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Abstract Bone metastases occur in the majority of advanced breast cancer patients, and the most common complications are osteolytic bone metastases. However, due to the limitations of models and methodologies for bone metastasis studies, the intricacies of bone metastasis have not been fully acknowledged and revealed in prior work. Our earlier study indicated that certain breast cancer cells undergo a pre-osteolytic stage before the establishment of overt metastatic lesions. Here, we further identify a differential bone morphology between ER (estrogen receptor)+ and ER− breast cancer. Specifically, we observe a more pronounced osteolytic phenotype in the bone metastatic lesions of ER− cells investigated, linked to elevated hypoxia signaling that stimulates the secretion of osteolytic inducers from cancer cells. In the in vivo mouse model, the application of the hypoxia-inducible factor (HIF) inhibitor 2-methoxyestradiol demonstrates a promising efficacy in suppressing tumor growth and osteoclast differentiation in the bone lesions established by bone-tropic subpopulation of ER− MDA-MB-231 cell. Overall, our findings explore the complexity of phenotype and morphology in bone metastatic lesions of ER+ and ER− breast cancer, which offers a compelling rationale for leveraging HIF inhibitors to the treatment targeting skeletal complications of breast cancer bone metastases, especially for ER− tumors.

Background: Intravenous thrombolysis with tissue plasminogen activator is used for off-label treatment of acute childhood stroke. Tenecteplase (TNK) is used to treat acute stroke in adults at many institutions, although there are extremely few data about TNK use in children. We aimed to characterize pediatric stroke experts' experience and preferences with regard to TNK use in children with stroke., Methods: Online survey distributed to members of the International Pediatric Stroke Organization in April 2023., Results: We received 33 responses. Most (81.2%) respondents reported only being "a little familiar" or "somewhat familiar" with TNK. Only six (18%) respondents reported being "familiar" or "very familiar" with TNK. Seventy percent of respondents were willing to treat pediatric stroke with TNK, at least in some situations. In a hypothetical scenario of a child in an outside emergency room with only TNK available, 81.8% would consider recommending treatment with TNK. However, only three (9.1%) respondents had TNK in their stroke protocol and seven (21.2%) had TNK on formulary at their hospital. Two respondents reported direct awareness of a child treated with TNK., Conclusions: The majority of pediatric stroke neurologists responding to this survey reported a willingness to consider TNK use in children. However, data on TNK use in children, provider experience, and pediatric hospital preparedness are limited., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose of Review: The purpose is to describe the latest research on epidemiology, causes, and morbidities of stroke in neonates and children., Recent Findings: The global incidence of childhood stroke is approximately 2 per 100 000 person-years, which is significantly lower compared to neonates (20-40 per 100 000 live births) and adults (80-90 per 100 000 person-years). Placental abnormalities are a risk factor for perinatal stroke, although cause is usually multifactorial. In children, nonatherosclerotic arteriopathies and arteriovenous malformations are major causes of ischemic and hemorrhagic strokes, respectively. The perinatal period confers a high risk of stroke and can lead to long-term disability, including motor delay, cognitive or speech impairment, and epilepsy. Recent studies suggest that at least 50% of survivors of perinatal stroke have abnormal neurodevelopmental scores in long-term follow up. Childhood stroke is associated with significant morbidity, including epilepsy, motor impairments, and behavioral disability. Recent studies have also identified an association between pediatric stroke and behavioral disorders, such as attention deficit hyperactivity disorder and autism., Summary: Perinatal and childhood strokes are important causes of neurological morbidity. Given the low incidence of childhood stroke, prospective research studies on epidemiology, causes, and outcomes remain limited, highlighting the need for continued multisite collaborations., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Chronic pain is defined as pain lasting longer than 3 months. This often causes persistent emotional distress and functional disability that is refractory to conventional treatments. Emerging evidence suggests that oral Ketamine therapy may have a specific role in managing treatment-resistant chronic pain. This study aimed to assess the effectiveness of oral ketamine within a tertiary chronic pain management clinic., Methods: This study was a clinic-based retrospective descriptive study of 79 patients with a broad range of chronic pain diagnoses and treated with oral ketamine over a period up to 12 years. Changes in pain, mood and quality of life (QoL) were assessed using a numerical pain severity score, the Brief Pain Inventory (BPI), the Public Health Questionnaire (PHQ-9) and American Chronic Pain Association Quality of Life (QoL) scale., Results: 73 patients were accessible for follow-up (mean daily dose and treatment duration were 193.84 mg and 22.6 months respectively). Pain scores decreased ( p  < 0.0001) on both numerical scores (41.6% decrease) and BPI scoring (mean decrease 2.61). Mood improved ( p  < 0.0001) across both PHQ-9 and BPI measurements. Patients also reported less difficulty with daily activities and improved QoL. The most common adverse reaction was drowsiness (21.9%), with 30.1% reporting no adverse reactions from Ketamine., Discussion: This work adds to the growing body of evidence that under the supervision of a pain specialist, oral ketamine therapy may be a safe, tolerable and effective treatment for chronic pain conditions which have not responded to other management options. Further research is required to produce a more accurate understanding of its chronic use., Key Message: This real-world study shows that patients being treated with oral ketamine for chronic pain report decreased severity of pain, improved mood and increased quality of life across all conditions., Competing Interests: KL has received previous funding from Medtronic Ltd not related to this research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Al Mukhaizeem, Nasa, Waldron, McDaid, Gorman, Featherstone, Barry, Murphy, Gallagher, Nair, O'Connor, Kelly, O'Hora, Dolan, Mac Colgain, McGrath, Blouin, Roman, Gaffney, Roddy and Levins.)

