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Summary: The locomotor role of dopaminergic neurons is traditionally attributed to their ascending projections to the basal ganglia, which project to the mesencephalic locomotor region (MLR). In addition, descending dopaminergic projections to the MLR are present from basal vertebrates to mammals. However, the neurons targeted in the MLR and their behavioral role are unknown in mammals. Here, we identify genetically defined MLR cells that express D1 or D2 receptors and control different motor behaviors in mice. In the cuneiform nucleus, D1-expressing neurons promote locomotion, while D2-expressing neurons stop locomotion. In the pedunculopontine nucleus, D1-expressing neurons promote locomotion, while D2-expressing neurons evoke ipsilateral turns. Using RNAscope, we show that MLR dopamine-sensitive neurons comprise a combination of glutamatergic, GABAergic, and cholinergic neurons, suggesting that different neurotransmitter-based cell types work together to control distinct behavioral modules. Altogether, our study uncovers behaviorally relevant cell types in the mammalian MLR based on the expression of dopaminergic receptors.

ABSTRACTThe increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has sparked global concern due to the dwindling availability of effective antibiotics. To increase our treatment options, researchers have investigated naturally occurring antimicrobial compounds and have identified MC21-A (C58), which has potent antimicrobial activity against MRSA. Recently, we have devised total synthesis schemes for C58 and its chloro-analog, C59. Here, we report that both compounds eradicate 90% of the 39 MRSA isolates tested [MIC90 and minimum bactericidal concentration (MBC90)] at lower or comparable concentrations compared to several standard-of-care (SoC) antimicrobials including daptomycin, vancomycin, and linezolid. Furthermore, a stable, water-soluble sodium salt of C59, C59Na, demonstrates antimicrobial activity comparable to C59. C59, unlike vancomycin, kills stationary-phase MRSA in a dose-dependent manner and completely eradicates MRSA biofilms. In contrast to vancomycin, exposing MRSA to sub-MIC concentrations of C59 does not result in the emergence of spontaneous resistance. Similarly, in a multi-step study, C59 demonstrates a low propensity of resistance acquisition when compared to SoC antimicrobials, such as linezolid and clindamycin. Our findings suggest C58, C59, and C59Na are non-toxic to mammalian cells at concentrations that exert antimicrobial activity; the lethal dose at median cell viability (LD50) is at least fivefold higher than the MBC90 in the two mammalian cell lines tested. A morphological examination of the effects of C59 on a MRSA isolate suggests the inhibition of the cell division process as a mechanism of action. Our results demonstrate the potential of this naturally occurring compound and its analogs as non-toxic next-generation antimicrobials to combat MRSA infectionsIMPORTANCEThe rapid emergence of methicillin-resistant Staphylococcus aureus (MRSA) isolates has precipitated a critical need for novel antibiotics. We have developed a one-pot synthesis method for naturally occurring compounds such as MC21-A (C58) and its chloro-analog, C59. Our findings demonstrate that these compounds kill MRSA isolates at lower or comparable concentrations to standard-of-care (SoC) antimicrobials. C59 eradicates MRSA cells in biofilms, which are notoriously difficult to treat with SoC antibiotics. Additionally, the lack of resistance development observed with C59 treatment is a significant advantage when compared to currently available antibiotics. Furthermore, these compounds are non-toxic to mammalian cell lines at effective concentrations. Our findings indicate the potential of these compounds to treat MRSA infections and underscore the importance of exploring natural products for novel antibiotics. Further investigation will be essential to fully realize the therapeutic potential of these next-generation antimicrobials to address the critical issue of antimicrobial resistance.

Background Restorative justice interventions can help address the harm created by gun violence, although few restorative justice programs focus solely on survivors or loved ones of victims of gun violence. Our aim was to assess how gun violence impacts those injured by firearms through qualitative analysis of their lived experiences.Methods From August 2022 to October 2023, we operated a program entitled Prescriptions for Repair in Durham, North Carolina, USA, which was supported by community groups, public government, and academia. Through a series of structured listening sessions using a restorative justice framework, trained community-based facilitators helped 30 participants (11 survivors of gun violence and 19 loved ones of victims of gun violence) tell their stories through a non-judgmental narrative process. We conducted a qualitative thematic analysis of the listening sessions from 19 participants to define the major lessons learned from survivors of gun violence. We summarized participant responses into individual-level and community-level views on how to ‘make things as right as possible’.Results The lived experiences of gun violence survivors and their loved ones confirmed the inherent value of structured listening programs, how poverty, race and racism impact gun violence, and the need to focus resources on children and youth.Conclusions Listening to the survivors of gun violence through restorative justice programs can help address the personal and community harm resulting from gun violence.Level of evidence Level IV, prospective observational study.

The N-terminal portion of the octapeptide angiotensin II (DRVYIHPF; AngII), a vasopressor peptide that favorably binds to, and activates, AngII type 1 receptor (AT1R), has an important role in maintaining bioactive conformation. It involves all three charged groups, namely (i) the N-terminal amino group cation, (ii) the Asp sidechain anion and (iii) the Arg guanidino cation. Neutralization of any one of these three charged groups results in a substantial reduction (1R; however, replacement of Asp in AngII with sarcosine (N-methyl-glycine) not only restores bioactivity but increases the activity of agonist, antagonist, and inverse agonist analogues. A bend produced at the N-terminus by the introduction of the secondary amino acid sarcosine is thought to realign the functional groups that chaperone the C-terminal portion of AngII, allowing transfer of the negative charge originating at the C-terminus to be transferred to the Tyr hydroxyl-forming tyrosinate anion, which is required to activate the receptor and desensitizes the receptor (tachyphylaxis). Peptide (sarilesin) and nonpeptide (sartans) moieties, which are long-acting inverse agonists, appear to desensitize the receptor by a mechanism analogous to tachyphylaxis. Sartans/bisartans were found to bind to alpha adrenergic receptors resulting in structure-dependent desensitization or resensitization. These considerations have provided information on the mechanisms of receptor desensitization/tolerance and insights into possible avenues for treating addiction. In this regard sartans, which appear to cross the blood–brain barrier more readily than bisartans, are the preferred drug candidates.

IntroductionAnimal movements are influenced by landscape features; disturbances to the landscape can alter movements, dispersal, and ultimately connectivity among populations. Faster or longer movements adjacent to a localized disturbance or within disturbed areas could indicate reduced habitat quality whereas slower or shorter movements and reduced movements may indicate greater availability of resources. The Mojave desert tortoise (Gopherus agassizii) is a threatened species that is challenged by anthropogenic disturbances.MethodsWe studied tortoise movements using Global Positioning System (GPS) loggers at multiple sites in the Mojave Desert of Nevada and California. Tortoises at our sites encountered localized, linear human infrastructure, including paved roads, dirt roads, and fences, as well as landscape-scale disturbances [wildfire, off highway vehicle use (OHV), livestock grazing area]. We fit two-state (moving and encamped) Hidden Markov models to GPS logger data to infer how tortoise movement behavior relates to anthropogenic and natural features.ResultsWe found that temporal covariates, individual-level random effects (intercepts), and sex best explained state transition probability in all sites. We compared relationships between tortoise movement and linear disturbances, which varied depending on site and context. Tortoises made longer movements within the OHV recreation area, near most dirt roads, and near a low-traffic paved road, indicating that tortoises avoid these habitat disturbances. Conversely, tortoises made shorter movements in areas of higher slope and near highways, suggesting that these features may restrict movement or provide resources that result in prolonged use (e.g., forage or drinking locations). Tortoises that encountered fences around utility-scale solar installations were more active and made longer movements near fences, indicative of pacing behavior.DiscussionThese results provide insight into how different disturbances alter tortoise movement behavior and modify tortoise habitat use, providing information that can be used to manage tortoise habitat.

