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Complications of cholesteatoma result from characteristic inflammatory and resorptive processes that erode the structures of the middle and inner ear with potential to spread locally. Common intratemporal complications include hearing loss, facial nerve palsy, labyrinthine fistula, and dysgeusia. Extratemporal complications, though less common, may be life-threatening, and include cerebrospinal fluid leak and encephalocele, meningitis, epidural and intraparenchymal abscesses, subdural empyema, and otic hydrocephalus., Competing Interests: Disclosure The authors have no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tamoxifen is known to raise the risk of endometrial hyperplasia and cancer. There is virtually limited literature on how to handle Tamoxifen-induced endometrial hyperplasia (EH) in a breast cancer survivor. Levonorgestrel-releasing intrauterine system (LNG-IUS) has been explored as preventive strategies, but its impact on breast cancer recurrence especially in Progesterone receptor (PR)-positive patient is not clear. Aromatase Inhibitors (AIs) have shown beneficial results in EH after tamoxifen and their role should be explored in further trials., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

One hurdle to understanding how molecular machines work, and how they evolve, is our inability to see their structures in situ . Here we describe a minicell system that enables in situ cryogenic electron microscopy imaging and single particle analysis to investigate the structure of an iconic molecular machine, the bacterial flagellar motor, which spins a helical propeller for propulsion. We determine the structure of the high-torque Campylobacter jejuni motor in situ, including the subnanometre-resolution structure of the periplasmic scaffold, an adaptation essential to high torque. Our structure enables identification of new proteins, and interpretation with molecular models highlights origins of new components, reveals modifications of the conserved motor core, and explain how these structures both template a wider ring of motor proteins, and buttress the motor during swimming reversals. We also acquire insights into universal principles of flagellar torque generation. This approach is broadly applicable to other membrane-residing bacterial molecular machines complexes., Competing Interests: Declaration of Interests The authors declare no competing interests.

Aim: This study aims to evaluate the long-term treatment outcome of conventional and hypofractionation radiotherapy in postmastectomy cancer breast patients., Material and Methods: A total of 140 postmastectomy breast cancer patients were included in this retrospective study, who were treated from 2012 to 2014 with chemotherapy and various fractionation radiotherapy schedules. Radiotherapy treatment records for study group-I received radiotherapy 4256 cGy in 16 fractions over 3½ weeks, group-II patients received 4005 cGy in 15 fractions over 3 weeks, and conventional radiotherapy group-III received 5000 cGy in 25 fractions over 5 weeks., Results: The median follow-up of patients from all groups was 60 months (range 9 to 111 months). There were 39 cases with disease failure, 13 (26%) in group I (42.56 Gy), 16 (40%) in group II (40.05 Gy), and 10 (20%) in group III (50 Gy). There were 4 locoregional recurrences (LRRs), two isolated, and 11 distant failures in group I, 3 LRRs (1 isolated LRR) and 15 distant failures in group II, and only one LRR and 9 distant failures in group III. The disease-free survival (DFS) were 74%, 60%, and 80%, respectively, in groups I, II, and III (P =0.044)., Conclusion: The long-term results of this study show that hypofractionation radiotherapy in postmastectomy cases is well tolerated and acute and late side effects are also comparable to conventional fractionation. In our study, locoregional and distant failure seems slightly higher with hypofractionation schedules than in other studies, highlighting the need for more studies with long-term follow-up in postmastectomy patients., (Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.)

Background: Bone scintigraphy imaging is frequently used to investigate patients with suspected transthyretin cardiac amyloidosis (ATTR-CM). However, the reported accuracy for interpretation approaches has changed over time. We performed a systematic review and meta-analysis to determine the diagnostic accuracy of visual planar grading, heart-to-contralateral (HCL) ratio, and quantitative analysis of SPECT imaging and evaluate reasons for shifts in reported accuracy., Methods: We performed a systematic review to identify studies of the diagnostic accuracy of bone scintigraphy for ATTR-CM from 1990 until February 2023 using PUBMED and EMBASE. Studies were reviewed separately by two authors for inclusion and for risk of bias assessment. Summary receiver operating characteristic curves and operating points were determined with hierarchical modeling., Results: Out of a total of 428 identified studies, 119 were reviewed in detail and 23 were included in the final analysis. The studies included a total of 3954 patients, with ATTR-CM diagnosed in 1337 (39.6%) patients and prevalence ranging from 21 to 73%. Visual planar grading and quantitative analysis had higher diagnostic accuracy (.99) than HCL ratio (.96). Quantitative analysis of SPECT imaging had the highest specificity (97%) followed by planar visual grade (96%) and HCL ratio (93%). ATTR-CM prevalence accounted for some of the observed between study heterogeneity., Conclusions: Bone scintigraphy imaging is highly accurate for identifying patients with ATTR-CM, with between study heterogeneity in part explained by differences in disease prevalence. We identified small differences in specificity, which may have important clinical implications when applied to low-risk screening populations., (© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Solute carriers (SLCs) are membrane transporters that import and export a range of endogenous and exogenous substrates, including ions, nutrients, metabolites, neurotransmitters, and pharmaceuticals. Despite having emerged as attractive therapeutic targets and markers of disease, this group of proteins is still relatively underdrugged by current pharmaceuticals. Drug discovery projects for these transporters are impeded by limited structural, functional, and physiological knowledge, ultimately due to the difficulties in the expression and purification of this class of membrane-embedded proteins. Here, we demonstrate methods to obtain high-purity, milligram quantities of human SLC transporter proteins using codon-optimized gene sequences. In conjunction with a systematic exploration of construct design and high-throughput expression, these protocols ensure the preservation of the structural integrity and biochemical activity of the target proteins. We also highlight critical steps in the eukaryotic cell expression, affinity purification, and size-exclusion chromatography of these proteins. Ultimately, this workflow yields pure, functionally active, and stable protein preparations suitable for high-resolution structure determination, transport studies, small-molecule engagement assays, and high-throughput in vitro screening.

