Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.

BACKGROUND: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility. METHODS: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues. RESULTS: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma. CONCLUSION: SPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.

FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154∗) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10-7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154∗, and p.Arg202∗-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

Harms and benefits of opioids for management of non-surgical acute and chronic low back pain: a systematic review.

BACKGROUND: Consequences of prescription opioid use involve harms, addiction, tolerance and death. Despite routine prescription, opioids are not recommended for initial intervention by any major multidisciplinary low back pain (LBP) guideline. OBJECTIVE: Our primary purpose was to improve overall understanding of the harms and benefits associated with oral opioid interventions prescribed for treatment of acute or chronic back pain. Our second goal was to evaluate pain intensity and to compare and contrast these data with the harms. Our last objective was to evaluate conflicts of interest among the study authors and the findings. DESIGN/DATA/ELIGIBILITY CRITERIA: Studies incorporating oral prescription opioid management of non-surgical LBP were evaluated. After systematic assessment, no studies that met inclusion included participants with specifically acute LBP. Therefore, extracted data reflects only populations with subacute and chronic LBP. Data on reported harms, severe harms, pain outcomes and withdrawal rates were extracted and meta-analyses were completed for opioid versus placebo trials and opioids versus non-opioid trials. RESULTS: Fourteen studies met inclusion/exclusion requirements. All trials involved short-term management with limited follow-up. A high percentage of harms were identified across most studies. Opioids were not shown to be superior to other medications, and only showed superiority to placebo comparators (at cost of additional harms). CONCLUSION: This review identified trends of higher harms rates and higher percentages of severe harms in opioid arms for the management of subacute and chronic LBP. The majority of trials that demonstrated benefits with opioids also had potential conflicts of interest. Lastly, non-opioid medications demonstrated statistically significant pain improvement compared with opioids. We feel that the results of the trial are supportive of current LBP guidelines and do not condone the initial use of opioids in management of subacute or chronic LBP. TRIAL REGISTRATION NUMBER: CRD42017070914.

Prediction of readiness to decannulation from venovenous extracorporeal membrane oxygenation.

OBJECTIVE: The criteria and process for liberation from extracorporeal membrane oxygenation in patients with severe acute respiratory distress syndrome are not standardized. The predictive accuracy of the oxygen challenge test as a diagnostic test in determining weaning and decannulation from venovenous extracorporeal membrane oxygenation was tested. DESIGN: A single-centre, retrospective, observational cohort study. SETTING: Tertiary referral severe respiratory failure centre in a university hospital in the United Kingdom. PATIENTS: 253 adults with severe acute respiratory distress syndrome requiring extracorporeal membrane oxygenation. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patients had median age: 43 years (interquartile range: 32-52) years, extracorporeal membrane oxygenation days: 9 (interquartile range: 6-14) and acute physiology and chronic health evaluation II score 17.5 (interquartile range: 15-20). Oxygen challenge test value (PaO2-OCT) with best prediction was 31 kPa (232 mmHg; sensitivity 0.74; specificity 0.70; area under curve 0.77 (confidence interval: 0.73-0.81)). PaO2-OCT did not perform well as a prospective test to identify readiness to decannulation. Only 24 patients (10%) were decannulated 48 hours after their first positive oxygen challenge test (true positive) and 73.4% patients were false positives (positive oxygen challenge test but not decannulated). True positives had higher tidal volume (541 ± 218 vs 368 mL ± 210; p < 0.05) and minute ventilation (9.34 ± 5.36 vs 6.33 L/min ± 4.43; p < 0.05). Blood flow (3.17 ± 0.23 vs 3.53 L/min ± 0.56; p < 0.05), sweep gas flow (1.42 ±1.83 vs 3.74 L/min ± 2.43; p < 0.05) and extracorporeal membrane oxygenation minute volume at time of first positive oxygen challenge test was lower in true positives (1.66 ± 2.26 vs 4.82 ± 3.43 L/min). This was a strong predictor for decannulation within 48 hours (area under curve: 0.88, confidence interval: 0.88-0.89). CONCLUSIONS: In severe acute respiratory distress syndrome requiring venovenous extracorporeal membrane oxygenation, the PaO2-OCT is a poor predictor of readiness to decannulate from extracorporeal membrane oxygenation. Additional factors involved in the control of respiratory drive and carbon dioxide clearance, particularly native lung dead space and total minute ventilation, should be assessed.

