New Payment Models: What’s driving them, and what do they mean for what it takes to be a good doctor?

Learning Objectives: Describe details of new non-fee for service payment models, including Bundled Payment, Accountable Care Organizations and Advanced Primary Care Explain administrative structures required to implement these kinds of models Articulate the new values-congruent roles physicians will play under new payment models and the skills they will need to play them. PowerPoint slides only

Development and Validation of a Novel Decision Aid for WALANT Hand Surgeries: Investigating Patient Preferences

INTRODUCTION: This study aims to develop a novel decision aid packet (DAP) for hand surgery patients deciding between Wide-Awake-Local-Anesthesia-No-Tourniquet (WALANT) and traditional anesthesia. METHODS: Development: The DAP was developed following International Patient Decision Aid Standards. Validation: Alpha Testing Seven hand surgeons experienced in WALANT and traditional surgeries belonging to the WALANT Research Consortium in the U.S. commented on the DAP through three rounds of editing utilizing the Delphi method. Seven patient advocates provided readability feedback. Beta Testing Orthopedic hand surgery patients were assigned to the control or experimental group. The experimental group was given the DAP pre-surgery. Both groups completed a validated regret scale at follow-up. A paired t-test was conducted to analyze the difference between average scores on the regret scale and pre- and post-DAP knowledge tests (p RESULTS: The experimental group (n=58) demonstrated a 145% increase (p DISCUSSION: Increased knowledge test scores following the DAP suggest that patients are better informed after DAP usage. Low decisional conflict scores suggest that the DAP increases patients’ confidence. Lower average regret scale scores among the experimental group indicate a relationship between DAP administration and reduced post-surgical regret. The greater patient preference for WALANT following DAP usage, alongside the lower postoperative regret, elucidates a general preference in informed patients towards the WALANT modality

Impaired Competence for Pretense in Children with Autism: Exploring Potential Cognitive Predictors.

Lack of pretense in children with autism has been explained by a number of theoretical explanations, including impaired mentalising, impaired response inhibition, and weak central coherence. This study aimed to empirically test each of these theories. Children with autism (n=60) were significantly impaired relative to controls (n=65) when interpreting pretense, thereby supporting a competence deficit hypothesis. They also showed impaired mentalising and response inhibition, but superior local processing indicating weak central coherence. Regression analyses revealed that mentalising significantly and independently predicted pretense. The results are interpreted as supporting the impaired mentalising theory and evidence against competing theories invoking impaired response inhibition or a local processing bias. The results of this study have important implications for treatment and intervention

Developmental white matter microstructure in autism phenotype and corresponding endophenotype during adolescence.

During adolescence, white matter microstructure undergoes an important stage of development. It is hypothesized that the alterations of brain connectivity that have a key role in autism spectrum conditions (ASCs) may interact with the development of white matter microstructure. This interaction may be present beyond the phenotype of autism in siblings of individuals with ASC, who are 10 to 20 times more likely to develop certain forms of ASC. We use diffusion tensor imaging to examine how white matter microstructure measurements correlate with age in typically developing individuals, and how this correlation differs in n=43 adolescents with ASC and their n=38 siblings. Correlations observed in n=40 typically developing individuals match developmental changes noted in previous longitudinal studies. In comparison, individuals with ASC display weaker negative correlation between age and mean diffusivity in a broad area centred in the right superior longitudinal fasciculus. These differences may be caused either by increased heterogeneity in ASC or by temporal alterations in the group's developmental pattern. Siblings of individuals with ASC also show diminished negative correlation between age and one component of mean diffusivity-second diffusion eigenvalue-in the right superior longitudinal fasciculus. As the observed differences match for location and correlation directionality in our comparison of typically developing individuals to those with ASC and their siblings, we propose that these alterations constitute a part of the endophenotype of autism.This research was funded by an MRC Clinician Scientist Fellowship to MDS from the UK Medical Research Council (G0701919). LRC was supported by the Gates Cambridge Scholarship Trust. SB-C was supported by the Wellcome Trust, the MRC and the Autism Research Trust, during the period of this work.This is the final published version. It first appeared at http://www.nature.com/tp/journal/v5/n3/full/tp201523a.html

Whole-brain functional hypoconnectivity as an endophenotype of autism in adolescents.