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole-N-biphenyl tetrazole (ACC519T), benzimidazole-bis-N,N′-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K+)2), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K+)2 to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K+)2 significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K+)2 to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension.

The shift in modern dietary regimens to “Western style” and sedentary lifestyles are believed to be partly responsible for the increase in the global burden of cardiovascular diseases. Natural products have been used throughout human history as treatments for a plethora of pathological conditions. Taurine and, more recently, black pepper have gained attention for their beneficial health effects while remaining non-toxic even when ingested in excess. Taurine, black pepper, and the major terpene constituents found in black pepper (i.e., β-caryophyllene; α-pinene; β-pinene; α-humulene; limonene; and sabinene) that are present in PhytoCann BP® have been shown to have cardioprotective effects based on anti-inflammatory, antioxidative, anti-hypertensive and anti-atherosclerotic mechanisms. This comprehensive review of the literature focuses on determining whether the combination of taurine and black pepper extract is an effective natural treatment for reducing cardiovascular diseases risk factors (i.e., hypertension and hyperhomocysteinemia) and for driving anti-inflammatory, antioxidative and anti-atherosclerotic mechanisms to combat coronary artery disease, heart failure, myocardial infarction, and atherosclerotic disease.

Cardiovascular diseases (CVDs) are the main contributors to global morbidity and mortality. Major pathogenic phenotypes of CVDs include the development of endothelial dysfunction, oxidative stress, and hyper-inflammatory responses. These phenotypes have been found to overlap with the pathophysiological complications of coronavirus disease 2019 (COVID-19). CVDs have been identified as major risk factors for severe and fatal COVID-19 states. The renin–angiotensin system (RAS) is an important regulatory system in cardiovascular homeostasis. However, its dysregulation is observed in CVDs, where upregulation of angiotensin type 1 receptor (AT1R) signaling via angiotensin II (AngII) leads to the AngII-dependent pathogenic development of CVDs. Additionally, the interaction between the spike protein of severe acute respiratory syndrome coronavirus 2 with angiotensin-converting enzyme 2 leads to the downregulation of the latter, resulting in the dysregulation of the RAS. This dysregulation favors AngII/AT1R toxic signaling pathways, providing a mechanical link between cardiovascular pathology and COVID-19. Therefore, inhibiting AngII/AT1R signaling through angiotensin receptor blockers (ARBs) has been indicated as a promising therapeutic approach to the treatment of COVID-19. Herein, we review the role of AngII in CVDs and its upregulation in COVID-19. We also provide a future direction for the potential implication of a novel class of ARBs called bisartans, which are speculated to contain multifunctional targeting towards COVID-19.

A substantial fraction of the human genome is difficult to interrogate with short-read DNA sequencing technologies due to paralogy, complex haplotype structures, or tandem repeats. Long-read sequencing technologies, such as Oxford Nanopore's MinION, enable direct measurement of complex loci without introducing many of the biases inherent to short-read methods, though they suffer from relatively lower throughput. This limitation has motivated recent efforts to develop amplification-free strategies to target and enrich loci of interest for subsequent sequencing with long reads. Here, we present CaBagE, a method for target enrichment that is efficient and useful for sequencing large, structurally complex targets. The CaBagE method leverages the stable binding of Cas9 to its DNA target to protect desired fragments from digestion with exonuclease. Enriched DNA fragments are then sequenced with Oxford Nanopore's MinION long-read sequencing technology. Enrichment with CaBagE resulted in a median of 116X coverage (range 39-416) of target loci when tested on five genomic targets ranging from 4-20kb in length using healthy donor DNA. Four cancer gene targets were enriched in a single reaction and multiplexed on a single MinION flow cell. We further demonstrate the utility of CaBagE in two ALS patients with C9orf72 short tandem repeat expansions to produce genotype estimates commensurate with genotypes derived from repeat-primed PCR for each individual. With CaBagE there is a physical enrichment of on-target DNA in a given sample prior to sequencing. This feature allows adaptability across sequencing platforms and potential use as an enrichment strategy for applications beyond sequencing. CaBagE is a rapid enrichment method that can illuminate regions of the 'hidden genome' underlying human disease.

Introduction: Emergency department (ED) patient care often hinges on the result of a diagnostic test. Frequently there is a lag time between a test result becoming available for review and physician decision-making or disposition based on that result. We implemented a system that electronically alerts ED providers when test results are available for review via a smartphone- and smartwatch-push notification. We hypothesized this would reduce the time from result to clinical decision-making. Methods: We retrospectively assessed the impact of the implementation of a push notification system at three EDs on time-to-disposition or time-to-follow-up order in six clinical scenarios of interest: chest radiograph (CXR) to disposition, basic metabolic panel (BMP) to disposition, urinalysis (UA) to disposition, respiratory pathogen panel (RPP) to disposition, hemoglobin (Hb) to blood transfusion order, and abnormal D-dimer to computed tomography pulmonary angiography (CTPA) order. All ED patients during a one-year period of push-notification availability were included in the study. The primary outcome was median time in each scenario from result availability to either disposition order or defined follow-up order. The secondary outcome was the overall usage rate of the opt-in push notification system by providers. Results: During the study period there were 6115 push notifications from 4183 ED encounters (2.7% of all encounters). Of the six clinical scenarios examined in this study, five were associated with a decrease in median time from test result availability to patient disposition or follow-up order when push notifications were employed: CXR to disposition, 80 minutes (interquartile range [IQR] 32–162 minutes) vs 56 minutes (IQR 18–141 minutes), difference 24 minutes (p

Background: Access to safe, effective, and affordable surgical care is a pressing contemporary public health issue. Deaths from surgically treated conditions exceed those from HIV, tuberculosis, and malaria combined. Community outreach is a potential driver of access to surgical treatment, yet education among community health workers (CHWs) about such conditions is insufficient. Here, we describe the development and testing of a picture-based curriculum—El Manual Para el Pueblo (The Manual for the People)—to help CHWs to identify and refer surgical conditions in a largely illiterate population. Methods: Central American rural multi-ethnic indigenous groups and surgical providers provided context-specific expertise and advice for the development of El Manual Para el Pueblo, established in 2017. During a pilot implementation in July, 2018, the Ministry of Education and a local community leader recruited groups of CHWs, parents in the communities, and groups of students from the Olancho department of Honduras. We assessed participants before and after the teaching programme for situational problem-solving. Participants completed quantitative surveys to measure the efficacy of an accompanying curriculum on the scheme and iconography of the manual; we also collected qualitative data from participants about the utility of the programme for their practice patterns. Findings: The surgical manual includes 13 chapters with 133 different medical and surgical conditions represented. For the surveys, participants used three sample pages of the manual to answer the questions. We included 403 participants; 68% were women and mean age was 26 years. Overall, 245 participants (61%) had scores of 75% or more on the pre-intervention survey and 170 (42%) had scores of 85% or more. Manual understanding and utilisation abilities improved from pre-intervention mean score of 15·37 (SD 3·10) to 15·91 (3·09) post-intervention out of a maximum score of 20 (p