Veno-arterio-venous ECMO for septic cardiomyopathy: a single-centre experience.

INTRODUCTION: The role of extracorporeal support for patients with septic shock remains unclear. METHODS: We conducted a retrospective analysis of our single-centre experience with veno-arterio-venous extracorporeal membrane oxygenation (VAV ECMO) in adult patients with severe respiratory failure and septic cardiomyopathy. Clinical data was extracted from electronic medical records including a dedicated ECMO referral and follow-up database. RESULTS: Twelve patients were commenced on VAV ECMO for septic cardiomyopathy for a median of four days (IQR 3.0 to 5.3) between 01/2014 and 12/2017. Five patients (41.7%) had a cardiac arrest prior to initiation of ECMO support. At baseline, median left ventricular ejection fraction was 16.25% (IQR 13.13 to 17.5) and median PaO2/FiO2 ratio was 9 kPa (IQR 6.5 to 12.0) [67.50 mmHg (IQR 48.75 to 90.00)]. The survival rate to hospital discharge for VAV ECMO was 75% in this cohort. None of the surviving patients died within the follow-up period (median six month). CONCLUSION: VAV ECMO is a feasible rescue strategy for a small proportion of patients with combined respiratory and cardiac failure secondary to septic shock with septic cardiomyopathy. We provide a detailed report of our experience with this technique. Further research is required comparing the different extracorporeal strategies directly to conventional resuscitation and against each other.

Telemanagement of Heart Failure Patients Across the Post-Acute Care Continuum.

BACKGROUND: Heart failure (HF) is a chronic condition causing nearly 1 million hospital admissions annually in the United States with 25% of patients rehospitalized within 30 days. INTRODUCTION: The purpose of this study was to investigate whether telemanagement of HF patients throughout the post-acute continuum of care would reduce rehospitalization rates and improve patient self-care knowledge and satisfaction. MATERIALS AND METHODS: HF patients discharged to a skilled nursing facility (SNF) received telemanagement by HF clinicians with opportunity for continuation at home with assistance of home healthcare (HHC) nurses. Wireless sensors worn at SNF and home captured continuous health information visible to HF clinicians on secure cloud database. Point-of-care devices were available at SNF. Patients had scheduled and as-needed video visits with audio and auscultation capacity with HF clinician. HF education was provided by SNF and HHC nursing. Patients were compared with historical control group receiving standard care at same SNF. RESULTS: Patients receiving telemanagement had 29% lower rehospitalization rates (17% vs. 24%), despite higher predicted rehospitalization risk. Median age was 81. Seven of eight patients who were rehospitalized in the telemanagement group had advanced HF symptoms (New York Heart Association Class IV). Five patients in telemanagement group were receiving continuous inotrope infusions. Patients reported good satisfaction and self-care knowledge. DISCUSSION: Reduction of rehospitalization rates was clinically significant in population of advanced age and HF symptoms. Technology enhanced communication content and timeliness across the post-acute care continuum. CONCLUSION: Post-acute telemanagement may reduce rehospitalization rates even in high-risk, older HF populations.

Severe Respiratory Failure, Extracorporeal Membrane Oxygenation, and Intracranial Hemorrhage.