Tenecteplase is replacing alteplase as the fibrinolytic agent of choice for the acute management of ischemic stroke in many adult stroke centers due to practical and pharmacokinetic advantages in the setting of similar outcomes. Although thrombolytic use is increasing for acute childhood stroke, there is very limited experience with tenecteplase in children for any indication, and importantly, there are no data on safety, dosing, or efficacy of tenecteplase for childhood stroke. Changes in fibrinolytic capacity over childhood, pediatric pharmacological considerations such as age-specific differences in drug clearance and volume of distribution, and practical aspects of drug delivery such as availability in children's hospitals may impact decisions about transitioning from alteplase to tenecteplase for acute pediatric stroke treatment. Pediatric and adult neurologists should prepare institution-specific guidelines and organize prospective data collection., Competing Interests: Disclosures Dr Sun receives research and salary support from the American Heart Association (Career Development Award 850044). Dr Goldenberg receives research and salary support from the National Institutes of Health, National Heart Lung and Blood Institute for investigation into venous thromboembolism in patients <21 years old. He receives or recently received consultancy fees from Anthos Therapeutics, Bayer, Boehringer-Ingelheim, Chiesi, Daiichi Sankyo, and the University of Colorado-affiliated Academic Research Organization CPC Clinical Research for roles in clinical trial planning or oversight committees in pharmaceutical industry-sponsored pediatric clinical trials of antithrombotics. The other authors report no conflicts.

Background: Communication around serious illness is a core competency for all residencies. One-fifth of neurology residencies have no curriculum. Published curricula use didactics or role-play to assess confidence performing this skill without evaluation in clinical settings. The SPIKES mnemonic (Setting, Perception, Invitation, Knowledge, Empathy, Strategy/Summary) outlines 6 evidence-based steps for communication around serious illness. It is unknown whether child neurology residents can incorporate SPIKES into communication around serious illness in clinical settings. Objective: To develop and evaluate a curriculum on communication around serious illness using SPIKES for child neurology residents that shows long-term skill retention in clinical settings at a single institution. Methods: In 2019, we created a pre-post survey and skills checklist based on SPIKES, with 20 total including 10 core skills. Faculty observed residents' (n  =  7) communication with families and completed both preintervention and postintervention checklists for comparison. Residents underwent training in SPIKES during a 2-hour session using didactic and coached role-play. Results: All (n  =  7) residents completed preintervention surveys, 4 of 6 completed postintervention. All (n  =  6) participated in the training session. Following the training, 75% of residents reported improved confidence in use of SPIKES, though 50% were still unsure about appropriately responding to emotions. There was improvement in all SPIKES skills, with significant improvement in 6 of 20 skills up to 1 year following training. Conclusion: This is the first evaluation of the implementation of a communication around serious illness curriculum for child neurology residents. We identified improved comfort with SPIKES after training. Successful acquisition and utilization of this framework in our program suggests it could be incorporated into any residency program.