Background:. Although efforts to improve access to care for patients with cleft lip in the developing world have grown tremendously, there is a dearth of data regarding aesthetic outcomes after cleft lip repairs in this setting. Defining severity-outcome relationships has the potential to improve efficiency of care delivery in resource-limited settings, and to improve overall results. In this study, we investigate the relationship between initial cleft lip severity and early aesthetic outcomes following surgical repair of primary unilateral cleft lip. Methods:. Using previously validated tools to assess unilateral cleft lip severity and aesthetic outcome after repair, we evaluated 1,823 consecutive patients who underwent primary unilateral cleft lip/nose (UCL/N) repair. Three separate evaluators scored each case for a total of 5,469 total independent evaluations. Results:. Our results show that with increasing severity of UCL/N deformity, there is a corresponding decrease in early aesthetic outcome scores. Using our results, we established normative early aesthetic outcomes following repair for each severity grade of UCL/N deformity. Conclusions:. In conclusion, this study has achieved a standardized, timely, and cost-effective evaluation of 1,823 surgical cases of primary UCL/N repair. This data set provides a normal distribution of aesthetic results according to initial cleft severity and defines a standard of “expected” aesthetic results after primary UCL/N repair. Our results also show a clear correlation between initial severity and immediate aesthetic result after surgery, though we also show that excellent results are possible regardless of initial cleft severity.

Objective: To assess risk factors for high-grade cervical dysplasia among southwestern Hispanic and non-Hispanic white women.Design: Clinic-based case-control study.Setting: University-affiliated gynecology clinics.Subjects: Cases were Hispanic and non-Hispanic white women with biopsy-proven high-grade cervical dysplasia (n = 201). Controls were Hispanic and non-Hispanic white women from the same clinics with normal cervical epithelium (n = 337).Methods: Study design included interviews focused on histories of sexually transmitted diseases, sexual behavior, reproductive histories, hygienic practices, contraceptive use, cigarette smoking, and diet. Laboratory studies included bacterial and protozoal cultures of the cervix; hybridization tests to identify human papillomavirus (HPV) genome with commercial (ViraPap and ViraType) and polymerase chain reaction-based assays; and serum antibody tests for herpes simplex virus, Chlamydia trachomatis, syphilis, hepatitis B, and hepatitis C.Results: For both ethnic groups combined, after adjustment for ethnicity, age, and sexual behavior, the strongest risks for cervical dysplasia were associated with cervical HPV infection as identified by ViraPap (odds ratio [OR], 12.8; 95% confidence interval [CI], 8.2 to 20.0) or with polymerase chain reaction (OR, 20.8; 95% CI, 10.8 to 40.2). Other factors associated with dysplasia included cigarette smoking at the time of diagnosis (OR, 1.8; 95% CI, 1.2 to 2.8); low income (OR, 2.2; 95% CI, 1.2 to 4.0); low educational level (OR, 6.2; 95% CI, 3.4 to 11.1); history of any sexually transmitted disease (OR, 1.9; 95% CI, 1.3 to 2.7); and seroprevalence of antibodies to hepatitis B (OR, 1.8; 95% CI, 0.9 to 3.5). For Hispanic women, HPV 16/18 identified by ViraType was strongly associated with cervical dysplasia (OR, 171.0; 95% CI, 22.8 to 1280.5). Antibodies to herpes simplex virus type 2 were not associated with dysplasia in Hispanic women but were significantly associated with dysplasia among non-Hispanic whites. Risks associated with cigarette smoking also varied by ethnic group.Conclusions: The strongest risk factor associated with high-grade cervical dysplasia among clinic attendees was HPV infection. Although most of the risk factors we examined showed similar associations for dysplasia for both ethnic groups, our data suggest that several different risk factors may be relevant to the development of cervical dysplasia in Hispanics compared with non-Hispanic whites who attend the same clinics. [ABSTRACT FROM AUTHOR]

Background: To improve access to surgical care in rural Nicaragua, a collaboration was established between the Global Initiative for Children's Surgery (GICS), Operation Smile Nicaragua, and the Nicaragua Ministry of Health. Prior to implementation of the surgical programme Surgery for the People Nicaragua, our aim was to perform a baseline assessment of the Nicaraguan health system's capacity to provide safe surgical care in its rural zones. Methods: In June and July 2017, a retrospective baseline evaluation of safe surgical care provision was performed at two rural district hospitals in Las Minas using the GICS Optimal Resources tool, the WHO/Program in Global Surgery & Social Change (PGSSC) Surgical Assessment tool, the World Federation of Societies of Anesthesiologists Assessment tool, and the PGSSC Qualitative Assessment tool. Main outcome measures were: surgical workforce density, surgical volume, perioperative mortality rates, level of infrastructure, access to essential medicines, and health system financing. Findings: The surgical workforce density was six per 100 000 population, including one paediatric surgeon (the WHO target surgical workforce density is 20 per 100 000 population). The surgical volume was 1050 procedures per 100 000 population per year; less than 10% of the surgical volume was paediatric. Perioperative mortality rates were low but not routinely collected: range 0·12%–0·50%. There were major needs in infrastructure including: additional operating theatres; running water at one site; post-anaesthetic recovery room areas; and paediatric-specific surgical wards. There was adequate access to essential medications including oxygen, anaesthetics, and antibiotics. Care at the two district hospitals was free, and there were no recorded out-of-pocket expenses for surgical patients. Interpretation: A major success of the Nicaraguan health system is free surgical care, protecting patients from catastrophic expenditure. However, to improve access to surgical care in rural Nicaragua, there is a need for investments in human resources, particularly in anaesthesia and paediatric providers. Furthermore, there is a need for monitoring and evaluation of key indicators including perioperative mortality and complication rates. Funding: UBS Optimus Foundation.

