Voxel-based morphometric magnetic resonance imaging postprocessing in non-lesional pediatric epilepsy patients using pediatric normal databases.

BACKGROUND AND PURPOSE: Pre-surgical evaluation of pediatric patients with drug-resistant focal epilepsy and negative (non-lesional) magnetic resonance imaging (MRI) is particularly challenging. Focal cortical dysplasia (FCD), a frequent pathological substrate in such setting, may be subtle on MRI and evade detection. The aim of this study was to use voxel-based MRI postprocessing to improve the detection of subtle FCD in pediatric surgical candidates. METHODS: A consecutive cohort of pediatric patients undergoing pre-surgical evaluation with a negative MRI by visual analysis was included. MRI postprocessing was performed using a voxel-based morphometric analysis program (MAP) on T1-weighted volumetric MRI, with comparison to an age-specific normal pediatric database. The pertinence of MAP-positive areas was confirmed by surgical outcome and pathology. RESULTS: A total of 78 patients were included. Forty-four patients (56%) had positive MAP regions. Complete resection of the MAP-positive regions was positively associated with seizure-free outcome compared with the no/partial resection group (P < 0.001). Patients with no/partial resection of the MAP-positive regions had worse seizure outcomes than the MAP-negative group (P = 0.002). The MAP-positive rate was 100%, 77%, 63% and 40% in the 3-5, 5-10, 10-15 and 15-21 year age groups, respectively. MAP-positive rates were 45% in patients with temporal resection and 63% in patients with extratemporal resection. Complete resection of the MAP-positive regions was positively associated with seizure-free outcome in the extratemporal group (P = 0.001) but not in the temporal group (P = 0.070). CONCLUSION: Our data suggest the importance of using MRI postprocessing in the pre-surgical evaluation process of pediatric epilepsy patients with apparently normal MRI.

Correction to: Direct oral anticoagulants for the treatment of venous thromboembolism in patients with active malignancy: a systematic review and meta-analysis.

Unfortunately the author list in the original article is incomplete. The correct list of contributing authors is given in this Correction.

Lanreotide vs octreotide LAR for patients with advanced gastroenteropancreatic neuroendocrine tumors: An observational time and motion analysis.

BACKGROUND: Lanreotide and octreotide acetate suspension for injectable (LAR) are both recommended for clinical use in patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors. However, each agent possesses unique attributes in terms of their drug-delivery characteristics. The study objective was to compare overall drug-delivery efficiency between lanreotide and octreotide LAR in gastroenteropancreatic neuroendocrine tumor patients. METHODS: This study employed an observational time and motion design among patients treated with lanreotide or octreotide LAR across five US cancer centers. Baseline patient data collection included age, disease grade and duration, prior therapies and performance status. Drug-delivery time (drug preparation and administration), total patient time and resource use data were collected for gastroenteropancreatic neuroendocrine tumors receiving lanreotide (n = 22) or octreotide LAR (n = 22). Following each administration, qualitative data on the drug-delivery experience was collected from patients and nurses. RESULTS: Lanreotide was associated with a significant reduction in mean delivery time (2.5 min; 95% CI:2.0 to 3.1) compared to octreotide LAR (6.2 min; 95%CI: 4.4 to 7.9; p = 0.004). The mean total patient time for lanreotide and octreotide LAR was comparable between groups (32.1 vs. 36.6 minutes; p = 0.97). Nurses reported increased concerns with octreotide LAR related to needle clogging (p = 0.034) and device failures (p = 0.057). Overall, lanreotide had a median satisfaction score of 5.0 compared to a score of 4.0 with octreotide LAR (p = 0.03). CONCLUSIONS: Lanreotide was associated with significant reductions in drug-delivery time compared to octreotide LAR, which contributed to an improvement in overall healthcare efficiency. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03017690.

Microstructurally-based constitutive modelling of the skin - Linking intrinsic ageing to microstructural parameters.