OBJECTIVES: For patients supported with veno-venous extracorporeal membrane oxygenation, the occurrence of intracranial hemorrhage is associated with a high mortality. It is unclear whether intracranial hemorrhage is a consequence of the extracorporeal intervention or of the underlying severe respiratory pathology. In a cohort of patients transferred to a regional severe respiratory failure center that routinely employs admission brain imaging, we sought 1) the prevalence of intracranial hemorrhage; 2) survival and neurologic outcomes; and 3) factors associated with intracranial hemorrhage. DESIGN: A single-center, retrospective, observational cohort study. SETTING: Tertiary referral severe respiratory failure center, university teaching hospital. PATIENTS: Patients admitted between December 2011 and February 2016. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Three hundred forty-two patients were identified: 250 managed with extracorporeal support and 92 managed using conventional ventilation. The prevalence of intracranial hemorrhage was 16.4% in extracorporeal membrane oxygenation patients and 7.6% in conventionally managed patients (p = 0.04). Multivariate analysis revealed factors independently associated with intracranial hemorrhage to be duration of ventilation (d) (odds ratio, 1.13 [95% CI, 1.03-1.23]; p = 0.011) and admission fibrinogen (g/L) (odds ratio, 0.73 [0.57-0.91]; p = 0.009); extracorporeal membrane oxygenation was not an independent risk factor (odds ratio, 3.29 [0.96-15.99]; p = 0.088). In patients who received veno-venous extracorporeal membrane oxygenation, there was no significant difference in 6-month survival between patients with and without intracranial hemorrhage (68.3% vs 76.0%; p = 0.350). Good neurologic function was observed in 92%. CONCLUSIONS: We report a higher prevalence of intracranial hemorrhage than has previously been described with high level of neurologically intact survival. Duration of mechanical ventilation and admission fibrinogen, but not exposure to extracorporeal support, are independently associated with intracranial hemorrhage.

An international survey: the role of specialist nurses in adult respiratory extracorporeal membrane oxygenation.

BACKGROUND: The last decade has seen an increase in the number of centres able to provide venovenous extracorporeal membrane oxygenation (VV-ECMO) internationally across different health care systems. To support this growth, a variety of staffing arrangements have been adopted depending on local need and availability of resources, both in terms of manpower and finances to safely meet the complex needs of the patient and circuit management. AIM: The aim of the survey was to describe current staffing arrangements of care provision for adult patients on VV-ECMO, with a focus on understanding the professional roles and responsibilities of staff managing the circuit in order to inform further discussion around different approaches to staffing. METHODS: We conducted a cross-sectional international survey using an electronic questionnaire emailed to 177 worldwide ECMO centres treating adult patients with acute respiratory failure. The survey questions were generated through an internal and external iterative process and assessed for clarity, content and face validity. RESULTS: The response rate was 82%. Respondents managed extracorporeal oxygenation for adult respiratory alone (75%) or in combination with adult cardiac (67%), paediatric respiratory (62%) and paediatric cardiac (58%). The specialist nurse to patient ratio was 1:1 in 59% of centres, with 24-h/day presence in 74%. Overall, the specialist nurse provided the 24-h/day management of the circuit, including interventions. Perfusionists were responsible for the technical aspects of circuit management. CONCLUSIONS: A specialist nurse with perfusion backup is the staffing arrangement implemented by most centres and likely reflects the most efficient use of the professional competences available. RELEVANCE TO CLINICAL PRACTICE: Staffing for adult respiratory extracorporeal support has important implications for the planning of workforce, training and education, quality of service and the number of ECMO beds available.

Prevalence of Venous Thrombosis Following Venovenous Extracorporeal Membrane Oxygenation in Patients With Severe Respiratory Failure.

