Longitudinal Assessment of Emergency Responders' Attitudes Toward People Who Overdose and Naloxone Following an Overdose Education Training.

BACKGROUND: In addition to teaching overdose recognition and response, overdose education and naloxone distribution (OEND) trainings for emergency responders aim to improve trainee attitudes toward people who use drugs and toward naloxone. This study examines the training effectiveness long term, as well as the extent to which improvements are dependent on profession type or recent experience administering naloxone. METHODS: A total of 774 emergency responders, consisting of law enforcement officers (LEOs) (n = 624, 81%) and emergency medical service (EMS) personnel (n = 150, 19%), attended OEND trainings and completed surveys immediately prior to ("pre") and following ("post") the training, as well as 6 months later ("follow-up"). Survey items assessed attitudes toward people who have overdosed, naloxone-related risk compensation (ie, "enabling") beliefs, and whether participants had administered naloxone since attending the training. Multiple regression and estimated marginal means were used to evaluate changes in scores. RESULTS: Emergency responders showed improved attitudes (pre = 2.60, follow-up = 2.45, P < .001) and risk compensation beliefs (pre = 2.97, follow-up = 2.67, P < .001) 6 months following the training. Follow-up scores differed by profession, with LEOs endorsing worse attitudes (difference = 0.55, P = .013) and more risk compensation beliefs (difference = 0.67, P = .014) than EMS. In addition, having recently administered naloxone predicted more negative attitudes (EMS: difference = 0.55, P = .01; LEO: difference = 0.54, P = .004) and risk compensation beliefs (EMS = 0.73, P = .006; LEO = 0.69, P = .002) at follow-up. CONCLUSION: Six months after an OEND training, emergency responders' attitudes toward people who overdose, and their risk compensation beliefs remained improved. However, LEOs had more negative follow-up attitudes and beliefs compared to EMS. Emergency responders who had administered naloxone had worse attitudes and beliefs at follow-up than those who had not. Of note, our sample evidenced sizable attrition between pre and follow-up assessments, leaving room for selection bias. Future studies should investigate how to mitigate negative effects of administering naloxone on attitudes toward those who overdose, and belief that naloxone is "enabling."

Antibody-Based Imaging of Bioreductive Prodrug Release in Hypoxia.

Regions of hypoxia occur in most tumors and are a predictor of poor patient prognosis. Hypoxia-activated prodrugs (HAPs) provide an ideal strategy to target the aggressive, hypoxic, fraction of a tumor, while protecting the normal tissue from toxicity. A key challenge associated with the development of novel HAPs, however, is the ability to visualize the delivery of the prodrug to hypoxic regions and determine where it has been activated. Here, we report a modified version of the commonly used nitroimidazole bioreductive group that incorporates the fluoroethyl epitope of the antibody-based hypoxia imaging agent, EF5. Attachment of this group to the red fluorescent dye, dicyanomethylene (DCM), enabled us to correlate the release of the DCM dye with imaging of the reduced bioreductive group using the EF5 antibody. This study confirmed that the antibody was imaging reduction and fragmentation of the pro-fluorophore. We next employed the modified bioreductive group to synthesize a new prodrug of the KDAC inhibitor Panobinostat, EF5-Pano. Release of EF5-Pano in hypoxic multiple myeloma cells was imaged using the EF5 antibody, and the presence of an imaging signal correlated with apoptosis and a reduction in cell viability. Therefore, EF5-Pano is an imageable HAP with a proven cytotoxic effect in multiple myeloma, which could be utilized in future in vivo experiments.

Feasibility and Usability of a Mobile App-Based Interactive Care Plan for Migraine in a Community Neurology Practice: Development and Pilot Implementation Study.