Up to more than half of previously healthy children presenting with their first arterial ischemic stroke have a cerebral arteriopathy. Cerebral arteriopathies during childhood can be congenital, reflecting abnormal vessel development, or acquired when caused by disruption of vascular homeostasis. Distinguishing different types of cerebral arteriopathies in children can be challenging but of great clinical value as they may dictate different disease and treatment courses, and clinical and radiologic outcomes. Furthermore, children with stroke due to a specific arteriopathy exhibit distinctive features when compared to those with stroke due to other causes or a different type of arteriopathy. These features become crucial in the management of pediatric stroke by choosing appropriate diagnostic and treatment strategies. The objective of this article is to provide the reader with a comprehensive up-to-date review of the classification, symptoms, diagnosis, treatment, and outcome of cerebral arteriopathies in children., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Younger stroke patients may suffer worse outcomes than older patients; however, the extent to which age at stroke impacts remote areas of the brain remains unclear. The objective of this study was to determine thalamic volume changes ipsilateral to middle cerebral artery territory strokes based on age at acute ischemic stroke onset. Methods: Acute ischemic stroke patients <9 years, 9-18 years, and >18 years old were retrospectively recruited from a large quaternary care system. Each subject underwent an acute (<72 hours from AIS) and chronic (>90 days) magnetic resonance imaging (MRI) scan. Manual thalamic segmentation was performed. Results: Younger and older children had significantly greater stroke-side thalamic volume loss compared to adults (48.2%, P  = .022; 40.7%, P  = .044, respectively). Conclusions: Stroke-side thalamic volumes decreased across the age spectrum but to a greater degree in pediatric patients. This observation can affect functional and cognitive outcomes post stroke and warrants further research.

Objective: To determine the incidence, clinical correlates and exposure risk of medical encounters during community-based physical activity events in the UK., Methods: An analysis of medical data from weekly, community-based physical activity events (parkrun) at 702 UK locations over a 6-year period (29 476 294 participations between 2014 and 2019) was conducted in order to define the incidence and clinical correlates of serious life-threatening, non-life-threatening and fatal medical encounters., Results: 84 serious life-threatening encounters (overall incidence rate=0.26/100 000 participations) occurred including 18 fatalities (0.056/100 000 participations). Statistical modelling revealed that the probabilities of serious life-threatening encounters were exceptionally low, however, male sex, increasing age, slower personal best parkrun time and less prior running engagement/experience (average number of runs per year and number of years as a parkrun participant) were associated with increased probability of serious life-threatening encounters. These were largely accounted for by cardiac arrest (48/84, 57%) and acute coronary syndromes (20/84, 24%). Non-life-threatening medical encounters were mainly attributed to tripping or falling, with a reported incidence of 39.2/100 000 participations., Conclusions: Serious life-threatening and fatal medical encounters associated with parkrun participation are extremely rare. In the context of a global public health crisis due to inactivity, this finding underscores the safety and corollary public health value of community running/walking events as a strategy to promote physical activity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Mobile health platforms can facilitate social support and address HIV (human immunodeficiency virus) stigma but pose challenges for intervention design and participant engagement. Giddens's structuration theory, that individuals are shaped by-and shape-their communities through rules and resources that give them power to operate within these environments, provides a useful analytic framework for exploring these dynamic intervention spaces., Method: Data were drawn from an online randomized controlled trial intervention (HealthMpowerment) for young Black men who have sex with men to reduce condomless anal intercourse. We applied a conversational analysis informed by structuration theory to 65 user-generated conversations that included stigma content. We aimed to understand how the interdependent relationship between the intervention space and participants' contributions might contribute to behavior change., Results: Thirty five intervention participants contributed to the analyzed conversations. Our analysis identified three types of conversational processes that may underlie behavior change: (1) Through intervention engagement, participants established norms and expectations that shaped their discussions; (2) participants used anecdotes and anonymity to reinforce norms; and (3) intervention staff members sought to improve engagement and build knowledge by initiating discussions and correcting misinformation, thus playing an integral role in the online community., Conclusions: The lens of structuration theory usefully reveals potential behavior change mechanisms within the social interactions of an online intervention. Future design of these interventions to address HIV stigma should explicitly characterize the context in which individuals (study staff and participants) engage with one another in order to assess whether these processes are associated with improved intervention outcomes.

