Evaluation of a Multidisciplinary Integrated Treatment Approach Versus Standard Model of Care for Functional Gastrointestinal Disorders (FGIDS): A Matched Cohort Study.

BACKGROUND: Functional gastrointestinal disorders (FGID) are linked to a variety of potential causes, and treatments include reassurance, life-style (including diet), psychological, or pharmacologic interventions. AIMS: To assess whether a multidisciplinary integrated treatment approach delivered in a dedicated integrated care clinic (ICC) was superior to the standard model of care in relation to the gastrointestinal symptom burden. METHODS: A matched cohort of 52 consecutive patients with severe manifestation of FGID were matched with 104 control patients based upon diagnosis, gender, age, and symptom severity. Patients in the ICC received structured assessment and 12-weeks integrated treatment sessions provided as required by gastroenterologist and allied health team. Control patients received standard medical care at the same tertiary center with access to allied health services as required but no standardized interprofessional team approach. Primary outcome was reduction in gastrointestinal symptom burden as measured by the Structured Assessment of Gastrointestinal Symptoms Scale (SAGIS). Secondary outcome was reduction in anxiety and depressive symptoms as measured by the Hospital Anxiety and Depression Scale (HADS). RESULTS: Mixed models estimated the within ICC change in SAGIS total as -9.7 (95% CI -13.6, -5.8; p < 0.0001), compared with -1.7 (95% CI -4.0, 0.6; p = 0.15) for controls. The difference between groups reached statistical significance, -7.6 (95% CI -11.4, -3.8; p < 0.0001). Total HADS scores in ICC patients were 3.4 points lower post-intervention and reached statistical significance (p = 0.001). CONCLUSION: This matched cohort study demonstrates superior short-term outcomes of FGID patients in a structured multidisciplinary care setting as compared to standard care.

Late first acute rejection in pediatric kidney transplantation: A North American Pediatric Renal Trials and Collaborative Studies special study.

Rates of early AR in pediatric kidney transplantation have declined in every era but the most recent NAPRTCS cohort has shown an increase in late first AR rates. We hypothesized this was due to an increased proportion of deceased donor utilization and early steroid taper utilization. Using the NAPRTCS database, we compared the most recent three cohorts of patients transplanted between 2002-2006, 2007-2011, and 2012-2017. To determine variables that predict late first AR, we used two multivariable models: a standard Cox regression model and LASSO model. From the LASSO model, deceased donor source (P = .002), higher recipient age (P = .019), black race (P = .010), and transplant cohort 2012-17 (P = .014) were all significant predictors of more late first AR. On standard Cox regression analysis, those same variables, minus donor source, were significant, in addition to mycophenolates usage (P = .007) and lower eGFR at 12 months (P = .02). The most recent 2012-2017 cohort remains an independently significant risk factor for late first AR, suggesting unmeasured variables. Further research is needed to determine whether these higher late first AR rates will impact long-term graft survival in the most recent cohort.

The light at the end of the tunnel: an unusual case of acute kidney injury in a pediatric patient: Answers.

Monoclonal gammopathies are a rare diagnosis in pediatric patients. A 19-year-old female patient with past medical history of hypogammaglobulinemia and natural killer cell deficiency and stage III follicular lymphoma, in remission, presented with a right-sided pneumonia, noted to have acute kidney injury and proteinuria. Complement C3 and C4 levels were normal. Anti-double-stranded DNA antibodies, antinuclear antibodies, anti-extractable nuclear antigen antibodies, and antineutrophil cytoplasmic antibodies were negative. A renal biopsy showed numerous fractured tubular casts that were periodic acid-Schiff and silver-stain negative and fuchsinophilic on trichrome stain, with associated giant cells, tubulitis, acute tubular injury, and tubular rupture. The tubular casts had 3+ staining for lambda light chains and 0-1+ staining for kappa light chains. These findings were consistent with light chain cast nephropathy (LCCN). Serum free light chains, serum immunofixation, urine protein electrophoresis, and urine immunofixation studies supported the renal biopsy diagnosis of LCCN. A bone marrow biopsy showed normal trilineage hematopoiesis and also revealed an atypical B cell population detected by flow cytometry. Pathology specimens from lesions in the distal small bowel were characteristic of diffuse large B cell lymphoma (DLBCL). Chemoreduction therapy followed by chemotherapy was initiated for the DLBCL. Three months after initiation of chemotherapy, the patient's creatinine has improved by > 50%. The likely cause of her LCCN was the new diagnosis of a DLBCL. Other risk factors include her history of hypogammaglobulinemia, natural killer (NK) cell deficiency, community-acquired pneumonia, and prior follicular lymphoma. Our patient may be the youngest reported case of LCCN. Treatment of LCCN is based on treating the underlying clonal plasma cell or B cell proliferation, typically with chemotherapy.