Background: Sublingual immunotherapy (SLIT) adherence in the literature is often evaluated in closely monitored trials that may impact patient behavior; real-world SLIT adherence is relatively unknown. This systematic review intends to assess SLIT adherence in studies that reflect real-world settings., Methods: A literature search of PubMed, Embase, Cochrane, Web of Science, and Scopus for real-world studies examining SLIT adherence was performed. Monitored clinical trials were excluded. Paired investigators independently reviewed all articles. For this review, "persistence" was defined as continuing therapy and not being lost to follow-up and "adherence" as persistence in accordance with prescribed SLIT dose, dosing schedule, and duration. Article quality was assessed using a modified Newcastle-Ottawa scale and then converted to AHRQ standards (good, fair, and poor)., Results: The search yielded 1596 nonduplicate abstracts, from which 32 articles (n = 63,683 patients) met criteria. Twenty-six (81%) studies reported persistence rates ranging from 7.0% to 88.7%, and 18 (56%) reported adherence rates ranging from 9.6% to 97.0%. Twenty-one (66%) studies surveyed reasons for discontinuing SLIT. All studies were Oxford level of evidence 2b and of good (n = 12) to fair (n = 20) quality., Conclusion: Reported rates of real-world SLIT persistence and adherence varied widely by study methodology (e.g., follow-up duration, objective vs. subjective assessment). Studies with longer follow-up generally reported lower rates; 3-year persistence ranged from 7% to 59.0% and 3-year adherence from 9.6% to 49.0%. Future studies of SLIT adherence would benefit from following concordant definitions of persistence/adherence and standardized reporting metrics., (© 2022 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Given that subcutaneous immunotherapy (SCIT) adherence in the literature is often studied in closely monitored trials, few studies report real-world SCIT adherence. The purpose of this review is to assess SCIT adherence in real-world settings., Methods: A literature search of PubMed, Embase, Cochrane Library, Web of Science, and Scopus for real-world studies examining SCIT adherence was performed. Paired investigators independently reviewed all articles. For this review, "persistence" was defined as continuing therapy and not being lost to follow-up after initiating SCIT, and "adherence" defined as persistence in accordance with prescribed SCIT dose, dosing schedule, and duration. Article quality was first assessed using a modified Newcastle-Ottawa scale and then converted to Agency for Healthcare Research and Quality standards (good, fair, and poor)., Results: The search yielded 1596 nonduplicate abstracts, from which 17 articles (n = 263,221 patients) met inclusion criteria. Fourteen (82%) studies reported persistence rates, ranging from 16.0% to 93.7%. Seven (41%) studies reported adherence rates, ranging from 15.1% to 99%. Five (29%) studies (n = 416 patients) collected original data on reasons for discontinuing SCIT, of which inconvenience was most cited. All studies were Oxford level of evidence 2b and of good (n = 10) to fair (n = 7) quality., Conclusion: Real-world SCIT persistence and adherence rates are poor, with the majority of included studies reporting rates <80%; however, they range widely, explained in part by inter-study differences in measuring and reporting adherence-related findings. Future studies on SCIT adherence may benefit from following concordant definitions of persistence and adherence in addition to standardized reporting metrics., (© 2022 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Patients with hematological malignancies (HM) are at risk of acute respiratory failure (ARF). Malnutrition, a common association with HM, has the potential to influence ICU outcomes. Geriatric nutritional risk index (G-NRI) is a score derived from albumin and weight, which reflects risk of protein-energy malnutrition. We evaluated the association between G-NRI at ICU admission and ICU mortality in HM patients with ARF. We conducted a single center retrospective study of ventilated HM patients between 2014 and 2018. We calculated G-NRI for all patients using their ICU admission albumin and weight. Our primary outcome was ICU mortality. Secondary outcomes included duration of mechanical ventilation and ICU length of stay. Two hundred eighty patients were admitted to the ICU requiring ventilation. Median age was 62 years (IQR 51-68), 42% (n = 118) were females, and median SOFA score was 11 (IQR 9-14). The most common type of HM was acute leukemia (54%) and 40% underwent hematopoietic cell transplant. Median G-NRI was 87 (IQR 79-99). ICU mortality was 51% (n = 143) with a median duration of ventilation of 4 days (IQR 2-7). Mortality across those at severe malnutrition (NRI < 83.5) was 59% (65/111) compared to 46% (76/164) across those with moderate-no risk (p = 0.047). On multivariable analysis, severe NRI (OR 2.34, 95% CI 1.04-5.27, p = 0.04) was significantly associated with ICU mortality. In this single center, exploratory study, severe G-NRI was prognostic of ICU mortality in HM patients admitted with respiratory failure., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Catheter-related bloodstream infection (CRBSI) can lead to ICU admission in patients with hematologic malignancy (HM). Variability exists in the management of catheters given the need for long-term access and co-existing thrombocytopenia or coagulopathy. We conducted a systematic review to evaluate catheter management in patients with CRBSI. Literature searches were conducted up to December 20, 2021 across MEDLINE, EMBASE, CENTRAL, CINAHL, and PubMed. Observational studies and RCTs of adults (> 16) with HM were included. Our primary outcome was mortality and secondary outcomes included infection recurrence and ICU admission. We identified 23 studies (N = 2026 patients), of which 22 were observational. Across the 12 studies (N = 801) that reported on bacterial organisms, 528 (65.9%) were gram positive, and 273 (34.1%) were gram negative. Catheters were removed in 1266 (62%) and retained in 760 (38%) patients. Removal was associated with a mean 30-day mortality of 13.14% (SD 9.12; 90/685) and reinfection rate of 5.49% (SD 2.88; 22/401) compared to 39.23% (SD 14.58; 122/311) and 10.75% (SD 21.07; 10/93), respectively, if retained. Catheter retention may be associated with a higher risk of mortality and infection recurrence. Further prospective research should assess catheter management in this population, including potential harms associated with retention., (© 2022. Crown.)

