remained significant across different locations of cancer, treatment modality, tumor stages and geographical region, and did not differ between univariate and multivariate HRs. Statistically significant correlations were observed between the C3 and L3 cross-sectional area, skeletal muscle mass, and skeletal muscle index. CONCLUSIONS: Among patients with head and neck cancers, CT-defined sarcopenia was consistently associated with poorer survival and greater toxicity.

Postoperative radiotherapy versus surgery alone in pN1 oral cavity cancer patients: A meta-analysis.

Objectives: The aim of this meta-analysis is to evaluate the potential benefits of postoperative radiotherapy (PORT) in patients with pN1 oral cavity squamous cell carcinoma. Methods: A literature search through major databases was conducted until January 2023. The adjusted hazard ratio (aHR) or risk ratio (RR) with 95% confidence intervals (CIs) of different survival outcomes were extracted and pooled. Results: Ten studies published between 2005 and 2022, with a pooled patient population of 2888, were included in this meta-analysis. Due to differences in study design and reported outcomes, the studies were categorized into distinct groups. In pN1 patients without extranodal extension (ENE), PORT was associated with a significant improvement in overall survival (OS) (aHR 0.76, 95% CI: 0.61-0.94). In pN1 patients without ENE and positive margins, PORT improved OS (aHR 0.71, 95% CI: 0.56-0.89) and was associated with a lower regional recurrence rate (RR 0.35, 95% CI: 0.15-0.83). However, in pN1 patients without ENE, positive margins, perineural invasion, and lymphovascular invasion, there were no significant differences observed between the PORT and observation groups in either 5-year OS (RR 0.48, 95% CI: 0.07-3.41) or 5-year disease-free survival (RR 0.37, 95% CI: 0.07-2.06). Conclusions: The current study demonstrated that PORT has the potential to improve OS in pN1 disease. However, the decision of whether to administer PORT still hinges on diverse clinical scenarios, and additional research is necessary to furnish a more conclusive resolution. Level of Evidence: 2.

Serum Biomarkers after Adenotonsillectomy for Pediatric OSA: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess whether adenotonsillectomy improves levels of inflammatory and cardiometabolic markers in children with polysomnographically diagnosed obstructive sleep apnea (OSA). DATA SOURCES: Two authors independently searched PubMed, Embase, and Cochrane databases up to August 16, 2022, for studies relating to pre- and post-operative levels of serum markers in pediatric patients undergoing adenotonsillectomy. REVIEW METHODS: Data were extracted from included articles into a structured proforma. Meta-analyses of the standardized mean difference (SMD) were conducted in random-effects models. We calculated the probability of benefit (POB) and number needed to treat (NNT) for outcomes that demonstrated a statistically significant effect after adenotonsillectomy. The primary outcomes were changes in serum markers including C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), Insulin-like growth factor 1 (IGF-1), interleukin-10 (IL-10), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), Brain natriuretic peptide (BNP), insulin, glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL). RESULTS: We screened 1616 studies and included 26 studies with 1331 participants. Meta-analysis was performed on 20 of the included studies. Adenotonsillectomy was associated with a significant decrease in insulin levels (SMD = -0.322, 95% Confidence Interval (CI) = -0.583 to -0.061), CRP (SMD = -0.946, 95% CI = -1.578 to -0.314), and BNP (SMD = -1.416, 95% CI = -2.355 to -0.477) and significant increase in levels of IGF-1 (SMD = 0.691, 95% CI = 0.207 to 1.176). There were no significant changes in levels of triglyceride, total cholesterol, TNF-α, LDL, HDL, glucose, IL-10, and IL-6. CONCLUSION: In children with polysomnographically diagnosed OSA, adenotonsillectomy was associated with improvements in serum biomarkers, comprising lower CRP, insulin, and BNP, and higher IGF-1. Laryngoscope, 134:3030-3037, 2024.

Concordance of the ACR TI-RADS Classification With Bethesda Scoring and Histopathology Risk Stratification of Thyroid Nodules.