Horner-Wadsworth-Emmons approach to piperlongumine analogues with potent anti-cancer activity.

Natural products with anti-cancer activity play a vital role in lead and target discovery. We report here the synthesis and biological evaluation of the plant-derived alkaloid, piperlongumine and analogues. Using a Horner-Wadsworth-Emmons coupling approach, a selection of piperlongumine-like compounds were prepared in good overall yield from a novel phosphonoacetamide reagent. A number of the compounds displayed potent anti-cancer activity against colorectal (HCT 116) and ovarian (IGROV-1) carcinoma cell lines, via a mechanism of action which may involve ROS generation. Contrary to previous reports, no selective action in cancer cell (MRC-5) was observed for piperlongumine analogues.

Soft tissue sarcoma - A review of presentation, management and outcomes in 110 patients.

UNLABELLED: Soft tissue sarcomas are a rare group of mesenchymal tumours the treatment of which poses oncological and reconstructive challenges. Limb-salvage surgery aims to balance adequate excision margins for disease control and preservation of important structures to retain function. Reported here is the review of the Hull Plastic surgery sarcoma service over a twelve year period. METHOD: We performed a review of the Hull sarcoma database over a twelve year period between 1997 and 2009. Demographic data, tumour grade, operative details complications and outcomes were recorded. RESULTS: The database contained a total of 435 patients with a diagnosis of sarcoma. 110 were treated at the Plastic Surgery department over a period of 12 years between 1997 and 2009. The patients treated in our department consisted of 67 males and 43 females (median age 70 years). The most common histological type was leiomyosarcoma (n = 23). Distribution of anatomical sites affected were head and neck (n = 15), upper limb (n = 17), lower limb (n = 56), trunk (n = 22). Large tumours (greater than 8 cm) n = 30, deep tumours n = 48, and high grade (Trojani 3) n = 33. Patients were treated with surgical excision and postoperative radiotherapy in the high grade groups (2 and 3). A range of reconstructive procedures were required from skin grafting, functional muscle transfer and free flap reconstruction. Nine patients developed regional recurrence, six patients had grade 3 tumours. Three were not resectable. Fourteen patients developed distant metastases, seven had grade 3 tumours, six underwent chemotherapy, two were treated palliatively. There were twenty deaths in this group, of which sixteen were sarcoma related. Deaths in the high risk groups was seven (high grade), nine (deep tumours) and eight (tumour size >8 cm). There were six survivors from eleven in the group with all three of these risk factors. CONCLUSION: This study summarises the management of sarcoma form one unit over a twelve year period and lends further evidence to the fact that the principles of limb-salvage surgery are applicable to a wide range of tumour-types and grades, to all patient age groups and anatomical sites with good functional results and that local and free flap reconstruction provides wound cover robust enough to withstand courses of radiotherapy. Early recurrence of high-grade disease and the development of metastasis carry a worse prognosis, especially if adjuvant therapy cannot be given. LEVEL OF EVIDENCE: 4.

Implementing trials of complex interventions in community settings: the USC-Rancho Los Amigos pressure ulcer prevention study (PUPS).

