Evaluating the comparability of osteoporosis treatments using propensity score and negative control outcome methods in UK and Denmark electronic health record databases.

Evidence on the comparative effectiveness of osteoporosis treatments is heterogeneous. This may be attributed to different populations and clinical practice, but also to differing methodologies ensuring comparability of treatment groups before treatment effect estimation and the amount of residual confounding by indication. This study assessed the comparability of denosumab vs oral bisphosphonate (OBP) groups using propensity score (PS) methods and negative control outcome (NCO) analysis. A total of 280 288 women aged ≥50 years initiating denosumab or OBP in 2011-2018 were included from the UK Clinical Practice Research Datalink (CPRD) and the Danish National Registries (DNR). Balance of observed covariates was assessed using absolute standardised mean difference (ASMD) before and after PS weighting, matching, and stratification, with ASMD >0.1 indicating imbalance. Residual confounding was assessed using NCOs with ≥100 events. Hazard ratio (HR) and 95% confidence interval (CI) between treatment and NCO was estimated using Cox models. Presence of residual confounding was evaluated with two approaches1: >5% of NCOs with 95% CI excluding 1,2 >5% of NCOs with an upper CI <0.75 or lower CI >1.3. The number of imbalanced covariates before adjustment (CPRD 22/87; DNR 18/83) decreased, with 2-11% imbalance remaining after weighting, matching or stratification. Using approach 1, residual confounding was present for all PS methods in both databases (≥8% of NCOs), except for stratification in DNR (3.8%). Using approach 2, residual confounding was present in CPRD with PS matching (5.3%) and stratification (6.4%), but not with weighting (4.3%). Within DNR, no NCOs had HR estimates with upper or lower CI limits beyond the specified bounds indicating residual confounding for any PS method. Achievement of covariate balance and determination of residual bias were dependent upon several factors including the population under study, PS method, prevalence of NCO, and the threshold indicating residual confounding.

Treatment groups in clinical practice may not be comparable as patient characteristics differ according to the need for the prescribed medication, known as confounding. We assessed comparability of two common osteoporosis treatments, denosumab and oral bisphosphonate, in 280 288 postmenopausal women using electronic health records from UK Clinical Practice Research Datalink (CPRD) and Danish National Registries (DNR). We evaluated comparability of recorded patient characteristics with three propensity score (PS) methods, matching, stratification, and weighting. We assessed residual confounding from unrecorded patient characteristics via negative control outcomes (NCO), events known not to be associated with treatment such as delirium. We found that achieving comparability of osteoporosis treatment groups depended on the study population, PS method, and definition of residual confounding. Weighting and stratification performed the best in DNR and CPRD, respectively. Using a stricter threshold based on statistical significance for the NCO suggested the treatment groups were not comparable, except for PS stratification in DNR. Applying clinically significant thresholds of treatment effect size showed comparability using weighting in CPRD and all PS methods in DNR. Studies should consider more than one PS method to test robustness and identify the largest number of NCO to give the greatest flexibility in detecting residual confounding.

Integration of population genetics with oceanographic models reveals strong connectivity among coral reefs across Seychelles.

Many countries with tropical reef systems face hard choices preserving coral reefs in the face of climate change on limited budgets. One approach to maximising regional reef resilience is targeting management efforts and resources at reefs that export large numbers of larvae to other reefs. However, this requires reef connectivity to be quantified. To map coral connectivity in the Seychelles reef system we carried out a population genomic study of the Porites lutea species complex using 241 sequenced colonies from multiple islands. To identify oceanographic drivers of this connectivity and quantify variability, we further used a 2 km resolution regional ocean simulation coupled with a larval dispersal model to predict the flow of coral larvae between reef sites. Patterns of admixture and gene flow are broadly supported by model predictions, but the realised connectivity is greater than that predicted from model simulations. Both methods detected a biogeographic dispersal barrier between the Inner and Outer Islands of Seychelles. However, this barrier is permeable and substantial larval transport is possible across Seychelles, particularly for one of two putative species found in our genomic study. The broad agreement between predicted connectivity and observed genetic patterns supports the use of such larval dispersal simulations in reef system management in Seychelles and the wider region.

The buccal frenum: Trends in diagnosis and indications for treatment of buccal-ties among 466 healthcare professionals.