Importance: Although most thyroid nodules are benign, 10% to 15% of them harbor cancer. Thyroid ultrasonography is useful for risk stratification of nodules, and American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) classification provides recommendations for fine-needle aspiration cytology (FNAC) based on objective ultrasonographic features of these nodules. Objective: To validate the concordance of ACR TI-RADS classification with Bethesda classification and histopathology. Design, Setting, and Participants: This retrospective cohort study was performed to evaluate the concordance of ACR TI-RADS classification with Bethesda classification and histopathology and was conducted in Singapore General Hospital Outpatient Otolaryngology clinic in March 2021 to May 2021. Data analysis was performed in May 2021. Main Outcomes and Measures: Results were deemed concordant when ACR TI-RADS recommendations aligned with Bethesda scores. Conversely, results were classified as nonconcordant with Bethesda scores and/or histopathology results when nodules that were recommended for FNAC yielded benign results or nodules that were not recommended for FNAC yielded malignant results. Results: A total of 446 patients (370 women [83%]; mean [range] age, 60 [24-89] years) who underwent ultrasonography of the thyroid and ultrasonography-guided thyroid FNACs were identified. A total of 492 of 630 nodules (78.1%) were benign on FNAC (Bethesda II). Score 3 ACR TI-RADS nodules yielded the highest negative predictive values: 94.6% (95% CI, 92.9%-95.9%; P < .001) compared with Bethesda scoring and 100.0% (95% CI, 15.8%-100.0%; P = .003) compared with histopathology. Score 4 or 5 ACR TI-RADS nodules yielded positive predictive values of 2.8% and 16.2%, respectively, compared with Bethesda scoring and 6.1% and 66.7%, respectively, compared with histopathology. Small (<1.5 cm) ACR TI-RADS nodules of scores of 4 and 5 that were not recommended for FNAC yielded a malignant risk of 5.7% and 25.0% on Bethesda 5 and 6, respectively. On surgical excision, 5 of 46 (10.9%) ACR TI-RADS 4 nodules and 15 of 21 (71.4%) of ACR TI-RADS 5 nodules were confirmed to be malignant. Among nodules initially not recommended for FNAC, histopathology-proven cancer was found in 4 of 13 (30.7%) and 3 of 6 (50.0%) of nodules, respectively. Conclusions and Relevance: These findings suggest that ACR TI-RADS score 3 nodules have a low risk of cancer and should be considered for FNAC only if nodules are 2.5 cm or larger. Patients with small (<1.5 cm) ACR TI-RADS 4 and 5 nodules should be appropriately counseled for FNAC to exclude cancer.

The association of obstructive sleep apnea with blood and cerebrospinal fluid biomarkers of Alzheimer's dementia - A systematic review and meta-analysis.

Alzheimer's disease (AD) is the most common type of dementia and is characterized by the aggregation of extracellular amyloid-beta and intracellular hyperphosphorylation of tau proteins. Obstructive Sleep Apnea (OSA) is associated with increased AD risk. We hypothesize that OSA is associated with higher levels of AD biomarkers. The study aims to conduct a systematic review and meta-analysis of the association between OSA and levels of blood and cerebrospinal fluid biomarkers of AD. Two authors independently searched PubMed, Embase, and Cochrane Library for studies comparing blood and cerebrospinal fluid levels of dementia biomarkers between patients with OSA and healthy controls. Meta-analyses of the standardized mean difference were conducted using random-effects models. From 18 studies with 2804 patients, meta-analysis found that cerebrospinal fluid amyloid beta-40 (SMD:-1.13, 95%CI:-1.65 to -0.60), blood total amyloid beta (SMD:0.68, 95%CI: 0.40 to 0.96), blood amyloid beta-40 (SMD:0.60, 95%CI: 0.35 to 0.85), blood amyloid beta-42 (SMD:0.80, 95%CI: 0.38 to 1.23) and blood total-tau (SMD: 0.664, 95% CI: 0.257 to 1.072, I2 = 82, p<0.01, 7 studies) were significantly higher in OSA patients compared with healthy controls. These findings suggest that OSA is associated with an elevation of some biomarkers of AD.

Obstructive sleep apnoea and glaucoma: a systematic review and meta-analysis.

