Missense mutations in Myc Box I influence nucleocytoplasmic transport to promote leukemogenesis.

PURPOSE: Somatic missense mutations in the phosphodegron domain of the MYC gene (MYC Box I or MBI) are detected in the dominant clones of a subset of acute myeloid leukemia (AML) patients, but the mechanisms by which they contribute to AML are unknown. EXPERIMENTAL DESIGN: To investigate the effects of MBI MYC mutations on hematopoietic cells, we employed a multi-omic approach to systematically compare the cellular and molecular consequences of expressing oncogenic doses of wild type, threonine-58 and proline-59 mutant MYC proteins in hematopoietic cells, and we developed a knockin mouse harboring the germline MBI mutation p.T58N in the Myc< gene. RESULTS: Both wild type and MBI mutant MYC proteins promote self-renewal programs and expand highly selected subpopulations of progenitor cells in the bone marrow. Compared to their wild type counterparts, mutant cells display decreased cell death and accelerated leukemogenesis in vivo, changes that are recapitulated in the transcriptomes of human AML bearing MYC mutations. The mutant phenotypes feature decreased stability and translation of mRNAs encoding proapoptotic and immune-regulatory genes, increased translation of RNA binding proteins and nuclear export machinery, and distinct nucleocytoplasmic RNAs profiles. MBI MYC mutant proteins also show a higher propensity to aggregate in perinuclear regions and the cytoplasm. Like the overexpression model, heterozygous p.T58N knockin mice displayed similar changes in subcellular MYC localization, progenitor expansion, transcriptional signatures, and develop hematopoietic tumors. CONCLUSIONS: This study uncovers that MBI MYC mutations alter RNA nucleocytoplasmic transport mechanisms to contribute to the development of hematopoietic malignancies.

Controlling Interfacial Hydrogen Bonding at a Gold Surface: The Effect of Organic Cosolvents.

Water often serves as both a reactant and solvent in electrocatalytic reactions. Interfacial water networks can affect the transport and kinetics of these reactions, e.g., hydrogen evolution reaction and CO2 reduction reaction. Adding cosolvents that influence the hydrogen-bonding (H-bonding) environment, such as dimethyl sulfoxide (DMSO), has the potential to tune the reactivity of these important electrocatalytic reactions by regulating the interfacial local environment and water network. We investigate interfacial H-bonding networks in water-DMSO cosolvent mixtures on gold surfaces by using surface-enhanced infrared absorption spectroscopy and molecular dynamics simulations. Experiments and simulations show that the gold surface is enriched with dehydrated DMSO molecules and the mixture phase-separates to form water clusters. Simulations show a "buckled" water conformation at the surface, further constraining interfacial H-bonding. The small size of these water clusters and the energetically unfavorable H-bond conformations might inhibit H-bonding with bulk water, suppressing the proton diffusion required for efficient hydrogen evolution reaction processes.

Auranofin Inhibition of Thioredoxin Reductase Sensitizes Lung Neuroendocrine Tumor Cells (NETs) and Small Cell Lung Cancer (SCLC) Cells to Sorafenib as well as Inhibiting SCLC Xenograft Growth.

Thioredoxin Reductase (TrxR) is a key enzyme in hydroperoxide detoxification through peroxiredoxin enzymes and in thiol-mediated redox regulation of cell signaling. Because cancer cells produce increased steady-state levels of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide), TrxR is currently being targeted in clinical trials using the anti-rheumatic drug, auranofin (AF). AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the lung atypical (neuroendocrine tumor) NET cell line H727. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, a multi-kinase inhibitor that was shown to decrease intracellular glutathione. The pharmacokinetic and pharmacodynamic properties of AF treatment in a mouse SCLC xenograft model was examined to maximize inhibition of TrxR activity without causing toxicity. AF was administered intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1 to 5 days in mice with DMS273 xenografts. Plasma levels of AF were 10-20 µM (determined by mass spectrometry of gold) and the optimal inhibition of TrxR (50 %) was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. When this daily AF treatment was extended for 14 days a significant prolongation of median survival from 19 to 23 days (p=0.04, N=30 controls, 28 AF) was observed without causing changes in animal bodyweight, CBCs, bone marrow toxicity, blood urea nitrogen, or creatinine. These results show that AF is an effective inhibitor of TrxR both in vitro and in vivo in SCLC, capable of sensitizing NETs and SCLC to sorafenib, and supports the hypothesis that AF could be used as an adjuvant therapy with agents known to induce disruptions in thiol metabolism to enhance therapeutic efficacy.

