Frailty is Not Associated with Worse Outcomes following Lower Extremity Angiograms for Limb Ischemia in Nonagenarians.

BACKGROUND: Endovascular interventions are performed routinely with minimal risk in younger populations. The safety and efficacy of endovascular interventions in nonagenarians is under examined. We sought to examine the following (1) mortality and limb salvage rates in the nonagenarian population and (2) whether frailty was associated with outcomes following lower extremity (LE) interventions for both acute limb ischemia (ALI) and chronic limb threatening ischemia (CLTI). METHODS: A retrospective review of patients ≥90 years who underwent a LE angiogram for ALI or CLTI over a 12-year period at a single institution was performed. Primary outcomes were 30-day and 12-month limb salvage and mortality rates. Patient demographics, 30-day complications, and 12-month target vessel reintervention (TVR) were reviewed. Frailty scores were calculated using the 11-factor modified frailty index (MFI-11). RESULTS: From 2009 to 2021, 76 patients (36% male) with a mean age of 93 (range: 90-102) underwent endovascular procedures for ALI (n = 13) and CLTI (n = 63). 30-day amputation and mortality rates were 6% and 8%, respectively. Patient demographics, preoperative functional status, and TVR rates were not different between patients who had early amputation (≤30 days) and those who achieved limb salvage. Seventy-two patients (94%) had follow-up data at 30 days. There was an 8% mortality rate at 30 days. Of those alive at 30 days, 94% of patients had successful limb salvage. Fifty-eight patients had complete follow-up data at 12 months. Of the patients alive at 12-month follow-up (75%), the limb salvage rate was 98%. Patients with amputation at 30 days had a significantly higher mortality rate at 12 months compared to those who did not (83% vs. 19%; P < 0.01). Based on MFI-11 scoring, 35% of the population was considered frail (≥0.27). Frail patients did not have significantly different 30-day outcomes (limb salvage: 94% vs. 88%; mortality 8% vs. 9%, P = 0.41 and 0.94, respectively) or 12-month outcomes (limb salvage: 82% vs. 94%; mortality: 32% vs. 22%, P = 0.28 and 0.39, respectively). CONCLUSIONS: Endovascular procedures can be done safely in nonagenarians with low mortality and amputation rates. Patients with early amputation are at significantly higher risk of death at 12 months. Frailty, as measured by a validated index, was not associated with early or late outcomes. When compared to immediate amputation, nonagenarian patients and their families should be counseled as to the benefit from a minimally invasive endovascular procedure.

Obesity is Associated With Increased Risk of Crohn's disease, but not Ulcerative Colitis: A Pooled Analysis of Five Prospective Cohort Studies.

BACKGROUND AND AIMS: It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs). RESULTS: Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I2 = 0%) compared with normal BMI (18.5 to <25 kg/m2). Each 5 kg/m2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). Similarly, with each 5 kg/m2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I2 = 0%). No associations were observed between measures of obesity and risk of UC. CONCLUSIONS: In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.

Carotid Duplex Poorly Predicts Stroke Risk During Transcatheter Aortic Valve Replacement.