Background: Nonbinary individuals assigned female at birth are increasingly presenting for gender-affirming chest surgery (GCS). However, little is known about psychosocial outcomes in this group. We compare patient-reported and clinical outcomes after GCS between nonbinary and binary transmasculine individuals who underwent GCS., Methods: We performed an institutional retrospective chart review. Demographic information, medical comorbidities, history of gender-affirming medical care, operative details, and complications were collected and compared between nonbinary and binary patients. Two validated patient-reported outcomes measures, the Gender Congruence and Life Satisfaction (GCLS) scale and the chest dysphoria measure were administered postoperatively., Results: A total of 281 patients were included, of which 40.6% (114) identified as nonbinary and 59.4% (167) identified as binary transgender men. Fewer nonbinary patients used testosterone ( P < 0.001). Nonbinary patients underwent a wider variety of masculinizing chest operations than binary patients, with fewer nonbinary patients electing for free nipple-areolar complex grafts ( P < 0.001) and more nonbinary patients undergoing breast reduction ( P = 0.001). A total of 137 (48.7%) patients responded to postoperative surveys. Nonbinary and binary respondents had comparable scores on the overall GCLS ( P = 0.86), GCLS chest subscale ( P = 0.38), and chest dysphoria measure ( P = 0.40). The absence of nipple-areolar complex grafts was associated with higher GCLS chest scores ( P = 0.004)., Conclusions: Nonbinary individuals have similarly positive outcomes following GCS compared with binary individuals. Surgeons should be aware of greater medical and surgical heterogeneity in this population and seek to understand individual patients' goals and priorities., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. Dr. Hackenberger’s time was supported in part by a training grant from the National Institute of Mental Health (T32MH130325; PI: Newcomb)., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Developing nerve grafts with intact mesostructures, superior conductivity, minimal immunogenicity, and improved tissue integration is essential for the treatment and restoration of neurological dysfunctions. A key factor is promoting directed axon growth into the grafts. To achieve this, biohybrid nerves are developed using decellularized rat sciatic nerve modified by in situ polymerization of poly(3,4-ethylenedioxythiophene) (PEDOT). Nine biohybrid nerves are compared with varying polymerization conditions and cycles, selecting the best candidate through material characterization. These results show that a 1:1 ratio of FeCl 3 oxidant to ethylenedioxythiophene (EDOT) monomer, cycled twice, provides superior conductivity (>0.2 mS cm -1 ), mechanical alignment, intact mesostructures, and high compatibility with cells and blood. To test the biohybrid nerve's effectiveness in promoting motor axon growth, human Spinal Cord Spheroids (hSCSs) derived from HUES 3 Hb9:GFP cells are used, with motor axons labeled with green fluorescent protein (GFP). Seeding hSCS onto one end of the conduit allows motor axon outgrowth into the biohybrid nerve. The construct effectively promotes directed motor axon growth, which improves significantly after seeding the grafts with Schwann cells. This study presents a promising approach for reconstructing axonal tracts in humans., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Peripheral nerve and large-scale muscle injuries result in significant disability, necessitating the development of biomaterials that can restore functional deficits by promoting tissue regrowth in an electroactive environment. Among these materials, graphene is favored for its high conductivity, but its low bioactivity requires enhancement through biomimetic components. In this study, we extrusion printed graphene-poly(lactide-co-glycolide) (graphene) lattice scaffolds, aiming to increase bioactivity by incorporating decellularized extracellular matrix (dECM) derived from mouse pup skeletal muscle. We first evaluated these scaffolds using human-induced pluripotent stem cell (hiPSC)-derived motor neurons co-cultured with supportive glia, observing significant improvements in axon outgrowth. Next, we tested the scaffolds with C2C12 mouse and human primary myoblasts, finding no significant differences in myotube formation between dECM-graphene and graphene scaffolds. Finally, using a more complex hiPSC-derived 3D motor neuron spheroid model co-cultured with human myoblasts, we demonstrated that dECM-graphene scaffolds significantly improved axonal expansion towards peripheral myoblasts and increased axonal network density compared to graphene-only scaffolds. Features of early neuromuscular junction formation were identified near neuromuscular interfaces in both scaffold types. These findings suggest that dECM-graphene scaffolds are promising candidates for enhancing neuromuscular regeneration, offering robust support for the growth and development of diverse neuromuscular tissues., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Sexual orientation, gender identity, and sex recorded at birth (SOGI) have been routinely excluded from demographic data collection tools, including in electronic medical record (EMR) systems. We assessed the ability of adding structured SOGI data capture to improve identification of transgender and nonbinary (TGNB) patients compared to using only International Classification of Diseases (ICD) codes and text mining and comment on the ethics of these cohort formation methods. Methods: We conducted a retrospective chart review to classify patient gender at a single institution using ICD-10 codes, structured SOGI data, and text mining for patients presenting for care between March 2019 and February 2021. We report each method's overall and segmental positive predictive value (PPV). Results: We queried 1,530,154 EMRs from our institution. Overall, 154,712 contained relevant ICD-10 diagnosis codes, SOGI data fields, or text mining terms; 2964 were manually reviewed. This multipronged approach identified a final 1685 TGNB patient cohort. The initial PPV was 56.8%, with ICD-10 codes, SOGI data, and text mining having PPV of 99.2%, 47.9%, and 62.2%, respectively. Conclusion: This is one of the first studies to use a combination of structured data capture with keyword terms and ICD codes to identify TGNB patients. Our approach revealed that although structured SOGI documentation was <10% in our health system, 1343/1685 (79.7%) of TGNB patients were identified using this method. We recommend that health systems promote patient EMR documentation of SOGI to improve health and wellness among TGNB populations, while centering patient privacy.

Purpose: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected transgender and nonbinary (TGNB) persons. We evaluated COVID-19 testing and vaccination rates among TGNB patients at our institution. Methods: We compared COVID-19 testing and vaccination rates between TGNB patients and a cisgender population matched by age, race, and ethnicity. Data were collected through September 22, 2021. Demographic variables, testing rates, and vaccination rates were collected. Descriptive statistics were calculated, and regression was performed on outcomes of interest: any vaccination dose, at least one test, and at least one positive test. Gender modality was the exposure of interest. Results: There were 5050 patients: 1683 cisgender men, 1682 cisgender women, and 1685 TGNB individuals. TGNB patients were more likely to be on Medicaid/Medicare and more likely to be single. The number of patients with at least one test was similar between TGNB ( n  = 894, 53.1%) and cisgender ( n  = 1853, 55.1%) groups. The number of patients who had at least one positive test was higher among cisgender patients ( n  = 238, 7.1%) compared with TGNB patients ( n  = 73, 4.3%). Vaccination rates were significantly greater among TGNB patients. Compared with cisgender patients, TGNB patients had greater odds of vaccination (adjusted odds ratio [aOR] = 1.25 [95% confidence interval; CI 1.06-1.48]). Compared with cisgender patients, TGNB patients had lower odds of having at least one positive COVID-19 test (aOR = 0.51 [95% CI 0.36-0.72]). Conclusion: Our institutional experience found that vaccination rates for TGNB patients were higher and COVID-19 positivity lower than for cisgender patients.