Background: Patients with acquired, idiopathic olfactory dysfunction (OD) commonly undergo magnetic resonance imaging (MRI) evaluation to rule out intracranial pathologies. This practice is highly debated given the expense of MRI relative to the probability of detecting a treatable lesion. This, combined with the increasing use of MRI in research to investigate the mechanisms underlying OD, provided the impetus for this comprehensive review., Objective: The purpose of this systematic review was to both assess the utility of MRI in diagnosis of idiopathic OD and to describe MRI findings among mixed OD etiologies to better understand its role as a research tool in this patient population., Methods: A literature search of PubMed, Embase, Cochrane, Web of Science, and Scopus for studies with original MRI data for patients with OD was completed. Studies exclusively investigating patients with neurocognitive deficits or those studying traumatic or congenital etiologies of OD were excluded., Results: From 1758 candidate articles, 33 studies were included. Four studies reviewed patients with idiopathic OD for structural pathologies on MRI, of which 17 of 372 (4.6%) patients had a potential central cause identified, and 3 (0.8%) had an olfactory meningioma or olfactory neuroblastoma. Fourteen studies (42.4%) reported significant correlation between olfactory bulb volume and olfactory outcomes, and 6 studies (18.8%) reported gray matter volume reduction, specifically in the orbitofrontal cortex, anterior cingulate cortex, insular cortex, parahippocampal, and piriform cortex areas, in patients with mixed OD etiologies. Functional MRI studies reported reduced brain activation and functional connectivity in olfactory network areas., Conclusion: MRI uncommonly detects intracranial pathology in patients with idiopathic OD. Among patients with mixed OD etiologies, reduced olfactory bulb and gray matter volume are the most common abnormal findings on MRI. Further research is required to better understand the role of MRI and its cost-effectiveness in patients with acquired, idiopathic OD.

Background: Bitter and sweet taste receptors (T2Rs and T1Rs), respectively, are involved in the innate immune response of the sinonasal cavity and associated with chronic rhinosinusitis (CRS). Growing evidence suggests extraoral TRs as relevant biomarkers, but the current understanding is incomplete. This systematic review synthesizes current evidence of extraoral taste receptors in CRS., Methods: PubMed, Embase, Cochrane, Web of Science, and Scopus were reviewed in accordance with Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines and included studies of genotypic and phenotypic T2R/T1R status in CRS patients., Results: Twenty-two studies with 3845 patients were included. Seventeen studies evaluated genotype and 10 evaluated taste phenotypes. Four of 6 studies examining the haplotype distribution of the T2R, TAS2R38, demonstrated increased AVI/AVI haplotype ("nontaster") frequency in CRS. Meanwhile, 2 studies demonstrated decreased bitter sensitivity in CRS with nasal polyposis (CRSwNP), whereas 3 other studies reported decreased bitter sensitivity only in CRS without nasal polyposis (CRSsNP). Findings regarding sweet sensitivity were mixed. Three studies with cystic fibrosis patients (n = 1393) were included. Studies investigating the association between clinical outcomes and TAS2R38 alleles were limited, but the nonfunctional combination of AVI/AVI was associated with increased utilization of sinus surgery and, in CRSsNP patients, with poorer improvement of symptoms postoperatively., Conclusion: Both genotypic and phenotypic assessments of T2Rs suggest a potential association with CRS, particularly CRSsNP. However, limited evidence and mixed conclusions cloud the role of T2Rs in CRS. Future investigations should aim to increase diverse populations, broaden institutional diversity, examine T1Rs, and utilize uniform assessments., (© 2021 ARS-AAOA, LLC.)

Background: Frailty is a syndrome characterized by reduced physiologic reserve and increased vulnerability to poor health outcomes. Disruption of sensorineural function appears to serve as a novel biomarker of frailty. Using population-level data, we sought to characterize the association between otolaryngic sensory dysfunction and frailty., Methods: A cross-sectional analysis of the 2011-2012 US National Health and Nutrition Examination Survey was performed on adults ≥40 years of age (n = 2138). Participants were grouped by subjective gustatory dysfunction (sGD), olfactory dysfunction (sOD), hearing loss (sHL), and measured hearing loss (mHL) with pure tone averages (PTAs). Frailty was operationalized using a continuous 36-item frailty index (FI) scored from 0 to 1, stratified in 4 categories ("non-frail," "vulnerable," "frail," or "most frail")., Results: All sensory loss groups had significantly higher FI scores than those without sensory loss (sGD = 0.15; sOD = 0.14; sHL = 0.15; low-frequency mHL = 0.16; high-frequency mHL = 0.14 vs control = 0.11; p < 0.007 for all). "Vulnerable" individuals had increased odds of sOD (adjusted odds ratio [aOR], 1.45; 95% confidence interval [CI], 1.05-2.00), whereas "frail" individuals had increased odds of sOD (aOR, 1.85; 95% CI, 1.26-2.71) and low-frequency mHL (aOR, 4.01; 95% CI, 1.27-12.63). The "most frail" individuals had increased odds of sHL (aOR, 11.72; 95% CI, 2.88-47.66) and high-frequency mHL (aOR 5.10; 95% CI, 1.72-15.12). PTAs were linearly associated with FI (low: β = 10.15; 95% CI, 1.78-18.51; high: β = 19.85; 95% CI, 5.19-34.53)., Conclusion: Otolaryngic sensory loss is associated with increased frailty. Independent association of frailty with measures of olfaction and hearing suggests that olfactory and hearing assessments may help identify at-risk individuals with modifiable risk factors., (© 2021 ARS-AAOA, LLC.)