INTRODUCTION: Patients undergoing surgical aortic valve replacement, in isolation or with concomitant coronary artery bypass grafting, have historically been screened for carotid artery disease prior to surgery. Over the past decade, transcatheter aortic valve replacement (TAVR) has incrementally become the predominant technique for the treatment of severe aortic stenosis. The relationship between internal carotid artery stenosis (ICAS) and risk of periprocedural stroke in the TAVR population is uncertain. We sought to evaluate our institution's outcomes with the TAVR procedure and the association with preoperative carotid duplex scan (CDS) results. METHODS: A retrospective review of a single institution TAVR registry over a 5-year period was performed. All patients with pre-operative carotid imaging were included. Outcomes included in-hospital, 30-day, and 1-year stroke and all-cause mortality rates. The diagnosis of post-operative stroke was based on neurological exam and confirmed by radiologic imaging. Standard statistical analysis was performed. RESULTS: A total of 436 patients met inclusion criteria. The prevalence of ICAS >50% was 18.3% and 70-99% stenosis was 4.8%. The in-hospital stroke and mortality rates were 2.3% and 1.2%, respectively. The cumulative 30-day and 1- year stroke rates were 3.7% and 6%, respectively. All were ischemic in nature. Bilateral infarcts were identified in 46.2% of stroke patients and 11.5% had an ipsilateral ICAS >50%. A large majority of stroke patients (23, 88.5%) had an ipsilateral ICAS of <50%. Less than 0.5% of patients had ICAS >70% and subsequently had an ipsilateral stroke within 30 days of procedure. CONCLUSIONS: The preoperative CDS identified carotid lesions that met criteria for elective repair in only 4.8% of patients. Of these, 9.5% suffered a stroke in the first 30 days after surgery. Over 90% of patients who had a stroke had less than 70% stenosis present in either carotid artery and there was no correlation between degree of ICAS and risk of stroke during the follow-up period. Routine CDS prior to TAVR does not predict in-hospital or 30-day stroke. As TAVR programs evolve, expand, and proliferate across the country, routine preoperative CDS is unlikely to determine the need for pre-operative carotid revascularization or predict stroke risk.

Birth weight is associated with adolescent brain development: A multimodal imaging study in monozygotic twins.

Previous research has shown that the prenatal environment, commonly indexed by birth weight (BW), is a predictor of morphological brain development. We previously showed in monozygotic (MZ) twins associations between BW and brain morphology that were independent of genetics. In the present study, we employed a longitudinal MZ twin design to investigate whether variations in prenatal environment (as indexed by discordance in BW) are associated with resting-state functional connectivity (rs-FC) and with structural connectivity. We focused on the limbic and default mode networks (DMNs), which are key regions for emotion regulation and internally generated thoughts, respectively. One hundred and six healthy adolescent MZ twins (53 pairs; 42% male pairs) followed longitudinally from birth underwent a magnetic resonance imaging session at age 15. Graph theoretical analysis was applied to rs-FC measures. TrackVis was used to determine track count as an indicator of structural connectivity strength. Lower BW twins had less efficient limbic network connectivity as compared to their higher BW co-twin, driven by differences in the efficiency of the right hippocampus and right amygdala. Lower BW male twins had fewer tracks connecting the right hippocampus and right amygdala as compared to their higher BW male co-twin. There were no associations between BW and the DMN. These findings highlight the possible role of unique prenatal environmental influences in the later development of efficient spontaneous limbic network connections within healthy individuals, irrespective of DNA sequence or shared environment.

Successful Return to Active Duty after First Rib Resection for Thoracic Outlet Syndrome.

BACKGROUND: The optimal surgical approach and treatment algorithm for thoracic outlet syndrome (TOS) remain controversial. We sought to examine the outcomes of patients treated at a military medical treatment facility (MTF) for TOS. METHODS: A retrospective review was performed on all patients who had a first rib resection (FRR) for TOS over a 9-year period at a single MTF. Patient demographics, perioperative details, and patient outcomes were examined. Active duty (AD) status and return to AD were reviewed. RESULTS: From 2008 to 2016, 33 FRRs were performed in 32 patients. Of these, 30 patients were on AD with a mean age of 27 years (range, 19-44). The 29 male and 4 female patients were treated for symptoms of venous (23), neurogenic (6), or arterial (4) TOS. The mean time from onset of symptoms was 11 months (range, 1 to 120). The FRR was performed via a transaxillary (13), supraclavicular (12), or paraclavicular (8) approach. Of 21 AD patients with venous TOS, 16 (76%) underwent preoperative thrombolysis. A postoperative venogram or ultrasound was performed in 20 patients, documenting vein patency in 18 (90%). Nine patients underwent subsequent venoplasty or stent placement. Most patients (15) were placed on anticoagulation for 1-6 months. Two AD patients had perioperative complications including a lymph leak and brachial plexus palsy. Twenty-four (89%) patients returned to AD status. One recruit never returned to AD after successful FRR, and two other patients did not return for medical reasons unrelated to the FRR. CONCLUSIONS: Despite a variety of surgical approaches and often delayed presentation, we identified a high percentage of postoperative vein patency and return to AD status in our population. The debate over surgical approach remains; however, a multimodal approach individualized to the patient's presentation and meticulous surgical technique led to successful outcomes in our healthy military population.