BACKGROUND: Randomized trials of complex, non-pharmacologic interventions implemented in home and community settings, such as the University of Southern California (USC)-Rancho Los Amigos National Rehabilitation Center (RLANRC) Pressure Ulcer Prevention Study (PUPS), present unique challenges with respect to (1) participant recruitment and retention, (2) intervention delivery and fidelity, (3) randomization and assessment, and (4) potential inadvertent treatment effects. PURPOSE: We describe the methods employed to address the challenges confronted in implementing PUPS. In this randomized controlled trial, we are assessing the efficacy of a complex, preventive intervention in reducing the incidence of, and costs associated with, the development of medically serious pressure ulcers in people with spinal cord injury. METHODS: Individuals with spinal cord injury recruited from RLANRC were assigned to either a 12-month preventive intervention group or a standard care control group. The primary outcome is the incidence of serious pressure ulcers with secondary endpoints including ulcer-related surgeries, medical treatment costs, and quality of life. These outcomes are assessed at 12 and 24 months after randomization. Additionally, we are studying the mediating mechanisms that account for intervention outcomes. RESULTS: PUPS has been successfully implemented, including recruitment of the target sample size of 170 participants, assurance of the integrity of intervention protocol delivery with an average 90% treatment adherence rate, and enactment of the assessment plan. However, implementation has been replete with challenges. To meet recruitment goals, we instituted a five-pronged approach customized for an underserved, ethnically diverse population. In intervention delivery, we increased staff time to overcome economic and cultural barriers to retention and adherence. To ensure treatment fidelity and replicability, we monitored intervention protocol delivery in accordance with a rigorous plan. Finally, we have overcome unanticipated assessment and design concerns related to (1) determining pressure ulcer incidence/severity, (2) randomization imbalance, and (3) inadvertent potential control group contamination. LIMITATIONS: We have addressed the most daunting challenges encountered in the recruitment, assessment, and intervention phases of PUPS. Some challenges and solutions may not apply to trials conducted in other settings. CONCLUSIONS: Overcoming challenges has required a multifaceted approach incorporating individualization, flexibility, and persistence, as well as the ability to implement needed mid-course corrections.

Risk factors for complications following breast reduction: results from a randomized control trial.

Reduction mammoplasty has been shown to benefit physical, physiological, and psycho-social health. However, there are some recognized complications. It would be beneficial if one could identify and modify the factors which increase the rate of complications. To determine the effects of resection weight, BMI, age, and smoking on complication rates following reduction mammoplasty. Data were gathered as a part of randomized control trial (RCT) examining psycho-social & QOL benefits of reduction mammoplasty. Sixty-seven consecutive female patients referred to either the Hull Breast Unit or Hull Plastic and Reconstructive Surgery Unit and underwent Inferior pedicle reduction mammoplasty were recruited. Complications were recorded prospectively. Data gathered included resection weight, BMI, age, and smoking status. Smoking status was categorized into current; ex; and never. Prospective records of all complications were noted. SPSS was used for purposes of statistical analysis. Of the 67 patients, 16 (23.9%) had complications. Higher resection weight, increased BMI, and older age are associated with high rate of complications with significance reaching p-values of p < 0.001, p = 0.034, and p = 0.004, respectively. Among the 67 women who had surgery, nine (13.4%) were current smokers, 20 (29.9%) were ex-smokers, and 38 (56.7%) never smoked. The incidence of complications was highest among current smokers and lowest among those who had never smoked. When comparing the current smokers with those who are not currently smoking, there is a 37% difference in the occurrence of complication. The chi-squared test shows that this is a significant difference (p < 0.01) at the 99% confidence interval. Higher resection weight, increased BMI, older age, and smoking are risk factors for complications. Patients should be adequately counseled about losing weight and stopping smoking.

Microvesicle-mediated release of soluble LH/hCG receptor (LHCGR) from transfected cells and placenta explants.

Placental hCG and pitutary LH transduce signals in target tissues through a common receptor (LHCGR). We demonstrate that recombinant LHCGR proteins which include the hormone-binding domain are secreted from transfected cells and that natural LHCGR is also secreted from human placental explants. LHCGR recombinant proteins representing varying lengths of the N-terminal extracellular domain were expressed in Chinese Hamster Ovary cells in suspension culture. Secretion was minimal up to 72h but by 96h 24-37% of the LHCGR had been released into the culture medium. The secreted proteins were folded and sensitive to glycosidases suggesting N-linked glycosylation. Secretion was independent of recombinant size and was mediated via structurally defined membrane vesicles (50-150nm). Similarly cultured human early pregnancy placental explants also released LHCGR via microvesicles. These studies provide the first experimental evidence of the possible mechanistic basis of the secretion of LHCGR.