A multiphasic constitutive model of the skin that implicitly accounts for the process of intrinsic (i.e. chronological) ageing via variation of the constitutive parameters is proposed. The structurally-motivated constitutive formulation features distinct mechanical contributions from collagen and elastin fibres. The central hypothesis underpinning this study is that the effects of ageing on the mechanical properties of the tissue are directly linked to alterations in the microstructural characteristics of the collagen and elastin networks. Constitutive parameters in the model, corresponding to different ages, are identified from published experimental data on bulge tests of human skin. The numerical results demonstrate that degradation of the elastin meshwork and variations in anisotropy of the collagen network are plausible mechanisms to explain ageing in terms of macroscopic tissue stiffening. Whereas alterations in elastin affect the low-modulus region of the skin stress-strain curve, those related to collagen have an impact on the linear region.

Key Matrix Proteins Within the Pancreatic Islet Basement Membrane Are Differentially Digested During Human Islet Isolation.

Clinical islet transplantation achieves insulin independence in selected patients, yet current methods for extracting islets from their surrounding pancreatic matrix are suboptimal. The islet basement membrane (BM) influences islet function and survival and is a critical marker of islet integrity following rodent islet isolation. No studies have investigated the impact of islet isolation on BM integrity in human islets, which have a unique duplex structure. To address this, samples were taken from 27 clinical human islet isolations (donor age 41-59, BMI 26-38, cold ischemic time < 10 h). Collagen IV, pan-laminin, perlecan and laminin-α5 in the islet BM were significantly digested by enzyme treatment. In isolated islets, laminin-α5 (found in both layers of the duplex BM) and perlecan were lost entirely, with no restoration evident during culture. Collagen IV and pan-laminin were present in the disorganized BM of isolated islets, yet a significant reduction in pan-laminin was seen during the initial 24 h culture period. Islet cytotoxicity increased during culture. Therefore, the human islet BM is substantially disrupted during the islet isolation procedure. Islet function and survival may be compromised as a consequence of an incomplete islet BM, which has implications for islet survival and transplanted graft longevity.

Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly.

Post-translational protein modifications exponentially expand the functional complement of proteins encoded by the human genome. One such modification is the covalent addition of a methyl group to arginine or lysine residues, which is used to regulate a substantial proportion of the proteome. Arginine and lysine methylation are catalyzed by protein arginine methyltransferase (PRMTs) and protein lysine methyltransferase proteins (PKMTs), respectively; each methyltransferase has a specific set of target substrates. Here, we report a male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism and seizures who was found to have a homozygous 15,309 bp deletion encompassing the transcription start site of PRMT7, which we confirmed is functionally a null allele. We show that the patient's cells have decreased levels of protein arginine methylation, and that affected proteins include the essential histones, H2B and H4. Finally, we demonstrate that patient cells have altered Wnt signaling, which may have contributed to the skeletal abnormalities. Our findings confirm the recent disease association of PRMT7, expand the phenotypic manifestations of this disorder and provide insight into the molecular pathogenesis of this new condition.

Retrospective review of intravenous pentamidine for Pneumocystis pneumonia prophylaxis in allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at risk of numerous opportunistic infections. Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening infection that can develop in immunocompromised individuals. Current prophylaxis for PJP includes trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, atovaquone, or inhaled pentamidine (PEN), often with varying breakthrough rates. The use of intravenous (IV) PEN for PJP prophylaxis has been evaluated in pediatric patients. METHODS: A single-institution retrospective review of electronic medical records was conducted for patients who underwent allo-HSCT between January 2001 and May 2013 and who had received at least 1 dose of IV PEN for PJP prophylaxis. Data collected included patient demographics, diagnosis, previous chemotherapy, pre-transplant conditioning regimen, other medications, microbiology test results, and clinical outcomes. RESULTS: A total of 113 patients were included in the study. The median number of PEN doses administered per patient was 3 (range 1-23). IV PEN was primary PJP prophylaxis in 74 of the patients (65%) and second-line prophylaxis in 39 (35%) post transplant, with the majority switching from oral TMP-SMX. Side effects of IV PEN administration were minimal. No patients who received IV PEN prophylaxis developed PJP infection. No case of PJP was seen in patients who received other agents for PJP prophylaxis. CONCLUSION: This retrospective study showed that IV PEN is very effective and well-tolerated prophylaxis for PJP; IV PEN can be considered a favorable alternative for PJP in situations where other agents might be contraindicated. Our findings provide strong support for prospective studies of IV PEN for PJP prophylaxis in adult HSCT recipients.