Importance: Transgender and nonbinary (TGNB) adolescents and young adults (AYA) designated female at birth (DFAB) experience chest dysphoria, which is associated with depression and anxiety. Top surgery may be performed to treat chest dysphoria., Objective: To determine whether top surgery improves chest dysphoria, gender congruence, and body image in TGNB DFAB AYA., Design, Setting, and Participants: This is a nonrandomized prospective cohort study of patients who underwent top surgery between December 2019 and April 2021 and a matched control group who did not receive surgery. Patients completed outcomes measures preoperatively and 3 months postoperatively. This study took place across 3 institutions in a single, large metropolitan city. Patients aged 13 to 24 years who presented for gender-affirming top surgery were recruited into the treatment arm. Patients in the treatment arm were matched with individuals in the control arm based on age and duration of testosterone therapy., Exposures: Patients in the surgical cohort underwent gender-affirming mastectomy; surgical technique was at the discretion of the surgeon., Main Outcomes and Measures: Patient-reported outcomes were collected at enrollment and 3 months postoperatively or 3 months postbaseline for the control cohort. The primary outcome was the Chest Dysphoria Measure (CDM). Secondary outcomes included the Transgender Congruence Scale (TCS) and Body Image Scale (BIS). Baseline demographic and surgical variables were collected, and descriptive statistics were calculated. Inverse probability of treatment weighting (IPTW) was used to estimate the association of top surgery with outcomes. Probability of treatment was estimated using gradient-boosted machines with the following covariates: baseline outcome score, age, gender identity, race, ethnicity, insurance type, body mass index, testosterone use duration, chest binding, and parental support., Results: Overall, 81 patients were enrolled (mean [SD] age, 18.6 [2.7] years); 11 were lost to follow-up. Thirty-six surgical patients and 34 matched control patients completed the outcomes measures. Weighted absolute standardized mean differences were acceptable between groups with respect to body mass index, but were not comparable with respect to the remaining demographic variables baseline outcome measures. Surgical complications were minimal. IPTW analyses suggest an association between surgery and substantial improvements in CDM (-25.58 points; 95% CI, -29.18 to -21.98), TCS (7.78 points; 95% CI, 6.06-9.50), and BIS (-7.20 points; 95% CI, -11.68 to -2.72) scores., Conclusions and Relevance: Top surgery in TGNB DFAB AYA is associated with low complication rates. Top surgery is associated with improved chest dysphoria, gender congruence, and body image satisfaction in this age group.

Background: There has been a significant increase in the volume of gender-affirming surgical (GAS) procedures over the past decade. The objective of this paper is to use online search data from Google Trends (GT) to describe national search trends for GAS procedures., Methods: GT was queried for search terms relating to GAS from January 2004 to February 2021. The 19 selected keywords covered a broad range of GAS topics. United States (US) search interest was collected as relative search volumes (RSVs) and then analyzed by geographic region. The number of plastic surgery providers offering GAS and academic surgery centers was collected from the World Professional Association for Transgender Health (WPATH) and Trans-health.com. RSVs were analyzed by metro area to determine the relationship between search demand and personal income. State Medicaid policies for transgender health services were also collected., Results: All search terms demonstrated a positive increase in RSVs over time except "sex reassignment surgery" and "penectomy". The Mountain/Pacific and East South Central/West South Central had the greatest search volume for GAS and most providers offering care. The East South Central/West South Central region​​ ranked last for providers offering care, despite the relatively high search interest. This region also had no states with explicit Medicaid policies covering gender-affirming care. Metro areas in the top five for RSV but bottom quartile for per capita personal income were identified., Conclusions: Online search interest for GAS-related terms has increased. Search interest for GAS has regional variation and did not show a specific pattern with provider availability., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Merrick et al.)

Background: Adherence to screening guidelines among transgender and non-binary (TGNB) populations is not well studied. This study examines breast cancer screening patterns among TGNB patients at an urban academic medical center., Methods: Demographic information, risk factors, and screening mammography were collected. Mammography rates were calculated in populations of interest according to national guidelines, and mammogram person-years were also calculated. Univariate and multivariate logistic regression was performed., Results: Overall, 253 patients were analyzed: 193 transgender women and non-binary people designated male at birth (TGNB DMAB) and 60 transgender men and non-binary people designated female at birth (TGNB DFAB). The median (interquartile range) age was 53.2 years (42.3-62.6). Most patients had no family history of breast cancer (n = 163, 64.4%) and were on hormone therapy (n = 191, 75.5%). Most patients where White (n = 164, 64.8%), employed (n = 113, 44.7%), and had public insurance (n = 128, 50.6%). TGNB DFAB breast screening rates were low, ranging from 2.0 to 50.0%, as were TGNB DMAB screening rates, ranging from 7.1 to 47.6%. The screening rates among the TGNB DFAB and TGNB DMAB groups did not significantly differ from one another. Among TGNB DFAB patients, univariate analyses showed no significant predictors for mammography. Among TGNB DMAB patients, not being on hormone therapy resulted in fewer odds of undergoing mammography. There were no significant findings on multivariate analyses., Conclusion: Mammography rates in the TGNB population are lower than institutional and national rates for cisgender patients, which are 77.3% and 66.7-78.4%, respectively. Stage of transition, organs present, hormone therapy, and risk factors should be considered to guide screening., (© 2021. Society of Surgical Oncology.)

Peripheral nerve interfaces are frequently used in experimental neuroscience and regenerative medicine for a wide variety of applications. Such interfaces can be sensors, actuators, or both. Traditional methods of peripheral nerve interfacing must either tether to an external system or rely on battery power that limits the time frame for operation. With recent developments of wireless, battery-free, and fully implantable peripheral nerve interfaces, a new class of devices can offer capabilities that match or exceed those of their wired or battery-powered precursors. This paper describes methods to (i) surgically implant and (ii) wirelessly power and control this system in adult rats. The sciatic and phrenic nerve models were selected as examples to highlight the versatility of this approach. The paper shows how the peripheral nerve interface can evoke compound muscle action potentials (CMAPs), deliver a therapeutic electrical stimulation protocol, and incorporate a conduit for the repair of peripheral nerve injury. Such devices offer expanded treatment options for single-dose or repeated dose therapeutic stimulation and can be adapted to a variety of nerve locations.

Background: Over 200 million women and girls worldwide have suffered from the partial to total removal of external female genitalia for nonmedical purposes, referred to as female genital mutilation (FGM). Survivors of FGM may develop debilitating physical and psychological long-term sequelae. This is the first study to examine the scope of the extant surgical literature on the management of FGM-related morbidity., Methods: A systematic scoping review of five major research citation databases was conducted., Results: A total of 190 articles from 29 countries met the inclusion criteria. The majority (76%) were primary source articles and from obstetrics and gynecology literature (71%). Reported interventions for FGM-related morbidity were defibulation, cyst excision, clitoral and vulvar reconstruction, urological reconstruction, peripartum procedures, labial adhesion release, and reinfibulation., Conclusions: Surgery for FGM complications spans multiple specialties, which suggests multidisciplinary collaboration benefit. Plastic and reconstructive surgeons have a clear role in the multidisciplinary care team for these patients. This scoping review identified a paucity of high-quality evidence with respect to functional quality of life outcomes and long-term follow-up., Competing Interests: Declaration of Competing Interest None to disclose., (Copyright © 2021. Published by Elsevier Ltd.)