Ultrafast Spectroscopy Reveals Slow Water Dynamics in Biocondensates.

Cells achieve high spatiotemporal control over biochemical processes through compartmentalization to membrane-bound as well as membraneless organelles that assemble by liquid-liquid phase separation. Characterizing the balance of forces within these environments is essential to understanding their stability and function, and water is an integral part of the condensate, playing an important role in mediating electrostatic and hydrogen-bonding interactions. Here, we investigate the ultrafast, picosecond hydrogen-bond dynamics of a model biocondensate consisting of a peptide poly-l-arginine (Poly-R) and the nucleic acid adenosine monophosphate (AMP) using coherent two-dimensional infrared (2D IR) spectroscopy. We investigated three vibrational modes: the arginine side-chain C═N stretches, an AMP ring mode, and the amide backbone carbonyl stretching modes. Dynamics slow considerably between the dilute phase and the condensate phase for each vibrational probe. For example, the arginine side-chain C═N modes slow from 0.38 to 2.26 ps due to strong electrostatic interactions. All-atom molecular dynamics simulations provide an atomistic interpretation of the H-bond network disruption resulting from electrostatic contributions as well as collapse within the condensate. Simulations predict that a fraction of water molecules are highly constrained within the condensate, explaining the observed slowdown in the H-bond dynamics.

Missense mutations in Myc Box I influence MYC cellular localization, mRNA partitioning and turnover to promote leukemogenesis.

Somatic missense mutations in the phosphodegron domain of the MYC gene ( M YC Box I) are detected in the dominant clones of a subset of acute myeloid leukemia (AML) patients, but the mechanisms by which they contribute to AML are unknown. To unveil unique proprieties of MBI MYC mutant proteins, we systematically compared the cellular and molecular consequences of expressing similar oncogenic levels of wild type and MBI mutant MYC. We found that MBI MYC mutants can accelerate leukemia by driving unique transcriptional signatures in highly selected, myeloid progenitor subpopulations. Although these mutations increase MYC stability, they overall dampen MYC chromatin localization and lead to a cytoplasmic accumulation of the mutant proteins. This phenotype is coupled with increased translation of RNA binding proteins and nuclear export machinery, which results in altered RNA partitioning and accelerated decay of select transcripts encoding proapoptotic and proinflammatory genes. Heterozygous knockin mice harboring the germline MBI mutation Myc p.T73N exhibit cytoplasmic MYC localization, myeloid progenitors' expansion with similar transcriptional signatures to the overexpression model, and eventually develop hematological malignancies. This study uncovers that MBI MYC mutations alter MYC localization and disrupt mRNA subcellular distribution and turnover of select transcripts to accelerate tumor initiation and growth.

Updates on Total Ankle Arthroplasty.

The newer generation total ankle arthroplasty constructs afford higher levels of long-term survivability, and for the first in the history of ankle arthroplasty procedures, results are comparable to arthrodesis. Much of the success hinges on appropriate patient selection. A comprehensive workup of the patient will allow selection of adjunctive procedures as well as allowing for the determination of single versus 2-stage deformity correction. With the continual addition of implants, it is important to understand the specialization and indications that are assigned to certain models because this will help in selecting the most appropriate implant for any given patient.

Pediatric-Onset Relapsing Polychondritis With Otolaryngeal Manifestations.

Relapsing polychondritis (RP) is a rare autoimmune disease that can present with various clinical manifestations. Among the affected sites, the ear, nose, and throat cartilages are frequently involved, often leading to subtle and episodic symptoms that can be challenging to diagnose. A high index of suspicion is necessary for the early identification of these subtle signs, which can aid in early diagnosis and prompt management. In this report, we present a rare case of pediatric-onset relapsing polychondritis that was initially misdiagnosed as laryngotracheobronchitis.

Intersex manifestation in the rainbow darter (Etheostoma caeruleum): Are adult male fish susceptible to developing and recovering from intersex after exposure to endocrine active compounds?