Birth weight discordance, DNA methylation, and cortical morphology of adolescent monozygotic twins.

BACKGROUND: Several studies have shown that the in utero environment, which can be indexed by birth weight (BW), is associated with cortical morphology in adolescence and adulthood. Work in monozygotic (MZ) twins suggests that this association is driven by non-shared environmental factors. This correlation could be the result of in utero impacts on DNA methylation. The aim of the present study with MZ twins is to replicate the association between discordance in BW and brain morphology and test whether discordance in DNA methylation mediates this relationship. METHODS: One hundred and four adolescent MZ twins (52 pairs, of which 42% were male pairs) who have been followed regularly since birth underwent T1 weighted structural MRI, and epigenome-wide assessment of DNA methylation from saliva at age 15. RESULTS: Co-twins had very similar measures of DNA methylation and cortical morphology. Higher BW members of a twin pair had increased total cortical surface area, and decreased cortical thickness compared to their lower BW sibling. BW Discordance was positively associated with both cortical surface area and cortical volume discordance. Genes involved in neurodevelopment were tentatively identified as mediators of both the BW - cortical volume, and BW- cortical surface area relationships. CONCLUSIONS: The association between BW and cortical morphology in adolescence appears to be attributable to in utero environmental effects, and DNA methylation may play a role in mediating this relationship. Hum Brain Mapp 38:2037-2050, 2017. © 2017 Wiley Periodicals, Inc.

A two-state comparative implementation of peer-support intervention to link veterans to health-related services after incarceration: a study protocol.

BACKGROUND: Approximately 600,000 persons are released from prison annually in the United States. Relatively few receive sufficient re-entry services and are at risk for unemployment, homelessness, poverty, substance abuse relapse and recidivism. Persons leaving prison who have a mental illness and/or a substance use disorder are particularly challenged. This project aims to create a peer mentor program to extend the reach and effectiveness of reentry services provided by the Department of Veterans' Affairs (VA). We will implement a peer support for reentry veterans sequentially in two states. Our outcome measures are 1) fidelity of the intervention, 2) linkage to VA health care and, 3) continued engagement in health care. The aims for this project are as follows: (1) Conduct contextual analysis to identify VA and community reentry resources, and describe how reentry veterans use them. (2) Implement peer-support, in one state, to link reentry veterans to Veterans' Health Administration (VHA) primary care, mental health, and SUD services. (3) Port the peer-support intervention to another, geographically, and contextually different state. DESIGN: This intervention involves a 2-state sequential implementation study (Massachusetts, followed by Pennsylvania) using a Facilitation Implementation strategy. We will conduct formative and summative analyses, including assessment of fidelity, and a matched comparison group to evaluate the intervention's outcomes of veteran linkage and engagement in VHA health care (using health care utilization measures). The study proceeds in 3 phases. DISCUSSION: We anticipate that a peer support program will be effective at improving the reentry process for veterans, particularly in linking them to health, mental health, and SUD services and helping them to stay engaged in those services. It will fill a gap by providing veterans with access to a trusted individual, who understands their experience as a veteran and who has experienced justice involvement. The outputs from this project, including training materials, peer guidebooks, and implementation strategies can be adapted by other states and regions that wish to enhance services for veterans (or other populations) leaving incarceration. A larger cluster-randomized implementation-effectiveness study is planned. TRIAL REGISTRATION: This protocol is registered with clinicaltrials.gov on November 4, 2016 and was assigned the number NCT02964897 .

A decade of pelvic vascular injuries during the Global War on Terror.