INTRODUCTION: Obstructive sleep apnoea (OSA) has been thought to be associated with glaucoma, however there are many conflicting studies on this topic. With many new studies having been published since the previous meta-analysis, we believe it is important to clarify this association. Hence, in this study we meta-analyse the recent literature regarding the association between OSA and glaucoma. METHODS: Pubmed, Embase, Scopus and Cochrane Library were searched from inception till the 28th February 2022 for observational as well as cross-sectional studies examining the association between OSA and glaucoma. Two reviewers selected studies, extracted data, graded the quality of included non-randomized studies using the Newcastle-Ottawa scale. The overall quality of evidence was assessed using GRADE. Random-effects models were used to meta-analyse the maximally covariate- adjusted associations. RESULTS: 48 studies were included in our systematic review, with 46 suitable for meta-analysis. Total study population was 4,566,984 patients. OSA was associated with a higher risk of glaucoma (OR 3.66, 95% CI 1.70 to 7.90, I2 = 98%, p < 0.01). After adjustment for various important confounders including age, gender and patient comorbidities such as hyperlipidaemia, hypertension, cardiovascular diseases and diabetes, patients with OSA had up to 40% higher odds of glaucoma. Substantial heterogeneity was eliminated through subgroup and sensitivity analyses after consideration of glaucoma subtype, OSA severity and adjustment for confounders. CONCLUSIONS: In this meta-analysis, OSA was associated with higher risk of glaucoma, as well as more severe ocular findings characteristic of the glaucomatous disease process. We suggest more clinical studies looking into the effects of OSA treatment on the progression of glaucoma to help clinical decision making for patients.

Efficacy of Anti-PD1 Blockade in Treating Recurrent or Metastatic Nasopharyngeal Cancer: A Systematic Review and Meta-analysis.

OBJECTIVES: Anti-PD1 antibody has emerged as a promising immunotherapeutic option in patients with recurrent and/or metastatic nasopharyngeal cancers (RM-NPC). We aim to summarise existing evidence on the use of anti-PD1 antibodies in the treatment of these patients and compare its effectiveness with standard-of-care palliative chemotherapy. Our secondary aim is to explore potential combination therapies with anti-PD1 antibodies. MATERIALS AND METHODS: PubMed, Embase and Cochrane databases were systematically searched for studies comparing the efficacy of various anti-PD1 antibodies in the treatment of RM-NPC (either as first or second line treatment) from inception to 2 September 2022. Meta-analyses were performed to correlate the various anti-PD1 antibodies with primary endpoints including overall response rate disease control rate (DCR), progression free survival (PFS) and overall survival (OS). RESULTS: Eighteen studies with 1,887 patients met the inclusion criteria. The use of anti-PD1 antibody monotherapy as second-line treatment of RM-NPC revealed an ORR of 23 % (95 % CI = 19 %-28 %) and DCR of 51 % (95 % CI = 42 %-60 %). The ORRs for first-line as well as a combination of first and second-line treatments were 21 % (95 % CI = 15 % - 30 %) and 22 % (95 % CI = 6 % - 56 %, I2 = 75 %) respectively. The 12-month PFS and 12-month OS was also 27 % (95 % CI = 21 %-33 %) and 63 % (95 % CI = 53 %-72 %) respectively. ORR was much higher at 73 % (95 % CI = 32 %-94 %) when anti-PD1 antibodies were combined with Gemcitabine plus Cisplatin. CONCLUSION: Anti-PD1 antibody demonstrate considerable activity in previously treated RM-NPC patients. Combining anti-PD1 antibodies with gemcitabine and cisplatin chemotherapy enhanced the efficacy of treatment.

Association between obstructive sleep apnea and floppy eyelid syndrome: A systematic review and metaanalysis.