Background: In dogs, antiepileptic drugs (AED) cause lethargy but quantitative data regarding the effects of AED on activity levels are not available, and little is known about how AEDs affect sleep quality., Objective: To quantitatively compare activity levels and nocturnal activity in dogs previously diagnosed with idiopathic epilepsy (IE) receiving AEDs compared to age- and breed-matched control dogs., Animals: Sixty-two dogs with IE and 310 control dogs., Methods: This is a 3-month prospective parallel observational study. An activity monitoring device for dogs was used to measure daily activity levels and sleep scores in all dogs., Results: Dogs with IE treated with AEDs had an 18% average lower baseline activity level compared to control dogs (P = .005; point estimate = 0.82, 95% confidence interval [CI], 0.75-0.90). The combination of phenobarbital and potassium bromide (KBr) was associated with an average 28% decrease in activity in dogs with IE compared to control dogs (P = .03; point estimate = 0.72; CI, 0.62-0.82). Mean sleep scores were not significantly different in dogs with IE receiving AEDs compared to control dogs (P = .43). However, higher dosages of KBr were associated with lower sleep scores (P = .01)., Conclusions: Dogs with IE receiving AEDs have lower activity levels, but no difference in sleep scores, compared to controls. The combination of phenobarbital and KBr had the largest decrease in activity between groups. Higher doses of KBr may affect nocturnal activity in epileptic dogs., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background and Purpose: Because children often have lifelong morbidity after stroke, there is considerable enthusiasm to pursue mechanical thrombectomy in childhood stroke based on literature reports. However, current published data may reflect inconsistent reporting and publication bias, which limit the ability to assess safety and efficacy of mechanical thrombectomy in childhood stroke., Methods: This retrospective cohort study compared reporting quality and clinical outcomes for mechanical thrombectomy between a trial-derived cohort of 42 children treated with mechanical thrombectomy for acute stroke at study sites and 133 patients reported in the literature. National Institutes of Health Stroke Scale at baseline, 24 hours after mechanical thrombectomy, and at discharge were compared between study site patients and literature patients. Odds ratios (ORs) were used to compare reporting frequencies. Proportional odds logistic regression was used to compare outcomes., Results: Premechanical thrombectomy National Institutes of Health Stroke Scale was available in 93% of study patients compared with 74% of patients in the literature (OR, 4.42 [95% CI, 1.47-19.89]). Postmechanical thrombectomy National Institutes of Health Stroke Scale was available in 69% of study patients compared with 29% of literature cases at 24 hours (OR, 5.48 [95% CI, 2.62-12.06]), and 64% of study patients compared with 32% of cases at discharge (OR, 3.85 [95% CI, 1.87-8.19]). For study sites, median scores were 12 at baseline, 9 at 24 hours, and 5 at discharge. Median scores in case reports were 15 at baseline, 4 at 24 hours, and 3 at discharge. ORs for differences in outcomes between groups were 5.97 (95% CI, 2.28-15.59) at 24 hours and 3.68 (95% CI, 1.45-9.34) at discharge., Conclusions: Study site patients had higher rates of National Institutes of Health Stroke Scale reporting and worse short-term outcomes compared with literature reports. Rigorous data collection is needed before treatment guidelines for pediatric mechanical thrombectomy can be developed.