BACKGROUND: The buccal frenum is connective tissue that adheres the mucosa of the cheek to the alveolar process. When restricted, this condition is commonly known as a buccal- or cheek-tie. Restrictive buccal frena are often treated during tongue- and lip-tie procedures, yet widely accepted classification, diagnostic and treatment guidelines are lacking. OBJECTIVE: Provide a scoping review on the evaluation and management of buccal-ties, including diagnosis, classification, symptoms and treatment, by surveying healthcare providers with experience evaluating and managing oral restrictions. METHODS: Literature review and IRB-approved survey to assess practice patterns among healthcare providers identified from online directories of tongue-tie release providers and associated allied health professionals. RESULTS: A multidisciplinary group of 466 providers responded. About 87% indicated that they assess buccal restrictions. Evaluation methods included finger sweep (89.1%), visual inspection (76.4%), tissue blanching (66.5%) and functional assessment (53.4%). Around 94% of providers reported that objective and subjective findings are both needed for diagnosis and that an estimated 5%-10% of infants may be affected. About 70% of providers release buccal-ties (if needed) simultaneously with tongue-ties, and 76.8% recommend post-operative stretches as necessary for optimal healing. Respondents indicated a need for further research, evidence-based assessments, a classification system and treatment protocols. CONCLUSION: Evaluating a buccal frenum to diagnose a symptomatic buccal-tie relies upon visual inspection, palpation and assessment of oral function. Survey data and clinical experience are summarized to review classification systems, diagnostic/evaluation criteria and treatment recommendations as a foundational cornerstone for future works to build upon.

Pectoral Muscle Re-Attachment with Breast Implant Removal.

Breast implant removal is an increasingly requested procedure. An uncommon but important reason for this is breast animation deformity (BAD). Although methods such as the split muscle have been used for prevention and correction of animation deformity successfully for many years, [1, 2] we occasionally see patients who have undergone explantation and present with unresolved animation. These patients have had prior unsuccessful attempts at correction by further muscle release, and explantation was done as a final attempt at resolution. We regard muscle re-attachment as key to correction of animation. Herein we present illustrative cases and discuss technical points.

Oncogenic Mutations in the DNA-Binding Domain of FOXO1 that Disrupt Folding: Quantitative Insights from Experiments and Molecular Simulations.

FOXO1, a member of the family of winged-helix motif Forkhead box (FOX) transcription factors, is the most abundantly expressed FOXO member in mature B cells. Sequencing of diffuse large B-cell lymphoma (DLBCL) tumors and cell lines identified specific mutations in the forkhead domain linked to loss of function. Differential scanning calorimetry and thermal shift assays were used to characterize how eight of these mutations affect the stability of the FOX domain. Mutations L183P and L183R were found to be particularly destabilizing. Electrophoresis mobility shift assays show these same mutations also disrupt FOXO1 binding to their canonical DNA sequences, suggesting that the loss of function is due to destabilization of the folded structure. Computational modeling of the effect of mutations on FOXO1 folding was performed using alchemical free energy perturbation (FEP), and a Markov model of the entire folding reaction was constructed from massively parallel molecular simulations, which predicts folding pathways involving the late folding of helix α3. Although FEP can qualitatively predict the destabilization from L183 mutations, we find that a simple hydrophobic transfer model, combined with estimates of unfolded-state solvent-accessible surface areas from molecular simulations, is able to more accurately predict changes in folding free energies due to mutations. These results suggest that the atomic detail provided by simulations is important for the accurate prediction of mutational effects on folding stability. Corresponding disease-associated mutations in other FOX family members support further experimental and computational studies of the folding mechanism of FOX domains.

Superstoichiometric Binding of the Anticancer Agent Titanocene Dichloride by Human Serum Transferrin and the Accompanying Lobe Closure.

Titanocene dichloride (TDC) is an anticancer agent that delivers Ti(IV) into each of the two Fe(III) binding sites of bilobal human serum transferrin (Tf). This protein has been implicated in the selective transport of Ti(IV) to cells. How Ti(IV) might be released from the Tf Fe(III) binding site has remained a question, and crystal structures have raised issues about lobe occupancy and lobe closure in Ti(IV)-loaded Tf, compared with the Fe(III)-loaded form. Here, inductively coupled plasma optical emission spectroscopy reveals that Tf can stabilize toward hydrolytic precipitation more than 2 equiv of Ti, implying superstoichiometric binding beyond the two Fe(III) binding sites. Further studies support the inability of TDC to induce a complete lobe closure of Tf. Fluorescence data for TDC binding at low equivalents of TDC support an initial protein conformational change and lobe closure upon Ti binding, whereas data at higher equivalents support an open lobe configuration. Spectroscopic titration reveals less intense protein-metal electronic transitions as TDC equivalents are increased. Denaturing urea-PAGE gels and small angle X-ray scattering studies support an open lobe conformation. The concentrations of bicarbonate used in some earlier studies are demonstrated here to cause a pH change over time, which may contribute to variation in the apparent molar absorptivity associated with Ti(IV) binding in the Fe binding site. Finally, Fe(III)-bound holo-Tf still stabilizes TDC toward hydrolytic precipitation, a finding that underscores the importance of the interactions of Tf and TDC outside the Fe(III) binding site and suggests possible new pathways of Ti introduction to cells.