BACKGROUND: Pelvic vascular injuries (PVIs) rarely occur in isolation and are often associated with significant morbidity. The purpose of this study was to examine the incidence, trends, and early outcomes of PVIs sustained in combat. METHODS: The Department of Defense Trauma Registry was queried to identify all patients treated with PVIs during the first 10 years of Operation Enduring Freedom. Patient demographics, mechanism of injury, type of vascular injury, in-theater complications, and early clinical outcomes were examined. RESULTS: From 2003 to 2012, 143 patients (99% male) sustained a PVI in Afghanistan. During this period, there was a persistent increase in the percentage of patient visits (0.4% in 2003 to 2.0% in 2012). The mean Injury Severity Score (ISS) was 24. Sixty-six percent of patient injuries were secondary to explosions. Improvised explosive devices (IEDs) encountered by dismounted personnel accounted for 47% of all injuries and were associated with a significantly higher ISS (28) compared with all other mechanisms of injury (P < .01). There were 85 (43%) arterial and 112 (57%) venous PVIs. The most frequent arterial injury was the common iliac artery. Injury to the femoral vein was associated with a higher median transfusion requirement. One patient died in combat theater. Injuries from IEDs had higher rates of coagulopathy, acidosis, and hypothermia compared with other mechanisms of injury (P = .03). Forty-two patients (29%) sustained early infectious complications. Injuries from explosions were also associated with a significantly higher rate of infectious complications compared with other mechanisms of injury (P < .01). CONCLUSIONS: PVIs have occurred with increasing frequency during Operation Enduring Freedom. Despite a persistently low mortality, complication and infection rates remain high, particularly when injuries are secondary to explosions. IEDs are associated with higher ISS and complication rates. Future studies must continue to focus on the prevention and treatment of PVIs sustained in combat, particularly those caused by explosions.

Cocaine cue-induced dopamine release in the human prefrontal cortex.

BACKGROUND: Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown. METHODS: We used high-resolution positron emission tomography with [18F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence. RESULTS: Twelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [18F]fallypride binding potential (BPND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BPND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical DA cell bodies, midbrain BPND values were significantly correlated with changes in BPND within the striatum but not the cortex. The lower the midbrain D2 receptor levels, the greater the striatal change in BPND and self-reported craving. LIMITATIONS: Limitations of this study include its modest sample size, with only 2 female participants. Newer tracers might have greater sensitivity to cortical DA release. CONCLUSION: In people with cocaine use disorders, the presentation of drug-related cues induces DA release within cortical and striatal regions. Both effects are associated with craving, but only the latter is regulated by midbrain autoreceptors. Together, the results suggest that cortical and subcortical DA responses might both influence drug-focused incentive motivational states, but with separate regulatory mechanisms.

Series of Noncontrast Time-of-Flight Magnetic Resonance Angiographies to Identify Problems with Arteriovenous Fistula Maturation.

BACKGROUND: Successful maturation of arteriovenous fistulas (AVFs) remains a challenge for those managing patients with end-stage renal disease. Time-of-flight magnetic resonance angiography (TOF-MR) can be used to evaluate AVFs without the risk of radiation exposure, intravenous contrast, or reliance on the operator-dependent modality of color Doppler ultrasonography (CDUS). The objective of our study was to assess the utility of TOF-MR in the evaluation of nonmaturing AVFs and to identify the best clinical situations to use this technology. METHODS: Consecutive patients with abnormal findings on CDUS or physical examination after AVF creation underwent 3-dimensional (3D) TOF-MR. Imaging was performed at 3 T with a scan acquisition time of approximately 15 min. The technique was similar to head and neck magnetic resonance angiography (MRA), except presaturation bands were not used, thereby allowing simultaneous visualization of both arterial and venous flow. A total of 19 TOF-MR studies were performed. RESULTS: Nineteen patients underwent imaging and were the focus of this study. Seventeen of 19 TOF-MR studies were of diagnostic quality and yielded findings which enabled the vascular surgeon to take corrective measures. Findings included inflow stenosis, anastomotic narrowing, venous outflow stenosis, and hemodynamically significant venous tributaries. Twelve of 17 patients required conventional digital subtraction angiography (DSA). The congruence rate between TOF-MR and DSA was 83.3%. Four patients (21%) avoided DSA and went directly to definitive surgical treatment including branch ligation (3) or new access (1). CONCLUSIONS: This is the first report in the literature of successful implementation of 3D TOF-MR to assist in identifying AVF maturation problems. This unique noninvasive imaging modality provides actionable images without contrast or radiation exposure and can obviate the need for invasive diagnostic procedures or provide an anatomic map for planning corrective intervention.