Objective: Poliomyelitis results in changes to the anterior horn cell. The full extent of cortical network changes in the motor physiology of polio survivors has not been established. Our aim was to investigate how focal degeneration of the lower motor neurons (LMN) in infancy/childhood affects motor network connectivity in adult survivors of polio., Methods: Surface electroencephalography (EEG) and electromyography (EMG) were recorded during an isometric pincer grip task in 25 patients and 11 healthy controls. Spectral signal analysis of cortico-muscular (EEG-EMG) coherence (CMC) was used to identify the cortical regions that are functionally synchronous and connected to the periphery during the pincer grip task., Results: A pattern of CMC was noted in polio survivors that was not present in healthy individuals. Significant CMC in low gamma frequency bands (30-47 Hz) was observed in frontal and parietal regions., Conclusion: These findings imply a differential engagement of cortical networks in polio survivors that extends beyond the motor cortex and suggest a disease-related functional reorganisation of the cortical motor network., Significance: This research has implications for other similar LMN conditions, including spinal muscular atrophy (SMA). CMC has potential in future clinical trials as a biomarker of altered function in motor networks in post-polio syndrome, SMA, and other related conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Like adults, most children have lifelong morbidity after stroke. Revascularization therapies such as intravenous tissue plasminogen activator and mechanical thrombectomy may be options to decrease this morbidity in selected children, although currently there are no evidence-based recommendations to guide treatment. The utility and safety of mechanical thrombectomy in childhood stroke is unknown because of the lack of safety trials, case-controlled trials, and comprehensive retrospective studies. As such, the current rationale for the use of mechanical thrombectomy in childhood is based on extrapolation from adult experience, as well as consensus at individual institutions with many centers deciding care on a case-by-case basis. Nevertheless, the increasing use of recanalization therapies in appropriately selected adults with acute arterial ischemic stroke has led to an increase in consideration and use in childhood, and there are enough case reports and series, as well as experience, to suggest that some children with large vessel occlusion will likely benefit., Methods: We reviewed current literature regarding mechanical thrombectomy in childhood., Results: There are differences between pediatric and adult stroke which may impact safety, efficacy, and individual decision-making, including patient size, pathophysiology of stroke, deficit, experience, and lack of data regarding natural history of stroke in children., Conclusions: Hospitals planning to perform mechanical thrombectomy in children should establish local procedures and guidelines for considering thrombectomy. In our experience, care is best provided through multidisciplinary teams including a pediatric vascular neurologist, neurointerventionalist with pediatric experience, and pediatric neurocritical care., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Despite advances in stroke care, patients continue to incur significant disability, are at risk for future events, and are inconsistently comanaged with palliative care (PC) specialty teams. The purpose of this study was to review patients with stroke admitted to our institution, comparing patients with and without PC consultation. We retrospectively reviewed medical record data of all patients with stroke admitted to our neurosciences ICU (NICU) in July 2014 to June 2015 with and without PC consultation. Review focused on stroke type, patient demographics, median days to discharge and death, and posthospitalization discharge. Of 463 patients admitted to the NICU with a stroke diagnosis, 27% (125/463) had (PC) consultation. A higher percentage of the patients with PC consult presented with hemorrhagic stroke than those without PC consult (38% vs 21%, P < .001). Patients with PC consult had longer median days to discharge and death ( P < .001) and a higher percentage of mortality (32% vs 11%). Of the 301 patients without PC consult who discharged (89.1%), 36.5% discharged to inpatient rehab while 10% discharged to a skilled nursing facility. In comparison, of the patients with PC consultation who discharged alive (41.1%), 15.7% discharged to inpatient rehab whereas 39% discharged to skilled nursing ( P < .001). The uncertainty of which patients with stroke benefit most from specialty PC is highlighted in that although sicker patients are referred to PC, a substantial portion (41%) of these patients discharge alive, of which 39.2% discharged to skilled nursing. Future research should focus on which patients with stroke would benefit from specialty PC.

Objectives: To refine the Centers for Disease Control and Prevention (CDC)'s contraceptive education poster using patient-centered design., Study Design: We conducted cognitive interviews with 26 women aged 18-44 living in North Carolina who spoke and read English and had ever had sex. We interviewed women about both a CDC and a patient-centered poster in alternating order. Participants were contraceptive users and non-users that we selected purposively to have a range of characteristics that might influence their perspective: age, race/ethnicity, previous births and pregnancies, contraceptive method(s) used in the past three months, pregnancy intentions, and numeracy. The initial response rate for participants was 55%. We used cognitive theory to code interviews for comprehension, relevance, and acceptability, as well as design and overall preference. We structured the 26 interviews into four rounds and revised the patient-centered poster after each round to improve these measures., Results: By the final round, 83% of women preferred the patient-centered poster. The majority of women favored this poster's relevance (86%), and design (100%) and ease of comprehension (86%). Women raised few concerns about the acceptability of the final version of the patient-centered poster. Women identified many issues with both posters that the researchers did not anticipate, highlighting the value of patient-centered design approaches to educational materials., Conclusions: This study refined a patient-centered poster so that its language is clear and it addresses the informational needs of its target audience., Implications: The Centers for Disease Control and Prevention and the Office of Population Affairs recommend that clinicians educate women about contraception. This study developed a poster that could help clinicians follow this recommendation. Before widespread implementation, more research is needed to evaluate the poster's impact on contraceptive knowledge and behaviors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Pediatric stroke alerts or "code strokes" allow for rapid evaluation, imaging, and treatment of children presenting with stroke-like symptoms. In a previous study of emergency department-initiated pediatric stroke alerts, 24% of children had confirmed strokes. The purpose of this study was to characterize in-hospital pediatric stroke alerts., Methods: Demographic and clinical information was obtained from a quality improvement database and medical records for children (zero to 20 years) at a single institution for whom a stroke alert was activated after hospital admission between April 2011 and December 2016. Stroke alert activation criteria included a new focal neurological defect occurring within 48 hours. A neurologist evaluated the patient within 15 minutes and rapid magnetic resonance imaging was available., Results: Medical personnel activated in-hospital stroke alerts for 56 children (median age 6.5 years, interquartile range 1 to 13, 52% male). Stroke was the final diagnosis of 25 (45%), 72% ischemic, and 28% hemorrhagic strokes. Other diagnoses included neurological urgencies: seizure (21%), posterior reversible encephalopathy syndrome (7%), transient ischemic attack (5%), and acute disseminated encephalomyelitis (4%). Of the stroke diagnoses, 68% were stroke alerts called in the pediatric intensive care unit or pediatric cardiac intensive care unit. Rapid neuroimaging was completed in 91%; magnetic resonance imaging brain was the first image in 55%., Conclusions: Of in-hospital pediatric stroke alerts, 45% were stroke while 38% were other neurological conditions requiring urgent evaluation. In-hospital stroke alerts were commonly activated for children with complicated medical histories. Rapid neurological evaluation facilitated care. No child underwent thrombolysis or thrombectomy., (Copyright © 2018. Published by Elsevier Inc.)