BACKGROUND: Migraine is a common and major cause of disability, poor quality of life, and high health care use. Access to evidence-based migraine care is limited and projected to worsen. Novel mobile health app-based tools may effectively deliver migraine patient education to support self-management, facilitate remote monitoring and treatment, and improve access to care. The risk that such an intervention may increase the care team workload is a potential implementation barrier. OBJECTIVE: This study aims to describe a novel electronic health record-integrated mobile app-based Migraine Interactive Care Plan (MICP) and evaluate its feasibility, usability, and impact on care teams in a community neurology practice. METHODS: Consecutive enrollees between September 1, 2020, and February 16, 2022, were assessed in a single-arm observational study of usability, defined by 74.3% (127/171) completing ≥1 assigned task. Task response rates, rate and type of care team escalations, and patient-reported outcomes were summarized. Patients were prospectively recruited and randomly assigned to routine care with or without the MICP from September 1, 2020, to September 1, 2021. Feasibility was defined by equal to or fewer downstream face-to-face visits, telephone contacts, and electronic messages in the MICP cohort. The Wilcoxon rank-sum test was used to compare continuous variables, and the chi-square test was used for categorical variables for those with at least 3 months of follow-up. RESULTS: A total of 171 patients were enrolled, and of these, 127 (74.3%) patients completed ≥1 MICP-assigned task. Mean escalations per patient per month was 0.9 (SD 0.37; range 0-1.7). Patient-confirmed understanding of the educational materials ranged from 26.6% (45/169) to 56.2% (95/169). Initial mean headache days per week was 4.54 (SD 2.06) days and declined to 2.86 (SD 1.87) days at week 26. The percentage of patients reporting favorable satisfaction increased from a baseline of 35% (20/57) to 83% (15/18; response rate of 42/136, 30.9% to 28/68, 41%) over the first 6 months. A total of 121 patients with MICP were compared with 62 patients in the control group. No differences were observed in the rate of telephone contacts or electronic messages. Fewer face-to-face visits were observed in the MICP cohort (13/121, 10.7%) compared with controls (26/62, 42%; P<.001). CONCLUSIONS: We describe the successful implementation of an electronic health record-integrated mobile app-based care plan for migraine in a community neurology practice. We observed fewer downstream face-to-face visits without increasing telephone calls, medication refills, or electronic messages. Our findings suggest that the MICP has the potential to improve patient access without increasing care team workload and the need for patient input from diverse populations to improve and sustain patient engagement. Additional studies are needed to assess its impact in primary care.

MEG correlates of speech planning in simple vs. interactive picture naming in children and adults.

The picture naming task is common both as a clinical task and as a method to study the neural bases of speech production in the healthy brain. However, this task is not reflective of most naturally occurring productions, which tend to happen within a context, typically in dialogue in response to someone else's production. How the brain basis of the classic "confrontation picture naming" task compares to the planning of utterances in dialogue is not known. Here we used magnetoencephalography (MEG) to measure neural activity associated with language production using the classic picture naming task as well as a minimal variant of the task, intended as more interactive or dialogue-like. We assessed how neural activity is affected by the interactive context in children, teenagers, and adults. The general pattern was that in adults, the interactive task elicited a robust sustained increase of activity in frontal and temporal cortices bilaterally, as compared to simple picture naming. This increase was present only in the left hemisphere in teenagers and was absent in children, who, in fact, showed the reverse effect. Thus our findings suggest a robustly bilateral neural basis for the coordination of interaction and a very slow developmental timeline for this network.

An efficient method for high molecular weight bacterial DNA extraction suitable for shotgun metagenomics from skin swabs.