The Impact of the in utero and Early Postnatal Environments on Grey and White Matter Volume: A Study with Adolescent Monozygotic Twins.

Prenatal and early postnatal adversities have been shown to be associated with brain development. However, we do not know how much of this association is confounded by genetics, nor whether the postnatal environment can moderate the impact of in utero adversity. This study used a monozygotic (MZ) twin design to assess (1) the association between birth weight (BW) and brain volume in adolescence, (2) the association between within-twin-pair BW discordance and brain volume discordance in adolescence, and (3) whether the association between BW and brain volume in adolescence is mediated or moderated by early negative maternal parenting behaviours. These associations were assessed in a sample of 108 MZ twins followed longitudinally since birth and scanned at age 15. The total grey matter (GM) and white matter (WM) volumes were obtained using the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) toolbox in the Statistical Parametric Mapping version 8 (SPM8). We found that the BW was significantly associated with the total GM and WM volumes, particularly in the superior frontal gyrus and thalamus. Within-twin-pair discordance in BW was also significantly associated with within-pair discordance in both the GM and the WM volumes, supporting the hypothesis that the specific in utero environment is associated with brain development independently of genetics. Early maternal hostile parenting behaviours and depressive symptoms were associated with total GM volume but not WM volume. Finally, greater early maternal hostility may moderate the association between the BW and GM volume in adolescence, since the positive association between the BW and total GM volume appeared stronger at higher levels of maternal hostility (trend). Together, these findings support the importance of the in utero and early environments for brain development.

Limb salvage after vascular reconstruction followed by tissue transfer during the Global War on Terror.

BACKGROUND: Combat extremity wounds are complex and frequently require an immediate vascular reconstruction in the operational environment followed by delayed tissue coverage at a stateside medical treatment facility. The purpose of this study was to evaluate limb salvage outcomes after combat-related vascular reconstruction that subsequently required delayed soft tissue coverage during the Global War on Terror. METHODS: Patients who incurred a war-related extremity injury necessitating an immediate vascular intervention followed by definitive limb reconstruction requiring flap coverage from combat injuries were reviewed. Patient demographics, types of vascular and extremity injuries, and surgical interventions were examined. Outcomes included limb salvage, primary and secondary graft patency, flap outcomes, and complications. Differences between upper extremities (UEs) and lower extremities (LEs) were compared. RESULTS: From 2003 to 2012, 27 patients were treated for combat-related extremity injuries with an immediate vascular reconstruction followed by delayed tissue coverage. Fifteen LEs and 12 UEs were treated. The mean age was 24 years. An explosion was the cause in 77% of patients, with a mean Injury Severity Score (ISS) of 19. An autogenous vein bypass was the most common reconstruction performed in 20 patients (74%). Other vascular repairs included a primary repair, a patch angioplasty with bovine pericardium, and a bypass with use of a prosthetic graft. Eight patients (30%) had a concomitant venous injury, and 23 (85%) had a bone fracture. Thirty flaps were performed at a mean of 33 days from the original injury. Pedicle flaps were used in 24 limbs and free tissue flaps in six limbs. Muscle, fasciocutaneous, bone, and composite flaps were used for tissue coverage. At a mean follow-up of 16 months, primary patency rates of all arterial reconstructions were 66% in the UE and 53% in the LE (P = .69). Secondary patency rates were 100% in the UE and 86% in the LE (P = .48). The overall limb salvage rate was 81%. Limb salvage rates were 66% in the LE and 100% in the UE (P = .04). Three amputated lower limbs (60%) had inline flow to the foot. The flap success rate was 96%. Reasons for amputation included arterial thrombosis, flap failure, persistent soft tissue infection, osteomyelitis, and debilitating peripheral nerve injuries with associated chronic pain. CONCLUSIONS: Immediate vascular repair followed by delayed tissue coverage can be performed with a high (>80%) limb salvage rate after combat trauma. Limb salvage rates were higher in the UE despite equivocally high arterial patency rates. Wounded warriors can expect limb salvage by use of this international algorithm.

