Nicotine-induced ER Stress and ASM Cell Proliferation is Mediated by α7nAChR and Chaperones-RIC-3 and TMEM35.

Nicotine exposure in the context of smoking or vaping worsens airway function. Although commonly thought to exert effects through the peripheral nervous system, we previously showed airway smooth muscle (ASM) expresses nicotinic acetylcholine receptors (nAChRs), particularly alpha7 subtype (α7nAChR) with functional effects on contractility and metabolism. However, the mechanisms of nAChR regulation and downstream effects in ASM are not fully understood. Using human ASM cells from non-asthmatics vs. mild-moderate asthmatics, we tested the hypothesis that nAChR-specific ER chaperones RIC-3 and TMEM35 promote cell surface localization of α7nAChR with downstream influence on its functionality: effects exacerbated by inflammation. We found that mild-moderate asthma and exposure to pro-inflammatory cytokines relevant to asthma promote chaperone and α7nAChR expression in ASM. Downstream, ER stress was linked to nicotine/α7nAChR signaling, where RIC-3 and TMEM35 regulate nicotine-induced ER stress, Ca2+ regulation and ASM cell proliferation. Overall, our data highlights the importance α7nAChR chaperones in mediating and modulating nicotine effects in ASM towards airway contractility and remodeling.

"Toward Breast Reinnervation- What is our Endpoint" A systematic review of normal breast sensibility.

BACKGROUND: To restore breast sensibility, some centers are offering nerve reconstruction as a component of implant and flap-based breast reconstruction. To interpret and contextualize the results of these procedures, it is necessary to understand the normal range of breast sensibility, the factors that affect it, and the best methods for its objective measurement. METHODS: We conducted systematic and comprehensive searches across PubMed, Web of Science, and Cochrane Library databases using keywords and controlled vocabulary for the concepts of the breast, nipple, areola, and measurement. The search results were imported into Rayyan QCRI for a blinded screening of titles and abstracts. Studies were evaluated for bias using RevMan 5 software. The results of sensory measurements were pooled, and a quantitative summary of breast sensibility was generated. RESULTS: A total of 36 articles were identified, including retrospective, cross-sectional, and prospective studies. Although there were some consistent findings across studies, such that breast sensibility is inversely related to breast volume, there was wide variability in the following parameters: population, breast condition, measurement modality, anatomic areas of measurement, and sensibility findings. This heterogeneity precluded the generation of normative breast sensibility measurements. Furthermore, we detected a high degree of bias in most studies, due to self-selection of participants and failure to record patient characteristics that may alter sensibility. CONCLUSIONS: The literature lacks consistent data delineating normative values for breast sensibility. Standardized measurements of healthy volunteers with various breast characteristics are necessary to elucidate normative values and interpret efforts to restore sensibility in breast reconstruction.

Mechanosensitive Channels in Lung Health and Disease.

The lung is an inherently mechanosensitive organ, where cells of the airway and parenchyma experience a range of mechanical forces throughout life including shear, stretch, and compression, in both health and disease. In this regard, pediatric and adult lung diseases such as wheezing and asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF) all involve macroscopic and cellular changes to the mechanical properties of the bronchial airways and/or parenchyma to varying extents. Accordingly, understanding how mechanical forces are sensed in the lung, and the responses of cells and tissues in the context of normal development and health versus disease conditions becomes highly relevant. There is increasing recognition that transduction of mechanical forces into cellular responses involves a number of channels, some of which are inherently mechanosensitive. Such channels trigger mechanotransduction pathways that may further mediate cellular remodeling, inflammation, and other pathophysiologic mechanisms in response to stretch, stiffness, and inflammatory cascades. Two particularly important channel families have emerged in pulmonary pathophysiology: the transient receptor potential vanilloid family with focus on member TRPV4 and the recently identified Piezo (PZ) channels. Here, we explore current understanding of the contributions of TRPV4 and PZ channels in lung health and disease states, focusing on the interactions between these mechanosensitive channels and their local environment including immune cells, the extracellular matrix, and cellular cytoskeletal elements. We further discuss potential areas for future research to better understand the impact of mechanical channels on pulmonary health and disease. © 2023 American Physiological Society. Compr Physiol 13:5157-5178, 2023.