Objectives: Diverse perspectives improve the quality of scholarly initiatives. The demographic and professional diversity of scientists who contribute to critical care research and publications has not been described for the Canadian Critical Care Trials Group. Our objective was to describe the diversity of authors of publications from the Canadian Critical Care Trials Group., Design: We conducted a quantitative content analysis of peer-reviewed articles published on behalf of the Canadian Critical Care Trials Group., Setting: All peer-reviewed articles that were published on behalf of the Canadian Critical Care Trials Group between 1994 and October 2020., Subjects: For each publication, we recorded the study design, the number of authors, and national or international collaboration. For the lead author, the senior author, and each coauthor, we recorded the following facets of diversity: gender, professional role, medical discipline, geographic location, academic stage, and visible minority status., Interventions: None., Measurements and Main Results: We identified 354 eligible publications; 74% (263/354) reported observational cohort studies, randomized trials, and surveys. Of 4,246 authors, 1,205 were unique individuals. The mean (sd) number of authors per publication was 12 (7.1). Of all 4,246 authors, 37% were women, and 13.7% were members of a visible minority group. Of all lead or senior authors, 40% and 34% respectively were women; 15% of lead and 10% of senior authors were members of a visible minority group. Three-quarters (73%) of publications listed authors from more than one profession, and more than half (54%) listed authors from more than one medical discipline. Nearly half of publications (45%) listed authors who were early career faculty, 33% listed authors who were trainees, and 67% listed authors who were from visible minority groups. Authors from different provinces and from different countries were listed in 67% and 40% of publications, respectively., Conclusions: Authors of Canadian Critical Care Trials Group publications are diverse with regard to demographic and professional characteristics., Competing Interests: Dr. Burns disclosed that she holds a career award from the Physician Services Incorporated Foundation and that she is the current chair of the Women in Critical Care Interest Group of the American Thoracic Society. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: The underlying mechanism of the association between olfactory impairment and dementia may be explained by neurodegenerative changes detected on magnetic resonance imaging (MRI). The purpose of this systematic review is to describe neurodegenerative changes on MRI in patients with olfactory impairment and mild cognitive impairment (MCI) or dementia., Study Design: Systematic review., Methods: A literature search encompassing PubMed, Embase, Cochrane Library, Web of Science, Scopus, and Google Scholar for studies with MRI and olfactory testing among participants diagnosed with MCI or dementia was performed. Sample size, study design, cognitive impairment type, olfactory testing, and MRI findings were abstracted. Two investigators independently reviewed all articles., Results: The search yielded 556 nonduplicate abstracts, from which 86 articles were reviewed and 24 were included. Seventeen (71%) of 24 studies reported hippocampal volume findings, with 14 studies reporting a relationship between hippocampal volume and olfactory performance. Two (50%) of four prospective studies reported the potential utility of baseline hippocampal volume as a marker of dementia conversion from MCI. Five (21%) of 24 studies reporting olfactory functional MRI (fMRI) findings highlighted the utility of olfactory fMRI to identify individuals in the early stages of cognitive decline., Conclusion: Current evidence suggests hippocampal volume correlates with olfactory performance in individuals with cognitive impairment, and that olfactory fMRI may improve early detection of AD. However, the predictive utility of these imaging markers is limited in prospective studies. MRI may be a useful modality for selecting patients at high risk of future cognitive decline for enrollment in early treatment trials. Laryngoscope, 132:177-187, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: As endoscopic endonasal skull base surgery (EESBS) for sellar pathology has become routine, there is increasing awareness of quality-of-life (QOL) outcomes related to this approach. Similarly, there is a growing interest in postoperative chemosensory function, with notable emphasis on olfaction and the corresponding psychosocial implications of olfactory dysfunction. Meanwhile, there has been minimal direct investigation into gustatory outcomes, and the association between these 2 chemosensory functions remains poorly understood., Objective: To investigate patient-reported chemosensory function and rhinologic-specific QOL following EESBS for routine sellar pathologies., Methods: Comprehensive clinical characteristics and sinonasal QOL assessments, measured using Anterior Skull Base Nasal Inventory-12 (ASK Nasal-12), were collected from 46 patients undergoing EESBS for sellar pathology., Results: Forty-six patients were included: 65.2% female, average age 52.8 yr (range: 27-89). The most common pathology was nonfunctioning pituitary adenoma (n = 28). Preoperative ASK Nasal-12 scores (mean = 0.81) demonstrated postoperative worsening at 2 wk (mean = 2.52, P < .0001) and 1 mo (mean = 1.33, P = .0031), with no difference at 3 mo postoperatively (mean = 0.89, P = .92). Meanwhile, there was significant worsening of preoperative subjective smell (mean = 0.62) and taste function (mean = 0.42) at 2 wk (mean = 3.48, P < .0001; mean = 2.69, P < .0001) and 1 mo (mean = 2.40, P < .0001; mean = 2.03, P < .0001) postoperatively, which persisted at approximately 3 mo postoperatively (mean = 1.26, P = .04; mean = 1.15, P = .0059)., Conclusion: Patients undergoing EESBS for sellar pathologies experience anticipated, temporary disruptions in sinonasal QOL but may have longer lasting perturbations in subjective olfaction and gustation. Given the increasing use of the endoscopic endonasal corridor, further investigation in postoperative chemosensory function is essential., (© Congress of Neurological Surgeons 2021.)