OBJECTIVES: Venovenous extracorporeal membrane oxygenation for patients with severe respiratory failure is increasingly common. There has been a significant change in the population, technology, and approach used for venovenous extracorporeal membrane oxygenation over the last 10 years. The objective of this study is to describe the prevalence of postdecannulation deep vein thrombosis in the cannulated vessel in adults who have received venovenous extracorporeal membrane oxygenation for severe respiratory failure. DESIGN: A single-center, retrospective, observational cohort, electronic note review study. SETTING: Tertiary referral university teaching hospital. PATIENTS: Patients commenced on venovenous extracorporeal membrane oxygenation for severe respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 103 patients commenced on extracorporeal membrane oxygenation with 81 survivors from December 2011 to February 2014. We performed postdecannulation venous Doppler ultrasound in 88.9% of extracorporeal membrane oxygenation survivors. The prevalence of deep vein thrombosis in the cannulated vessel following extracorporeal membrane oxygenation is 8.1/1,000 cannula days in patients who were screened. CONCLUSIONS: The prevalence of deep vein thrombosis following decannulation from extracorporeal membrane oxygenation for severe respiratory failure is clinically significant, and routine venous Doppler ultrasound following decannulation is warranted in this population.

The Relationship Among Heart Failure Disease Management, Quality of Care, and Hospitalizations.

Heart failure (HF) affects 5.1 million adult patients, accounting for over 1 million hospitalizations, 1.8 million office visits, and nearly 680,000 emergency department visits annually. HF hospitalizations have been incorporated into a national measure of hospital and provider quality, with associated financial penalties based on the 30-day readmission rate after an index hospitalization for HF. However, it is not clear whether the number of HF-related hospitalizations or 30-day readmissions is consistently related to quality of care. The relationships between various measures of HF care quality and hospitalization rates were evaluated by performing a cohort study of an HF disease management program in a clinical practice setting. Following the statistical analyses assessing outcomes and survival, the conclusion was that an HF disease management program in clinical practice associated with improved utilization of evidence-based medical and device therapies tends to improve ejection fraction and survival, and reduce sex and race disparities, but not with an associated reduction in hospitalizations or total hospital days.

Evaluation of an outreach programme for patients with COVID-19 in an integrated healthcare delivery system: a retrospective cohort study.

OBJECTIVES: In the first year of the COVID-19 pandemic, health systems implemented programmes to manage outpatients with COVID-19. The goal was to expedite patients' referral to acute care and prevent overcrowding of medical centres. We sought to evaluate the impact of such a programme, the COVID-19 Home Care Team (CHCT) programme. DESIGN: Retrospective cohort. SETTING: Kaiser Permanente Northern California. PARTICIPANTS: Adult members before COVID-19 vaccine availability (1 February 2020-31 January 2021) with positive SARS-CoV-2 tests. INTERVENTION: Virtual programme to track and treat patients with 'CHCT programme'. OUTCOMES: The outcomes were (1) COVID-19-related emergency department visit, (2) COVID-19-related hospitalisation and (3) inpatient mortality or 30-day hospice referral. MEASURES: We estimated the average effect comparing patients who were and were not treated by CHCT. We estimated propensity scores using an ensemble super learner (random forest, XGBoost, generalised additive model and multivariate adaptive regression splines) and augmented inverse probability weighting. RESULTS: There were 98 585 patients with COVID-19. The majority were followed by CHCT (n=80 067, 81.2%). Patients followed by CHCT were older (mean age 43.9 vs 41.6 years, p<0.001) and more comorbid with COmorbidity Point Score, V.2, score ≥65 (1.7% vs 1.1%, p<0.001). Unadjusted analyses showed more COVID-19-related emergency department visits (9.5% vs 8.5%, p<0.001) and hospitalisations (3.9% vs 3.2%, p<0.001) in patients followed by CHCT but lower inpatient death or 30-day hospice referral (0.3% vs 0.5%, p<0.001). After weighting, there were higher rates of COVID-19-related emergency department visits (estimated intervention effect -0.8%, 95% CI -1.4% to -0.3%) and hospitalisation (-0.5%, 95% CI -0.9% to -0.1%) but lower inpatient mortality or 30-day hospice referral (-0.5%, 95% CI -0.7% to -0.3%) in patients followed by CHCT. CONCLUSIONS: Despite CHCT following older patients with higher comorbidity burden, there appeared to be a protective effect. Patients followed by CHCT were more likely to present to acute care and less likely to die inpatient.