Injured peripheral nerves typically exhibit unsatisfactory and incomplete functional outcomes, and there are no clinically approved therapies for improving regeneration. Post-operative electrical stimulation (ES) increases axon regrowth, but practical challenges from the cost of extended operating room time to the risks and pitfalls associated with transcutaneous wire placement have prevented broad clinical adoption. This study presents a possible solution in the form of advanced bioresorbable materials for thin, flexible, wireless implant that provides precisely controlled ES of the injured nerve for a brief time in the immediate post-operative period. Afterward, rapid, complete and safe modes of bioresorption naturally and quickly eliminate all of the constituent materials in their entirety, without the need for surgical extraction. The unusually high rate of bioresorption follows from the use of a unique, bilayer enclosure that combines two distinct formulations of a biocompatible form of polyanhydride as an encapsulating structure, to accelerate the resorption of active components and confine fragments until complete resorption. Results from mouse models of tibial nerve transection with re-anastomosis indicate that this system offers levels of performance and efficacy that match those of conventional wired stimulators, but without the need to extend the operative period or to extract the device hardware., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Background: Female sexual function is a complex model of biological and nonbiological factors. The impact of self-perceived vulvar appearance on female sexual function is not well understood., Objectives: The aim of this study was to determine the influence of vulvar appearance on sexual function in adult women. The primary aim was to assess the relation between self-perceived vulvar appearance and sexual function. The secondary aim was to assess the influence of prior genital procedures on vulvar appearance and sexual function., Methods: An observational study of adult women was conducted utilizing Amazon Mechanical Turk, an online crowdsourcing platform. The survey instrument included demographic information, subjective vulvar appearance measures, and the Female Sexual Function Index (FSFI) questionnaire., Results: Out of 398 respondents, 148 (37.2%) reported concern about their vulvar appearance and 134 (33.7%) reported a history of genital cosmetic procedures. Women who were uncomfortable with their vulvar appearance had lower FSFI scores than those comfortable with their vulvar appearance, 24.6 vs 27.0 (P = 0.01), respectively. Among women uncomfortable with their vulvar appearance, 70.9% of subjects met the criteria for sexual dysfunction. Women who were uncomfortable with their vulvar appearance were significantly more at risk of sexual dysfunction (adjusted odds ratio: 2.43; 95% CI: 1.46-4.10; P < 0.001). Women with a history of cosmetic genital procedures were significantly more at risk of sexual dysfunction (adjusted odds ratio: 2.46; 95% CI: 1.43-4.23)., Conclusions: Women who are uncomfortable with their vulvar appearance had higher rates of sexual dysfunction. Women seeking cosmetic genital procedures should be screened for sexual dysfunction to facilitate realistic expectations and optimal care., (© 2021 The Aesthetic Society. Reprints and permission: journals.permissions@oup.com.)

Purpose: The purpose of this study was to determine the existence and strength of association between chest dysphoria and mental health in transmasculine and nonbinary adolescents., Methods: This is a cross-sectional cohort study of transmasculine and nonbinary adolescents designated female at birth between 12 and 18 years old. None had undergone prior top surgery. Patients complete the Chest Dysphoria Measure and Youth Inventory-4 (YI-4) upon presentation to our institution. Outcomes were retrospectively reviewed. The primary outcome of interest was the association between chest dysphoria and anxiety and depression symptom severity, as measured by the YI-4., Results: One hundred fifty-six patients met inclusion criteria. Mean age was 15.3 years (standard deviation [SD] = 1.7). Most patients identified as transmasculine (n = 132); 18 identified as nonbinary and 6 as questioning. Mean (SD) YI-4 symptom severity scores were 10.67 (6.64) for anxiety and 11.99 (7.83) for depression. Mean (SD) Chest Dysphoria Measure composite score was 30.15 (9.95); range 2-49. Chest dysphoria was positively correlated with anxiety (r = .146; p = .002) and depression (r = .207; p < .001). In multivariate linear regression models, chest dysphoria showed a significant, positive association with anxiety and depression, after accounting for gender dysphoria, degree of appearance congruence, and social transition status., Conclusions: Chest dysphoria is associated with higher anxiety and depression in transmasculine and nonbinary adolescents designated female at birth. This association is independent of level of gender dysphoria, degree of appearance congruence, and social transition status. Treatment options aimed at alleviating chest dysphoria should be made accessible to adolescents and tailored to individual needs., (Copyright © 2021 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Abstract: Mastectomy for chest masculinization is a commonly performed gender-affirming surgery in minor patients, a vulnerable population with unique developmental and psychosocial needs. We aimed to use principles of medical ethics (eg, autonomy, beneficence, nonmaleficence, and justice) as a framework to analyze preoperative clinical decision making by pediatric plastic surgeons who work with transmasculine and nonbinary adolescents designated female at birth presenting for chest masculinization. Two patients were selected for inclusion in this case series based on the senior author's (J.F.C.) clinical experience. A retrospective chart review was conducted to extract relevant psychosocial and clinical information from clinic notes and supplemental documentation (eg, letters from outside providers) available in the electronic medical record. In case A, a 17-year-old patient presented to a plastic surgery clinic with mixed parental support and restrictive insurance requirements. In case B, a 16-year-old patient presented to the emergency room after an attempt to remove his own breasts. The cases highlight the role of the plastic surgeon in advocating for adolescent autonomy and justice by facilitating shared family decision making and navigating barriers to care. In addition, we recommend multidisciplinary care, including trusted, transcompetent mental health professionals, to ensure beneficence and nonmaleficence by providing timely care when appropriate., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Targeted muscle reinnervation (TMR) is a technique for the management of peripheral nerves in amputation. Phantom limb pain (PLP) and residual limb pain (RLP) trouble many patients after amputation, and TMR has been shown to reduce this pain when performed after the initial amputation. We hypothesize that TMR at the time of amputation may improve pain for patients after major upper-extremity amputation., Methods: We conducted a retrospective review of patients who underwent major upper-extremity amputation with TMR performed at the time of the index amputation (early TMR). Phantom limb pain and RLP intensity and associated symptoms were assessed using the numeric rating scale (NRS), the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Intensity Short-Form 3a, the Pain Behavior Short-Form 7a, and the Pain Interference Short-Form 8a. The TMR cohort was compared with benchmarked data from a sample of upper-extremity amputees., Results: Sixteen patients underwent early TMR and were compared with 55 benchmark patients. More than half of early TMR patients were without PLP (62%) compared with 24% of controls. Furthermore, half of all patients were free of RLP compared with 36% of controls. The median PROMIS PLP intensity score for the general sample was 47 versus 38 in the early TMR sample. Patients who underwent early TMR reported reduced pain behaviors and interference specific to PLP (50 vs 53 and 41 vs 50, respectively). The PROMIS RLP intensity score was lower in patients with early TMR (36 vs 47)., Conclusions: This study demonstrates that early TMR is a promising strategy for treating pain and improving the quality of life in the upper-extremity amputee. Early TMR may preclude the need for additional surgery and represents an important technique for peripheral nerve surgery., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2021 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background: Complex regional pain syndrome (CRPS) is a chronic, posttraumatic condition defined by severe pain and sensorimotor dysfunction. In cases of severe CRPS, patients request amputation, which may cause phantom limb pain (PLP) and residual limb pain (RLP). Targeted muscle reinnervation (TMR) reduces the risk of PLP and RLP. This report describes the use of TMR at the time of amputation in a series of patients with CRPS., Patients and Methods: Four patients (ages 38-71 years) underwent TMR at the time of amputation for CRPS between April 2018 and January 2019. Three patients had a history of trauma and surgery to the affected limb. All patients attempted pharmacologic and interventional treatments for 1-7 years before requesting amputation. Three patients underwent below-knee amputations (BKA) and one had an above-knee amputation (AKA). Target muscles included the soleus, gastrocnemius, and flexor hallucis longus (BKA), and semitendinosus, biceps femoris, and vastus medialis (AKA). Postoperative phantom and residual limb pain symptoms were collected via a telephone survey adapted from the Patient-Reported Outcomes Measurement Information System (PROMIS)., Results: There were no complications related to the TMR procedure. Average follow-up time was 12.75 months. Patients reported varied outcomes: two had RLP and PLP, one had RLP only, and one had PLP only. All patients reported successful prosthetic use., Conclusion: TMR may be performed at the time of amputation for CRPS. Further study is necessary to determine the effect of TMR on pain, pain medication use, prosthesis use, and other domains of function., (© 2020 Wiley Periodicals LLC.)