RATIONALE: Obstructive sleep apnoea (OSA) has been linked to various ocular disorders, including floppy eyelid syndrome (FES). Previous studies have hypothesised the underlying association between the 2 , but results are currently still inconclusive. OBJECTIVE: To investigate the association between OSA and FES. METHODS: Four databases (Pubmed, Embase, Scopus, and Cochrane Library) were searched from inception until 28 February 2022 for observational studies and randomized controlled trials assessing the association between OSA and FES. Two reviewers selected studies, extracted data, graded the risk of bias using the Newcastle-Ottawa scale and the quality of assessment using the Grading of Recommendations Assessment, Development, and Evaluation system. Random-effects models were used to metaanalyze the associations. RESULTS: Twelve studies were included in the systematic review, of which nine were suitable for metaanalysis, with a combined cohort of 1,109 patients. Risk of bias was low to moderate. The overall analysis showed a significant positive association between OSA and FES (OR = 1.89, 95% CI = 1.27-2.83, I 2 = 44%). Further analysis revealed that the more severe the OSA was, the higher the risk of developing FES. Patients with severe OSA had the nominally highest risk of developing FES (OR = 3.06, 95% CI = 1.62-5.78, I 2 = 0%), followed by moderate OSA (OR = 2.53, 95% CI = 1.29-4.97, I 2 = 0%), and patients with mild OSA had the lowest risk (OR = 1.76, 95% CI = 0.85-3.62, I 2 = 0%). CONCLUSION: Our metaanalysis reports a positive association between OSA and FES, with increasing severity of OSA correlating with a significantly higher risk of FES. More longitudinal studies with sufficient duration of follow-up are needed to better characterise the relationship between OSA and FES.

The long-term results of modified maxillomandibular advancement in Asian OSA patients.

OBJECTIVE: Maxillomandibular advancement (MMA) surgery is considered a highly successful treatment for obstructive sleep apnea (OSA). Various modifications to the technique have been described. We aim to study the long-term results in Asian patients who underwent a modified MMA procedure intended to avoid bimaxillary protrusion and which involved four-quadrant bicuspid extractions with posterior maxillary alveolar setback. METHOD: A review of operative logs from 2000 to 2003 was conducted to identify Asian patients who underwent modified MMA during that period, for treatment of moderate and severe OSA. Sleep indices and psychometric performances were prospectively analyzed. RESULTS: Eight Asian patients were included. The mean length of follow-up was 14.4 years (range: 13.0-16.5). Mean preoperative apnea-hypopnea index (AHI) was 48.9 (range: 19.0 to 84.8). Mean post-operative AHI was 31.6 (range: 6.2 to 79.5). This reduction was statistically significant (p<0.05). Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire (FOSQ) revealed that majority of the patients (75%) did not have excessive daytime somnolence and all patients had high FOSQ totalled scores (mean 17.7, range 11.8 to 20), indicating good functional performance. CONCLUSION: This series is the longest follow-up of an Asian cohort who underwent modified MMA. With a mean follow-up of 14.4 years, improvement in AHI is still observed but not at a degree as large as prior studies with shorter lengths of follow-up. The purported efficacy of MMA for Caucasian patients may not be reproducible in Asian patients and long-term sustainability of this treatment's efficacy requires rigorous evaluation.

Improved Inflammatory and Cardiometabolic Profile After Soft-Tissue Sleep Surgery for Obstructive Sleep Apnea: A Systematic Review and Meta-analysis.