AP-2α/AP-2ß Transcription Factors Are Key Regulators of Epidermal Homeostasis.

AP-2 transcription factors regulate ectodermal development, but their roles in epidermal homeostasis in adult skin are unknown. We find that AP-2α is the predominant AP-2 family member in adult epidermis, followed by AP-2ß. Through inactivation of AP-2α, AP-2ß, or both in keratinocytes, we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (i) loss of AP-2ß in keratinocytes is compensated for by AP-2α, (ii) loss of AP-2α impairs terminal keratinocyte differentiation and hair morphogenesis, and (iii) the combined loss of AP-2α/AP-2ß results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede progressive neutrophilic skin inflammation. Inducible inactivation of AP-2α/AP-2ß in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2α or AP-2α/AP-2ß in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of reduced AP-2α-dependent gene expression of CXCL14 and the keratin 15 gene K15 as an early pathogenic event toward the manifestation of skin inflammation. Thus, AP-2α and AP-2ß are critical regulators of epidermal homeostasis in adult skin.

Intravenous Opioid Administration During Mechanical Ventilation and Use After Hospital Discharge.

Importance: Guidelines recommend an analgesia-first strategy for sedation during mechanical ventilation, but associations between opioids provided during mechanical ventilation and posthospitalization opioid-related outcomes are unclear. Objective: To evaluate associations between an intravenous opioid dose received during mechanical ventilation and postdischarge opioid-related outcomes in medical (nonsurgical) patients. Design, Setting, and Participants: This retrospective cohort study evaluated adults receiving mechanical ventilation lasting 24 hours or more for acute respiratory failure and surviving hospitalization. Participants from 21 Kaiser Permanente Northern California hospitals from January 1, 2012, to December 31, 2019, were included. Data were analyzed from October 1, 2020, to October 31, 2023. Exposures: Terciles of median daily intravenous fentanyl equivalents during mechanical ventilation. Main Outcomes and Measures: The primary outcome was the first filled opioid prescription in 1 year after discharge. Secondary outcomes included persistent opioid use and opioid-associated complications. Secondary analyses tested for interaction between opioid doses during mechanical ventilation, prior opioid use, and posthospitalization opioid use. Estimates were based on multivariable-adjusted time-to-event analyses, with death as a competing risk, and censored for hospice or palliative care referral, rehospitalization with receipt of opioid, or loss of Kaiser Permanente plan membership. Results: The study included 6746 patients across 21 hospitals (median age, 67 years [IQR, 57-76 years]; 53.0% male). Of the participants, 3114 (46.2%) filled an opioid prescription in the year prior to admission. The median daily fentanyl equivalent during mechanical ventilation was 200 µg (IQR, 40-1000 µg), with terciles of 0 to 67 µg, more than 67 to 700 µg, and more than 700 µg. Compared with patients who did not receive opioids during mechanical ventilation (n = 1013), a higher daily opioid dose was associated with opioid prescriptions in the year after discharge (n = 2942 outcomes; tercile 1: adjusted hazard ratio [AHR], 1.00 [95% CI, 0.85-1.17], tercile 2: AHR, 1.20 [95% CI, 1.03-1.40], and tercile 3: AHR, 1.25 [95% CI, 1.07-1.47]). Higher doses of opioids during mechanical ventilation were also associated with persistent opioid use after hospitalization (n = 1410 outcomes; tercile 3 vs no opioids: odds ratio, 1.44 [95% CI, 1.14-1.83]). No interaction was observed between opioid dose during mechanical ventilation, prior opioid use, and posthospitalization opioid use. Conclusions and Relevance: In this retrospective cohort study of patients receiving mechanical ventilation, opioids administered during mechanical ventilation were associated with opioid prescriptions following hospital discharge. Additional studies to evaluate risks and benefits of strategies using lower opioid doses are warranted.

AP-2α/AP-2ß transcription factors are key regulators of epidermal homeostasis.