The human skin microbiome represents a variety of complex microbial ecosystems that play a key role in host health. Molecular methods to study these communities have been developed but have been largely limited to low-throughput quantification and short amplicon-based sequencing, providing limited functional information about the communities present. Shotgun metagenomic sequencing has emerged as a preferred method for microbiome studies as it provides more comprehensive information about the species/strains present in a niche and the genes they encode. However, the relatively low bacterial biomass of skin, in comparison to other areas such as the gut microbiome, makes obtaining sufficient DNA for shotgun metagenomic sequencing challenging. Here we describe an optimised high-throughput method for extraction of high molecular weight DNA suitable for shotgun metagenomic sequencing. We validated the performance of the extraction method, and analysis pipeline on skin swabs collected from both adults and babies. The pipeline effectively characterised the bacterial skin microbiota with a cost and throughput suitable for larger longitudinal sets of samples. Application of this method will allow greater insights into community compositions and functional capabilities of the skin microbiome.

Particular genomic and virulence traits associated with preterm infant-derived toxigenic Clostridium perfringens strains.

Clostridium perfringens is an anaerobic toxin-producing bacterium associated with intestinal diseases, particularly in neonatal humans and animals. Infant gut microbiome studies have recently indicated a link between C. perfringens and the preterm infant disease necrotizing enterocolitis (NEC), with specific NEC cases associated with overabundant C. perfringens termed C. perfringens-associated NEC (CPA-NEC). In the present study, we carried out whole-genome sequencing of 272 C. perfringens isolates from 70 infants across 5 hospitals in the United Kingdom. In this retrospective analysis, we performed in-depth genomic analyses (virulence profiling, strain tracking and plasmid analysis) and experimentally characterized pathogenic traits of 31 strains, including 4 from CPA-NEC patients. We found that the gene encoding toxin perfringolysin O, pfoA, was largely deficient in a human-derived hypovirulent lineage, as well as certain colonization factors, in contrast to typical pfoA-encoding virulent lineages. We determined that infant-associated pfoA+ strains caused significantly more cellular damage than pfoA- strains in vitro, and further confirmed this virulence trait in vivo using an oral-challenge C57BL/6 murine model. These findings suggest both the importance of pfoA+ C. perfringens as a gut pathogen in preterm infants and areas for further investigation, including potential intervention and therapeutic strategies.

The role of substance use treatment in reducing stigma after release from incarceration: A qualitative analysis.

BACKGROUND: People with substance use disorders (SUD) who have been involved in the legal system often experience stigma upon reentry into the community after incarceration. Although substance use treatment can sometimes be a source of stigma, it may also reduce stigma by facilitating connections with providers, reducing distress, or helping people feel more integrated in their community. However, research has rarely examined the potential for treatment to reduce stigma. METHODS: This study examined stigma experiences and the degree to which substance use treatment reduced stigma among 24 people with SUDs who were receiving care in an outpatient treatment facility after release from incarceration. Qualitative interviews were conducted and analyzed using a content analysis approach. RESULTS: Participants reported negative self-judgements as well as perceiving negative judgments from the community upon reentry. With regard to stigma reduction, themes emerged around substance use treatment repairing strained family relationships and reducing participants' self-stigma. Aspects of treatment that reportedly reduced stigma included the treatment facility having a nonjudgmental atmosphere, patients trusting the staff, and working with peer navigators who had lived experience of SUD and incarceration. CONCLUSIONS: Results from this study suggest that substance use treatment has the potential to decrease the negative impacts of stigma upon release from incarceration, which continues to be a major barrier. Though more research on stigma reduction is needed, we suggest some preliminary considerations for treatment programs and providers.

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated ß2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or ß2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting ß2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive ß2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

The Facial Artery Perforator Flap.