For over a decade, intersex has been observed in rainbow darter (RD) (Etheostoma caeruleum) populations living downstream wastewater treatment plants (WWTPs) in the Grand River, Ontario, Canada. To further our understanding of intersex development in adult male fish, the current study addressed three objectives: i) can intersex be induced in adult male fish, ii) is there a specific window of exposure when adult male fish are more susceptible to developing intersex, and iii) can pre-exposed adult male fish recover from intersex? To assess intersex induction in adult male fish, wild male RD were exposed in the laboratory for 22 weeks (during periods of spawning, gonadal regression, and gonadal recrudescence) to environmentally relevant concentrations of 17α-ethinylestradiol (EE2) including nominal 0, 1, and 10 ng/L. Intersex rates and severity at 10 ng/L EE2 were similar to those observed historically in adult male populations living downstream WWTPs in the Grand River and confirmed previous predictions that 1-10 ng/L EE2 would cause these adverse effects. To assess a window of sensitivity in developing intersex, male RD were exposed to nominal 0, 1 or 10 ng/L EE2 for 4 weeks during three different periods of gonadal development, including (i) spawning, (ii) early recrudescence and (iii) late recrudescence. These short-term exposures revealed that intersex incidence and severity were greater when RD were exposed while gonads were fully developed (during spawning) compared to periods of recrudescence. To assess if RD recover from intersex, wild fish were collected downstream WWTPs in the Grand River and assessed for intersex both before and after a 22-week recovery period in clean water that included gonadal regression and recrudescence. Results showed that fish did not recover from intersex, with intersex rates and severity similar to those both before and after the transition to clean water. This study further advances our knowledge on intersex manifestation in adult male fish including their sensitivity to endocrine active compounds during different periods of their annual reproductive cycle and their limited ability to recover from intersex after onset of the condition.

Pedicle Screw Placement Accuracy in Robot-Assisted Spinal Fusion in a Multicenter Study.

Pedicle screw fixation is a spinal fusion technique that involves the implantation of screws into vertebral pedicles to restrict movement between those vertebrae. The objective of this research is to measure pedicle screw placement accuracy using a novel automated measurement system that directly compares the implanted screw location to the planned target in all three anatomical views. Preoperative CT scans were used to plan the screw trajectories in 122 patients across four surgical centers. Postoperative scans were fused to the preoperative plan to quantify placement accuracy using an automated measurement algorithm. The mean medial-lateral and superior-inferior deviations in the pedicle region for 500 screws were 1.75 ± 1.36 mm and 1.52 ± 1.26 mm, respectively. These deviations were measured using an automated system and were statistically different from manually determined values. The uncertainty associated with the fusion of preoperative to postoperative images was also quantified to better understand the screw-to-plan accuracy results. This study uses a novel automated measurement system to quantify screw placement accuracy as it relates directly to the planned target location, instead of analyzing for breaches of the pedicle, to quantify the validity of using of a robotic-guidance system for accurate pedicle screw placement.

Genetic association between the APOE ε4 allele, toxicant exposures and Gulf war illness diagnosis.

INTRODUCTION: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI. METHODS: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria. RESULTS: Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria. CONCLUSION: These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.

Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway.

Fragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients' neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD.

Metasurface-Enhanced Mid-Infrared Spectrochemical Imaging of Tissues.

Label-free and nondestructive mid-infrared vibrational hyperspectral imaging is an essential tissue analysis tool, providing spatially resolved biochemical information critical to understanding physiological and pathological processes. However, the chemically complex and spatially heterogeneous composition of tissue specimens and the inherently weak interaction of infrared light with biomolecules limit the analytical performance of infrared absorption spectroscopy. Here, an advanced mid-infrared spectrochemical tissue imaging modality is introduced using metasurfaces that support strong surface-localized electromagnetic fields to capture quantitative molecular maps of large-area murine brain tissue sections. The approach leverages polarization-multiplexed multi-resonance plasmonic metasurfaces to simultaneously detect various functional biomolecules. The surface-enhanced mid-infrared spectral imaging method eliminates the non-specific effects of bulk tissue morphology on quantitative spectral analysis and improves chemical selectivity. This study shows that metasurface enhancement increases the retrieval of amide I and II bands associated with protein secondary structures. Moreover, it is demonstrated that plasmonic metasurfaces enhance the chemical contrast in infrared images and enable detection of ultrathin tissue regions that are not otherwise visible to conventional mid-infrared spectral imaging. While this work uses murine brain tissue sections, the chemical imaging method is well-suited for other tissue types, which broadens its potential impact for translational research and clinical histopathology.

Phase Ib study of talimogene laherparepvec in combination with atezolizumab in patients with triple negative breast cancer and colorectal cancer with liver metastases.

