Impacts of Increasing Additions of Choline Chloride on Growth Performance and Carcass Characteristics of Broiler Chickens Reared to 66 Days of Age.

The most recent research cited by the NRC Nutrition Requirements of Poultry to establish choline recommendations was published in 1987, so choline guidelines for modern broilers are outdated and may be insufficient to optimize growth. The objective was to determine the effect of additional dietary choline chloride supplementation on growth performance and carcass characteristics of modern broilers reared for 66 days. As-hatched Ross 708 × Yield Plus broiler chicks (n = 2160; 30 birds per pen) were randomly allotted to one of six experimental corn and soybean meal-based diets formulated to contain an additional 0, 400, 800, 1200, 1600, or 2000 mg of choline chloride above the choline content of the basal diet ingredients. Diets were fed in four phases, and birds were processed at day 66 of age. Growth performance and breast myopathy incidence was not impacted by added choline. While there were differences in breast, wing, thigh, and drum yields, the effects of added choline were not linear. Supplemental choline chloride was not beneficial for growth performance but did impact the carcass characteristics of modern, large frame broilers reared for 66 days.

Prognostic Accuracy of Presepsis and Intrasepsis Characteristics for Prediction of Cardiovascular Events After a Sepsis Hospitalization.

OBJECTIVES: Sepsis survivors face increased risk for cardiovascular complications; however, the contribution of intrasepsis events to cardiovascular risk profiles is unclear. SETTING: Kaiser Permanente Northern California (KPNC) and Intermountain Healthcare (IH) integrated healthcare delivery systems. SUBJECTS: Sepsis survivors (2011-2017 [KPNC] and 2018-2020 [IH]) greater than or equal to 40 years old without prior cardiovascular disease. DESIGN: Data across KPNC and IH were harmonized and grouped into presepsis (demographics, atherosclerotic cardiovascular disease scores, comorbidities) or intrasepsis factors (e.g., laboratory values, vital signs, organ support, infection source) with random split for training/internal validation datasets (75%/25%) within KPNC and IH. Models were bidirectionally, externally validated between healthcare systems. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Changes to predictive accuracy (C-statistic) of cause-specific proportional hazards models predicting 1-year cardiovascular outcomes (atherosclerotic cardiovascular disease, heart failure, and atrial fibrillation events) were compared between models that did and did not contain intrasepsis factors. Among 39,590 KPNC and 16,388 IH sepsis survivors, 3,503 (8.8%) at Kaiser Permanente (KP) and 600 (3.7%) at IH experienced a cardiovascular event within 1-year after hospital discharge, including 996 (2.5%) at KP and 192 (1.2%) IH with an atherosclerotic event first, 564 (1.4%) at KP and 117 (0.7%) IH with a heart failure event, 2,310 (5.8%) at KP and 371 (2.3%) with an atrial fibrillation event. Death within 1 year after sepsis occurred for 7,948 (20%) KP and 2,085 (12.7%) IH patients. Combined models with presepsis and intrasepsis factors had better discrimination for cardiovascular events (KPNC C-statistic 0.783 [95% CI, 0.766-0.799]; IH 0.763 [0.726-0.801]) as compared with presepsis cardiovascular risk alone (KPNC: 0.666 [0.648-0.683], IH 0.660 [0.619-0.702]) during internal validation. External validation of models across healthcare systems showed similar performance (KPNC model within IH data C-statistic: 0.734 [0.725-0.744]; IH model within KPNC data: 0.787 [0.768-0.805]). CONCLUSIONS: Across two large healthcare systems, intrasepsis factors improved postsepsis cardiovascular risk prediction as compared with presepsis cardiovascular risk profiles. Further exploration of sepsis factors that contribute to postsepsis cardiovascular events is warranted for improved mechanistic and predictive models.

Sphagneticola trilobata (L.) Pruski-derived kaurenoic acid prevents ovalbumin-induced asthma in mice: Effect on Th2 cytokines, STAT6/GATA-3 signaling, NFκB/Nrf2 redox sensitive pathways, and regulatory T cell phenotype markers.