Endophenotypes are heritable and quantifiable markers that may assist in the identification of the complex genetic underpinnings of psychiatric conditions. Here we examined global hypoconnectivity as an endophenotype of autism spectrum conditions (ASCs). We studied well-matched groups of adolescent males with autism, genetically-related siblings of individuals with autism, and typically-developing control participants. We parcellated the brain into 258 regions and used complex-network analysis to detect a robust hypoconnectivity endophenotype in our participant group. We observed that whole-brain functional connectivity was highest in controls, intermediate in siblings, and lowest in ASC, in task and rest conditions. We identified additional, local endophenotype effects in specific networks including the visual processing and default mode networks. Our analyses are the first to show that whole-brain functional hypoconnectivity is an endophenotype of autism in adolescence, and may thus underlie the heritable similarities seen in adolescents with ASC and their relatives.The authors wish to thank the participants and their families for their participation and the autism support organisations who assisted with recruitment. We thank colleagues at the Brain Mapping Unit for methodological discussions and thank Meng-Chuan Lai, Amber Ruigrok and Richard Bethlehem for the same. Data collection was funded by a Clinical Scientist Fellowship from the UK Medical Research Council (MRC) (G0701919) to MDS. LRC was supported by the Gates Cambridge Scholarship Trust. The study was conducted in associated with the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for Cambridgeshire, and Peterborough National Health Service (NHS) Foundation Trust. The present analysis was funded by a NARSAD Young Investigator award (to MR) and by the Isaac Newton Trust (to MR); RJFY is additionally supported by a Rubicon Fellowship from the Netherlands Organisation for Scientific Research. The Brain Mapping Unit (MR, RLM, RJFY, JS and ETB) is part of the Behavioural & Clinical Neuroscience Institute, which is funded by the MRC and the Wellcome Trust. High performance computing facilities were supported by the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.nicl.2015.07.01

Evaluation of the Workplace Environment in the UK, and the Impact on Users’ Levels of Stimulation

The purpose of this study is to evaluate a number of recently completed workplaces in the UK. The first aim is to assess the impact of various aspects of the workplace environment on users’ levels of stimulation. The body of previous research undertaken into the workplace environment, identified the aspects to be investigated. Samples of employees from the sixteen businesses were surveyed to determine their perceptions of the workplaces. The results were entered into a regression analysis, and the most significant predictors of perceived stimulation identified. The data also revealed a dramatic reduction in staff arousal levels from mornings to afternoons. Thus, there is a second aim to determine whether changes to significant aspects of the workplace environment during the day can counteract the reduction in users’ stimulation. Two further workplaces were studied to enable changes to be made over a 12-week period. A sample of employees completed questionnaires, and semi-structured interviews revealed the reasons behind the results. It was found that provision of artwork, personal control of temperature and ventilation and regular breaks were the most significant contributions to increasing stimulation after lunch; while user choice of layout, and design and décor of workspaces and break areas, were the most significant aspects at design stage

Recommendations for the appropriate use of anti-inflammatory drugs in the era of the coxibs: Defining the role of gastroprotective agents

Treatment with anti-inflammatory drugs and the analgesic efficacy of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are compromised by a two-to fourfold increased risk of gastrointestinal complications. This increased risk has resulted in an increasing use of the new selective cyclooxygenase-2 inhibitors or coxibs, which, in clinical trials and outcomes studies, reduced gastrointestinal adverse events by 50% to 65% compared with conventional NSAIDs. However, the coxibs are not available to all patients who need them, and NSAIDs are still widely used. Moreover, treatment with a coxib cannot heal preexisting gastrointestinal lesions, and cotherapy with an antisecretory drug or mucosal protective agent may be required. This paper addresses the management of patients with risk factors for gastrointestinal complications who are taking NSAIDs and makes recommendations for the appropriate use of 'gastroproteccontinued on next pag