Functional α7 nicotinic receptors in human airway smooth muscle increase intracellular calcium concentration and contractility in asthmatics.

Although nicotinic acetylcholine receptors (nAChRs) are commonly associated with neurons in the brain and periphery, recent data indicate that they are also expressed in non-neuronal tissues. We recently found the alpha7 (α7nAChR) subunit is highly expressed in human airway smooth muscle (hASM) with substantial increase in asthmatics, but their functionality remains unknown. We investigated the location and functional role of α7nAChRs in hASM cells from normal versus mild-moderate asthmatic patients. Immunostaining and protein analyses showed α7nAChR in the plasma membrane including in asthmatics. In asthmatic hASM, patch-clamp recordings revealed significantly higher functional homomeric α7nAChR channels. Real-time fluorescence imaging showed nicotine, via α7nAChR, increases intracellular Ca2+ ([Ca2+]i) independent of ACh effects, particularly in asthmatic hASM, while cellular traction force microscopy showed nicotine-induced contractility including in asthmatics. These results indicate functional homomeric and heteromeric nAChRs that are increased in asthmatic hASM, with pharmacology that likely differ owing to different subunit interfaces that form the orthosteric sites. nAChRs may represent a novel target in alleviating airway hyperresponsiveness in asthma.NEW & NOTEWORTHY Cigarette smoking and vaping exacerbate asthma. Understanding the mechanisms of nicotine effects in asthmatic airways is important. This study demonstrates that functional alpha7 nicotinic acetylcholine receptors (α7nAChRs) are expressed in human airway smooth muscle, including from asthmatics, and enhance intracellular calcium and contractility. Although a7nAChRs are associated with neuronal pathways, α7nAChR in smooth muscle suggests inhaled nicotine (e.g., vaping) can directly influence airway contractility. Targeting α7nAChR may represent a novel approach to alleviating airway hyperresponsiveness in asthma.

Monoclonal antibody therapies for COVID-19: lessons learned and implications for the development of future products.

Several companies were authorized to treat COVID-19 patients with monoclonal antibodies within 1-2 years of the start of the pandemic. These products were discovered, developed, manufactured, clinically tested, and approved under emergency-use authorization at unprecedented speed. Pandemic urgency led to novel development approaches that reduced the time to clinical trials by 75% or more without creating unacceptable patient or product-safety risks. Hundreds of thousands of patients now benefit from these therapeutics that have reduced the rates of hospitalization and death. The chemistry, manufacturing, and control development strategies set a new precedent of speed, safety, and demonstrated clinical benefit and will likely have a lasting impact on the development of future monoclonal antibody therapies for not only infectious diseases but also for oncology, inflammation, and rare diseases.

Developing a Mechanistic Approach to Sudden Death Prevention in Mitral Valve Prolapse.

Sudden cardiac death (SCD) from ventricular fibrillation (VF) can occur in mitral valve prolapse (MVP) in the absence of other comorbidities including mitral regurgitation, heart failure or coronary disease. Although only a small proportion with MVP are at risk, it can affect young, otherwise healthy adults, most commonly premenopausal women, often as the first presentation of MVP. In this review, we discuss arrhythmic mechanisms in MVP and mechanistic approaches for sudden death risk assessment and prevention. We define arrhythmogenic or arrhythmic MVP (AMVP) as MVP associated with complex and frequent ventricular ectopy, and malignant MVP (MMVP) as MVP with high risk of SCD. Factors predisposing to AMVP are myxomatous, bileaflet MVP and mitral annular disjunction (MAD). Data from autopsy, cardiac imaging and electrophysiological studies suggest that ectopy in AMVP is due to inflammation, fibrosis and scarring within the left ventricular (LV) base, LV papillary muscles and Purkinje tissue. Postulated mechanisms include repetitive injury to these regions from systolic papillary muscle stretch and abrupt mitral annular dysmotility (excursion and curling) and diastolic endocardial interaction of redundant mitral leaflets and chordae. Whereas AMVP is seen relatively commonly (up to 30%) in those with MVP, MVP-related SCD is rare (2-4%). However, the proportion at risk (i.e., with MMVP) is unknown. The clustering of cardiac morphological and electrophysiological characteristics similar to AMVP in otherwise idiopathic SCD suggests that MMVP arises when specific arrhythmia modulators allow for VF initiation and perpetuation through action potential prolongation, repolarization heterogeneity and Purkinje triggering. Adequately powered prospective studies are needed to assess strategies for identifying MMVP and the primary prevention of SCD, including ICD implantation, sympathetic modulation and early surgical mitral valve repair. Given the low event rate, a collaborative multicenter approach is essential.