BACKGROUND: Reconstruction of facial melanoma defects can be challenging. Large defects of the midface, cheek, and nasolabial fold are often reconstructed using a cervicofacial flap which requires significant flap elevation and undermining. Surgeons are often hesitant to commit to such a large reconstruction without definitive pathologic evidence of negative margins. However, local perforator flaps may be used as an alternative to large flaps with less dissection and donor site morbidity and may also allow for more facile re-advancement in the event of a positive margin on final pathology. The goal of this study is to evaluate a perforator flap based on the facial artery to determine if it is a safe and cosmetically favorable option to immediately repair oncologic-related defects on the cheek and midface. METHODS: A retrospective review of all melanoma cases performed by the senior author between January 2016 and December 2021 was conducted. Patients who underwent reconstruction using a facial artery perforator flap were included. RESULTS: Sixteen patients were included in our cohort. The average age was 67.3 years and 53% (n=8) were female. Fourteen patients had the primary defect located on the cheek, 1 from the nasolabial fold, and 1 from the distal nasal sidewall. All patients received immediate reconstruction. Excisional margins ranged from 0.5 to 2 cm. Two patients had positive margins following pathology results with one undergoing treatment with imiquimod and the other opting for re-excision. No complications involving the defect or donor site were reported after an average follow-up time of 113.8 days. CONCLUSION: The facial artery perforator flap is a safe and cosmetically favorable option to immediately repair oncologic-related defects on the cheek and midface.

Overcoming Barriers to Tobacco Cessation and Lung Cancer Screening among Racial and Ethnic Minority Groups and Underserved Patients in Academic Centers and Community Network Sites: The City of Hope Experience.

BACKGROUND: Tobacco control is important for cancer patient health, but delivering effective low-dose CT (LDCT) screening and tobacco cessation is more difficult in underserved and patients from racial and ethnic minority groups. At City of Hope (COH), we have developed strategies to overcome barriers to the delivery of LDCT and tobacco cessation. METHODS: We performed a needs assessment. New tobacco control program services were implemented focusing on patients from racial and ethnic minority groups. Innovations included Whole Person Care with motivational counseling, placing clinician and nurse champions at points of care, training module and leadership newsletters, and a patient-centric personalized medicine Personalized Pathways to Success (PPS) program. RESULTS: Emphasis on patients from racial and ethnic minority groups was implemented by training cessation personnel and lung cancer control champions. LDCT increased. Tobacco use assessment increased and abstinence was 27.2%. The PPS pilot program achieved 47% engagement in cessation, with self-reported abstinence at 3 months of 38%, with both results slightly higher in patients from racial and ethnic minority groups than in Caucasian patients. CONCLUSIONS: Tobacco cessation barrier-focused innovations can result in increased lung cancer screening and tobacco cessation reach and effectiveness, especially among patients from racial and ethnic minority groups. The PPS program is promising as a personalized medicine patient-centric approach to cessation and lung cancer screening.

Paget's disease of the breast: diagnosis and management.

Paget's disease of the breast typically affects postmenopausal women and is associated with an underlying malignancy. Skin changes are a common presenting symptom, as well as a lump, nipple discharge, pain and changes to the nipple shape. Imaging options include ultrasound for women under the age of 35 years or mammogram and ultrasound for women over the age of 40 years. The definitive diagnostic investigation is a tissue core biopsy. Cases are discussed by a multidisciplinary team to decide on the optimal management strategy. Management options are typically surgical and include breast-conserving surgery or mastectomy in addition to oncoplastic techniques. Sentinel lymph node biopsy is performed in all patients undergoing surgery. Adjuvant chemotherapy, radiotherapy or endocrine therapy can be used to treat concomitant invasive disease or ductal carcinoma in situ.

Disparities in Access to Cranial Remodeling Orthosis for Deformational Plagiocephaly.