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

Immune Response and Mitochondrial Metabolism Are Commonly Deregulated in DMD and Aging Skeletal Muscle

Duchenne Muscular Dystrophy (DMD) is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed), of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1) or the mitochondrial metabolism (ESRRA). Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors

2002; 01

DLI is feasible with rapid engraftment and minimizes the risk of severe GVHD. Large prospective trials are required to prove that it preserves the GVL effect fully. ©2002, Ferrata Storti Foundation Key words: allogeneic transplantation, GVHD, GVL, CD34 selection, donor lymphocyte infusions. plication of DLI is GVHD, which is often associated with response to DLI. © F e r r a t a S t o r t i F o u n d a t i o n Design and Methods Patients and donors Twenty-four patients with hematologic malignancies, 18 males and 6 females, aged 14 to 56 years (median 46 years) were included. Their clinical characteristics are summarized in © F e r r a t a S t o r t i F o u n d a t i o n obtained from patients and donors and our institution's Ethical Committee approved the protocol. Clinical management The conditioning regimen depended on the clinical diagnosis. The following regimens were used: 1) Ara-C (12 g/m 2 ), cyclophosphamide (120 mg/m 2 ) and single dose total body irradiation-TBI (8 Gy) (AML and MDS patients); 2) Ara-C (18 g/m 2 ), melphalan (140 mg/m 2 ) and fractionated TBI (12 Gy) (ALL patients); 3) busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (CML and 2 nd transplant patients); 4) cyclophosphamide (120 mg/kg) and fractionated TBI (12 Gy) (NHL and CLL patients). All patients were treated with 5 µg/kg/d lenograstim (Granocyte®) from day +1 until the granulocyte count was > 10 9 /L for three consecutive days or > 10 10 /L for one day. Six early patients (4 not HLA-identical to their donor and 2 AML in CR1) received a short course of methotrexate in addition to cyclosporine (CyA). Because of the low incidence of acute GVHD observed in the first 9 patients, GVHD prophylaxis was carried out with CyA alone for patients 10 to 24. The diagnosis and grading of acute and chronic GVHD was established as previously reported. Stem cell mobilization, collection and selection Donors received human granulocyte colonystimulating factor (G-CSF) (Granocyte®, kindly provided by Rhône-Poulenc-Rorer, Brussels, Belgium) at a dose of 10-15 µg/kg from day -5 through day -1 before transplant. Collection of PBSC was carried out on days -1 and 0, using a continuous flow blood cell separator (CS3000+, Baxter-Fenwall Laboratories, Deerfield, IL, or Cobe Spectra, Lakewood, CO, USA). The volume of blood processed was 12-16 liters. The PBSC from the first day of harvest were stored overnight in the patient's own plasma. Immediately after the second harvest, PBSC from the first and the second days of harvest were pooled. CD34 + cell selection was carried out using the Isolex 300i® magnetic cell separator (Nexell International, Wemmel, Belgium), according to the manufacturer's recommendations. Donor lymphocyte infusions Around day 60 post-transplantation, donors underwent 12-16 liter leukophereses on 2 consecutive days to collect lymphocytes. The collection from the first day of harvest was stored overnight in the patient's own plasma and pooled with the second harvest before processing by CD8 + selection using the Nexell Isolex 300i®. The CD8-negative fraction was recovered and divided into 3 aliquots containing 2×10 6 , 1×10 7 and 5×10 7 CD3 + cells/kg recipient for patients from #1 to #13. The 2 nd and 3 rd aliquots were cryopreserved in 10% DMSO in a controlled-rate freezer. After an interim analysis showed little acute or chronic GVHD associated with DLI, the schedule of DLI was changed to 2 aliquots of 1×10 7 and 5×10 7 CD3 + cells/kg recipient for patients 14 to 21. Aliquot 1 was injected fresh immediately after the CD8 depletion procedure (around day 60). Around day 100 (and 140 for patients 1 to 