Safety and efficacy of antiplatelet/anticoagulation regimens after Viabahn stent graft treatment for femoropopliteal occlusive disease.

OBJECTIVE: We aimed to determine the safety and efficacy of antiplatelet/anticoagulation regimens after placement of Viabahn stent graft (W. L. Gore & Associates, Flagstaff, Ariz) for the treatment of femoropopliteal occlusive disease. METHODS: Clinical, angiographic, and procedural data for patients undergoing endovascular treatment of femoropopliteal occlusive disease using Viabahn covered stent grafts at a single institution between 2006 and 2013 were retrospectively reviewed. Graft patency and freedom from thrombolysis, major adverse limb event, and reintervention were determined by Kaplan-Meier analysis. The influence of relevant variables on clinical outcome was determined through univariate and multivariate Cox proportional hazards analyses. RESULTS: Viabahn stent grafts were placed in a total of 91 limbs in 61 patients (66% men; mean age, 69 ± 12 years) during the study period. Indication for intervention was either claudication (n = 59) or critical limb ischemia (n = 32), with the majority (70%) classified as TransAtlantic Inter-Society Consensus II C (n = 33) or D (n = 31) lesions. Mean follow-up was 38.3 months (range, 1-91 months). Postprocedural pharmacologic regimens included aspirin, clopidogrel, and warfarin (47%); indefinite aspirin and clopidogrel (46%); or aspirin and temporary clopidogrel (7%). Primary and secondary patency rates were 60%, 44%, and 36% and 95%, 82%, and 74% at 1 year, 3 years, and 5 years, respectively. Kaplan-Meier analysis demonstrated more aggressive antiplatelet/anticoagulation regimens to be associated with improved primary patency and freedom from reintervention. Cox proportional hazards analysis demonstrated TransAtlantic Inter-Society Consensus II D lesions, tobacco use, coronary artery disease, and smaller stent diameter to be independent risk factors for stent graft failure. Bleeding events were limited to those in the aspirin, clopidogrel, and warfarin group (11.6% [n = 5]; P = .052), although the majority of these events were not life-threatening, and only two cases required blood transfusion. CONCLUSIONS: Increasingly aggressive antithrombotic regimens after Viabahn stent graft placement trended toward improved overall clinical outcomes, although the marginal patency benefit observed with the addition of warfarin to dual antiplatelet therapy was tempered by an observed increased risk of bleeding complications. Longer term follow-up and multicenter studies are needed to further define optimal type and duration of antithrombotic therapy after endovascular peripheral interventions.

DNA methylation in individuals with anorexia nervosa and in matched normal-eater controls: A genome-wide study.

OBJECTIVE: Evidence associates anorexia nervosa (AN) with epigenetic alterations that could contribute to illness risk or entrenchment. We investigated the extent to which AN is associated with a distinct methylation profile compared to that seen in normal-eater women. METHOD: Genome-wide methylation profiles, obtained using DNA from whole blood, were determined in 29 women currently ill with AN (10 with AN-restrictive type, 19 with AN-binge/purge type) and 15 normal-weight, normal-eater control women, using 450 K Illumina bead arrays. RESULTS: Regardless of type, AN patients showed higher and less-variable global methylation patterns than controls. False Discovery Rate corrected comparisons identified 14 probes that were hypermethylated in women with AN relative to levels obtained in normal-eater controls, representing genes thought to be associated with histone acetylation, RNA modification, cholesterol storage and lipid transport, and dopamine and glutamate signaling. Age of onset was significantly associated with differential methylation in gene pathways involved in development of the brain and spinal cord, while chronicity of illness was significantly linked to differential methylation in pathways involved with synaptogenesis, neurocognitive deficits, anxiety, altered social functioning, and bowel, kidney, liver and immune function. DISCUSSION: Although pre-existing differences cannot be ruled out, our findings are consistent with the idea of secondary alterations in methylation at genomic regions pertaining to social-emotional impairments and physical sequelae that are commonly seen in AN patients. Further investigation is needed to establish the clinical relevance of the affected genes in AN, and, importantly, reversibility of effects observed with nutritional rehabilitation and treatment.