ETHNOPHARMACOLOGICAL RELEVANCE: Sphagneticola trilobata (L.) Pruski is used in traditional medicine in Brazil for inflammatory diseases treatment including asthma. The diterpene kaurenoic acid (KA) is one of its active compounds, but whether KA activity could explain the traditional use of S. trilobata in asthma is unknown. AIM: Investigate KA effect and mechanisms in asthma. METHODS: Experimental asthma was induced by ovalbumin immunization and challenge in male Swiss mice. KA (0.1-10 mg/kg, gavage) was administered 1 h before the ovalbumin challenge. Total leukocytes, eosinophil, and mast cell were counted in bronchoalveolar lavage fluid (BALF), and lung histopathology was performed. Lung mRNA expression of Th2 and regulatory T cells markers, and BALF type 2 cytokine production were quantitated. NFκB activation and oxidative stress-related components in pulmonary tissue were measured. RESULTS: KA inhibited the migration of total leukocytes and eosinophils to BALF, reduced lung histopathology (inflammatory cells and mast cells), mRNA expression of IL-33/ST2, STAT6/GATA-3 and NFκB activation in the lung, and reduced IL-33, IL-4, IL-5 production in the BALF. KA also reduced the mRNA expression of iNOS and gp91phox, and superoxide anion production accompanied by the induction of Nrf2, HO-1 and NQO1 mRNA expression, thus, exerting an antioxidant effect. Finally, KA induced nTreg-like and Tr1-like, but not Th3-like markers of suppressive T cell phenotypes in the lung tissue. CONCLUSION: KA prevents antigen-induced asthma by down-regulating Th2 and NFκB/cytokine-related pathways, and up-regulating Nrf2 and regulatory T cells' markers. Thus, explaining the ethnopharmacological use of S. trilobata for the treatment of lung inflammatory diseases.

Structural discrimination analysis for constraint selection in protein modeling.

MOTIVATION: Protein structure modeling can be improved by the use of distance constraints between amino acid residues, provided such data reflects-at least partially-the native tertiary structure of the target system. In fact, only a small subset of the native contact map is necessary to successfully drive the model conformational search, so one important goal is to obtain the set of constraints with the highest true-positive rate, lowest redundancy and greatest amount of information. In this work, we introduce a constraint evaluation and selection method based on the point-biserial correlation coefficient, which utilizes structural information from an ensemble of models to indirectly measure the power of each constraint in biasing the conformational search toward consensus structures. RESULTS: Residue contact maps obtained by direct coupling analysis are systematically improved by means of discriminant analysis, reaching in some cases accuracies often seen only in modern deep-learning-based approaches. When combined with an iterative modeling workflow, the proposed constraint classification optimizes the selection of the constraint set and maximizes the probability of obtaining successful models. The use of discriminant analysis for the valorization of the information of constraint datasets is a general concept with possible applications to other constraint types and modeling problems. AVAILABILITY AND IMPLEMENTATION: MSA for the targets in this work is available on https://github.com/m3g/2021_Bottino_Biserial. Modeling data supporting the findings of this study was generated at the Center for Computing in Engineering and Sciences, and is available from the corresponding author LM on request. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Neural changes following equine-assisted therapy for posttraumatic stress disorder: A longitudinal multimodal imaging study.

BACKGROUND: While effective treatments for posttraumatic stress disorder (PTSD) exist, many individuals, including military personnel and veterans fail to respond to them. Equine-assisted therapy (EAT), a novel PTSD treatment, may complement existing PTSD interventions. This study employs longitudinal neuro-imaging, including structural magnetic resonance imaging (sMRI), resting state-fMRI (rs-fMRI), and diffusion tensor imaging (DTI), to determine mechanisms and predictors of EAT outcomes for PTSD. METHOD: Nineteen veterans with PTSD completed eight weekly group sessions of EAT undergoing multimodal MRI assessments before and after treatment. Clinical assessments were conducted at baseline, post-treatment and at 3-month follow-up. RESULTS: At post-treatment patients showed a significant increase in caudate functional connectivity (FC) and reduction in the gray matter density of the thalamus and the caudate. The increase of caudate FC was positively associated with clinical improvement seen immediately at post-treatment and at 3-month follow-up. In addition, higher baseline caudate FC was associated with greater PTSD symptom reduction post-treatment. CONCLUSIONS: This exploratory study is the first to demonstrate that EAT can affect functional and structural changes in the brains of patients with PTSD. The findings suggest that EAT may target reward circuitry responsiveness and produce a caudate pruning effect from pre- to post-treatment.

Reduced cutaneous inflammation associated with antioxidant action after topical application of the aqueous extract of Annona muricata leaves.