Importance: Obstructive sleep apnea (OSA) is associated with a rise in serum inflammatory markers, which may be attenuated by sleep surgery. Objective: To evaluate whether sleep surgery was associated with improved levels of proinflammatory markers in adults with OSA. Data Sources: Two authors independently searched Cochrane, Embase, and PubMed databases from inception through June 14, 2022. Study Selection: Two authors searched the Cochrane, Embase, and PubMed databases for studies comparing preoperative and postoperative levels of serum biomarkers in patients undergoing sleep surgery. Data Extraction and Synthesis: Data were extracted from included articles into a structured proforma. Meta-analyses of the standardized mean difference (SMD) were conducted in random-effects models. To ensure relevance to clinicians and patients, the probability of benefit and number needed to treat were calculated for outcomes that demonstrated a statistically significant effect after sleep surgery. Main Outcomes and Measures: The primary outcome was the preoperative and postoperative levels of serum biomarkers in patients undergoing sleep surgery, including C-reactive protein (CRP), glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and interleukin-6 (IL-6). Data analysis was performed from April to May 2022. Results: Of the 3218 studies screened, 26 studies with 1187 patients (mean [SD] age, 42.8 [11.1] years; 932 [78.5%] men and 255 [21.5%] women) were included. Soft-tissue sleep surgery was associated with a large decrease in CRP (SMD, -0.377; 95% CI, -0.617 to -0.137), total cholesterol (SMD, -0.267; 95% CI, -0.417 to -0.116), LDL (SMD, -0.201; 95% CI, -0.344 to -0.058), IL-6 (SMD, -1.086; 95% CI, -1.952 to -0.221), tumor necrosis factor-α (SMD, -0.822; 95% CI, -1.617 to -0.027), triglyceride (SMD, -0.186; 95% CI, -0.301 to -0.071), and leptin (SMD, -0.519; 95% CI, -0.954 to -0.083) in patients with OSA. Meta-regression highlighted that increased age, higher preoperative score for cumulative sleep time percentage with oxyhemoglobin saturation less than 90% (CT90), and greater change in CT90 postoperatively were associated with a greater decrease in serum CRP levels after soft-tissue sleep surgery. A greater reduction in apnea hypopnea index (AHI) was strongly associated with a greater reduction in total cholesterol and LDL. A greater reduction in body mass index and AHI were also associated with a greater increase in HDL. Conclusions and Relevance: The findings of this systematic review and meta-analysis of 26 studies suggest that sleep surgery is associated with decreased levels of CRP, total cholesterol, LDL, triglyceride, IL-6, leptin, and TNF-α, which may improve the inflammatory and cardiometabolic profile of patients who undergo sleep surgery.

Prognosis and persistence of smell and taste dysfunction in patients with covid-19: meta-analysis with parametric cure modelling of recovery curves.

OBJECTIVE: To clarify in patients with covid-19 the recovery rate of smell and taste, proportion with persistent dysfunction of smell and taste, and prognostic factors associated with recovery of smell and taste. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Scopus, Cochrane Library, and medRxiv from inception to 3 October 2021. REVIEW METHODS: Two blinded reviewers selected observational studies of adults (≥18 years) with covid-19 related dysfunction of smell or taste. Descriptive prognosis studies with time-to-event curves and prognostic association studies of any prognostic factor were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data, evaluated study bias using QUIPS, and appraised evidence quality using GRADE, following PRISMA and MOOSE reporting guidelines. Using iterative numerical algorithms, time-to-event individual patient data (IPD) were reconstructed and pooled to retrieve distribution-free summary survival curves, with recovery rates reported at 30 day intervals for participants who remained alive. To estimate the proportion with persistent smell and taste dysfunction, cure fractions from Weibull non-mixture cure models of plateaued survival curves were logit transformed and pooled in a two stage meta-analysis. Conventional aggregate data meta-analysis was performed to explore unadjusted associations of prognostic factors with recovery. MAIN OUTCOME MEASURES: The primary outcomes were the proportions of patients remaining with smell or taste dysfunction. Secondary outcomes were the odds ratios of prognostic variables associated with recovery of smell and taste. RESULTS: 18 studies (3699 patients) from 4180 records were included in reconstructed IPD meta-analyses. Risk of bias was low to moderate; conclusions remained unaltered after exclusion of four high risk studies. Evidence quality was moderate to high. Based on parametric cure modelling, persistent self-reported smell and taste dysfunction could develop in an estimated 5.6% (95% confidence interval 2.7% to 11.0%, I2=70%, τ2=0.756, 95% prediction interval 0.7% to 33.5%) and 4.4% (1.2% to 14.6%, I2=67%, τ2=0.684, 95% prediction interval 0.0% to 49.0%) of patients, respectively. Sensitivity analyses suggest these could be underestimates. At 30, 60, 90, and 180 days, respectively, 74.1% (95% confidence interval 64.0% to 81.3%), 85.8% (77.6% to 90.9%), 90.0% (83.3% to 94.0%), and 95.7% (89.5% to 98.3%) of patients recovered their sense of smell (I2=0.0-77.2%, τ2=0.006-0.050) and 78.8% (70.5% to 84.7%), 87.7% (82.0% to 91.6%), 90.3% (83.5% to 94.3%), and 98.0% (92.2% to 95.5%) recovered their sense of taste (range of I2=0.0-72.1%, τ2=0.000-0.015). Women were less likely to recover their sense of smell (odds ratio 0.52, 95% confidence interval 0.37 to 0.72, seven studies, I2=20%, τ2=0.0224) and taste (0.31, 0.13 to 0.72, seven studies, I2=78%, τ2=0.5121) than men, and patients with greater initial severity of dysfunction (0.48, 0.31 to 0.73, five studies, I2=10%, τ2<0.001) or nasal congestion (0.42, 0.18 to 0.97, three studies, I2=0%, τ2<0.001) were less likely to recover their sense of smell. CONCLUSIONS: A substantial proportion of patients with covid-19 might develop long lasting change in their sense of smell or taste. This could contribute to the growing burden of long covid. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021283922.