Safety and efficacy of maxillary labial frenectomy in children: A retrospective comparative cohort study.

BACKGROUND: Maxillary frenectomy in children is a common procedure, but concerns about scar tissue affecting diastema closure prevent many clinicians from treating prior to orthodontics. OBJECTIVES: To determine if maxillary frenectomy is safe and if diastema size is affected by early treatment. MATERIALS AND METHODS: Paediatric patients with hypertrophic maxillary frena were treated under local anaesthesia with diode laser and CO2 laser. Diastema width was compared by calibrating and digitally measuring initial and postoperative intraoral photographs. RESULTS: In total, 109 patients were included: 95 patients with primary dentition (39% male; mean age 1.9 years±1.5 years) and 14 with mixed dentition (43% male; mean age 8.1±1.3 years) with a mean follow-up of 18.0±13.2 months. No adverse outcomes were noted other than minor pain and swelling. In the primary dentition, a decrease in diastema width was observed in 94.7% with a mean closure of -1.4±1.0mm (range +0.7 to -5.1mm). In the mixed dentition, a decrease in diastema width was observed in 92.9% with a mean closure of -1.8±0.8mm (range 0 to -3.5mm). 74.5% of patients in the primary dentition and 75% of patients in the mixed dentition with preoperative diastema>2mm improved to<2mm width postoperatively. CONCLUSIONS: Frenectomy is associated with cosmetic and oral hygiene benefits and when performed properly, does not impede diastema closure and may aid closure. Technique and case selection are critical to successful outcomes. IRB ethics approval was obtained from Solutions IRB protocol #2018/12/8, and this investigation was self-funded.

Low-coverage reduced representation sequencing reveals subtle within-island genetic structure in Aldabra giant tortoises.

Aldabrachelys gigantea (Aldabra giant tortoise) is one of only two giant tortoise species left in the world and survives as a single wild population of over 100,000 individuals on Aldabra Atoll, Seychelles. Despite this large current population size, the species faces an uncertain future because of its extremely restricted distribution range and high vulnerability to the projected consequences of climate change. Captive-bred A. gigantea are increasingly used in rewilding programs across the region, where they are introduced to replace extinct giant tortoises in an attempt to functionally resurrect degraded island ecosystems. However, there has been little consideration of the current levels of genetic variation and differentiation within and among the islands on Aldabra. As previous microsatellite studies were inconclusive, we combined low-coverage and double-digest restriction-associated DNA (ddRAD) sequencing to analyze samples from 33 tortoises (11 from each main island). Using 5426 variant sites within the tortoise genome, we detected patterns of within-island population structure, but no differentiation between the islands. These unexpected results highlight the importance of using genome-wide genetic markers to capture higher-resolution genetic structure to inform future management plans, even in a seemingly panmictic population. We show that low-coverage ddRAD sequencing provides an affordable alternative approach to conservation genomic projects of non-model species with large genomes.

Tongue Restriction Questionnaire: A New Screening Tool to Identify Tongue-Tied Patients.

PURPOSE: This study was intended to determine the prevalence of tongue restrictions in a pediatric population and develop a screening tool for tongue-tie symptoms. METHODS: Patients were screened for tongue elevation and common symptoms using a novel Tongue Restriction Questionnaire (TRQ) that assesses symptoms throughout the lifespan. RESULTS: In total, 314 children (47.5% male) with a mean age of 5.8 years were screened; 25.5% of children were grade 1 (could elevate the tongue >80% to the incisive papilla), 51.3% were grade 2 (50%-80%), 20.4% were grade 3 (25%-50%), and 2.9% were grade 4 (less than 25% elevation) or most restricted. Inter-rater reliability between the dentist and the hygienist's independent grades was highly significant (ᴋ = .915, P less than .001). With regard to consideration of the child's symptoms in addition to the functional grade (tongue elevation), 26.1% of parents were interested in a referral for possible treatment; 24.5% chose to wait and consider treatment in the future if symptoms worsened; 49.4% of children had excellent mobility and/or were unaffected. Childhood symptoms that correlated with more restricted tongue grades were spitting out food (P = .004) and slow eating (P = .021), and a history of prolonged feeding (P = .052) and milk dribbling out of the mouth (P = .027) as infants. A higher symptom score in infancy correlated with a higher score in childhood (r = .386, P less than .001) and a greater likelihood of referral in childhood (P less than .001). CONCLUSIONS: Tongue restrictions are common in pediatric patients presenting to dental practices, and symptom presentations vary between patients. Tongue elevation is an easy and reliable test of tongue mobility. Shared decision-making and proper assessments help prevent undertreatment and overtreatment.