Learning Objectives: After reading this article, the participants should be able to: 1. List current nonsurgical and surgical strategies for addressing postamputation neuroma pain and discuss their limitations. 2. Summarize the indications and rationale for targeted muscle reinnervation. 3. Develop an operative plan for targeted muscle reinnervation in an acute or delayed fashion for upper and lower extremity amputations. 4. Propose a management algorithm for treatment of symptomatic neuromas in an intact limb. 5. Discuss the risk of neuroma development after primary revision digital amputation or secondary surgery for a digital neuroma. 6. Compare and contrast targeted muscle reinnervation to the historical gold standard neuroma treatment of excision and burying the involved nerve in muscle, bone, or vein graft. 7. Interpret and discuss the evidence that targeted muscle reinnervation improves postamputation neuroma and phantom pain when performed either acutely or in a delayed fashion to treat existing pain., Summary: Symptomatic injured nerves resulting from amputations, extremity trauma, or prior surgery are common and can decrease patient quality of life, thus necessitating an effective strategy for management. Targeted muscle reinnervation is a modern surgical strategy for prevention and treatment of neuroma pain that promotes nerve regeneration and healing rather than neuroma formation. Targeted muscle reinnervation involves the transfer of cut peripheral nerves to small motor nerves of adjacent, newly denervated segments of muscle and can be easily performed without specialized equipment. Targeted muscle reinnervation strategies exist for both upper and lower extremity amputations and for symptomatic neuromas of intact limbs. Targeted muscle reinnervation has been shown in a prospective, randomized, controlled trial to result in lower neuroma and phantom pain when compared to the historical gold standard of burying cut nerves in muscle.

Background: Targeted muscle reinnervation is an emerging surgical technique to treat neuroma pain whereby sensory and mixed motor nerves are transferred to nearby redundant motor nerve branches. In a recent randomized controlled trial, targeted muscle reinnervation was recently shown to reduce postamputation pain relative to conventional neuroma excision and muscle burying., Questions/purposes: (1) Does targeted muscle reinnervation improve residual limb pain and phantom limb pain in the period before surgery to 1 year after surgery? (2) Does targeted muscle reinnervation improve Patient-reported Outcome Measurement System (PROMIS) pain intensity and pain interference scores at 1 year after surgery? (3) After 1 year, does targeted muscle reinnervation improve functional outcome scores (Orthotics Prosthetics User Survey [OPUS] with Rasch conversion and Neuro-Quality of Life [Neuro-QOL])?, Methods: Data on patients who were ineligible for randomization or declined to be randomized and underwent targeted muscle reinnervation for pain were gathered for the present analysis. Data were collected prospectively from 2013 to 2017. Forty-three patients were enrolled in the study, 10 of whom lacked 1-year follow-up, leaving 33 patients for analysis. The primary outcomes measured were the difference in residual limb and phantom limb pain before and 1 year after surgery, assessed by an 11-point numerical rating scale (NRS). Secondary outcomes were change in PROMIS pain measures and change in limb function, assessed by the OPUS Rasch for upper limbs and Neuro-QOL for lower limbs before and 1 year after surgery., Results: By 1 year after targeted muscle reinnervation, NRS scores for residual limb pain from 6.4 ± 2.6 to 3.6 ± 2.2 (mean difference -2.7 [95% CI -4.2 to -1.3]; p < 0.001) and phantom limb pain decreased from 6.0 ± 3.1 to 3.6 ± 2.9 (mean difference -2.4 [95% CI -3.8 to -0.9]; p < 0.001). PROMIS pain intensity and pain interference scores improved with respect to residual limb and phantom limb pain (residual limb pain intensity: 53.4 ± 9.7 to 44.4 ± 7.9, mean difference -9.0 [95% CI -14.0 to -4.0]; residual limb pain interference: 60.4 ± 9.3 to 51.7 ± 8.2, mean difference -8.7 [95% CI -13.1 to -4.4]; phantom limb pain intensity: 49.3 ± 10.4 to 43.2 ± 9.3, mean difference -6.1 [95% CI -11.3 to -0.9]; phantom limb pain interference: 57.7 ± 10.4 to 50.8 ± 9.8, mean difference -6.9 [95% CI -12.1 to -1.7]; p ≤ 0.012 for all comparisons). On functional assessment, OPUS Rasch scores improved from 53.7 ± 3.4 to 56.4 ± 3.7 (mean difference +2.7 [95% CI 2.3 to 3.2]; p < 0.001) and Neuro-QOL scores improved from 32.9 ± 1.5 to 35.2 ± 1.6 (mean difference +2.3 [95% CI 1.8 to 2.9]; p < 0.001)., Conclusions: Targeted muscle reinnervation demonstrates improvement in residual limb and phantom limb pain parameters in major limb amputees. It should be considered as a first-line surgical treatment option for chronic amputation-related pain in patients with major limb amputations. Additional investigation into the effect on function and quality of life should be performed., Level of Evidence: Level IV, therapeutic study.