BACKGROUND: Talimogene laherparepvec (T-VEC), a first-in-class oncolytic viral immunotherapy, enhances tumor-specific immune activation. T-VEC combined with atezolizumab, which blocks inhibitor T-cell checkpoints, could provide greater benefit than either agent alone. Safety/efficacy of the combination was explored in patients with triple negative breast cancer (TNBC) or colorectal cancer (CRC) with liver metastases. METHODS: In this phase Ib, multicenter, open-label, parallel cohort study of adults with TNBC or CRC with liver metastases, T-VEC (106 then 108 PFU/ml; ≤4 ml) was administered into hepatic lesions via image-guided injection every 21 (±3) days. Atezolizumab 1200 mg was given on day 1 and every 21 (±3) days thereafter. Treatment continued until patients experienced dose-limiting toxicity (DLT), had complete response, progressive disease, needed alternative anticancer treatment, or withdrew due to an adverse event (AE). The primary endpoint was DLT incidence, and secondary endpoints included efficacy and AEs. RESULTS: Between 19 March 2018 and 6 November 2020, 11 patients with TNBC were enrolled (safety analysis set: n = 10); between 19 March 2018 and 16 October 2019, 25 patients with CRC were enrolled (safety analysis set: n = 24). For the 5 patients in the TNBC DLT analysis set, no patient had DLT; for the 18 patients in the CRC DLT analysis set, 3 (17%) had DLT, all serious AEs. AEs were reported by 9 (90%) TNBC and 23 (96%) CRC patients, the majority with grade ≥3 [TNBC, 7 (70%); CRC, 13 (54%)], and 1 was fatal [CRC, 1 (4%)]. Evidence of efficacy was limited. Overall response rate was 10% (95% confidence interval 0.3-44.5) for TNBC; one (10%) patient had a partial response. For CRC, no patients had a response; 14 (58%) were unassessable. CONCLUSIONS: The safety profile reflected known risks with T-VEC including risks of intrahepatic injection; no unexpected safety findings from addition of atezolizumab to T-VEC were observed. Limited evidence of antitumor activity was observed.

Tibialis Anterior Tendon Rupture Surgical Treatments and Outcomes: A Systematic Review and Meta-Analysis.

Tibialis anterior tendon ruptures are a rare condition with an often-delayed diagnosis due to transient pain and compensation of remaining anterior compartment tendons. Previous systematic reviews have limited their recommendations to surgical treatment over nonoperative cares given the relatively small sample size in the literature. This current systematic review and meta-analysis was performed to compare the outcomes amongst the various surgical techniques and define factors that may affect long term patients results. Twenty-six references (217 cases) were identified. Use of extensor tendon autograft (odds ratio [OR] 5.55; I2=46%), autograft repair through semitendinosus/gracilis/ plantaris/ Achilles tendon/ peroneus longus ([OR] 4.14; I2=71%), or direct repair ([OR] 3.59; I2=57%), provided the best postoperative outcomes, whereas allograft repair ([OR] .52; I2=77%),and ipsilateral split/ turn-down tibialis anterior tendon ([OR] .69; I2=71%), were associated with poorer outcomes. Ruptures fixed in the acute phase ([OR] 8.3; I2=26%), were associated with statistically significant better outcomes when compared to these ruptures fixed in the chronic phase ([OR] .52; I2=77%). Results of this systematic review and meta-analysis suggests that ruptures should be surgically repaired in the acute phase whenever possible and comparable outcomes can be achieved through extensor tendon autograft repair, autograft repair, and direct repair.

Wild fish responses to wastewater treatment plant upgrades in the Grand River, Ontario.

Municipal wastewater treatment plant (WWTP) effluent is one of several point sources of contaminants (nutrients, pharmaceuticals, estrogens, etc.) which can lead to adverse responses in aquatic life. Studies of WWTP effluent impacts on rainbow darter (Etheostoma caeruleum) collected downstream of WWTPs in the Grand River, Ontario have reported disruption at multiple levels of biological organization, including altered vitellogenin gene expression, lower levels of in vitro steroid production, and high frequency of intersex. However, major upgrades have occurred at treatment plants in the central Grand River over the last decade. Treatment upgrades to the Waterloo WWTP were initiated in 2009 but due to construction delays, the upgrades came fully on-line in 2017/2018. Responses in rainbow darter have been followed at sites associated with the outfall consistently over this entire time period. The treatment plant upgrade resulted in nitrification of effluent, and once complete there was a major reduction in effluent ammonia, selected pharmaceuticals, and estrogenicity. This study compared several key responses in rainbow darter associated with the Waterloo WWTP outfall prior to and post upgrades. Stable isotopes signatures in fish were used to track exposure to effluent and changed dramatically over time, corresponding to the effluent quality. Disruptions in in vitro steroid production and intersex in the darters that had been identified prior to the upgrades were no longer statistically different from the upstream reference sites after the upgrades. Although annual variations in water temperature and flow can potentially mask or exacerbate the effects of the WWTP effluent, major capital investments in wastewater treatment targeted at improving effluent quality have corresponded with the reduction of adverse responses in fish in the receiving environment.