Heart-Brain Relationship in Stroke.

The patient presenting with stroke often has cardiac-related risk factors which may be involved in the mechanism of the stroke. The diagnostic assessment is predicated on recognition of this potential relationship. Naturally, an accurate history is of utmost importance in discerning a possible cause and effect relationship. The EKG is obviously an important clue as well as it allows immediate assessment for possible cardiac arrhythmia, such as atrial fibrillation, for possible acute ischemic changes reflective of myocardial ischemia, or there may be indirect factors such as the presence of left ventricular hypertrophy, typically seen with longstanding hypertension, which could be indicative of a hypertensive mechanism for a patient presenting with intracerebral hemorrhage. For all presentations in the emergency room, the vital signs are important. An elevated body temperature in a patient presenting with acute stroke raises concern about possible infective endocarditis. An irregular-irregular pulse is an indicator of atrial fibrillation. A markedly elevated blood pressure is not uncommon in both the acute ischemic and acute hemorrhagic stroke setting. One tends to focus on possible cardioembolic stroke if there is the sudden onset of maximum neurological deficit versus the stepwise progression more characteristic of thrombotic stroke. Because of the more sudden loss of vascular supply with embolic occlusion, seizure or syncope at onset tends to be supportive of this mechanism. Different vascular territory involvement on neuroimaging is also a potential indicator of cardioembolic stroke. Identification of a cardiogenic source of embolus in such a setting certainly elevates this mechanism in the differential. There have been major advances in management of acute cerebrovascular disease in recent decades, such as thrombolytic therapy and endovascular thrombectomy, which have somewhat paralleled the advances made in cardiovascular disease. Unfortunately, the successful limitation of myocardial damage in acute coronary syndrome, with intervention, does not necessarily mirror a similar salutary effect on functional outcome with cerebral infarction. The heart can also affect the brain from a cerebral perfusion standpoint. Transient arrhythmias can result in syncope, while cardiac arrest can result in hypoxic-ischemic encephalopathy. Cardiogenic dementia has been identified as a mechanism of cognitive impairment associated with severe cardiac failure. Structural cardiac abnormalities can also play a role in brain insult, and this can include tumors, such as atrial myxoma, patent foramen ovale, with the potential for paradoxical cerebral embolism, and cardiomyopathies, such as Takotsubo, can be associated with precipitous cardioembolic events.

Out-of-Pocket Spending for Thumb Carpometacarpal Arthritis: Capitation Matters.

Background: Patients are increasingly responsible for direct medical expenditures with a growth in out-of-pocket (OOP) expenses, which can impede access to care and affect treatment. This study aims to investigate the impact of capitation on OOP expenses for surgical and presurgical treatment for thumb carpometacarpal (CMC) joint arthritis. Methods: Patients with a diagnosis of thumb CMC arthritis who underwent surgery (2009-2016) comprised our study cohort. Sociodemographic data, total cost, and OOP expenses were collected at the time of surgery and 2 years prior. Patients were stratified by insurance type: fee-for-service (FFS), managed care (MC), Medicare-MC, and Medicare-FFS. Capitated plans were included in the MC and Medicare-MC groups. A generalized linear regression was performed to investigate the association between OOP expenses and insurance type. Results: Our cohort consisted of 7780 patients with FFS insurance, 953 with MC insurance, 2136 with Medicare-FFS, and 265 with Medicare-MC. There was no difference in total costs for FFS and MC (FFS $7281 vs. MC $7306, P = .73; Medicare-FFS $6663 vs. Medicare-MC $6183, P = .19). However, patients with FFS incurred significantly greater OOP costs (FFS $952 vs. MC $434, P < .01; Medicare-FFS $343 vs. Medicare-MC $232, P < .01). In the adjusted regression, MC, Medicare-FFS, and Medicare-MC had approximately 21% to 46% of the predicted OOP expenses of patients with FFS plans (P < .01). Conclusion: Despite similar total costs, OOP expenses were significantly greater for patients with FFS or Medicare-FFS insurance. With healthcare costs transitioning to patients, providers should consider cost sharing when conferring care to help alleviate the financial burden placed on patients.