Annona muricata L. is used in folk medicine for treatment of diseases related to inflammatory and oxidative processes. This study investigated the effect of the aqueous extract of A. muricata leaves (AEAM) on TPA-induced ear inflammation and antioxidant capacity, both in vitro and in vivo. The in vitro antioxidant capacity of AEAM was measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing/antioxidant power (FRAP) and lipoperoxidation assays. Cytotoxicity and reactive oxygen species (ROS) release were evaluated in the L929 fibroblasts. Swiss mice were submitted to TPA application and were topically treated with AEAM (0.3, 1 or 3 mg/ear). After 6 h, inflammatory and oxidative parameters were evaluated. Quercetin 3-glucoside, rutin, chlorogenic acid, catechin and gallic acid were identified in AEAM. It also presented antioxidant activity in all in vitro assays used. Incubation with AEAM did not cause cell cytotoxicity but reduced ROS release from fibroblasts. Compared with the control group, treatment with AEAM significantly reduced ear oedema and mieloperoxidase activity in inflamed ears, as well as histological parameters of inflammation. These results were associated with the reduction of total hydroperoxides and modulation of catalase, but not superoxide dismutase activity. These findings show the anti-inflammatory effect of AEAM is associated with antioxidant capacity.

Use of Hydrocortisone, Ascorbic Acid, and Thiamine in Adults with Septic Shock.

Rationale: In December 2016, a single-center study describing significant improvements in mortality among a small group of patients with severe sepsis and septic shock treated with hydrocortisone, high-dose ascorbic acid, and thiamine (HAT therapy) was published online.Objectives: This study aims to describe the administration of HAT therapy among U.S. adults with septic shock before and after study publication and to compare outcomes between patients who received and did not receive HAT therapy.Methods: We performed a retrospective cohort study of 379 acute care hospitals in the Premier Healthcare Database including patients discharged from October 1, 2015, to September 30, 2018. Exposure was quarter year of hospital discharge; postpublication was defined as January 2017 onward (July 2017 for effectiveness analyses). The primary outcome was receipt of HAT at least once during hospitalization. We conducted unadjusted segmented regression analyses to examine temporal trends in HAT administration. In patients with early septic shock, we compared the association of early HAT therapy (within 2 d of hospitalization) with hospital mortality using multivariable modeling and propensity score matching.Measurements and Main Results: Among 338,597 patients, 3,574 (1.1%) received HAT therapy, 98.7% in the postpublication period. HAT administration increased from 0.03% of patients (95% confidence interval [CI], 0.02-0.04) before publication to 2.65% (95% CI, 2.46-2.83) in the last quarter, with a significant step up in use after December 2016 (P < 0.001). Receipt of early HAT was associated with higher hospital mortality (28.2% vs. 19.7%; P < 0.001; adjusted odds ratio, 1.17 [95% CI, 1.02-1.33]; primary propensity-matched model adjusted odds ratio, 1.19 [95% CI, 1.02-1.40]).Conclusions: Publication of a single-center retrospective study was associated with significantly increased administration of HAT. Among patients with early septic shock, receipt of HAT was not associated with mortality benefit.

Toward a Regional Phosphorus (Re)cycle in the US Midwest.

Redirecting anthropogenic waste phosphorus (P) flows from receiving water bodies to high P demand agricultural fields requires a resource management approach that integrates biogeochemistry, agronomy, engineering, and economics. In the US Midwest, agricultural reuse of P recovered from spatially colocated waste streams stands to reduce point-source P discharges, meet agricultural P needs, and-depending on the speciation of recovered P-mitigate P losses from agriculture. However, the speciation of P recovered from waste streams via its chemical transformation-referred to here as recovered P (rP) differs markedly based on waste stream composition and recovery method, which can further interact with soil and crop characteristics of agricultural sinks. The solubility of rP presents key tensions between engineered P recovery and agronomic reuse because it defines both the ability to remove organic and inorganic P from aqueous streams and the crop availability of rP. The potential of rP generation and composition differs greatly among animal, municipal, and grain milling waste streams due to the aqueous speciation of P and presence of coprecipitants. Two example rP forms, phytin and struvite, engage in distinct biogeochemical processes on addition to soils that ultimately influence crop uptake and potential losses of rP. These processes also influence the fate of nitrogen (N) embodied in rP. The economics of rP generation and reuse will determine if and which rP are produced. Matching rP species to appropriate agricultural systems is critical to develop sustainable and financially viable regional exchanges of rP from wastewater treatment to agricultural end users.

The citrus flavanone naringenin attenuates zymosan-induced mouse joint inflammation: induction of Nrf2 expression in recruited CD45+ hematopoietic cells.