Outcomes after long-term follow-up of combat-related extremity injuries in a multidisciplinary limb salvage clinic.

BACKGROUND: Although the incidence of casualties from the Global War on Terror is decreasing, there remains a focus on the long-term sequelae from injuries sustained in the combat. Patients with prior significant limb injuries remain at risk of future complications. This study examines our institution's experience with a multidisciplinary team approach toward this challenging patient population. METHODS: A retrospective review was performed on all patients treated in a single institution Limb Preservation Clinic over a 2-year period. Those patients who sustained a combat-related injury in theater were examined. Patient demographics, mechanism of injury, amputation rates, time to amputation, and reasons for failure were examined. RESULTS: Ninety-four patients were evaluated in our multidisciplinary Limb Preservation Clinic over a 2-year period. Twenty patients (21%) were seen for combat-related injuries. Sixteen patients were evaluated and treated for chronic complications at a median of 13 months from their injury. All 16 patients were male with a median age of 24 years (range, 20-35). Ten patients sustained injuries secondary to a dismounted improvised explosive device (IED). All 16 patients had extensive soft tissue injuries and associated fractures. Only 2 patients sustained a vascular injury. The median number of prior surgeries to the affected limb was 8 (range, 3-19). The limb salvage rate of 37% was lower than our noncombat cohort (47%). The most common reasons for delayed amputation included chronic pain, osteomyelitis, and soft tissue infections. CONCLUSIONS: The high secondary amputation rates seen in this cohort underscores the need for long-term follow-up. Despite successful initial outcomes, many patients eventually progress to limb loss. Patients who sustain a dismounted IED are at greatest risk for a delayed amputation. Identifying and addressing those factors which lead to delayed amputation should be a priority for returning war veterans and focus of future studies.

A pulseless limb poorly predicts an arterial injury in combat trauma.

BACKGROUND: A pulseless limb is considered a hard sign of an arterial injury after penetrating trauma in the civilian population. However, the reliability of this finding has never been examined in combat trauma. The purpose of this study was to examine the reliability of the pulseless limb in the combat trauma population. Reasons for false positive physical examination findings were also identified. METHODS: The Joint Theater Trauma Registry identified all patients who presented to a military treatment facility (MTF) in Kandahar, Afghanistan, with a penetrating extremity injury over a 2-year period. Patients found to have a pulse deficit on initial physical examination were followed, and the results of the subsequent computed tomographic angiogram or arteriogram recorded. Patient demographics, injury patterns, and physiological data were examined. Standard statistical analysis was performed. RESULTS: From 2011 to 2012, 644 patients were treated at a single MTF for lower extremity penetrating injuries. The most common mechanisms of injury were explosions (62%) and gunshot wounds (20%). Of the 577 patients with complete medical records, 448 patients (78%) presented with palpable pulses, 115 patients (20%) presented with a pulseless limb, and 14 (2%) presented with hard signs of vascular injury. Of those with a pulseless limb and abnormal ankle-brachial index (ABI) or no ABI obtained who underwent further radiologic imaging, 38 patients (77%) had no arterial injury identified. Compared with those with a palpable pulse, patients with a pulseless limb without an arterial injury were more likely to have a higher Injury Severity Score (ISS), lower hematocrit, lower pH, greater base deficit, higher heart rate, more frequent use of tranexamic acid, and received greater volumes of packed red blood cells, plasma, and crystalloids. CONCLUSIONS: Our results demonstrate that a pulseless limb is a poor predictor of arterial injury and should not be considered a hard sign of vascular injury in the combat population. Variables including a high ISS, anemia, acidosis, and need for resuscitation products, each a surrogate for injury severity, may contribute to the decreased accuracy of the physical examination in our troops. This may translate into unnecessary immediate exploration or other interventions in patients who present with more significant injuries from the battlefield. Future studies must continue to focus on improved algorithms for diagnostic accuracy of extremity vascular injuries in this population.