Regenerative Peripheral Nerve Interfaces for the Management of Symptomatic Hand and Digital Neuromas.

Painful neuromas result from traumatic injuries of the hand and digits and cause substantial physical disability, psychological distress, and decreased quality of life among affected patients. The regenerative peripheral nerve interface (RPNI) is a novel surgical technique that involves implanting the divided end of a peripheral nerve into a free muscle graft for the purposes of mitigating neuroma formation and facilitating prosthetic limb control. The RPNI is effective in treating and preventing neuroma pain in major extremity amputations. The purpose of this study was to determine if RPNIs can be used to effectively treat neuroma pain following partial hand and digital amputations. We retrospectively reviewed the use of RPNI to treat symptomatic hand and digital neuromas at our institutions. Between November 2014 and July 2019, we performed 30 therapeutic RPNIs on 14 symptomatic neuroma patients. The average patient follow-up was 37 weeks (6-128 weeks); 85% of patients were pain-free or considerably improved at the last office visit. The RPNI can serve as a safe and effective surgical solution to treat symptomatic neuromas after hand trauma.

Effect of Time to Hand Therapy following Zone II Flexor Tendon Repair.

This population-based study aimed to define how time to hand therapy following isolated zone II flexor tendon repairs impacts complications and secondary procedures. METHODS: Insurance claims from the Truven MarketScan Databases were used to evaluate outcomes after isolated zone II flexor tendon repairs between January 2009 and October 2015. Cohorts differing in time to hand therapy were compared to evaluate the impact on complications, reoperation, and number of therapy sessions. Secondary outcomes analyzed how the number of therapy sessions affected rates of reoperation. RESULTS: Hand therapy was identified in 82% of patients (N = 2867) following tendon reconstruction. Therapy initiation occurred within 1 week, 1-4 weeks, and after 4 weeks in 56%, 35%, and 9% of patients, respectively. Univariate analysis showed no difference in non-tendinous complications (27%, 30%, 29%; P = 0.29) or tendon rupture rates (13%, 13%, 10%; P = 0.42) within 90 days between cohorts. Multivariable analysis showed no difference in rates of tenolysis (6.3%, 6%, 4.4%; P > 0.01). In the early initiation cohort, >23 hand therapy sessions were associated with the highest rates of tenolysis (19%). CONCLUSIONS: Despite being a common fear of hand surgeons, early initiation of hand therapy was not associated with increased tendon rupture rates. Although delayed therapy is a concern for tendon scarring, it did not confer a higher risk of tenolysis. Complication rates do not appear to correlate with timing of hand therapy. Therefore, hand surgeons should promote early mobility following isolated flexor tendon injuries given the known functional outcome benefits.

Implementing Precision Medicine and Artificial Intelligence in Plastic Surgery: Concepts and Future Prospects.

Precision medicine, or the individualization of evidence-based medicine, is forthcoming. As surgeons, we must be prepared for the integration of patient and system factors. Plastic surgeons regard themselves as innovators and early adopters. As such, we need our adaptability now more than ever to implement digital advancements and precision medicine into our practices. The integration of artificial intelligence (AI) technology and the capture of big data techniques should foster the next great leaps in medicine and surgery, allowing us to capture the detailed minutiae of precision medicine. The algorithmic process of artificial neural networks will guide large-scale analysis of data, including features such as pattern recognition and rapid quantification, to organize and distribute data to surgeons seamlessly. This vast digital collection of information, commonly termed "big data," is only one potential application of AI. By incorporating big data, the cognitive abilities of a surgeon can be complemented by the computer to improve patient-centered care. Furthermore, the use of AI will provide individual patients with increased access to the broadening world of precision medicine. Therefore, plastic surgeons must learn how to use AI within the contexts of our practices to keep up with an evolving field in medicine. Although rudimentary in its practice, we present a glimpse of the potential applications of AI in plastic surgery to incorporate the practice of precision medicine into the care that we deliver.