AP-2 transcription factors regulate ectodermal development but their roles for epidermal homeostasis in the adult skin are unknown. We find that AP-2α is the predominant AP-2 family member in adult epidermis, followed by AP-2ß. Through inactivation of AP-2α, AP-2ß, or both in keratinocytes we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (1) loss of AP-2ß in keratinocytes is compensated for by AP-2α, (2) loss of AP-2α impairs terminal keratinocyte differentiation and hair morphogenesis, and (3) the combined loss of AP-2α/AP-2ß results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede a progressive neutrophilic skin inflammation. Inducible inactivation of AP-2α/AP-2ß in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2α or AP-2α/AP-2ß in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of loss of AP-2α-dependent gene expression of CXCL14 and KRT15 as an early pathogenic event towards the manifestation of skin inflammation. Thus, AP-2α/AP-2ß are critical regulators of epidermal homeostasis in the adult skin.

KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis.

Aplasia cutis congenita (ACC) is a congenital epidermal defect of the midline scalp and has been proposed to be due to a primary keratinocyte abnormality. Why it forms mainly at this anatomic site has remained a long-standing enigma. KCTD1 mutations cause ACC, ectodermal abnormalities, and kidney fibrosis, whereas KCTD15 mutations cause ACC and cardiac outflow tract abnormalities. Here, we found that KCTD1 and KCTD15 can form multimeric complexes and can compensate for each other's loss and that disease mutations are dominant negative, resulting in lack of KCTD1/KCTD15 function. We demonstrated that KCTD15 is critical for cardiac outflow tract development, whereas KCTD1 regulates distal nephron function. Combined inactivation of KCTD1/KCTD15 in keratinocytes resulted in abnormal skin appendages but not in ACC. Instead, KCTD1/KCTD15 inactivation in neural crest cells resulted in ACC linked to midline skull defects, demonstrating that ACC is not caused by a primary defect in keratinocytes but is a secondary consequence of impaired cranial neural crest cells, giving rise to midline cranial suture cells that express keratinocyte-promoting growth factors. Our findings explain the clinical observations in patients with KCTD1 versus KCTD15 mutations, establish KCTD1/KCTD15 complexes as critical regulators of ectodermal and neural crest cell functions, and define ACC as a neurocristopathy.

Characterization and Genome Sequence of Arthrobacter Phage Iter.

Arthrobacter phage Iter was isolated in North Georgia. Its genome is 43,963 bp with 70 open reading frames (ORFs) and a GC content of 67.4%. It shares 89.11% nucleotide identity with Arthrobacter phage Phives. Actinobacteriophages that share over 50% nucleotide identity are sorted into clusters, with Iter in cluster AZ.

A randomised controlled trial of non-invasive ventilation compared with extracorporeal carbon dioxide removal for acute hypercapnic exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Patients presenting with acute hypercapnic respiratory failure due to exacerbations of chronic obstructive pulmonary disease (AECOPD) are typically managed with non-invasive ventilation (NIV). The impact of low-flow extracorporeal carbon dioxide removal (ECCO2R) on outcome in these patients has not been explored in randomised trials. METHODS: Open-label randomised trial comparing NIV (NIV arm) with ECCO2R (ECCO2R arm) in patients with AECOPD at high risk of NIV failure (pH < 7.30 after ≥ 1 h of NIV). The primary endpoint was time to cessation of NIV. Secondary outcomes included device tolerance and complications, changes in arterial blood gases, hospital survival. RESULTS: Eighteen patients (median age 67.5, IQR (61.5-71) years; median GOLD stage 3 were enrolled (nine in each arm). Time to NIV discontinuation was shorter with ECCO2R (7:00 (6:18-8:30) vs 24:30 (18:15-49:45) h, p = 0.004). Arterial pH was higher with ECCO2R at 4 h post-randomisation (7.35 (7.31-7.37) vs 7.25 (7.21-7.26), p < 0.001). Partial pressure of arterial CO2 (PaCO2) was significantly lower with ECCO2R at 4 h (6.8 (6.2-7.15) vs 8.3 (7.74-9.3) kPa; p = 0.024). Dyspnoea and comfort both rapidly improved with commencement of ECCO2R. There were no severe or life-threatening complications in the study population. There were no episodes of major bleeding or red blood cell transfusion in either group. ICU and hospital length of stay were longer with ECCO2R, and there was no difference in 90-day mortality or functional outcomes at follow-up. INTERPRETATION: There is evidence of benefit associated with ECCO2R with time to improvement in respiratory acidosis, in respiratory physiology and an immediate improvement in patient comfort and dyspnoea with commencement of ECCO2R. In addition, there was minimal clinically significant adverse events associated with ECCO2R use in patients with AECOPD at risk of failing or not tolerating NIV. However, the ICU and hospital lengths of stay were longer in the ECCO2R for similar outcomes. Trial registration The trial is prospectively registered on ClinicalTrials.gov: NCT02086084. Registered on 13th March 2014, https://clinicaltrials.gov/ct2/show/NCT02086084?cond=ecco2r&draw=2&rank=8.