Thermoelastic modelling of the skin at finite deformations.

The modelling and computation of the coupled thermal and mechanical response of human skin at finite deformations is considered. The model extends current thermal models to account for thermally- and mechanically-induced deformations. Details of the solution of the highly nonlinear system of governing equations using the finite element method are presented. A representative numerical example illustrates the importance of considering the coupled response for the problem of a rigid, hot indenter in contact with the skin.

Economic evaluation for the UK of nab-paclitaxel plus gemcitabine in the treatment of metastatic pancreas cancer.

BACKGROUND: The combination of nab-paclitaxel plus gemcitabine (NAB-P+GEM) has shown superior efficacy over GEM monotherapy in metastatic pancreas cancer (MPC). Independent cost-effectiveness/utility analyses of NAB-P+GEM from the payer perspective have not been conducted for the UK. METHODS: A Markov model simulating the health outcomes and total costs was developed to estimate the life years gained (LYG) and quality-adjusted life years gained (QALY) and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) for patients with MPC in a base case and in a probabilistic (PSA) sensitivity analysis. Total cost included the cost of supportive care medications, administration, chemotherapy, disease monitoring, and adverse reactions; and was discounted at 3.5% per year. A full lifetime horizon and third party payer perspective was chosen. RESULTS: The total cost of NAB-P+GEM was £5466 higher than the cost for GEM. Respectively, LYGs were 0.97 vs 0.79 and QALYs were 0.52 vs 0.45, with ICER of £30 367/LYG and ICUR of £78 086/QALY, confirmed by PSA. CONCLUSIONS: The superior survival efficacy of NAB-P+GEM over GEM in the management of MPC is associated with positive cost-effectiveness and cost-utility.

A family history of knee joint replacement increases the progression of knee radiographic osteoarthritis and medial tibial cartilage volume loss over 10 years.

OBJECTIVES: Osteoarthritis (OA) has a genetic component but it is uncertain if the offspring of those with knee OA are at a greater risk. The aim of this study was to describe radiographic OA (ROA) progression and cartilage loss over 10 years in a midlife cohort with some having a family history of OA and some community based controls. METHODS: 220 participants [mean-age 45 (26-61); 57% female] were studied at baseline and 10 years. Half were adult offspring of subjects who underwent knee replacement for OA and the remainder were randomly selected controls. Joint space narrowing (JSN) and osteophytes were assessed on radiographs and cartilage volume (tibial, femoral and patellar), cartilage defects, bone marrow lesions (BMLs) and meniscal tears were assessed on Magnetic resonance imaging (MRI). RESULTS: For ROA, there was a significant difference between offspring and controls in unadjusted analysis for change in total ROA, medial JSN, total medial, total lateral and total osteophyte scores. This difference persisted for medial JSN (difference in ratios = +1.93 (+1.04, +3.51)) only, after adjustment for confounders and baseline differences. In unadjusted analysis for cartilage loss, offspring lost more cartilage at the medial tibial (difference in means = -79.13 (-161.92, +3.71)) site only. This difference became of borderline significance after adjustment for baseline differences (P = 0.055). CONCLUSION: The offspring of subjects having a total knee replacement have a greater worsening of ROA (both JSN and osteophytes) and higher medial tibial cartilage volume loss over 10 years. Most of these changes are mediated by differences in baseline characteristics of offspring and controls except for increase in medial JSN.

Expression of apoptotic genes in immature and in vitro matured equine oocytes and cumulus cells.

The gene expression of Bax, Bcl-2, survivin and p53, following in vitro maturation of equine oocytes, was compared in morphologically distinct oocytes and cumulus cells. Cumulus-oocyte complexes (COC) were harvested and divided into two groups: G1 - morphologically healthy cells; and G2 - less viable cells or cells with some degree of atresia. Total RNA was isolated from both immature and in vitro matured COC and real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to quantify gene expression. Our results showed there was significantly higher expression of survivin (P < 0.05) and lower expression of p53 (P < 0.01) in oocytes compared with cumulus cells in G1. No significant difference in gene expression was observed following in vitro maturation or in COC derived from G1 and G2. However, expression of the Bax gene was significantly higher in cumulus cells from G1 (P < 0.02).