Persistent Opioid Use and High-Risk Prescribing in Body Contouring Patients.

BACKGROUND: Opioid misuse occurs commonly among obese patients and after bariatric surgery. However, the risk of new persistent use following postbariatric body contouring procedures remains unknown. METHODS: The authors examined insurance claims from Clinformatics Data Mart (OptumInsight, Eden Prairie, Minn.) between 2001 and 2015 for opioid-naive patients undergoing five body contouring procedures: abdominoplasty/panniculectomy, breast reduction, mastopexy, brachioplasty, and thighplasty (n = 11,257). Their primary outcomes included both new persistent opioid use, defined as continued prescription fills between 90 and 180 days after surgery, and the prevalence of high-risk prescribing. They used multilevel logistic regression to assess the risk of new persistent use, adjusting for relevant covariates. RESULTS: In this cohort, 6.1 percent of previously opioid-naive patients developed new persistent use, and 12.9 percent were exposed to high-risk prescribing. New persistent use was higher in patients with high-risk prescribing (9.2 percent). New persistent use was highest after thighplasty (17.7 percent; 95 percent CI, 0.03 to 0.33). Increasing Charlson comorbidity indices (OR, 1.11; 95 percent CI, 1.05 to 1.17), mood disorders (OR, 1.27; 95 percent CI, 1.05 to 1.54), anxiety (OR, 1.41; 95 percent CI, 1.16 to 1.73), tobacco use (OR, 1.22; 95 percent CI, 1.00 to 1.49), neck pain (OR, 1.23; 95 percent CI, 1.04 to 1.46), arthritis (OR, 1.30; 95 percent CI, 1.08 to 1.58), and other pain disorders (OR, 1.36; 95 percent CI, 1.16 to 1.60) were independently associated with persistent use. CONCLUSIONS: Similar to other elective procedures, 6 percent of opioid-naive patients developed persistent use, and 12 percent were exposed to high-risk prescribing practices. Plastic surgeons should remain aware of risk factors and offer opioid alternatives. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Postoperative Ketorolac in Breast and Body Contouring Procedures: A Nationwide Claims Analysis.

BACKGROUND: Nonsteroidal antiinflammatory drugs are useful alternatives to narcotics for analgesia. However, concerns remain regarding their safety. The authors evaluated ketorolac use and complications. We hypothesized that no association between ketorolac and morbidity exists in patients undergoing body contouring. METHODS: Truven MarketScan claims database was analyzed for patients undergoing breast and body contouring surgery. Patients selected received ketorolac and were enrolled a minimum of 90 days. The authors performed a multivariable logistic regression to calculate risk of morbidity, adjusting for clinical and sociodemographic factors. RESULTS: Among the 106,279 patients enrolled, 4924 (4.6 percent) received postoperative ketorolac. In multivariable regression analysis, ketorolac was not associated with hematoma (OR, 1.20; 95 percent CI, 0.99 to 1.46; p > 0.05). There was an increased rate of reoperation within 72 hours (OR, 1.22; 95 percent CI, 1.00 to 1.49; p < 0.05; number needed to harm, 262 patients). Ketorolac was associated with fewer readmissions (OR, 0.76; 95 percent CI, 0.62 to 0.93; p < 0.05; number needed to treat, 87 patients), with a reduction in the rate of pain as a readmission diagnosis (0.6 percent versus 4.3 percent; p = 0.021). Ketorolac was associated with seroma, but this association may not be causal (OR, 1.28; 95 percent CI, 1.05 to 1.57; p < 0.05; number needed to harm, 247 patients). Ketorolac provided an estimated savings of $157 per patient. CONCLUSIONS: The benefits of ketorolac likely outweigh the risks after surgery. Absolute differences in reoperation rates were low, and improved rates of hospital admission impact cost savings. The authors advocate postoperative ketorolac once the wound is hemostatic. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Use of Routine Pathologic Evaluation of Nonmalignant Lesions in Hand Surgery: A National Study.