The association between iron deficiency and outcomes: a secondary analysis of the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial.

In the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial, the use of intravenous iron did not reduce the need for blood transfusion or reduce patient complications or length of hospital stay. As part of the trial protocol, serum was collected at randomisation and on the day of surgery. These samples were analysed in a central laboratory for markers of iron deficiency. We performed a secondary analysis to explore the potential interactions between pre-operative markers of iron deficiency and intervention status on the trial outcome measures. Absolute iron deficiency was defined as ferritin <30 µg.l-1 ; functional iron deficiency as ferritin 30-100 µg.l-1 or transferrin saturation < 20%; and the remainder as non-iron deficient. Interactions were estimated using generalised linear models that included different subgroup indicators of baseline iron status. Co-primary endpoints were blood transfusion or death and number of blood transfusions, from randomisation to 30 days postoperatively. Secondary endpoints included peri-operative change in haemoglobin, postoperative complications and length of hospital stay. Most patients had iron deficiency (369/452 [82%]) at randomisation; one-third had absolute iron deficiency (144/452 [32%]) and half had functional iron deficiency (225/452 [50%]). The change in pre-operative haemoglobin with intravenous iron compared with placebo was greatest in patients with absolute iron deficiency, mean difference 8.9 g.l-1 , 95%CI 5.3-12.5; moderate in functional iron deficiency, mean difference 2.8 g.l-1 , 95%CI -0.1 to 5.7; and with little change seen in those patients who were non-iron deficient. Subgroup analyses did not suggest that intravenous iron compared with placebo reduced the likelihood of death or blood transfusion at 30 days differentially across subgroups according to baseline ferritin (p = 0.33 for interaction), transferrin saturation (p = 0.13) or in combination (p = 0.45), or for the number of blood transfusions (p = 0.06, 0.29, and 0.39, respectively). There was no beneficial effect of the use of intravenous iron compared with placebo, regardless of the metrics to diagnose iron deficiency, on postoperative complications or length of hospital stay.

Exposure-response relationship between K. brevis blooms and reporting of upper respiratory and neurotoxin-associated symptoms.

In southwest Florida, Karenia brevis (K. brevis) blooms occur frequently, can be very intense and persist over several years. Individuals living in coastal communities around the Gulf of Mexico are particularly vulnerable to brevetoxins released by K. brevis in seawater and carried inland within marine aerosol. Exposure to K. brevis occurs during residential, recreational, and occupational activities and has been associated with upper respiratory tract (URT) symptoms in healthy and medically vulnerable individuals. Additionally, ingestion of brevetoxin-contaminated seafood causes neurotoxic shellfish poisoning (NSP), and severe headaches prompting emergency department visits which occur in excess during K. brevis blooms. The current study examined a dose-response relationship between K. brevis in coastal waters and URT and NSP-like symptoms and headaches among southwest Florida residents. Data on past medical history (PMH) and medical symptoms were collected from the participants (n = 258) in five southwest Florida counties between June 2019 to August 2021. A dose-response relationship was observed between K. brevis blooms and reporting of URT and NSP-like symptoms and headaches. Reporting of NSP-like symptoms was higher among participants with a PMH of migraines, chronic fatigue syndrome (CFS) and mild memory loss, while the association of headaches with K. brevis blooms was accentuated among individuals with a PMH of migraines. These results suggest further investigations into the threshold of aerosolized brevetoxin dose required to elicit URT, headaches and/or NSP-like symptoms. These symptoms ultimately cause significant public health safety concerns, primarily among vulnerable populations with preexisting neurological conditions.

Impact of Airline Secondhand Tobacco Smoke Exposure on Respiratory Health and Lung Function Decades After Exposure Cessation.