OBJECTIVE: Moderate to severe cases of deformational plagiocephaly (DP) may be treated with cranial remolding orthoses (CRO). This study investigated the socioeconomic disparities in access to care for CRO for DP correction. DESIGN: This was a retrospective review of medical records from a single CRO company in Connecticut from 2014 to 2020. METHODS: Demographic variables were collected from all patients. Univariable logistic regressions were used to identify differences for presenting age at consultation, whether CRO was pursued, and length of CRO treatment by insurance payor and household income quartile. RESULTS: Of the 5620 patients identified, 4100 (73.0%) received CRO, with 674 (12.0%) receiving a second helmet. Of those receiving CRO, 1536 (37.5%) had Medicaid insurance while 2558 (62.4%) were commercially insured. Patients on Medicaid were 1.30 times more likely to have delayed presentation (P = .017), while patients from the lowest income quartile were 1.26 1.50 (P < .001) and 1.58 (P < .001) times more likely to have a delayed presentation relative to those in the highest and second-highest income quartiles, respectively. Patients in the highest and second-highest income quartiles were also 1.55 (P < .001) and 1.45 (P < .001) more likely, respectively, to receive CRO after consultation than those from the lowest income quartile. CONCLUSIONS: Lower income and Medicaid-insured patients had delayed presentation for CRO consultation. Those from the lowest income quartile were more likely to never receive CRO than those from wealthier backgrounds. Low socioeconomic status and Medicaid insurance, which can have more restrictive coverage policies for CRO, may result in the delayed treatment of DP.

Crucial Business Model Elements for Medical Device Startup Companies in Emerging Markets.

OBJECTIVES: Medical devices that suit the needs and challenges of low- and middle-income countries are desperately needed. To provide sustainable access to such devices, business approaches must be developed to meet the demands of individual economic, healthcare, and innovation ecosystems. Currently, there is a gap in the literature regarding business models for medical devices in low- and middle-income countries. METHODS: A multimodal approach using literature review and key informant interviews was performed to determine critical components of business models for medical device organizations operating in LMICs, specifically focusing on models in emerging markets. RESULTS: The search resulted in 4,674 articles, of which 31 were determined to be relevant and were reviewed. Additional sources included 1 government website, 5 nongovernmental organization websites, 2 private enterprises, and 6 publicly available, non-peer reviewed websites and 1 video. From these sources, four major criteria were found to be necessary for successful development of medical device business models in emerging markets: value proposition, partnerships, strategic pricing, and funding models. CONCLUSIONS: Innovators must custom tailor their business model when implementing these elements to the regulatory, cultural, and economic landscapes of each setting. This will improve access to safer, affordable medical care and successfully bring innovative technologies to emerging markets.

Sociodemographic Disparities in Access to Cleft Rhinoplasty.

Various sociodemographic factors affect patient access to care. This study aims to assess how factors such as government-funded insurance and socioeconomic status impact the ability of adolescents with cleft lip-associated nasal deformities to access secondary rhinoplasty procedures. Patients older than 13 years old with a history of cleft lip/palate were identified in the National Inpatient Sample database from 2010 to 2012. Those who received a secondary rhinoplasty were identified using the International Classification of Diseases, Ninth Revision (ICD-9) procedural codes. A multivariate logistic regression model with post hoc analyses was performed to analyze if insurance status, socioeconomic status, and hospital-level variables impacted the likelihood of undergoing rhinoplasty. Of the 874 patients with a cleft lip/palate history, 154 (17.6%) underwent a secondary rhinoplasty. After controlling for various patient-level and hospital-level variables, living in a higher income quartile (based on zip code of residence) was an independent predictor of receiving a secondary cleft rhinoplasty (odds ratio=1.946, P =0.024). Patients had lower odds of receiving a cleft rhinoplasty if care occurred in a private, nonprofit hospital compared with a government-owned hospital (odds ratio=0.506, P =0.030). Income status plays a significant role in cleft rhinoplasty access, with patients from lower income households less likely to receive a secondary cleft rhinoplasty. Hospital-specific factors such as geographic region, bed size, urbanization, and teaching status may also create barriers for patients and their families in accessing surgical care for cleft lip nasal deformities.

Adverse Childhood Experiences and Pathways to Violent Behavior for Women and Men.