Therapeutic agents designed to stimulate the immune system are now cornerstones in the treatment of metastatic melanoma. These drugs promote lymphocyte growth and survival, which could plausibly result in clinical lymphoproliferative disorders. We report the case of a 62-year-old female with metastatic melanoma who developed primary cutaneous small/medium CD4 T-cell lymphoproliferative disorder (PC-SMTCL) after treatment with vemurafenib and recombinant high-dose interleukin-2 (IL-2). The patient developed a painless red papule behind the ear. A biopsy showed a dense population of CD4 lymphocytes with a T-follicular helper cell phenotype. Molecular studies confirmed the presence of a clonal population of T cells, and the process was classified as PC-SMTCL. The patient was diagnosed with metastatic melanoma approximately 3 years before the development of the cutaneous lymphoma and had been treated with vemurafenib followed by 2 courses of IL-2. The patient's last course of IL-2 was completed in April of 2013. She developed the cutaneous lymphoma behind her ear in December of 2015. An association between PC-SMTCL and vemurafenib treatment for advanced melanoma has been reported previously in one patient; however, an association between PC-SMTCL and IL-2 treatment has not been documented. The immunostimulatory properties of IL-2 or vemurafenib may be responsible for the development of PC-SMTCL in our patient. Additionally, antigenic stimulation of the immune system by melanoma itself could contribute to clonal selection of lymphocytes.

Basal cell carcinomas represent one of the most common skin cancers and often present initially in the primary care setting. Subtle basal cell carcinomas may be difficult to detect, and early detection of these carcinomas remains important in limiting patient morbidity. In this article, we present a simple diagnostic maneuver, "basal cell blanche," to increase early detection of basal cell carcinomas., (© Copyright 2016 by the American Board of Family Medicine.)

Context: Although expanding research has found that relationship characteristics can shape contraceptive use among young adults, limited research has examined how relationship characteristics intersect to form distinct types of relationships and how relationship types are linked to contraceptive use., Methods: Data from the 2002-2005 rounds of the National Longitudinal Survey of Youth 1997 cohort were used to examine contraceptive use in 3,485 young adult dating relationships. Latent class analysis was employed to develop a typology of relationships using measures of relationship structure (duration) and quality (intimacy, commitment and conflict). Multinomial logistic regression analyses were used to estimate associations between relationship type and contraceptive use and method choice at last sex., Results: Four types of relationships were identified, two shorter term and two longer term, differentiated by levels of intimacy, commitment and conflict. Young adults in longer term relationships with greater conflict and lower intimacy and commitment were less likely than those in other long-term relationships to use hormonal and dual methods versus no method (relative risk ratios, 0.6-0.7). Hormonal method use, versus no method use or condom use, was more prevalent in short-term relationships with greater intimacy and commitment and lower conflict than in other short-term relationships (1.7 and 1.9, respectively)., Conclusions: Classifying short-term relationships as "casual" or long-term ones as "serious" may ignore heterogeneity within these categories that may have implications for contraceptive use. Future qualitative research could provide a better understanding of relationship types and couples' fertility intentions and access to and use of contraceptives., (Copyright © 2014 by the Guttmacher Institute.)