Association of obstructive sleep apnea with thyroid cancer incidence: a systematic review and meta-analysis.

PURPOSE: Obstructive sleep apnea (OSA) is a postulated carcinogen based on epidemiological associations with all-cancer incidence and non-thyroid biological models. However, associations with thyroid carcinoma are unclear. METHODS: We included observational/randomized studies of associations of OSA with thyroid carcinoma incidence/mortality in adults, from four databases. Random-effects meta-analyses and the population attributable fraction (PAF; from published global OSA prevalence estimates) were computed. RESULTS: We included four observational studies (N = 2,839,325), all with moderate/low risk of bias. OSA diagnosis was associated with twofold incidence of thyroid carcinoma (pooled HR 2.32, 95% CI 1.35-3.98, I2 = 95%), after multi-adjustment for demographics, BMI, smoking, alcohol, and comorbidities. Subgroup analysis of studies with at least 5 years of follow-up showed a stronger association of OSA with thyroid cancer incidence (pooled HR 3.27, 95% CI 2.80-3.82, I2 = 0%). Up to 14.5% (95% CI 4.29-27.6%) of incident thyroid carcinomas globally may be associated with OSA. Thyroid carcinoma mortality data was unavailable. CONCLUSIONS: OSA is associated with higher thyroid carcinoma incidence, though this does not prove causation. Biological/clinical studies should investigate OSA severity in relation to thyroid carcinoma progression and mortality, stratified by tumor histology.

Association of Olfactory Impairment With All-Cause Mortality: A Systematic Review and Meta-analysis.

Importance: Olfactory impairment is highly prevalent and associated with multiple comorbidities, including neurodegenerative, cardiovascular, nutritional, and immune disorders. However, epidemiologic associations between olfactory impairment and mortality are discordant. Objective: To systematically clarify the epidemiologic associations between olfactory impairment and mortality. Data Sources: The PubMed, Embase, and Cochrane Library databases were searched from inception to August 13, 2021. Study Selection: Two blinded reviewers selected observational studies published as full-length, English-language articles in peer-reviewed journals that reported the presence or severity of chronic olfactory impairment, whether objectively measured or self-reported, in association with any mortality estimate, among adults aged 18 years or older. Data Extraction and Synthesis: Two reviewers independently extracted data, evaluated study bias using the Newcastle-Ottawa Scale, and appraised the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation framework, following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and a PROSPERO-registered protocol. Maximally adjusted estimates were pooled using mixed-effects models, heterogeneity was measured using I2 statistics, sources of heterogeneity were investigated using meta-regression and subgroup meta-analyses, and publication bias was qualitatively and quantitatively assessed. Main Outcomes and Measures: Hazard ratios for all-cause mortality. Results: One retrospective cohort study and 10 prospective cohort studies (with a total of 21 601 participants) from 1088 nonduplicated records were included. Ten studies had a low risk of bias, whereas 1 study had a moderate risk; exclusion of the latter did not alter conclusions. Nine studies were included in the meta-analysis. Olfactory loss was associated with a significantly higher pooled hazard of all-cause mortality (hazard ratio, 1.52; 95% CI, 1.28-1.80; I2 = 82%). Meta-regression sufficiently explained heterogeneity, with longer mean follow-up duration weakening the pooled association, accounting for 91.3% of heterogeneity. Self-reported and objective effect sizes were similar. Associations were robust to trim-and-fill adjustment and the Egger test for publication bias. The overall quality of evidence was moderate. Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that olfactory impairment is associated with all-cause mortality and may be a marker of general health and biological aging. Further research is required to establish the underlying mechanisms and the scope for interventions.