BACKGROUND: Twenty-five percent to 45% of COPD is caused by exposures other than active smoking. Secondhand tobacco smoke (SHS) has been suggested as an independent cause of COPD, based on its association with increased respiratory symptoms and a small decrease in lung function, but its impact on respiratory health and lung function after exposure cessation has not been explored. RESEARCH QUESTION: What are the consequences of airline SHS exposure on respiratory health and lung function decades after cessation? STUDY DESIGN AND METHODS: We performed a cohort study involving flight attendants because of their exposure to SHS that stopped > 20 years ago. We included subjects ≥ 50 years of age with > 1 year vs ≤ 1 year of airline SHS exposure (ie, exposed vs unexposed). Respiratory quality of life, as determined by the St. George's Respiratory Questionnaire (SGRQ), was the primary outcome for respiratory health. Key secondary outcomes included general quality of life (the Rand Corporation modification of the 36-item Short Form Health Survey Questionnaire; RAND-36), respiratory symptoms (COPD Assessment Test; CAT), and spirometry. RESULTS: The study enrolled 183 SHS-exposed and 59 unexposed subjects. Exposed subjects were 66.7 years of age, and 90.7% were female. They were hired at 23.8 years of age, were exposed to airline SHS for 16.1 years, and stopped exposure 27.5 years before enrollment. Prior SHS exposure was associated with worsened SGRQ (6.7 units; 95% CI, 2.7-10.7; P = .001), RAND-36 physical and social function, and CAT vs unexposed subjects. SHS exposure did not affect prebronchodilator spirometry or obstruction, but was associated with lower postbronchodilator FEV1 and FEV1/FVC, total lung capacity, and diffusing capacity of the lungs for carbon monoxide in a subset of subjects. Former smoking and SHS exposure synergistically worsened SGRQ (ß = 8.4; 95% CI, 0.4-16.4; P = .04). SHS exposure in people who never smoked replicated primary results and was associated with worsened SGRQ vs unexposed people (4.7 units; 95% CI, 0.7-7.0; P = .006). INTERPRETATION: Almost three decades after exposure ended, airline SHS exposure is strongly and dose-dependently associated with worsened respiratory health, but less robustly associated with airflow abnormalities used to diagnose COPD.

Does Age, Residency, or Feeding Guild Coupled with a Drought Index Predict Avian Health during Fall Migration?

Birds are good indicators of environmental change and are often studied for responses to climate. Many studies focus on breeding birds, while fewer look at the migration period, which is a critical time for many birds. Birds are more susceptible to unusual climatic events during their migration due to the metabolic stress of long-distance movements. In the fall of 2020, an unusual cold weather event coupled with drought and wildfire smoke led to a large avian mortality event in New Mexico. Later analysis pointed to the mortality being largely due to starvation. This was the impetus for our research. We used 11 years of fall bird banding data from two locations, along with local drought indices, to determine what predicts avian health during the migration period. We used fat score data from over 15,000 individual birds to assess whether drought indices, age, diet, or residency influenced avian health using multiple logistic regression. We found that the probability of positive fat scores decreased as drought severity increased for younger, insectivorous, migratory birds. Insectivores had a higher probability of receiving a fat score greater than zero relative to local drought conditions, which is important, since many North American insectivores are in steep decline. Migratory birds showed a greater response than year-round residents, and older birds showed a lower but significant response compared to hatch-year birds. Our results suggest that migratory insectivores in the southwestern United States may be less resilient to drought-related climate change.

Medial Malleolar Screw Length to Achieve Thread Purchase in the Dense Bone of the Tibial Epiphyseal Scar Location Based on CT Model.

Medial malleolar ankle fractures are one of the most common surgically treated fractures of the ankle joint. Current AO guidelines for medial malleolar fractures recommend 2 partially threaded cancellous screws across the fracture line. For these screws to cross the fracture line, the threads must purchase the distal tibial metaphysis, which is an area of decreased bone density especially in elderly osteoporotic bone. The epiphyseal scar of the tibia is the densest portion of distal metaphysis of the tibia, and it has been determined that bone density decreases significantly further proximal through the tibia. One hundred eighty-three individual weightbearing coronal CT scans were assessed to measure the location of the epiphyseal scar and propose an ideal screw length to purchase this area and remain within the distal most portion of the tibia. In following with this criteria it was determined that a 34 mm ⅓ thread pattern screw and a 38 mm ½ thread pattern screw would suffice for 92.6% and 75.3% of males, respectively. It was determined that a 30 mm ⅓ thread pattern screw and a 32 mm ½ thread pattern screw would suffice for 93.4% and 85.3% of females, respectively. This study proposes optimal screw lengths in a theoretical area of increased bone density that may decrease complications in patients with compromised bone quality.