Objectives: Sublingual immunotherapy (SLIT) has emerged as an effective treatment alternative to subcutaneous immunotherapy (SCIT) given its improved safety profile and more convenient dosing. However, SLIT still relies on daily dosing for many years to optimize effectiveness. This study sought to investigate factors that influence patient completion of SLIT., Methods: We performed an institutional retrospective review of patients who received SLIT (2008-2020). Completion was defined as completing at least 36 months of SLIT. Patient demographics and characteristics, including the number of allergens treated, history of asthma and sinus surgery, number of clinic visits, and total time undergoing SLIT, were documented. Multivariate models were used to analyze predictors of SLIT completion. Subgroup analysis was performed among pediatric patients and patients who discontinued SLIT., Results: Of the 404 total patients, 249 (61.6%) discontinued, 47 (11.6%) completed, and 108 (26.7%) were currently undergoing SLIT. The mean duration of therapy was 11.2 months for those who discontinued and 49.4 months for patients who completed SLIT. The odds of SLIT completion were twice as high with each additional clinic visit (P < .001), and twice as high when the dosage was increased during therapy (P = .06). Pediatric patients younger than age 12 with a history of asthma were over five times more likely to complete therapy (P = .045). Patients with more clinic visits (P < .001) and higher associated costs (P = .003) were less likely to be lost to follow-up., Conclusion: Increasing the frequency of clinic visits, improving therapy availability, and mitigating concerns about clinical efficacy may increase patient completion of SLIT., Level of Evidence: 4 Laryngoscope, 131:E2111-E2115, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Water is essential to human societies and a prerequisite for flourishing nature, especially in arid regions. Yet, climate change and socio-economic developments are expected to exacerbate current and future stresses on water resources, demanding innovative approaches to balance water needs for society and nature conservation. In this study, we use the IPBES conceptual framework to combine ecological and socio-economic insights and analyse the connections between people and nature in the water scarce Draa River Basin, southern Morocco. We study the diversity of desert benthic macroinvertebrates as one component of nature using DNA barcoding and their potential to serve as bioindicators of human impact by relating species occurrences to environmental parameters. Furthermore, based on 87 interviews with farmers and key institutional stakeholders, we investigate how farmers perceive water related changes and how water is managed in the basin. Regarding benthic macroinvertebrates, 41 families were identified, 475 DNA barcodes generated and assigned to 118 putative species (Barcode Index Numbers) of which 60 were first records. This indicates a lack of reference sequences for known, but also a potentially high number of undescribed species. Environmental parameters, which are partly influenced by human activities, such as aquatic stages, salinity and intermittency, were the most important variables explaining invertebrate richness and community composition in generalized linear models. We further describe farmers' perceptions of decreasing water quality and quantity. Farmers generally believe that they are able to cope with water related changes, although perceptions are regionally differentiated with farmers downstream being less optimistic. With growing concerns, water policies currently focus on increasing water supply and less on reducing water demands. Based on these findings, the usefulness of the IPBES framework for understanding social-ecological system dynamics is reflected, and recommendations for future freshwater management and research are derived., Competing Interests: Declaration of competing interest No conflict of interests., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: We conducted a systematic review and meta-analysis to evaluate the updated evidence regarding prediabetes for predicting mortality, macrovascular and microvascular outcomes., Research Design and Methods: We identified English language studies from MEDLINE, PubMed, OVID and Cochrane database indexed from inception to January 31, 2020. Paired reviewers independently identified 106 prospective studies, comprising nearly 1.85 million people, from 27 countries. Primary outcomes were all-cause mortality (ACM), cardiovascular mortality (CVDM), cardiovascular disease (CVD), coronary heart disease (CHD) and stroke. Secondary outcomes were heart failure, chronic kidney disease (CKD) and retinopathy., Results: Impaired glucose tolerance was associated with ACM; HR 1.19, 95% CI (1.15 to 1.24), CVDM; HR 1.21, 95% CI (1.10 to 1.32), CVD; HR 1.18, 95% CI (1.11 to 1.26), CHD; HR; 1.13, 95% CI (1.05 to 1.21) and stroke; HR 1.24, 95% CI (1.06 to 1.45). Impaired fasting glucose (IFG) 110-125 mg/dL was associated with ACM; HR 1.17, 95% CI (1.13 to 1.22), CVDM; HR 1.20, 95% CI (1.09 to 1.33), CVD; HR 1.21, 95% CI (1.09 to 1.33), CHD; HR; 1.14, 95% CI (1.06 to 1.22) and stroke; HR 1.22, 95% CI (1.07 to 1.40). IFG 100-125 mg/dL was associated with ACM; HR 1.11, 95% CI (1.04 to 1.19), CVDM; HR 1.14, 95% CI (1.03 to 1.25), CVD; HR 1.15, 95% CI (1.05 to 1.25), CHD HR; 1.10, 95% CI (1.02 to 1.19) and CKD; HR; 1.09, 95% CI (1.01 to 1.18). Glycosylated hemoglobin A1c (HbA1c) 6.0%-6.4% was associated with ACM; HR 1.30, 95% CI (1.03 to 1.66), CVD; HR 1.32, 95% CI (1.00 to 1.73) and CKD; HR 1.50, 95% CI (1.32 to 1.70). HbA1c 5.7%-6.4% was associated with CVD HR 1.15, 95% CI (1.02 to 1.30), CHD; HR 1.28, 95% CI (1.13 to 1.46), stroke; HR 1.23, 95% CI (1.04 to 1.46) and CKD; HR 1.32, 95% CI (1.16 to 1.50)., Conclusion: Prediabetes is an elevated risk state for macrovascular and microvascular outcomes. The prevention and management of prediabetes should be considered., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Post-viral olfactory dysfunction (PVOD) is one of the most common causes of olfactory loss. Despite its prevalence, optimal treatment strategies remain unclear. This article provides a comprehensive review of PVOD treatment options and provides evidence-based recommendations for their use., Methods: A systematic review of the Medline, Embase, Cochrane, Web of Science, Scopus, and Google Scholar databases was completed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies with defined olfactory outcomes of patients treated for PVOD following medical, surgical, acupuncture, or olfactory training interventions were included. The Clinical Practice Guideline Development Manual and Conference on Guideline Standardization (COGS) instrument recommendations were followed in accordance with a previously described, rigorous, iterative process to create an evidence-based review with recommendations., Results: From 552 initial candidate articles, 36 studies with data for 2183 patients with PVOD were ultimately included. The most common method to assess olfactory outcomes was Sniffin' Sticks. Broad treatment categories included: olfactory training, systemic steroids, topical therapies, a variety of heterogeneous non-steroidal oral medications, and acupuncture., Conclusion: Based on the available evidence, olfactory training is a recommendation for the treatment of PVOD. The use of short-term systemic and/or topical steroids is an option in select patients after careful consideration of potential risks of oral steroids. Though some pharmacological investigations offer promising preliminary results for systemic and topical medications alike, a paucity of high-quality studies limits the ability to make meaningful evidence-based recommendations for the use of these therapies for the treatment of PVOD., (© 2020 ARS-AAOA, LLC.)