Exploring Social Determinants of Health in Healthy Aging Among Older Adults: A Qualitative Study.

BACKGROUND: The U.S. population is aging and diversifying. Older Black Americans comprise the largest racial minority group and experience greater disability than White Americans. OBJECTIVES: Within a long-standing, community-based research partnership, we explored the determinants of healthy aging in Flint Michigan, a low-income, predominantly Black American community recovering from a water crisis. METHODS: Focus groups were conducted among older adults residing in Flint, Michigan. A grounded theory approach and constant comparison method was utilized for data analysis. RESULTS: Five focus groups were conducted with 49 total participants. We identified four themes that impacted healthy aging: economic instability, health care access and quality, neighborhood and built environment, and social and community context. Economic instability heavily influenced the other themes. CONCLUSIONS: Economic instability is a barrier to healthy aging. As a result, we are testing an innovative cross-sector partnership combining older adult affordable housing and health care.

The multifunctional histone-like protein Lsr2 protects mycobacteria against reactive oxygen intermediates.

Mycobacterium tuberculosis has evolved a number of strategies to survive within the hostile environment of host phagocytes. Reactive nitrogen and oxygen intermediates (RNI and ROI) are among the most effective antimycobacterial molecules generated by the host during infection. Lsr2 is a M. tuberculosis protein with histone-like features, including the ability to regulate a variety of transcriptional responses in mycobacteria. Here we demonstrate that Lsr2 protects mycobacteria against ROI in vitro and during macrophage infection. Furthermore, using macrophages derived from NOS(-/-) and Phox(-/-) mice, we demonstrate that Lsr2 is important in protecting against ROI but not RNI. The protection provided by Lsr2 protein is not the result of its ability to either bind iron or scavenge hydroxyl radicals. Instead, electron microscopy and DNA-binding studies suggest that Lsr2 shields DNA from reactive intermediates by binding bacterial DNA and physically protecting it. Thus, Lsr2 appears to be a unique protein with both histone-like properties and protective features that may be central to M. tuberculosis pathogenesis. In addition, evidence indicates that lsr2 is an essential gene in M. tuberculosis. Because of its essentiality, Lsr2 may represent an excellent candidate as a drug target.

Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene.

The tissue amyloid deposits that characterize systemic amyloidosis, Alzheimer's disease and the transmissible spongiform encephalopathies always contain serum amyloid P component (SAP) bound to the amyloid fibrils. We have previously proposed that this normal plasma protein may contribute to amyloidogenesis by stabilizing the deposits. Here we show that the induction of reactive amyloidosis is retarded in mice with targeted deletion of the SAP gene. This first demonstration of the participation of SAP in pathogenesis of amyloidosis in vivo confirms that inhibition of SAP binding to amyloid fibrils is an attractive therapeutic target in a range of serious human diseases.

A step toward understanding the mechanism of action of audit and feedback: a qualitative study of implementation strategies.

BACKGROUND: Audit and feedback (A&F) is a widely used implementation strategy. Understanding mechanisms of action of A&F increases the likelihood that the strategy will lead to implementation of an evidence-based practice. We therefore sought to understand one hospital's experience selecting and implementing an A&F intervention, to determine the implementation strategies that were used by staff and to specify the mechanism of action of those implementation strategies using causal pathway models, with the ultimate goal of improving acute stroke treatment practices. METHODS: We selected an A&F strategy in a hospital, initially based on implementation determinants and staff consideration of their performance on acute stroke treatment measures. After 7 months of A&F, we conducted semi-structured interviews of hospital providers and administrative staff to understand how it contributed to implementing guideline-concordant acute stroke treatment (medication named tissue plasminogen activator). We coded the interviews to identify the implementation strategies that staff used following A&F and to assess their mechanisms of action. RESULTS: We identified five implementation strategies that staff used following the feedback intervention. These included (1) creating folders containing the acute stroke treatment protocol for the emergency department, (2) educating providers about the protocol for acute stroke, (3) obtaining computed tomography imaging of stroke patients immediately upon emergency department arrival, (4) increasing access to acute stroke medical treatment in the emergency department, and (5) providing additional staff support for implementation of the protocol in the emergency department. We identified enablement, training, and environmental restructuring as mechanisms of action through which the implementation strategies acted to improve guideline-concordant and timely acute stroke treatment. CONCLUSIONS: A&F of a hospital's acute stroke treatment practices generated additional implementation strategies that acted through various mechanisms of action. Future studies should focus on how initial implementation strategies can be amplified through internal mechanisms.