More than 75% of major limb amputees experience chronic pain; however, data on severity and experience of pain are inconsistent. Without a benchmark using quantitative patient-reported outcomes, it is difficult to critically assess the efficacy of novel treatment strategies. Our primary objective is to report quantitative pain parameters for a large sample of amputees using the validated Patient-reported Outcomes Measurement System (PROMIS). Secondarily, we hypothesize that certain patient factors will be associated with worse pain., Methods: PROMIS and Numerical Rating Scales for residual limb pain (RLP) and phantom limb pain (PLP) were obtained from a cross-sectional survey of upper and lower extremity amputees recruited throughout North America via amputee clinics and websites. Demographics (gender, age, race, and education) and clinical information (cause, amputation level, and time since amputation) were collected. Regression modeling identified factors associated with worse pain scores ( P < 0.05)., Results: Seven hundred twenty-seven surveys were analyzed, in which 73.4% reported RLP and 70.4% reported PLP. Median residual PROMIS scores were 46.6 [interquartile range (IQR), 41-52] for RLP Intensity, 56.7 (IQR, 51-61) for RLP Behavior, and 55.9 (IQR, 41-63) for RLP Interference. Similar scores were calculated for PLP parameters: 46.8 (IQR, 41-54) for PLP Intensity, 56.2 (IQR, 50-61) for PLP Behavior, and 54.6 (IQR, 41-62) for PLP Interference. Female sex, lower education, trauma-related amputation, more proximal amputation, and closer to time of amputation increased odds of PLP. Female sex, lower education, and infection/ischemia-related amputation increased odds of RLP., Conclusion: This survey-based analysis provides quantitative benchmark data regarding RLP and PLP in amputees with more granularity than has previously been reported., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Management of postoperative pain is a challenge for healthcare providers in all surgical fields, especially in the context of the current opioid epidemic. We developed a cell phone application to monitor pain, medication use, and relevant quality of life domains (eg, mood, mobility, return to work, and sleep) in patients with neurogenic pain, including those with limb loss. A literature review was conducted to define application length and design parameters. The final application includes 12 questions for patients with limb loss and 8 for patients with neurogenic pain without limb loss. Pilot testing with 21 participants demonstrates acceptable time to complete the application (mean = 158 seconds, SD = 81 seconds) and usability, based on the mHealth App Usability Questionnaire. We aim for our application to serve as an outcome measure for evaluation of an evolving group of peripheral nerve procedures, including targeted muscle reinnervation. In addition, the application could be adapted for clinical use in patients undergoing these procedures for neurogenic pain and thus serve as a tool to monitor and manage pain medication use., Competing Interests: Disclosure: Dr. Ko is an advisor for Checkpoint Surgical, Inc., Medline Industries, Inc., Mesh Suture, Inc., and EDGe Surgical, Inc. Dr. Dumanian is a founder, equity holder, and science officer of Advanced Suture, Inc and Mesh Suture, Inc. The company TrialX hosted the initial version of the application used for the pilot testing described in this paper. The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Targeted Muscle Reinnervation (TMR) is a reproducible procedure for effective prevention and treatment of neuropathic pain. Recent studies have demonstrated that TMR is more successful in treating neuroma pain than the standard method of neuroma excision and burying into muscle. The fundamental concept of TMR is that providing severed nerve endings a place to go and something to do facilitates normal healing. Future studies will continue to support the use of TMR for any region of the body where an injured nerve may develop a painful neuroma., Competing Interests: Disclosure Dr G.A. Dumanian has consulted for the Checkpoint Surgical Company and has received support for his teaching course for Targeted Muscle Reinnervation. Dr S.W. Jordan and Dr A.G. Chappell have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Lymphedema after regional nodal irradiation is a severe complication that could be minimized without significantly compromising nodal coverage if the anatomic region(s) associated with lymphedema were better defined. This study sought to correlate dose-volume relationships within subregions of the axilla with lymphedema outcomes to generate treatment planning guidelines for reducing lymphedema risk., Methods and Materials: Women with stage II-III breast cancer who underwent breast surgery with axillary assessment and regional nodal irradiation were identified. Nodal targets were prospectively contoured per Radiation Therapy Oncology Group guidelines for field design. The axilla was divided into 8 distinct subregions that were retrospectively contoured. Lymphedema outcomes were assessed by arm circumferences. Multivariate Cox proportional hazards regression assessed patient, surgical, and dosimetric predictors of lymphedema outcomes., Results: Treatment planning computed tomography scans for 265 women treated between 2013 and 2017 were identified. Median post-radiation therapy follow-up was 3 years (interquartile range [IQR], 1.9-3.6). Dose to the axillary-lateral thoracic vessel juncture (ALTJ; superior to level I) was most associated with lymphedema risk (maximally selected rank statistic = 6.3, P < .001). The optimal metric was ALTJ minimum dose (D min ) <38.6 Gy (3-year lymphedema rate 5.7% vs 37.4%, P <.001), although multiple parameters relating to sparing of the ALTJ were highly correlated. Multivariate analysis confirmed ALTJ D min <38.6 Gy (hazard ratio [HR], 0.13; P < .001), body mass index (HR, 1.06/unit; P = .002), and number of lymph nodes removed (HR, 1.08/node; P < .001) as significant predictors. Women with ALTJ D min <38.6 Gy maintained median V 45Gy of 99% in the supraclavicular (IQR, 94-100%), 100% in level III (IQR, 97%-100%), 98% in level II (IQR, 86%-100%), and 91% in level I (IQR, 75%-98%) nodal basins., Conclusions: Anatomic studies suggest the ALTJ region is typically traversed by arm lymphatics and appears to be an organ at risk in breast radiation therapy. Ideally, avoidance of the ALTJ may be feasible while simultaneously encompassing breast-draining nodal basins. Confirmation of this finding in future prospective studies is needed., (Copyright © 2019. Published by Elsevier Inc.)

Background: We describe a multidisciplinary approach for comprehensive care of amputees with concurrent targeted muscle reinnervation (TMR) at the time of amputation., Methods: Our TMR cohort was compared to a cross-sectional sample of unselected oncologic amputees not treated at our institution (N = 58). Patient-Reported Outcomes Measurement Information System (NRS, PROMIS) were used to assess postamputation pain., Results: Thirty-one patients underwent amputation with concurrent TMR during the study; 27 patients completed pain surveys; 15 had greater than 1 year follow-up (mean follow-up 14.7 months). Neuroma symptoms occurred significantly less frequently and with less intensity among the TMR cohort. Mean differences for PROMIS pain intensity, behavior, and interference for phantom limb pain (PLP) were 5.855 (95%CI 1.159-10.55; P = .015), 5.896 (95%CI 0.492-11.30; P = .033), and 7.435 (95%CI 1.797-13.07; P = .011) respectively, with lower scores for TMR cohort. For residual limb pain, PROMIS pain intensity, behavior, and interference mean differences were 5.477 (95%CI 0.528-10.42; P = .031), 6.195 (95%CI 0.705-11.69; P = .028), and 6.816 (95%CI 1.438-12.2; P = .014), respectively. Fifty-six percent took opioids before amputation compared to 22% at 1 year postoperatively., Conclusions: Multidisciplinary care of amputees including concurrent amputation and TMR, multimodal postoperative pain management, amputee-centered rehabilitation, and peer support demonstrates reduced incidence and severity of neuroma and PLP., (© 2019 Wiley Periodicals, Inc.)

Objective: To compare targeted muscle reinnervation (TMR) to "standard treatment" of neuroma excision and burying into muscle for postamputation pain., Summary Background Data: To date, no intervention is consistently effective for neuroma-related residual limb or phantom limb pain (PLP). TMR is a nerve transfer procedure developed for prosthesis control, incidentally found to improve postamputation pain., Methods: A prospective, randomized clinical trial was conducted. 28 amputees with chronic pain were assigned to standard treatment or TMR. Primary outcome was change between pre- and postoperative numerical rating scale (NRS, 0-10) pain scores for residual limb pain and PLP at 1 year. Secondary outcomes included NRS for all patients at final follow-up, PROMIS pain scales, neuroma size, and patient function., Results: In intention-to-treat analysis, changes in PLP scores at 1 year were 3.2 versus -0.2 (difference 3.4, adjusted confidence interval (aCI) -0.1 to 6.9, adjusted P = 0.06) for TMR and standard treatment, respectively. Changes in residual limb pain scores were 2.9 versus 0.9 (difference 1.9, aCI -0.5 to 4.4, P = 0.15). In longitudinal mixed model analysis, difference in change scores for PLP was significantly greater in the TMR group compared with standard treatment [mean (aCI) = 3.5 (0.6, 6.3), P = 0.03]. Reduction in residual limb pain was favorable for TMR (P = 0.10). At longest follow-up, including 3 crossover patients, results favored TMR over standard treatment., Conclusions: In this first surgical RCT for the treatment of postamputation pain in major limb amputees, TMR improved PLP and trended toward improved residual limb pain compared with conventional neurectomy., Trial Registration: NCT02205385 at ClinicalTrials.gov.