The Association of Obstructive Sleep Apnea With Breast Cancer Incidence and Mortality: A Systematic Review and Meta-analysis.

PURPOSE: Emerging evidence from animal models suggests that intermittent hypoxia due to obstructive sleep apnea (OSA) is a risk factor for breast cancer. Despite their biological plausibility, human epidemiological studies have reported conflicting results. Therefore, we conducted a meta-analysis to delineate this relationship. METHODS: We searched the PubMed, Embase, Scopus, and Cochrane Library databases for eligible studies from inception until June 6, 2021. Two reviewers selected randomized trials or observational studies reporting the association between OSA and breast cancer incidence compared with those without OSA. Two reviewers extracted relevant data and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and Newcastle-Ottawa Scale (NOS). We pooled the maximally covariate-adjusted hazard ratios (HRs) using a random-effects inverse variance-weighted meta-analysis and performed pre-specified subgroup analyses. RESULTS: We included six studies out of 1,707 records, comprising a combined cohort of 5,165,200 patients. All studies used the International Classification of Diseases codes to classify OSA and breast cancer. OSA patients had a 36% increased breast cancer risk (HR, 1.36; 95% confidence interval [CI], 1.03-1.80; N = 6, I² = 96%) compared to those without OSA. Most studies adjusted for confounders, such as age, sex, obesity, diabetes mellitus, alcohol use, and hypertension. Subgroup analyses for studies with (1) multivariate adjustment and (2) at least five years of follow-up yielded HRs of 1.35 (95% CI, 0.98-1.87; N = 5, I² = 96%) and 1.57 (95% CI, 1.14-2.18; N = 4; I² = 90%), respectively. One Mendelian randomization study suggested a causal relationship, with a two-fold increase in the odds of breast cancer in patients with OSA. CONCLUSION: This meta-analysis suggested that OSA is a risk factor for breast cancer. Future studies should explore the dose-response relationship between OSA and breast cancer, and whether treatment may mitigate breast cancer risk or progression.

Neuroradiological Basis of COVID-19 Olfactory Dysfunction: A Systematic Review and Meta-Analysis.

OBJECTIVE: Olfactory dysfunction (OD) is a common presenting symptom of COVID-19 infection. Radiological imaging of the olfactory structures in patients with COVID-19 and OD can potentially shed light on its pathogenesis, and guide clinicians in prognostication and intervention. METHODS: PubMed, Embase, Cochrane, SCOPUS were searched from inception to August 1, 2021. Three reviewers selected observational studies, case series, and case reports reporting radiological changes in the olfactory structures, detected on magnetic resonance imaging, computed tomography, or other imaging modalities, in patients aged ≥18 years with COVID-19 infection and OD, following preferred reporting items for systematic reviews and meta-analyses guidelines and a PROSPERO-registered protocol (CRD42021275211). We described the proportion of radiological outcomes, and used random-effects meta-analyses to pool the prevalence of olfactory cleft opacification, olfactory bulb signal abnormalities, and olfactory mucosa abnormalities in patients with and without COVID-19-associated OD. RESULTS: We included 7 case-control studies (N = 353), 11 case series (N = 154), and 12 case reports (N = 12). The pooled prevalence of olfactory cleft opacification in patients with COVID-19 infection and OD (63%, 95% CI = 0.38-0.82) was significantly higher than that in controls (4%, 95% CI = 0.01-0.13). Conversely, similar proportions of cases and controls demonstrated olfactory bulb signal abnormalities (88% and 94%) and olfactory mucosa abnormalities (2% and 0%). Descriptive analysis found that 55.6% and 43.5% of patients with COVID-19 infection and OD had morphological abnormalities of the olfactory bulb and olfactory nerve, respectively, while 60.0% had abnormal olfactory bulb volumes. CONCLUSION: Our findings implicate a conductive mechanism of OD, localized to the olfactory cleft, in approximately half of the affected COVID-19 patients. Laryngoscope, 132:1260-1274, 2022.