Metal-Binding Q-Proline Macrocycles.

We introduce the efficient Fmoc-SPPS and peptoid synthesis of Q-proline-based, metal-binding macrocycles (QPMs), which bind metal cations and display nine functional groups. Metal-free QPMs are disordered, evidenced by NMR and a crystal structure of QPM-3 obtained through racemic crystallization. Upon addition of metal cations, QPMs adopt ordered structures. Notably, the addition of a second functional group at the hydantoin amide position (R2) converts the proline ring from Cγ-endo to Cγ-exo, due to steric interactions.

The CLIP-domain serine protease CLIPC9 regulates melanization downstream of SPCLIP1, CLIPA8, and CLIPA28 in the malaria vector Anopheles gambiae.

The arthropod melanization immune response is activated by extracellular protease cascades predominantly comprised of CLIP-domain serine proteases (CLIP-SPs) and serine protease homologs (CLIP-SPHs). In the malaria vector, Anopheles gambiae, the CLIP-SPHs SPCLIP1, CLIPA8, and CLIPA28 form the core of a hierarchical cascade downstream of mosquito complement that is required for microbial melanization. However, our understanding of the regulatory relationship of the CLIP-SPH cascade with the catalytic CLIP-SPs driving melanization is incomplete. Here, we report on the development of a novel screen to identify melanization pathway components based on the quantitation of melanotic mosquito excreta, eliminating the need for microdissections or hemolymph enzymatic assays. Using this screen, we identified CLIPC9 and subsequent functional analyses established that this protease is essential for the melanization of both Escherichia coli and the rodent malaria parasite Plasmodium berghei. Mechanistically, septic infection with E. coli promotes CLIPC9 cleavage and both full-length and cleaved CLIPC9 localize to this bacterium in a CLIPA8-dependent manner. The steady state level of CLIPC9 in the hemolymph is regulated by thioester-containing protein 1 (TEP1), suggesting it functions downstream of mosquito complement. In support, CLIPC9 cleavage is inhibited following SPCLIP1, CLIPA8, and CLIPA28 knockdown positioning it downstream of the CLIP-SPH cascade. Moreover, like CLIPA8 and CLIPA28, CLIPC9 processing is negatively regulated by serine protease inhibitor 2 (SRPN2). This report demonstrates how our novel excretion-based approach can be utilized to dissect the complex protease networks regulating mosquito melanization. Collectively, our findings establish that CLIPC9 is required for microbial melanization in An. gambiae and shed light on how the CLIP-SPH cascade regulates this potent immune response.

Functional Improvements of Speech, Feeding, and Sleep After Lingual Frenectomy Tongue-Tie Release: A Prospective Cohort Study.

Recent studies suggest that speech, solid feeding, and sleep difficulties may be linked to restricted tongue function. Children with tongue restrictions and speech, feeding, and sleep issues underwent lingual frenectomies with a CO2 laser, paired with myofunctional exercises. Questionnaires were completed before, 1 week after, and 1 month following treatment. Thirty-seven patients participated in the study (mean age 4.2 years [range 13 months to 12 years]). Overall, speech improved in 89%, solid feeding improved in 83%, and sleep improved in 83% of patients as reported by parents. Fifty percent (8/16) of speech-delayed children said new words after the procedure (P = .008), 76% (16/21) of slow eaters ate more rapidly (P < .001), and 72% (23/32) of restless sleepers slept less restlessly (P < .001). After tongue-tie releases paired with exercises, most children experience functional improvements in speech, feeding, and sleep. Providers should screen for oral restrictions in children and refer for treatment when functions are impaired.

Deletion 20q12 is associated with histological transformation of nodal marginal zone lymphoma to diffuse large B-cell lymphoma.