13), aliquot 2 (and 3) were thawed and infused into the patient. CD8-depleted DLI were not to be infused in case of an antecedent grade III or IV acute GVHD, or an antecedent extensive chronic GVHD, or active GVHD at the time of the scheduled infusion. Laboratory analyses Aliquots of the pooled PBSC as well as the CD34 + selected fraction were incubated with phycoerythrin-conjugated anti-CD34 monoclonal antibody (HPCA2; Becton-Dickinson, Palo-Alto, CA, USA) for 20 minutes at 20°C, washed and fixed. A total of 1×10 5 cells was analyzed using a FACS-scan analyzer (Becton-Dickinson). The percentage of CD34 + cells was defined with dot plot analysis using the whole nucleated cell population. The percentage of positive cells in the isotype control was subtracted from the CD34 + percentage to give the final percentage of CD34 + cells. Data acquisition was performed with the Cellquest software (BectonDickinson). Donor lymphocytes (before and after CD8 depletion) were similarly examined using double labeling with FITC-and PE-conjugated antibodies after treatment with a lysing solution. Complete blood counts were determined using a Technicon H2 cell counter (Bayer Diagnostics, Diegem, Belgium). Percentages of reticulocytes were obtained by an automated cytofluorometric method using the thiazole orange analog DEQTC. Statistical analyses Student's t-tests were used to compare cell subsets before and after CD8 depletion. The probability of GVHD, relapse, and survival as well as the speed of engraftment were studied by life-table analyses and Wilcoxon rank tests were used for comparisons between groups. Statistical analyses were carried out with Graphpad Prism (Graphpad Software, San Diego, CA, USA). Results Collection of PBSC, CD34 selection and engraftment kinetics PBSC were collected by leukophereses on two consecutive days, except in one 70-year old donor (patient #6) who had to undergo 4 consecutive leukophereses (and two CD34 selection procedures) because of poor yields. Most donors experienced bone pain and/or cephalalgia that were easily controlled with paracetamol, but no other complication was noted. A median of 10.15 (5.59 to 21.02) ×10 6 CD34 + cells/kg and 375 (127 to 656)×10 6 CD3 + cells/kg were collected CD8-depleted DLI after CD34-selected allo-PBSCT © F e r r a t a S t o r t i F o u n d a t i o n Collection of donor lymphocytes, CD8 depletion and CD8-depleted DLI Donor lymphocytes were collected on day 60 from all but 5 donors whose recipients died before or experienced serious complications Clinical data (Figure 1 and Table 4) Five patients died before receiving DLI. Patients #6 (second transplant) and #4 developed many early serious complications and died on day 81 of influenza pneumonia and on day 99 of a polymicrobial infection, respectively. Patient #19 developed severe renal and respiratory failure and died of infection at day 195. Patient #16 died of CLL and veno-occlusive disease of the liver on day 44 and patient #17 died of leukemia on day 38. The other 19 patients were in CR on day 60 and received the first DLI. Two ALL patients (patients #7 and 10) relapsed between days 60 and 100 and received the pooled 2 nd and 3 rd aliquots. Patient #7 achieved a CR with chemotherapy and DLI but relapsed later and died on day 313. Patient #10 died of leukemia on day 100. In addition, patient #12 died suddenly at home of unknown reason while enjoying continuous CR and presenting no complication other than depression. The other 16 received the scheduled 2 nd (and the 3 rd for patients #1, 2, 3, 5, 8, 9, 10, 13) DLI on days 100 (and 140). Fourteen of the 16 patients remain in CR 126 to 1344 (median 400) days post-transplantation. Patient #15 developed a central nervous system relapse on day 135, was reinduced into remission with chemotherapy and radiotherapy but relapsed again and died on day 309. Patient #3 experienced a biopsyproven massive relapse in the thymus on day 315 that completely regressed after cyclosporine discontinuation, but later relapsed again and she died on day 950. Finally, 3 