BACKGROUND: Naringenin is a biologically active analgesic, anti-inflammatory, and antioxidant flavonoid. Naringenin targets in inflammation-induced articular pain remain poorly explored. METHODS: The present study investigated the cellular and molecular mechanisms involved in the analgesic/anti-inflammatory effects of naringenin in zymosan-induced arthritis. Mice were pre-treated orally with naringenin (16.7-150 mg/kg), followed by intra-articular injection of zymosan. Articular mechanical hyperalgesia and oedema, leucocyte recruitment to synovial cavity, histopathology, expression/production of pro- and anti-inflammatory mediators and NFκB activation, inflammasome component expression, and oxidative stress were evaluated. RESULTS: Naringenin inhibited articular pain and oedema in a dose-dependent manner. The dose of 50 mg/kg inhibited leucocyte recruitment, histopathological alterations, NFκB activation, and NFκB-dependent pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-33), and preproET-1 mRNA expression, but increased anti-inflammatory IL-10. Naringenin also inhibited inflammasome upregulation (reduced Nlrp3, ASC, caspase-1, and pro-IL-1ß mRNA expression) and oxidative stress (reduced gp91phox mRNA expression and superoxide anion production, increased GSH levels, induced Nrf2 protein in CD45+ hematopoietic recruited cells, and induced Nrf2 and HO-1 mRNA expression). CONCLUSIONS: Naringenin presents analgesic and anti-inflammatory effects in zymosan-induced arthritis by targeting its main physiopathological mechanisms. These data highlight this flavonoid as an interesting therapeutic compound to treat joint inflammation, deserving additional pre-clinical and clinical studies.

2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis.

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial.

BACKGROUND: The current lack of pharmacological treatments for cannabis use disorder (CUD) warrants novel approaches and further investigation of promising pharmacotherapy. We previously showed that nabiximols (27 mg/ml Δ9-tetrahydrocannabinol (THC)/ 25 mg/ml cannabidiol (CBD), Sativex®) can decrease cannabis withdrawal symptoms. Here, we assessed in a pilot study the tolerability and safety of self-titrated nabiximols vs. placebo among 40 treatment-seeking cannabis-dependent participants. METHODS: Subjects participated in a double blind randomized clinical trial, with as-needed nabiximols up to 113.4 mg THC/105 mg CBD or placebo daily for 12 weeks, concurrently with Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT). Primary outcome measures were tolerability and abstinence, secondary outcome measures were days and amount of cannabis use, withdrawal, and craving scores. Participants received up to CDN$ 855 in compensation for their time. RESULTS: Medication was well tolerated and no serious adverse events (SAEs) were observed. Rates of adverse events did not differ between treatment arms (F1,39 = 0.205, NS). There was no significant change in abstinence rates at trial end. Participants were not able to differentiate between subjective effects associated with nabiximols or placebo treatments (F1,40 = 0.585, NS). Cannabis use was reduced in the nabiximols (70.5%) and placebo groups (42.6%). Nabiximols reduced cannabis craving but no significant differences between the nabiximols and placebo groups were observed on withdrawal scores. CONCLUSIONS: Nabiximols in combination with MET/CBT was well tolerated and allowed for reduction of cannabis use. Future clinical trials should explore the potential of high doses of nabiximols for cannabis dependence.

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1-34 for the treatment of osteoporosis.

Osteoporosis treatment with PTH 1-34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1-34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1-34 nasal spray formulation bioactivity. The chemically synthesised PTH 1-34 had an EC50 of 0.76nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1-34 within an in vitro cell culture model (p >0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1-34 into the blood via intranasal delivery produced a Cmax of 2.1±0.5ng/ml compared to 13.7±1.6ng/ml with Solutol® HS15 enhancer (p=0.016) and a Cmax14.8±8ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol® HS15 formulation therefore demonstrated potential as a PTH 1-34 nasal spray formulation for the treatment of osteoporosis.

Atypical hypocalcemia in 2 dairy cows, after having been fed discarded vegetable cooking oil.

Two mid-lactation dairy cows were presented sternally recumbent 4 days after the herd had been fed discarded vegetable cooking oil ad libitum. In both affected animals hypocalcemia was confirmed by clinical chemistry and response to treatment. This atypical presentation of hypocalcemia associated with feeding discarded cooking oil is previously unreported.

Hypocalcémie atypique chez 2 vaches laitières, après avoir consommé de l'huile de cuisson végétale usée. Deux vaches laitières en mi-lactation ont été présentées en décubitus sternal après que le troupeau ait été alimenté à volonté d'huile végétale de cuisson usée. L'hypocalcémie a été confirmée chez les deux animaux affectés par analyse chimique clinique et une réponse au traitement. Cette présentation atypique de l'hypocalcémie associée à l'alimentation d'huile de cuisson végétale usée n'a pas été déjà signalée.(Traduit par Isabelle Vallières).