Application of NMR-based metabolomics to the investigation of salt stress in maize (Zea mays).

INTRODUCTION: High salinity, caused by either natural (e.g. climatic changes) or anthropic factors (e.g. agriculture), is a widespread environmental stressor that can affect development and growth of salt-sensitive plants, leading to water deficit, the inhibition of intake of essential ions and metabolic disorders. OBJECTIVE: The application of an NMR-based metabolic profiling approach to the investigation of saline-induced stress in Maize plants is presented. METHODOLOGY: Zea Maize seedlings were grown in either 0, 50 or 150 mM saline solution. Plants were harvested after 2, 4 and 6 days (n = 5 per class and time point) and (1) H NMR spectroscopy was performed separately on shoot and root extracts. Spectral data were analysed and interpreted using multivariate statistical analyses. RESULTS: A distinct effect of time/growth was observed for the control group with relatively higher concentrations of acetoacetate at day 2 and increased levels of alanine at days 4 and 6 in root extracts, whereas concentration of alanine was positively correlated with the shoot extracts harvested at day 2 and trans-aconitic acid increased at days 4 and 6. A clear dose-dependent effect, superimposed on the growth effect, was observed for saline treated shoot and root extracts. This was correlated with increased levels of alanine, glutamate, asparagine, glycine-betaine and sucrose and decreased levels of malic acid, trans-aconitic acid and glucose in shoots. Correlation with salt-load shown in roots included elevated levels of alanine, γ-amino-N-butyric acid, malic acid, succinate and sucrose and depleted levels of acetoacetate and glucose. CONCLUSIONS: The metabolic effect of high salinity was predominantly consistent with osmotic stress as reported for other plant species and was found to be stronger in the shoots than the roots. Using multivariate data analysis it is possible to investigate the effects of more than one environmental stressor simultaneously.

Diagnostic accuracy of the interferon-gamma release assay (IGRA) for cases of feline mycobacteriosis.

The aim of this study was to evaluate the sensitivity and specificity of the interferon-gamma release assay (IGRA) for diagnosing infections with members of the Mycobacterium (M.) tuberculosis-complex (MTBC) and non-tuberculous mycobacteria (NTM) in domestic cats, and to generate defined feline-specific cut-off values using receiver operating characteristic (ROC) curve analysis to improve test performance. Records of 594 cats that had been tested by IGRA were explored to identify individuals that had a culture and/or polymerase chain reaction (PCR)-confirmed case of mycobacterial disease, and those that had a final diagnosis of non-mycobacterial disease. A total of 117 cats - 80 with mycobacterial disease and 37 diagnosed with a condition other than mycobacteriosis - were identified for further detailed analysis. This population was used to estimate test sensitivity and specificity, as well as likelihood ratios for the IGRA to correctly identify a cat with or without mycobacterial disease. Agreement between IGRA results and culture/PCR using current and proposed new cut-off values was also determined. ROC analysis of defined confirmed infected and non-mycobacterial disease control cats allowed an adjustment of current test cut-offs that increased the overall test sensitivity for MTBC infections from 83.1 % (95 % confidence interval [CI]: 71.5-90.5 %) to 90.2 % (95 % CI: 80.2-95.4%), and M. bovis infection from 43 % (95 % CI: 28.2-60.7%) to 68 % (95 % CI: 51.4-82.1%) while maintaining high test specificity (100 % in both cases). Overall agreement between IGRA results and culture/PCR, while recognising that neither culture nor PCR tests have perfect sensitivity, improved from weak (κ = 0.57) to moderate (κ = 0.71) using new proposed IGRA test cut-off values. Application of these results, based upon the statistical analysis of accumulated test data, can improve the diagnostic performance of the feline IGRA, particularly for identifying infections with M. bovis, without compromising specificity.