patients died in CR after day 100: patient #13 died of pulmonary aspergillosis on day 351, patient #18 died suddenly at home of unknown reason on day 288 and patient #21 of acute grade IV GVHD on day 150. The remaining 11 patients were alive and disease-free 126 to 1344 (median 550) days after transplantation. Bone marrow chimerism Evaluation of bone marrow chimerism was performed in 6/7 patients with a donor of the opposite sex (n=7) by FISH with X and Y probes ( Acute and chronic GVHD (Figure 3) Acute GVHD occurred in 15 patients. It was of grade I in 9 patients, of grade II in 5 patients (3 with 1 HLA mismatch) and of grade IV in 1 patient (HLA mismatch). Thus, grade II-IV acute GVHD occurred more frequently in HLA-mismatched (4/8 or 50%) than HLA-matched (2/16 or 13%) transplants (p<0.05). Before DLI, the 60-day actuarial incidence of grade II-IV GVHD was 17% (4 patients) but 2 additional patients developed grade II and IV GVHD after DLI to produce a 150-day (after DLI) incidence of 28%. For HLA-identical sibling transplants, the 60-and 150-day actuarial incidences of grade II-IV acute GVHD were 0 and 13%, respectively ( CMV reactivation Eleven of the 24 patients experienced CMV reactivation (PCR positivity) before day 60 that was successfully reversed by ganciclovir treatment and none of them presented a clinical CMV infection. Relapse and survival (Figure 4) There was no relapse in the 12 standard risk patients but 6 of the high-risk patients relapsed (p<0.005) ( Discussion In agreement with previous studies, 17,19,21 CD34-selection resulted in our study in a 3.3 log elimination of T-cells while preserving hematologic reconstitution. Engraftment of neutrophils and platelets was prompt and significantly faster in patients who did not receive methotrexate. However, within the range studied, the number of © F e r r a t a S t o r t i F o u n d a t i o n CD34 + cells did not influence the speed of engraftment significantly. Prompt engraftment occurred with CD34 + cell doses as low as 1.46×10 6 /kg. Therefore, CD34 -selection preserved the engraftment capability of allogeneic PBSC. As previously suggested by others, 17,22 our results evidenced that CD34 selection reduces the risk of acute GVHD. The actuarial 60-day (before DLI) probability of grade II-IV acute GVHD was 17% in our study. This rate compares very favorably with results from studies of HLA-identical siblings receiving unmanipulated PBSC or BM. Moreover, our results also compared favorably with those of previous studies of pre-emptive DLI after T-cell-depleted BMT or PBSC transplantation. A few other studies have investigated the feasibility of adding T-cells back, also to heterogeneous groups of patients, a few weeks to a few months after T-cell-depleted (TCD) transplantation. Barrett gave either 2×10 6 /kg on day 30 and 5×10 7 /kg on day 45 or 1×10 7 /kg on day 30 to HLA-identical siblings after TCD BMT. Contributions and Acknowledgments YB designed the study and wrote the paper. FB analyzed the data and wrote the paper. JS © F e r r a t a S t o r t i F o u n d a t i o n PEER REVIEW OUTCOMES What is already known on this topic Transplantation of CD34 + selected cells from peripheral blood of allogeneic donors associates with a lower risk of acute and chronic graft-versus-host disease than unmanipulated transplants. Relapse risk may be increased in this setting, as a consequence of T-cell depletion, which leads to a decreased graft-versusleukemia effect. What this study adds CD8-depleted lymphocyte infusions starting on day 60 may be safely administered without triggering acute or chronic graft-versus-host disease. The relapse rate after this approach was similar to that observed in a control group of non-T-cell depleted transplants. Manuscript processing Potential implications for clinical practice This report demonstrates the feasibility of allogeneic CD34 + selected stem cell transplantation followed by the infusion of engineered cell-depleted fractions. Jordi Sierra Gil, Deputy Editor © F e r r a t a S t o r t i F o u n d a t i o