Evaluation of newborn screening bloodspot-based genetic testing as second tier screen for bedside newborn hearing screening.

PURPOSE: : Bedside newborn hearing screening is highly successful in identifying deaf or hard-of-hearing infants. However, newborn hearing screening protocols have high loss to follow-up rates. We propose that bloodspot-based genetic testing for GJB2 alleles can provide a means for rapid confirmation in a subset of infants who fail bedside newborn hearing screening. METHODS: : We performed a case-control study comparing the prevalence of common GJB2 mutations from deidentified bloodspots designated as "refer" by newborn hearing screening and contemporaneously selected randomly chosen controls designated as "pass." Between March 2006 and December 2007, 2354 spots were analyzed for common alleles, c.35delG, c.167delT, c.235delC, and p.V37I in GJB2 with a subset reanalyzed by conventional Sanger sequencing to search for additional alleles. RESULTS: : The prevalence of biallelic GJB2 mutations in bloodspots from infants who referred by newborn hearing screening is approximately 1 in 50 (23/1177). In contrast, one bloodspot from an infant who passed newborn hearing screening was identified to harbor biallelic GJB2 mutations. CONCLUSIONS: : These findings show that when a newborn refers by newborn hearing screening, there is a significant chance that GJB2-related hearing loss is present. Bloodspot-based genetic testing for common GJB2 alleles should be considered as second tier testing for bedside newborn hearing screening.

Significant linkage at chromosome 19q for otitis media with effusion and/or recurrent otitis media (COME/ROM).

BACKGROUND: In previous analyses, we identified a region of chromosome 19 as harboring a susceptibility locus for chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). Our aim was to further localize the linkage signal and ultimately identify the causative variant or variants. We followed up our previous linkage scan with dense SNP genotyping across in a 5 Mb region. A total of 607 individuals from 139 families, including 159 affected sib pairs and 62 second-degree affected relative pairs, were genotyped at 1,091 SNPs. We carried out a nonparametric linkage analysis, modeling marker-to-marker linkage disequilibrium. RESULTS: The maximum log of the odds (LOD) score increased to 3.75 (P = 1.6 × 10(-5)) at position 63.4 Mb, with a LOD-1 support interval between 61.6 Mb and 63.8 Mb, providing significant evidence of linkage between this region and COME/ROM. The support interval contains over 90 known genes, including several genes involved in the inflammasome protein complex, a key regulator of the innate immune response to harmful exogenous or endogenous stimuli. Parametric linkage analysis suggests that for a sib of an affected individual, the recurrence risk of COME/ROM due to this linkage region is twice the recurrence risk in the population. We examined potential associations between the SNPs genotyped in this region and COME/ROM, however none provided evidence for association. CONCLUSION: This study has refined the 19q region of linkage with COME/ROM, and association results suggest that the linkage signal may be due to rare variants.