Serial Interferon-Gamma Release Assay (IGRA) Testing to Monitor Treatment Responses in Cases of Feline Mycobacteriosis.

The interferon-gamma release assay (IGRA) is used to diagnose cases of feline mycobacteriosis, but the use of serial testing to monitor treatment responses has not been evaluated in this species. From a population of cats that underwent IGRA testing for diagnostic investigation, individuals were identified with a pre- and end-of-treatment IGRA that passed control thresholds. The number of cats which reverted to negative at the end-of-treatment IGRA, changes in paired antigen-specific optical density (OD) values and differences in the pre-treatment antigen-specific OD values for those which underwent reversion were compared. Factors to explain reversion or recurrence of disease post-treatment were explored. Four of 18 cats (22%) reverted to negativity at the point of clinical resolution (p = 0.33), there was no difference in paired antigen-specific OD values (p ≥ 0.12), and cats that reverted did not have a lower baseline OD value (p = 0.63). No statistically significant factors were identified to predict reversion (p ≥ 0.08). Remaining positive at the end of treatment IGRA was not associated with recurrence of disease post-treatment (p = 0.34). Overall, these data suggest there is limited value in the use of the IGRA to monitor treatment responses in cats.

Lifestyle intervention for adults with spinal cord injury: Results of the USC-RLANRC Pressure Ulcer Prevention Study.

CONTEXT/OBJECTIVE: Medically serious pressure injuries (MSPrIs), a common complication of spinal cord injury (SCI), have devastating consequences on health and well-being and are extremely expensive to treat. We aimed to test the efficacy of a lifestyle-based intervention designed to reduce incidence of MSPrIs in adults with SCI. DESIGN: A randomized controlled trial (RCT), and a separate study wing involving a nonrandomized standard care control group. SETTING: Rancho Los Amigos National Rehabilitation Center, a large facility serving ethnically diverse, low income residents of Los Angeles County. PARTICIPANTS: Adults with SCI, with history of one or more MSPrIs over the past 5 years: N=166 for RCT component, N=66 in nonrandomized control group. INTERVENTIONS: The Pressure Ulcer Prevention Program, a 12-month lifestyle-based treatment administered by healthcare professionals, largely via in-home visits and phone contacts. OUTCOME MEASURES: Blinded assessments of annualized MSPrI incidence rates at 12 and 24 months, based on: skin checks, quarterly phone interviews with participants, and review of medical charts and billing records. Secondary outcomes included number of surgeries and various quality-of-life measures. RESULTS: Annualized MSPrI rates did not differ significantly between study groups. At 12 months, rates were .56 for intervention recipients, .48 for randomized controls, and .65 for nonrandomized controls. At follow-up, rates were .44 and .39 respectively for randomized intervention and control participants. CONCLUSIONS: Evidence for intervention efficacy was inconclusive. The intractable nature of MSPrI threat in high-risk SCI populations, and lack of statistical power, may have contributed to this inability to detect an effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT01999816.

Histologic and elemental microanalytical study of anorganic bovine bone substitution following sinus floor augmentation in humans.

BACKGROUND: Histologic data regarding the use of anorganic bovine bone (ABB) in humans are scarce. This study was a histologic evaluation and an examination of the elemental composition of ABB particles and adjacent bone in humans. METHODS: Ten biopsies were retrieved 20 months after maxillary sinus augmentation in five patients. The investigation was carried out using light microscopy in brightfield, fluorescence, and circularly polarized light and scanning electron microscopy (SEM) with energy-dispersive x-ray spectroscopy. RESULTS: The regenerated tissue consisted of 38% +/- 2.1% newly formed bone, 36% +/- 1.3% marrow spaces, and 29% +/- 1.8% residual ABB particles. Under polarized light, the newly formed bone was characterized by randomly oriented collagen fibers. Under fluorescence, the biomaterial showed close apposition to bone; under SEM, several projections of newly formed bone were seen penetrating the ABB particles. ABB and bone were distinguished by the lighter gray color of the biomaterial in back-scattered electron images; ABB particles were surrounded and linked by newly formed bone. Elemental analysis gave average calcium/phosphorus ratios (atomic %) approximately 1.9 for ABB and 1.4 for bone. Relatively high concentrations of calcium and phosphorus in the biomaterial decreased gradually toward the interface with bone. CONCLUSION: The persistence of ABB in the human tissue after 20 months might have been related to the relatively high calcium content of the biomaterial as well as the absence of proteins.