Development, Adaptation and Scale-up of a Community-wide, Health Behavior Theory-based Stroke Preparedness Intervention.

Objective: Acute stroke treatments reduce the likelihood of post-stroke disability, but are vastly underutilized. In this paper, we describe the development, adaptation, and scale-up of the Stroke Ready program - a health behavior theory-based stroke preparedness intervention that addresses underlying behavioral factors that contribute to acute stroke treatment underutilization. Methods: Through a community-based participatory research (CBPR) approach, we conducted needs and determinant assessments, which informed creation and pilot testing of Stroke Ready. Based on these results, we then scaled Stroke Ready to the entire community by greatly expanding the delivery system. Results: The scaled Stroke Ready program is a community-wide stroke preparedness education program consisting of peer-led workshops, print materials, and digital, social, and broadcast media campaigns. Whereas the Stroke Ready pilot workshop was delivered to 101 participants, 5945 participants have received the scaled Stroke Ready peer-led workshop to date. Additionally, we have sent mailers to over 44,000 households and reached approximately 35,000 people through our social media campaign. Conclusion: Strategies including an expanded community advisory board, adaptation of the intervention and community-engaged recruitment facilitated the scale-up of Stroke Ready, which may serve as a model to increase acute stroke treatment rates, particularly in majority African-American communities.

CR1/2 is an important suppressor of Adenovirus-induced innate immune responses and is required for induction of neutralizing antibodies.

Human complement receptors 1 and 2 are well described as important regulators of innate and adaptive immune responses, having pivotal roles in regulating complement activation (CR1) and B-cell maturation/survival. In contrast, the role of the murine homologs of CR1 and CR2 (mCR1/2) have been primarily defined as modulating activation of the adaptive immune system, with very little evidence available about the role of mCR1/2 in regulating the innate immune responses to pathogens. In this paper, we confirm that mCR1/2 plays an important role in regulating both the innate and adaptive immune responses noted after Adenovirus (Ad)-mediated gene transfer. Our results uncovered a novel role of mCR1/2 in downregulating several complement-dependent innate immune responses. We also unveiled the mechanism underlying the complement-dependent induction of neutralizing antibodies to Ad capsids as a CR1/2-dependent phenomenon that correlates with B-cell activation. These results confirm that Ad interactions with the complement system are pivotal in understanding how to maximize the safety or potency of Ad-mediated gene transfer for both gene therapy and vaccine applications.

Severity and Outcome Assessment score: a useful tool for auditing orthognathic surgery.

Many indices and scoring systems exist for assessing skeletal patterns and malocclusion but none have been universally adopted by teams providing orthognathic surgery in the UK. Using a standardised objective measure of a patient's condition is important both for service provision, treatment allocation, and other clinical governance domains. The Severity and Outcome Assessment tool (SOA) developed by the British Orthodontic Society (BOS) and British Association of Oral and Maxillofacial Surgeons (BAOMS) provides a standardised method of assessing patients throughout the orthognathic pathway and lends itself to case selection, resource allocation and auditing treatment outcomes. The SOA uses 7 cephalometric skeletal, dental and soft tissue measures to produce an overall score.The SOA has been used by the current NHS Tayside orthognathic team since August 2006 to audit treatment outcomes. While we recognise that cephalometric analysis forms only one part of orthognathic treatment we believe that having an objective measure on which to assess treatment is useful. We present our experience of using this quick, simple and reproducible tool in auditing orthognathic treatment outcomes.