The genetic and molecular abnormalities underlying histological transformation (HT) of nodal marginal zone lymphoma (NMZL) to diffuse large B-cell lymphoma (DLBCL) are not well known. While del(20q12) is commonly deleted in myelodysplastic syndrome it has not previously been associated with DLBCL. We recently described a case of DLBCL harboring del(20q12) in a patient with a history of MZL involving lymph nodes and skin. Here we report eight matched cases of transformed MZL(tMZL): six from nodal MZL (tNMZL) and two from splenic MZL (tSMZL). We found >20% del(20q12) in 4/6 tNMZL, but not in tSMZL, nor in unmatched DLBCL, MZL with increased large cells (MZL-ILC), or MZL cases. To examine whether transformation is associated with a specific gene signature, the matched cases were analyzed for multiplexed gene expression using the Nanostring PanCancer Pathways panel. The differential gene expression signature revealed enrichment of inflammatory markers, as previously observed in MZL. Also, tMZL and de novo DLBCL were enriched for extracellular matrix proteins such as collagen and fibronectin, vascular development protein PDGFRß, DNA repair protein RAD51, and oncogenic secrete protein Wnt11. A subset of genes is expressed differentially in del(20q12) tMZL cases vs non-del(20q12) tMZL cases. These results suggest a specific pathway is involved in the histological transformation of NMZL, which could serve as an indicator of aggressive clinical course in this otherwise indolent neoplasm.

Solution structure, glycan specificity and of phenol oxidase inhibitory activity of Anopheles C-type lectins CTL4 and CTLMA2.

Malaria, the world's most devastating parasitic disease, is transmitted between humans by mosquitoes of the Anopheles genus. An. gambiae is the principal malaria vector in Sub-Saharan Africa. The C-type lectins CTL4 and CTLMA2 cooperatively influence Plasmodium infection in the malaria vector Anopheles. Here we report the purification and biochemical characterization of CTL4 and CTLMA2 from An. gambiae and An. albimanus. CTL4 and CTLMA2 are known to form a disulfide-bridged heterodimer via an N-terminal tri-cysteine CXCXC motif. We demonstrate in vitro that CTL4 and CTLMA2 intermolecular disulfide formation is promiscuous within this motif. Furthermore, CTL4 and CTLMA2 form higher oligomeric states at physiological pH. Both lectins bind specific sugars, including glycosaminoglycan motifs with ß1-3/ß1-4 linkages between glucose, galactose and their respective hexosamines. Small-angle x-ray scattering data supports a compact heterodimer between the CTL domains. Recombinant CTL4/CTLMA2 is found to function in vivo, reversing the enhancement of phenol oxidase activity in dsCTL4-treated mosquitoes. We propose these molecular features underline a common function for CTL4/CTLMA2 in mosquitoes, with species and strain-specific variation in degrees of activity in response to Plasmodium infection.

Anopheles gambiae TEP1 forms a complex with the coiled-coil domain of LRIM1/APL1C following a conformational change in the thioester domain.

The complement-like protein thioester-containing protein 1 (TEP1) is a key factor in the immune response of the malaria vector Anopheles gambiae to pathogens. Multiple allelic variants of TEP1 have been identified in laboratory strains and in the field, and are correlated with distinct immunophenotypes. TEP1 is tightly regulated by conformational changes induced by cleavage in a protease-sensitive region. Cleaved TEP1 forms exhibit significant variation in stability from hours to days at room temperature. In particular, the refractory allele TEP1*R1 is significantly more stable than the susceptible allele TEP1*S1. This raises the question of whether the stability of cleaved TEP1 is linked to allelic variation and varying immunophenotypes. We have analyzed the stability of the cleaved form of additional TEP1 alleles and constructs. We show that stability is correlated with allelic variation within two specific loops in direct proximity to the thioester bond. The variable loops are part of an interface between the TED and MG8 domains of TEP1 that protect the thioester from hydrolysis. Engineering specific disulfide bonds to prevent separation of the TED-MG8 interface stabilizes the cleaved form of TEP1 for months at room temperature. Cleaved TEP1 forms a soluble complex with a heterodimer of two leucine-rich repeat proteins, LRIM1 and APL1C, and precipitates in the absence of this complex. The molecular structure and oligomeric state of the TEP1/LRIM1/APL1C complex is unclear. The C-terminal coiled-coil domain of the LRIM1/APL1C complex is sufficient to stabilize the cleaved form of TEP1 in solution but cleaved forms of disulfide-stabilized TEP1 do not interact with LRIM1/APL1C. This implies that formation of the TEP1cut/LRIM1/APL1C complex is related to the conformational change that induces the precipitation of cleaved TEP1.