Evaluation of buccal swabs for pharmacogenetics.

OBJECTIVE: A simple, non-invasive sample collection method is key for the integration of pharmacogenetics into clinical practice. The aim of this study was to gain samples for pharmacogenetic testing and evaluate the variation between dry-flocked and sponge-tipped buccal swabs in yield and quality of DNA isolated. RESULTS: Thirty-one participants collected samples using dry-flocked swabs and sponge-tipped swabs. Samples were assessed for DNA yield, quality and genotyping performance on a qPCR OpenArray platform of 28 pharmacogenetic SNPs and a CYP2D6 TaqMan copy number variant. DNA from sponge-tipped swabs had a significantly greater yield compared to DNA collected with dry-flocked swabs (p = 4.4 × 10-7). Moreover, highest genotyping call rates across all assays and highest CNV confidence scores were observed in DNA samples collected from sponge-tipped swabs (97% vs. 54% dry-flocked swabs; 0.99 vs. 0.88 dry-flocked swabs, respectively). Sample collection using sponge-tipped swabs provides a DNA source of sufficient quantity and quality for pharmacogenetic variant detection using qPCR.

Sustainable Syntheses of (-)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site.

The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (-)-jerantinines A and E from sustainably sourced (-)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (-)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin-(-)-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development.

Oral Vaccination of Free-Living Badgers (Meles meles) with Bacille Calmette Guérin (BCG) Vaccine Confers Protection against Tuberculosis.

A field trial was conducted to investigate the impact of oral vaccination of free-living badgers against natural-transmitted Mycobacterium bovis infection. For a period of three years badgers were captured over seven sweeps in three zones and assigned for oral vaccination with a lipid-encapsulated BCG vaccine (Liporale-BCG) or with placebo. Badgers enrolled in Zone A were administered placebo while all badgers enrolled in Zone C were vaccinated with BCG. Badgers enrolled in the middle area, Zone B, were randomly assigned 50:50 for treatment with vaccine or placebo. Treatment in each zone remained blinded until the end of the study period. The outcome of interest was incident cases of tuberculosis measured as time to seroconversion events using the BrockTB Stat-Pak lateral flow serology test, supplemented with post-mortem examination. Among the vaccinated badgers that seroconverted, the median time to seroconversion (413 days) was significantly longer (p = 0.04) when compared with non-vaccinated animals (230 days). Survival analysis (modelling time to seroconversion) revealed that there was a significant difference in the rate of seroconversion between vaccinated and non-vaccinated badgers in Zones A and C throughout the trial period (p = 0.015). For badgers enrolled during sweeps 1-2 the Vaccine Efficacy (VE) determined from hazard rate ratios was 36% (95% CI: -62%- 75%). For badgers enrolled in these zones during sweeps 3-6, the VE was 84% (95% CI: 29%- 97%). This indicated that VE increased with the level of vaccine coverage. Post-mortem examination of badgers at the end of the trial also revealed a significant difference in the proportion of animals presenting with M. bovis culture confirmed lesions in vaccinated Zone C (9%) compared with non-vaccinated Zone A (26%). These results demonstrate that oral BCG vaccination confers protection to badgers and could be used to reduce incident rates in tuberculosis-infected populations of badgers.

Biomimetic Approaches Towards The Synthesis of Complex Dimeric Natural Products.

We present a selection of elegant and diverse biomimetic syntheses of complex natural product dimers. The dimerisation pathways discussed encompass the most prevalent strategies, including: Diels-Alder, Aldol, Mannich, conjugate addition, oxidative, radical and photochemical approaches; each underpinned through rational biosynthetic speculation.