BACKGROUND: Most lesions of the upper extremity are common and benign, and many have questioned the need for routine pathologic evaluation of these specimens. The authors aim to examine the national use of routine pathologic examination of nonmalignant hand lesions to help guide health care policy and practice patterns. METHODS: The authors used a national level MarketScan database to form a cohort of adult patients who underwent excision of nonmalignant upper extremity lesions. The authors calculated the rate of submission for each surgical procedure and separately for each diagnosis. The authors also investigated demographic and clinical characteristics associated with the submission of surgical specimens using a multivariable logistic regression model. The authors calculated the total cost of routine pathologic evaluation. RESULTS: The final study cohort included 222,947 patients and 182,962 specimens from 153,518 cases. The mean rate of submission was 69 percent. Older age, Northeast region, and high comorbidity scores showed significant correlation with the odds of having a specimen submitted for pathologic evaluation. Excision of primary wrist ganglion was the most performed procedure, and benign lesions larger than 4.0 cm were most frequently submitted for pathologic evaluation. The mean cost of routine pathologic examination was $133 per specimen, and the annual expenditure was $5 million. CONCLUSIONS: The routine pathologic examination of benign hand lesions is used frequently but provides limited clinical benefit at a cost. To increase efficiency and improve quality of care, surgeons should be aware of the low value of routine pathologic evaluation and be more selective for cases for which diagnostic testing will change management.

An On-Top-Plasty Reconstruction for Complicated Radial Polydactyly.

Background: The clinical presentation of radial polydactyly can vary greatly. Careful planning and appreciation of the anatomic subtleties provides alternative surgical options to improve patient outcomes. Methods: We present a case of a well-formed accessory web space thumb and a hypoplastic primary thumb. Results: Rather than excising the accessory digit, we performed a spare-part, on-top-plasty reconstruction to replace the diminutive distal phalanx of the primary thumb. Conclusions: This novel case applied the principle of spare-part surgery to reconstruct a more aesthetic and functional reconstructed digit.

Developing, Conducting, and Publishing Appropriate Systematic Review and Meta-Analysis Articles.

The volume of medical literature is growing at a rate that renders decision-making difficult without specialized summary tools. Systematic reviews and meta-analyses are important research instruments used to condense and clarify a broad scope of information into manageable summaries. When used effectively, these reports can pool cumulative data across primary studies, formulate clinical guidelines, and guide future research endeavors. However, errors in study design can result in ineffective or misleading analyses. This article presents the appropriate uses for systematic review and meta-analysis by introducing a framework for creating summary studies, and supplying specific examples of pitfalls in study design and execution.

Temporary occipital fixation in young children with severe cervical-thoracic spinal deformity.

OBJECTIVE The long-term effects of instrumentation and fusion of the occipital-cervical-thoracic spine on spinal growth in young children are poorly understood. To mitigate the effects of this surgery on the growing pediatric spine, the authors report a novel technique used in 4 children with severe cervical-thoracic instability. These patients underwent instrumentation from the occiput to the upper thoracic region for stabilization, but without bone graft at the craniovertebral junction (CVJ). Subsequent surgery was then performed to remove the occipital instrumentation, thereby allowing further growth and increased motion across the CVJ. METHODS Three very young children (15, 30, and 30 months old) underwent occipital to thoracic posterior segmental instrumentation due to cervical or upper thoracic dislocation, progressive kyphosis, and myelopathy. The fourth child (10 years old) underwent similar instrumentation for progressive cervical-thoracic scoliosis. Bone graft was placed at and distal to C-2 only. After follow-up CT scans demonstrated posterior arthrodesis without unintended fusion from the occiput to C-2, 3 patients underwent removal of the occipital instrumentation. RESULTS Follow-up cervical spine flexion/extension radiographs demonstrated partial restoration of motion at the CVJ. One patient has not had the occipital instrumentation removed yet, because only 4 months have elapsed since her operation. CONCLUSIONS Temporary fixation to the occiput provides increased biomechanical stability for spinal stabilization in young children, without permanently eliminating motion and growth at the CVJ. This technique can be considered in children who require longer instrumentation constructs for temporary stabilization, but who only need fusion in more limited areas where spinal instability exists.