Objectives: Large vestibular aqueduct syndrome (LVAS) is a congenital inner ear malformation that commonly results in progressive sensorineural hearing loss (SNHL) and cochlear implantation (CI). Though LVAS accounts for approximately 15% of pediatric SNHL, little is known regarding the rate and severity of SNHL in these patients. We sought to characterize the timing of SNHL progression to CI in patients with LVAS., Methods: We performed a retrospective chart review at our institution from 2000 to 2018 using ICD-10 "large vestibular aqueduct syndrome," and through identifying patients with CI who had LVAS. Demographic, surgical, and audiometric data were collected. Theoretical CI candidacy was approximated using a pure tone average (PTA) HL threshold of 70 dB., Results: Of 103 patients, 96 had bilateral LVAS, and 7 had unilateral LVAS. Forty-one patients had bilateral implants, 52 had unilateral implants, and 10 were not implanted. The mean age at first implant was 8.62 years old [95%CI = 6.75,10.49], the mean age at second implant was 12.24 years old [95%CI = 8.33,16.15], and the mean time between implants was 4.37 years [95%CI = 3.02,5.73]. LVAS patients reached HL threshold of 70 dB at a mean age of 5.16 years old (SD = 3.04) for the "worse ear" and 9.08 years old (SD = 4.96) for the "better ear.", Conclusions: LVAS patients are a heterogenous population of patients, in which some may undergo progression of HL and some may not. Further, there may be a discrepancy in the timing between patients' theoretical CI candidacy and when they undergo CI. In order to optimize timing of CI, individual monitoring and close observation of LVAS patients is recommended., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

As the severity of the triple challenges of global inequality, climate change and biodiversity loss becomes clearer, governments and international development institutions must find effective policy instruments to respond. We examine the potential of social assistance policies in this context. Social assistance refers to transfers to poor, vulnerable and marginalized groups to reduce their vulnerability and livelihood risks, and to enhance their rights and status. Substantial public funds support social assistance programmes globally. Collectively, lower- and middle-income countries spend approximately 1.5% of their GDP on social assistance annually. We focus on the potential of paid employment schemes to promote effective ecosystem stewardship. Available evidence suggests such programmes can offer multiple benefits in terms of improvements in local ecosystems and natural capital, carbon sequestration and local biodiversity conservation. We review evidence from three key case studies: in India (the Mahatma Gandhi National Rural Employment Guarantee Scheme), Ethiopia (the Productive Safety Nets Programme) and Mexico (the Temporary Employment Programme). We conclude that, to realize the potential of employment-based social assistance for ecosystem benefits it will be necessary to address two challenges: first, the weak design and maintenance of local public works outputs in many schemes, and second, the concern that social protection schemes may become less effective if they are overburdened with additional objectives. Overcoming these challenges requires an evolution of institutional systems for delivering social assistance to enable a more effective combination of social and environmental objectives. This article is part of the theme issue 'Climate change and ecosystems: threats, opportunities and solutions'.

Introduction: Silent sinus syndrome (SSS) is a condition characterized by ophthalmologic features, such as spontaneous enophthalmos and hypoglobus with ipsilateral maxillary sinus atelectasis and an otherwise asymptomatic presentation. SSS has been documented secondary to a number of external causes, including trauma or surgery, but has less commonly been described in the setting of a potential mass in the deep masticator space., Case Presentation: A 56-year-old woman with a history of chronic headaches with normal prior sinonasal imaging presented with increasing right-sided facial pain and headaches that radiated to her occiput, subjective visual changes, sharp ear pain, and long-standing subjective diminished sense of smell. Physical examination was normal, while nasal endoscopy demonstrated lateral bowing of the medial maxillary wall on the right. Magnetic resonance imaging demonstrated a homogenous 2 × 2 × 2.4 cm T1- and T2-weighted, hyperintense mass lesion in the deep masticator space splaying the right medial and lateral pterygoid muscles concerning for a possible lipomatous lesion. Computed tomography revealed an atelectatic and opacified maxillary sinus with inward bowing of the posterior maxillary wall and increased orbital volume on that side. Endoscopic maxillary antrostomy was performed with biopsy of the retromaxillary space lesion and with near immediate resolution of the patient's symptoms. Histologic examination of the mass demonstrated mature adipose tissue with few aggregates of benign small vessels., Discussion: This is an unusual presentation of SSS, with an accompanying enlargement of the retromaxillary fat pad. We herein review our clinical experience with SSS and provide a literature review of the presentation, management, and perioperative considerations for SSS., (© The Author(s) 2020.)

Purpose: In a recent study, it was found that, although intrinsic midbrain signal abnormality (IMSA) on MRI is associated with Parinaud's syndrome (PS) in patients with pineal gland masses (PM), it had no predictive value with respect to resolution of PS. We sought to compare the PM and non-pineal etiologies (NPE) of PS by reviewing imaging features of PS and whether or not they are predictive of resolution of symptoms., Methods: We reviewed electronic medical records from 1980 to 2017 and identified 71 patients with PS from any etiology who had MR imaging: 26 with PM and 45 with NPE. We subdivided the 45 NPE patients into those with intrinsic midbrain lesions (IMBL) (n = 23) and those with extrinsic midbrain lesions (EMBL) (n = 22). PS resolution and hydrocephalus data were collected. Imaging studies were reviewed for the presence of IMSA and hydrocephalus., Results: PS patients with EMBL were less likely to have IMSA than those with PM or IMBL (p ≤0.001). PS resolution occurred more commonly with PM than IMBL and NPE (p = 0.03, p = 0.01). For all NPE patients, resolution of PS occurred with equal frequency in patients with and without IMSA (p = 1.00). Hydrocephalus occurred more frequently in patients with PM and EMBL than IMBL (p = 0.01, p = 0.03)., Conclusions: IMSA is present more often in patients with PS from PM or IMBL than in patients with EMBL. EMBL, including PM, have an increased likelihood for PS resolution. There is no predictive value of IMSA with respect to resolution of PS in NPE as well as PM., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Maintenance of a transparent corneal stroma is imperative for proper vision. The corneal stroma is composed of primarily collagen fibrils, small leucine-rich proteoglycans (SLRPs), as well as sparsely distributed cells called keratocytes. The lattice arrangement and spacing of the collagen fibrils that allows for transparency may be disrupted due to genetic mutations and injuries. The purpose of this study is to examine the therapeutic efficacy of human umbilical cord mesenchymal stem/stromal cells (UMSCs) in treating congenital and acquired corneal opacity associated with the loss of collagen V., Methods: Experimental mice, i.e., wild-type, Col5a1 f/f and Kera-Cre/Col5a1 f/f ( Col5a1 ∆st/∆st , collagen V null in the corneal stroma) mice in a C57BL/6J genetic background, were subjected to a lamellar keratectomy, and treated with or without UMSC (10 4 cells/cornea) transplantation via an intrastromal injection or a fibrin plug. In vivo Heidelberg retinal tomograph (HRT II) confocal microscopy, second harmonic generated (SHG) confocal microscopy, histology, and immunofluorescence microscopy were used to assess the corneal transparency of the regenerated corneas., Results: Col5a1 ∆st/∆st mice display a cloudy cornea phenotype that is ameliorated following intrastromal transplantation of UMSCs. Loss of collagen V in Col5a1 ∆st/∆st corneas augments the formation of cornea scarring following the keratectomy. UMSC transplantation with a fibrin plug improves the healing of injured corneas and regeneration of transparent corneas, as determined with in vivo HRT II confocal microscopy. Second harmonic confocal microscopy revealed the improved collagen fibril lamellar architecture in the UMSC-transplanted cornea in comparison to the control keratectomized corneas., Conclusions: UMSC transplantation was successful in recovering some corneal transparency in injured corneas of wild-type, Col5a1 f/f and Col5a1 ∆st/∆st mice. The production of collagen V by transplanted UMSCs may account for the regeneration of corneal transparency, as exemplified by better collagen fiber organization, as revealed with SHG signals.