Thin melanomas with partial or complete regression may provide clues about antitumor immunity, but their management remains controversial. We have characterized the management and clinical outcomes of regressed thin (<1 mm) T1a melanomas and hypothesized that regression increases the risk of regional metastases when compared with nonregressed thin melanomas. A prospectively collected clinical database was reviewed, and T1a melanomas with regression were identified. Histology, surgical approach, outcome, and survival were evaluated. The primary outcome measures were sentinel node positivity, subsequent lymph node metastasis, and survival. A total of 75 patients with T1a or in-situ melanomas were grouped into three subsets. Group 1: 35 underwent a sentinel node biopsy (SNBx), none of which were positive. No patients developed nodal recurrence. The 5-year survival of this group was 93%, with a median follow-up of 52 months. Group 2: 31 were followed up without SNBx; two developed regional nodal disease (6.5%), neither of whom died of subsequent distant disease. The 5-year survival was 89%, with a median follow-up of 38 months. There was no significant difference in the survival between groups 1 and 2. Group 3: nine patients presented with metastatic disease concurrent with a regressed thin melanoma. These patients had a median survival of 2.3 years and a 4-year survival estimate of 22%. Regression should not be used as an indication for SNBx in T1a melanomas; we recommend that such patients be managed with wide local excision and a long-term clinical follow-up. The poor prognosis of thin regressed primary melanoma with simultaneous metastatic disease may indicate the existence of immune escape phenotypes supporting melanoma progression.

Context: Young adults have high rates of unintended childbearing and STDs, yet little research has examined the role of relationship characteristics in their contraceptive use., Methods: Data collected from the 2002-2005 rounds of the National Longitudinal Survey of Youth yielded a sample of 4,014 dating relationships among sexually active 18-26-year-olds. Bivariate analysis and multivariate logistic and multinomial logistic regressions assessed associations between relationship characteristics and contraceptive use at last sex., Results: In three-quarters of the relationships, respondents had used some method at last intercourse; respondents in 26% of the relationships had used a condom only, in 26% a hormonal method only and in 23% dual methods. Compared with respondents in relationships in which first sex occurred within two months of starting to date, those who first had sex before dating were more likely to have used any method at last sex (odds ratio, 1.4), particularly condoms or dual methods (relative risk ratio, 1.5 for each). The relative risk of using a hormonal method only, rather than no method or condoms only, increased with relationship duration (1.01) and level of intimacy (1.1-1.2). Discussing marriage or cohabitation was associated with reduced odds of having used any method (0.7) and a reduced relative risk of having used condoms alone or dual methods (0.6 for each). Increasing levels of partner conflict and asymmetry were also linked to reduced odds of any method use (0.97 and 0.90, respectively)., Conclusions: Prevention programs should address relationship context in contraceptive decision making, perhaps by combining relationship and sex education curricula to foster communication and negotiation skills., (Copyright © 2011 by the Guttmacher Institute.)

Although variability in connective tissue parameters is widely reported and recognized, systematic examination of the effect of such parametric uncertainties on predictions derived from a full anatomical joint model is lacking. As such, a sensitivity analysis was performed to consider the behavior of a three-dimensional, non-linear, finite element knee model with connective tissue material parameters that varied within a given interval. The model included the coupled mechanics of the tibio-femoral and patello-femoral degrees of freedom. Seven primary connective tissues modeled as non-linear continua, articular cartilages described by a linear elastic model, and menisci modeled as transverse isotropic elastic materials were included. In this study, a multi-factorial global sensitivity analysis is proposed, which can detect the contribution of influential material parameters while maintaining the potential effect of parametric interactions. To illustrate the effect of material uncertainties on model predictions, exemplar loading conditions reported in a number of isolated experimental paradigms were used. Our findings illustrated that the inclusion of material uncertainties in a coupled tibio-femoral and patello-femoral model reveals biomechanical interactions that otherwise would remain unknown. For example, our analysis revealed that the effect of anterior cruciate ligament parameter variations on the patello-femoral kinematic and kinetic response sensitivities was significantly larger, over a range of flexion angles, when compared to variations associated with material parameters of tissues intrinsic to the patello-femoral joint. We argue that the systematic sensitivity framework presented herein will help identify key material uncertainties that merit further research and provide insight on those uncertainties that may not be as relative to a given response., (Copyright © 2010 Elsevier Ltd. All rights reserved.)