Childhood maltreatment is associated with risk for committing future violence, but the relationship between subgroups and biological sex is unknown. The relationship between adverse childhood experiences (ACEs), violence, and sex was examined using a nationally representative sample. Results from a latent class analysis suggested a four-class model (low adversity; moderate maltreatment with high household dysfunction; severe maltreatment with moderate household dysfunction; severe multi-type adversities). When compared to low adversity, all typology groups were at significantly higher risk to engage in violence (odds ratio > 2.10, ps < .013). The data supported a linear trajectory, meaning increased childhood trauma was associated with increased risk for violence. Although men endorsed more violent behavior, the relationship between ACEs and violence was significantly stronger among women. Prior findings identify that women are more negatively impacted by ACEs and the current findings newly identify that this extends to violent crime.

Dorsal Augmentation With the Dorsal Extension Spreader Graft.

Spreader grafts traditionally are used to improve airflow through opening the internal nasal valve, as well as enhance the cosmetic appearance of the nose. The graft's versatility proves useful in surgical correction of several nasal profiles by enhancing dorsal aesthetic lines and by maintenance of the nasal pyramid at midline. The authors describe a modified spreader graft that adds an additional benefit of dorsal augmentation in patients with underprojected or saddle noses. This technique utilizes harvested septal cartilage and fixation of the graft that extends beyond the septal and upper lateral cartilage dorsal border to improve nasal dorsum height. Patients who received this operative technique by the senior author were identified and their operative courses and surgical outcomes were analyzed. Case examples are provided to illustrate indications and outcomes. This grafting technique allows for improved functionality, defined dorsal aesthetic lines, changes in nasal width, and a more balanced profile in patients with underprojected noses.

Fibroadenoma: a guide for junior clinicians.

Fibroadenoma is the most common cause of benign breast lumps and is typically seen in women under the age of 40 years. Fibroadenomas are classified as simple, complex, giant, myxoid or juvenile. They present as smooth, rubbery, mobile masses on palpation. Ultrasonographic and mammographic features typical of fibroadenomas include solid, round, well-circumscribed masses, with or without lobulated features. They are predominantly treated conservatively although clinical pathways recommend referral for triple assessment. Surgical intervention is indicated by the presence of one or more of the following features: the presence of symptoms, a diameter greater than 2 cm, rapid growth rate, complex features, disease recurrence or patient anxiety.

A protocol paper for the MOTION Study-A longitudinal study in a cohort aged 60 years and older to obtain mechanistic knowledge of the role of the gut microbiome during normal healthy ageing in order to develop strategies that will improve lifelong health and wellbeing.

BACKGROUND: Advances in medicine and public health mean that people are living longer; however, a significant proportion of that increased lifespan is spent in a prolonged state of declining health and wellbeing which places increasing pressure on medical, health and social services. There is a social and economic need to develop strategies to prevent or delay age-related disease and maintain lifelong health. Several studies have suggested links between the gut microbiome and age-related disease, which if confirmed would present a modifiable target for intervention development. The MOTION study aims to determine whether and how changes in the gut microbiome are associated with physical and mental capacity. A comprehensive longitudinal multiparameter study such as this has not been previously undertaken. METHODS: MOTION is a longitudinal prospective cohort study with a focus on gut health and cognitive function. 360 healthy individuals aged 60 years and older, living in East Anglia, UK will be recruited to the study, stratified into one of three risk groups (cohorts) for developing dementia based on their cognitive function. Participants will attend study appointments every six months over four years, providing stool and blood samples and a health questionnaire. Participants will also undergo physical measurements and cognitive tests at alternating appointments, and undergo Optical Coherence Tomography scans at 3 timepoints. Two subgroups of participants in the study will provide colonic tissue biopsies (n = ≥30 from each cohort), and brain imaging (n = 30) at two timepoints. DISCUSSION: This study will provide new insights into the gut-(microbiota)-brain axis and the relationship between age-associated changes in gut microbe populations and cognitive health. Such insights could help develop new microbe-based strategies to improve lifelong health and wellbeing. TRIAL REGISTRATION: This study is registered in the ClinicalTrials.gov Database with ID: NCT04199195 Registered: May 14, 2019.