Objective: Chronic obstructive pulmonary disease (COPD) is mainly treated pharmaceutically with bronchodilators. The purpose of this study was to evaluate the clinical benefits of two-times-per-day aclidinium bromide (Acli-BID) compared with once-a-day tiotropium bromide hydrate (Tio-QD) in patients with COPD., Design: This study was a multicentre, open-label, randomised study., Setting: Fourcentres in Kagawa prefecture, Japan., Participant: Patients who were diagnosed to have COPD Grade 2-3 according to the Global Initiative for Chronic Obstructive Lung Disease 2015 criteria were enrolled., Interventions: Patients were randomly assigned to receive Acli-BID or Tio-QD at a 1:1 ratio, and followed for 8 weeks. Acli-BID was administered in the morning and night, and Tio-QD was administered in the night., Primary and Secondary Outcome Measures: Primary outcome was forced expiratory volume in one second area under the curve (FEV 1 AUC 0-3 ), and secondary outcomes were pulmonary function, physical activity, St George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC), the 8-item Short-Form Health Survey (SF-8) and COPD exacerbations. Adverse events were evaluated during the study., Results: 44 patients were included in this study. FEV 1 AUC 0-3 at week 8 was 4.62±1.43 L·hour in Acli-BID and 4.73±1.60 L·hour in Tio-QD (mean difference (MD) -0.11 L·hour; 95% CI), -1.04 to 0.83). Significant improvement was observed in activity-related subscales of SGRQ (MD -7.78; 95% CI -14.61 to -0.94) and SF-8 (MD 4.01; 95% CI 0.37 to 7.65), mMRC (MD -0.66; 95% CI -1.19 to -0.13) and rate ratio (0.52, 95% CI 0.27 to 0.99) of exacerbations in the Acli-BID compared with the Tio-QD. Acli-BID and Tio-QD significantly improved sedentary behaviour (MD -35.20 min; 95% CI -67.41 to -2.94 and MD -55.40 min; 95% CI -98.15 to -12.77) within each group, but there was no significant difference between the two groups., Conclusion: Acli-BID as with Tio-QD could be one of the therapeutic options for patients with COPD to improve pulmonary function. Also, our results suggest that intervention with bronchodilators enhanced physical activity in patients with COPD., Trial Registration Number: UMIN 000020020., Competing Interests: Competing interests: YMi has reported grants from Kyorin Pharmaceutical during the conduct of the study; personal fees from Boehringer Ingelheim outside the submitted work; TK has reported grants from Kyorin Pharmaceutical during the conduct of the study; KM has reported grants from Kyorin Pharmaceutical during the conduct of the study; YMo has reported grants from Kyorin Pharmaceutical during the conduct of the study; personal fees from Novartis Pharma, personal fees from GlaxoSmithKline Pharmaceutical, personal fees from AstraZeneca pharmaceutical, personal fees from Boehringer Ingelheim Pharmaceutical outside the submitted work; HN has reported grants from Kyorin Pharmaceutical during the conduct of the study; NN has reported grants from Kyorin pharmaceutical company during the conduct of the study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The association between MRI findings in patients with pineal lesions and the presence or absence of Parinaud's syndrome (PS) remains poorly described. We sought to better understand what MRI characteristics of a pineal lesion make PS more likely. Can these features predict prognosis for clinical resolution? Based on the anatomical relationship of the pineal gland and midbrain, we hypothesized that the degree of midbrain injury by a pineal mass as assessed by abutment, displacement, or intrinsic midbrain signal abnormality (IMSA) may predict PS., Methods: We reviewed our institution's databases to find patients with MRI evidence of an intrinsic lesion of the pineal gland. Seventy-seven patients with intrinsic pineal gland lesions, 26 with PS and 51 without PS (NPS), were identified. Data regarding clinical history were collected, and an experienced neuroradiologist reviewed all MRI studies and recorded mass size, midbrain abutment, displacement by the pineal lesion, and presence or absence of IMSA., Results: IMSA occurred with increased frequency in pineal lesions with PS (85%) when compared with NPS (39.2%) (p = 0.0001). Midbrain abutment, compression, and displacement occurred with similar frequencies in both groups, with no statistically significant difference. Hydrocephalus was present in 80.8% of patients with PS and 84% without PS (p = 0.75)., Conclusion: IMSA in a patient with an intrinsic pineal gland mass is associated with PS. Other findings such as hydrocephalus and midbrain displacement are common in patients with pineal masses both with and without PS and do not have any predictive value.