Obstructive Sleep Apnea and Lung Cancer: A Systematic Review and Meta-Analysis.

Rationale: In 2020, lung cancer was the leading cause of cancer deaths and the most common cancer in men. Although obstructive sleep apnea (OSA) has been postulated to be carcinogenic, epidemiological studies are inconclusive. Objectives: To investigate the associations between OSA and the incidence and mortality of lung cancer. Methods: Four electronic databases (PubMed, Embase, Cochrane Library, and Scopus) were searched from inception until 6 June 2021 for randomized controlled trials and observational studies examining the association between sleep apnea and incident lung cancer. Two reviewers selected studies, extracted data, graded the risk of bias using the Newcastle-Ottawa scale and the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Random-effects models were used to meta-analyze the maximally covariate-adjusted associations. Results: Seven studies were included in our systematic review, among which four were suitable for meta-analysis, comprising a combined cohort of 4,885,518 patients. Risk of bias was low to moderate. OSA was associated with a higher incidence of lung cancer (hazard ratio, 1.25; 95% confidence interval, 1.02-1.53), with substantial heterogeneity (I2 = 97%). Heterogeneity was eliminated, with a stable pooled effect size, when including the three studies with at least 5 years of median follow-up (hazard ratio, 1.32; 95% confidence interval, 1.27-1.37; I2 = 0%). Conclusions: In this meta-analysis of 4,885,518 patients from four observational studies, patients with OSA had an approximately 30% higher risk of lung cancer compared with those without OSA. We suggest more clinical studies with longer follow-up as well as biological models of lung cancer be performed to further elucidate this relationship.

Association of obstructive sleep apnea and nocturnal hypoxemia with all-cancer incidence and mortality: a systematic review and meta-analysis.

STUDY OBJECTIVES: Biological models suggest that obstructive sleep apnea (OSA) is potentially carcinogenic. We aimed to clarify the inconsistent epidemiological literature by considering various traditional and novel OSA severity indices. METHODS: We systematically searched PubMed, Embase, Scopus, and the Cochrane Library for observational or randomized studies of associations of OSA, measured by diagnostic codes or any index, each with all-cancer incidence or mortality in adults, compared with participants with no/mild OSA. Two reviewers independently selected studies, extracted data, and evaluated study bias using the Newcastle-Ottawa scale and quality of evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). We performed inverse variance-weighted, random-effects meta-analyses and sensitivity analyses. RESULTS: We included 20 observational studies (5,340,965 participants), all with moderate/low bias, from 1,698 records. Based on T90 (sleep duration with oxygen saturation < 90%), patients with OSA who had moderate (T90 > 1.2%, hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.07-1.54) and severe nocturnal hypoxemia (T90 > 12%, HR = 1.43, 95% CI = 1.16-1.76) experienced 30%-40% higher pooled all-cancer risk than normoxemic patients, after multiple adjustment for covariates including obesity. Furthermore, severe nocturnal hypoxemia nearly tripled all-cancer mortality (HR = 2.66, 95% CI = 1.21-5.85). Patients with apnea-hypopnea index-defined severe OSA, but not moderate OSA, had higher all-cancer risk (HR = 1.18, 95% CI = 1.03-1.35) but similar all-cancer mortality as patients without OSA. An OSA diagnosis was not associated with all-cancer risk. Evidence quality ranged from low to moderate. Insufficient evidence was available on the oxygen desaturation index, lowest/median saturation, and arousal index. CONCLUSIONS: In patients with OSA, nocturnal hypoxemia is independently associated with all-cancer risk and mortality. Future studies should explore if risk differs by cancer type, and whether cancer screening and OSA treatment are beneficial. SYSTEMATIC REVIEW REGISTRATION: Registry: PROSPERO; URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=220836; Identifier: CRD42021220836. CITATION: Tan BKJ, Teo YH, Tan NKW, et al. Association of obstructive sleep apnea and nocturnal hypoxemia with all-cancer incidence and mortality: a systematic review and meta-analysis. J Clin Sleep Med. 2022;18(5):1427-1440.