The Use of Poly-4-Hydroxybutyrate (P4HB) Scaffold in the Ptotic Breast: A Multicenter Clinical Study.

BACKGROUND: Mastopexy and reduction mammaplasty are often limited by the patient's poor native soft tissue quality, resulting in ptosis recurrence and loss of rejuvenated surgical results. Surgical scaffolds and acellular dermal matrices are used in these procedures to provide physical and mechanical stabilization of weakened or compromised tissue. GalaFLEX scaffold, made from poly-4-hydroxybutyrate (P4HB), is a next-generation product for soft tissue reinforcement that resorbs gradually while aiding tissue regeneration to achieve excellent outcomes. OBJECTIVES: To assess the clinical performance of GalaFLEX scaffold in soft tissue reinforcement during elective mastopexy and reduction mammaplasty. METHODS: This multicenter, single-arm, observational study assessed product performance and outcomes of GalaFLEX scaffold when used in breast surgery. Outcomes included ptosis correction and maintenance, associated adverse events, patient and surgeon satisfaction, and mammographic and ultrasound imaging evaluation. RESULTS: At 6 centers in the US, 62 of 69 enrolled patients were treated. Of this population, 89.7% had successful ptosis correction and maintenance at 1 year, with high patient and surgeon satisfaction for breast shape, droop/sag of the breast, and maintenance of results at 1 year. There were 5 adverse events deemed related to the device (8.0%), including nerve pain, breast swelling, ptosis, and 2 instances of asymmetry. CONCLUSIONS: GalaFLEX scaffold safely and successfully supports and elevates breast tissue in mastopexy and reduction mammaplasty, with maintained support at 1 year. Surgeon and patient satisfaction were high. No mammogram or ultrasound interference was detected.

The impact of long-term systemic glucocorticoid use in severe asthma: A UK retrospective cohort analysis.

OBJECTIVE: Systemic glucocorticoids (SGCs) are a treatment option for severe asthma but are associated with the development of adverse events (AEs). Evidence on the extent of SGC use and the relationship between SGC dose and AE risk in severe asthma is limited. METHODS: Patients with severe asthma (Global Initiative for Asthma step 4/5), with no SGC use during the <6-12 months before severe asthma determination (index date) were identified in the UK-based Clinical Practice Research Datalink database (2004-2012). Patients were assessed for SGC exposure and an incident diagnosis of an SGC-related AE (cataracts, diabetes, myocardial infarction [MI], osteoporosis, peptic ulcer or stroke) during the 8-year observation phase. The dose-related risk of an SGC-related AE was determined using AE-specific Cox proportional hazards models. RESULTS: Overall, 75% of 60,418 patients identified with severe asthma received SGC during the 8-year follow-up, with the majority receiving an average of >0-≤2.5 mg/day. The risk of diabetes (hazard ratio [HR]:1.20 [95% confidence interval (CI): 1.11, 1.30]), MI (HR: 1.25 [95% CI: 1.09, 1.43]) and osteoporosis (HR: 1.64 [95% CI: 1.51, 1.78]) was increased at low SGC doses (0-2.5 mg/day), with further risk increases at doses >2.5 mg/day versus no SGC use. Compared with no SGC use, SGC increased the risk of peptic ulcer in a non-dose-dependent manner, but the risk of stroke was unchanged. CONCLUSIONS: Most patients with severe asthma are exposed to SGC, which increases SGC-related AE risk. This suggests that SGC exposure should be minimized as recommended by asthma treatment guidelines.

Complement-Related Regulates Autophagy in Neighboring Cells.

Autophagy degrades cytoplasmic components and is important for development and human health. Although autophagy is known to be influenced by systemic intercellular signals, the proteins that control autophagy are largely thought to function within individual cells. Here, we report that Drosophila macroglobulin complement-related (Mcr), a complement ortholog, plays an essential role during developmental cell death and inflammation by influencing autophagy in neighboring cells. This function of Mcr involves the immune receptor Draper, suggesting a relationship between autophagy and the control of inflammation. Interestingly, Mcr function in epithelial cells is required for macrophage autophagy and migration to epithelial wounds, a Draper-dependent process. This study reveals, unexpectedly, that complement-related from one cell regulates autophagy in neighboring cells via an ancient immune signaling program.