Background: We aimed to determine the reasons for the high rate of asthma mortality in Kagawa Prefecture, Japan, by analyzing death certificates., Methods: We analyzed the death certificates between 2009 and 2011 in a demographic survey. Of 1187 patients with documented disease names suggesting bronchial asthma, analysis was performed on 103 patients in whom the cause of death was classified as asthma based on ICD-10 Codes. The patients were then classified into the following 4 groups: asthma death, asthma-related death, non-asthma death, and indistinguishable death. Based on this classification, consistency between ICD-10-based asthma death and asthma/asthma-related deaths was examined for each age group as well as for the site of death., Results: Of 103 asthma deaths based on the ICD-10 classification, 30 (29%) were classified as asthma death, 44 (43%) as asthma-related death, 16 (16%) as non-asthma death, and 13 (13%) as indistinguishable death. Asthma death based on our classification correlated with that of ICD-10-based classification as a cause of death in patients younger than the median age (87 years), but correlation was not observed in patients aged older than 87 years. Deaths occurred outside the hospital in 45% of patients, and many ICD-10-based deaths reported at nursing homes and geriatric health care facilities were classified as non-asthma deaths in this survey., Conclusion: Re-examination of the death certificate revealed that asthma deaths were reported incorrectly on the death certificates of elderly patients who died outside the hospital., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: We aimed to determine the presepsin concentration in pleural fluid from patients with pleural effusions of different aetiologies and to compare its diagnostic value with that of pleural fluid C-reactive protein (CRP) and procalcitonin (PCT)., Methods: We enrolled 132 patients with pleural effusion who underwent diagnostic evaluation, and we classified them into six categories: empyema, parapneumonic effusion, tuberculous effusion, malignant effusion, paramalignant effusion, and transudate effusion. Additionally, all pleural effusions were categorised as infectious or non-infectious effusions., Results: Receiver operating characteristic analysis was used to evaluate diagnostic performance. When diagnosing empyema, the marker with the highest sensitivity was pleural fluid presepsin (cut-off: 754 pg/mL; sensitivity: 90.9%, specificity: 74.4%) and that with the highest specificity was pleural fluid CRP (cut-off: 4.91 mg/dL; sensitivity: 63.6%, specificity: 89.3%). Pleural fluid PCT tended to be lower in patients with empyema than in those with parapneumonic effusion, but this was not useful for the diagnosis of empyema. When diagnosing infectious pleural effusion, a combination of pleural fluid CRP (cut-off: 2.59 mg/dL) and presepsin (cut-off: 680 pg/mL) produced the highest diagnostic accuracy (83.3%)., Conclusions: Pleural fluid presepsin was found at high levels in patients with empyema and parapneumonic effusion. This pattern closely resembles the previously reported pattern of pleural fluid CRP. Some combinations of pleural fluid inflammatory markers may be more clinically useful than these markers in isolation.

Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor. No effective curative therapy is currently available and no therapeutic advances have been made in several decades. BMI-1 is a member of the multimeric protein complex Polycomb repressor complex 1. It is highly expressed in a number of diseases and malignancies and has been implicated in self-renewal of normal and cancer cells, and in DNA damage signaling. The role of BMI-1 in DIPG is largely unknown. Here, we show that BMI-1 is highly expressed in tumor tissue samples of DIPG patients and in patient-derived cancer stem-like cells. BMI-1 downregulation leads to the inhibition of DIPG patient-derived neurosphere cell proliferation, cell cycle signaling, self-renewal, telomerase expression and activity, and suppresses DIPG cell migration. Moreover, targeted inhibition of BMI-1 sensitizes DIPG cells to radiomimetic drug-induced DNA damage. Together, our data validate BMI-1 as a potential therapeutic target to treat children with DIPG., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflict of interest.

Hepatic hydrothorax is defined as pleural effusion in patients with a cirrhotic liver. The pleural effusion occurs due to ascites flowing to the pleural cavity through a diaphragmatic communication. Recent literature has described the usefulness of a thoracoscopic repair and has shown that it can control pleural effusion very efficaciously. The patient was a 65-year-old woman who complained of dyspnea and was admitted to our hospital. A chest X-ray revealed marked right pleural effusion. We injected indigo carmine intraperitoneally and observed indigo carmine-colored pleural effusion; thus peritoneopleural communication was validated. After the failure of thoracic drainage and pleurodesis with minocycline hydrochloride, thoracoscopic surgery was performed 5 weeks after hospitalization. Obvious bulla formation was observed on the diaphragm, which was immediately resected with linear staplers. The postoperative course was excellent without any recurrence of pleural effusion.

It has been suggested that lung cancer sometimes aggregates in families. However, the familial occurrence of bronchioloalveolar carcinoma (BAC) is extremely rare. We present a family in which two brothers had BAC. The clinical features and immunohistochemical findings of BAC in the two brothers were compared. Immunohistochemical findings revealed that both cases of BAC had very similar immunopathological features in epithelial marker expression. A review of the literature revealed that this is the third case of BACs in a single family.

Nonspecific interstitial pneumonia/fibrosis (NSIP) was first described by Katzenstein and Fiorelli in 1994 (Am J Surg Pathol 18: 136-147). Many reports have described that corticosteroids are effective for NSIP. We describe a case of group II idiopathic NSIP in whom cyclophosphamide was administered since the initial response to corticosteroids had been insufficient. Lung biopsy was performed by video-assisted thoracoscopic surgery and NSIP was diagnosed pathologically, clinically and radiologically. Although the initial response to corticosteroids was insufficient, interstitial infiltrates on chest computed tomography improved dramatically after adding intravenous cyclophosphamide followed by oral cyclophosphamide. This case demonstrates that the addition of cyclophosphamide to corticosteroids might be a useful treatment for patients with NSIP.

A case of multilobar bronchioloalveolar carcinoma (BAC) is reported. To investigate the clonality of BAC, immunohistochemical staining as well as genetic analysis were performed. To investigate point mutations of the p53 gene, we used the polymerase chain reaction and fluorescence-based single strand conformation polymorphism analysis method. The BAC tissues of the right upper lobe, right lower lobe, and the other lobes were considered to be multiclonal. This case suggests that multilobar BAC might occur with multiclonality.