Effect of interfractional shoulder motion on low neck nodal targets for patients treated using volumetric-modulated arc therapy (VMAT).

VMAT is an important tool in the treatment of head and neck cancers, many of which also require treatment to the supraclavicular lymph nodes. However, full VMAT arcs treating this nodal region necessarily cause entrance beam to pass through patients' shoulders. Thus, interfractional variations in shoulder position may cause unwanted dose perturbations. To assess this possibility, six patients undergoing treatment at our institution for head and neck cancers with associated supraclavicular lymph node treatment were imaged with in-room CT-on-rails during the course of their treatments. This allowed for the establishment of a true record of the actual shoulder position during selected treatment fractions. Then, a full VMAT plan and a plan with VMAT arcs superior to the shoulder and a static anteroposterior field inferiorly were copied onto the patients' weekly image sets. The average one-dimensional shoulder motion was generally within 10 mm of the simulated position, with some notable exceptions. The standard deviation in week-to-week shoulder position relative to simulation was 4.3 mm and 4.2 mm in the SI and AP dimensions, respectively. The average nodal target mean dose across all fractions sampled was within 5% of planned for all patients and both plans. Similarly, the average D95 for the nodal target was within 5% of planned across all fractions sampled, with the single exception of the full VMAT plan for one patient. In most cases, the standard deviation in both target mean dose and D95 was smaller with the VMAT+static AP field plan than it was with the full VMAT plan.

Individual differences in frontal cortical thickness correlate with the d-amphetamine-induced striatal dopamine response in humans.

The meso-striatal dopamine system influences responses to rewards and the motivation to seek them out. Marked individual differences in these responses are seen in laboratory animals, related in part to input from the prefrontal cortex. Here we measured the relation between cortical morphology and drug-induced striatal dopamine release in healthy young people. Participants were 24 (17 male, 7 female; age 23.0 ± 6.2 years) stimulant drug-naive subjects who underwent PET [(11)C]raclopride scans with 0.3 mg/kg d-amphetamine orally and placebo, and an anatomical MRI scan for measuring cortical thickness. As expected, d-amphetamine produced significant reductions in [(11)C]raclopride binding potential in the striatum as a percentage of the value in the placebo condition. There was substantial individual variability in this response, which was correlated with cortical thickness in the frontal lobe as a whole. The association was strongest in the anterior part of the right lateral prefrontal cortex and bilateral supplementary motor area. A thicker cortex was correlated with a smaller dopamine response. Together, this work demonstrates in humans an association between cortical thickness and the striatal dopamine response to drugs of abuse. Although prefrontal regulation of striatal function has been well studied, it was unclear whether the thickness of the prefrontal cortex was an acceptable proxy to the function of that region. These results suggest it is.

Differential striatal dopamine responses following oral alcohol in individuals at varying risk for dependence.

BACKGROUND: The neurobiology of risk for alcohol use disorders (AUDs) remains poorly understood. Individual differences in vulnerability, though, have been indicated by subjective responses to alcohol ingestion and personality traits. METHODS: To investigate the relationship between these features and striatal dopamine (DA) responses to alcohol, we studied 26 healthy young social drinkers (21.3 ± 3.0 years old; 10.7 ± 8.8 drinks/wk) at varying risk for alcoholism. Each participant received 2 positron emission tomography [(11) C]raclopride scans after administration of either placebo or oral alcohol (1 ml/kg body weight of 94% alcohol, 0.75 g/kg) in a randomized and counterbalanced design. RESULTS: Subjects with high-risk subjective responses to alcohol had more family members with AUDs, greater alcohol use problems, and, in response to the alcohol challenge, significant decreases in [(11) C]raclopride binding indicative of increased extracellular DA. In contrast, low-risk subjects exhibited increases in [(11) C]raclopride binding in response to alcohol. The results were similar when risk groups were based on personality traits, although statistically less robust. CONCLUSIONS: Changes in striatal DA in response to alcohol ingestion may be a neurobiological marker of vulnerability to AUDs.