Dietary Iodine Exposure and Brain Structures and Cognition in Older People. Exploratory Analysis in the Lothian Birth Cohort 1936.

BACKGROUND: Iodine deficiency is one of the three key micronutrient deficiencies highlighted as major public health issues by the World Health Organisation. Iodine deficiency is known to cause brain structural alterations likely to affect cognition. However, it is not known whether or how different (lifelong) levels of exposure to dietary iodine influences brain health and cognitive functions. METHODS: From 1091 participants initially enrolled in The Lothian Birth Cohort Study 1936, we obtained whole diet data from 882. Three years later, from 866 participants (mean age 72 yrs, SD±0.8), we obtained cognitive information and ventricular, hippocampal and normal and abnormal tissue volumes from brain structural magnetic resonance imaging scans (n=700). We studied the brain structure and cognitive abilities of iodine-rich food avoiders/low consumers versus those with a high intake in iodine-rich foods (namely dairy and fish). RESULTS: We identified individuals (n=189) with contrasting diets, i) belonging to the lowest quintiles for dairy and fish consumption, ii) milk avoiders, iii) belonging to the middle quintiles for dairy and fish consumption, and iv) belonging to the middle quintiles for dairy and fish consumption. Iodine intake was secured mostly though the diet (n=10 supplement users) and was sufficient for most (75.1%, median 193 µg/day). In individuals from these groups, brain lateral ventricular volume was positively associated with fat, energy and protein intake. The associations between iodine intake and brain ventricular volume and between consumption of fish products (including fish cakes and fish-containing pasties) and white matter hyperintensities (p=0.03) the latest being compounded by sodium, proteins and saturated fats, disappeared after type 1 error correction. CONCLUSION: In this large Scottish older cohort, the proportion of individuals reporting extreme (low vs. high)/medium iodine consumption is small. In these individuals, low iodine-rich food intake was associated with increased brain volume shrinkage, raising an important hypothesis worth being explored for designing appropriate guidelines.

Sativex Associated With Behavioral-Relapse Prevention Strategy as Treatment for Cannabis Dependence: A Case Series.

OBJECTIVES: Cannabis is the most commonly used illicit drug; a substantial minority of users develop dependence. The current lack of pharmacological treatments for cannabis dependence warrants the use of novel approaches and further investigation of promising pharmacotherapy. In this case series, we assessed the use of self-titrated dosages of Sativex (1:1, Δ-tetrahydrocannabinol [THC]/cannabidiol [CBD] combination) and motivational enhancement therapy and cognitive behavioral therapy (MET/CBT) for the treatment of cannabis dependence among 5 treatment-seeking community-recruited cannabis-dependent subjects. METHODS: Participants underwent a 3-month open-label self-titration phase with Sativex (up to 113.4 of THC/105 mg of CBD) and weekly MET/CBT, with a 3-month follow-up. RESULTS: Sativex was well-tolerated by all participants (average dosage 77.5 THC/71.7 mg CBD). The combination of Sativex and MET/CBT reduced the amount of cannabis use and progressively reduced craving and withdrawal scores. THC/CBD metabolite concentration indicated reduced cannabis use and compliance with medication. CONCLUSIONS: In summary, this pilot study found that with Sativex in combination with MET/CBT reduced cannabis use while preventing increases in craving and withdrawal in the 4 participants completing the study. Further systematic exploration of Sativex as a pharmacological treatment option for cannabis dependence should be performed.

Geovariation in Fracture Risk among Patients Receiving Hemodialysis.

BACKGROUND AND OBJECTIVES: Fractures are a major source of morbidity and mortality in patients receiving dialysis. We sought to determine whether rates of fractures and tendon ruptures vary geographically. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the US Renal Data System were used to create four yearly cohorts, 2007-2010, including all eligible prevalent patients on hemodialysis in the United States on January 1 of each year. A secondary analysis comprising patients in a large dialysis organization conducted over the same period permitted inclusion of patient-level markers of mineral metabolism. Patients were grouped into 10 regions designated by the Centers for Medicare and Medicaid Services and divided by latitude into one of three bands: south, <35°; middle, 35° to <40°; and north, ≥40°. Poisson regression was used to calculate unadjusted and adjusted region-level rate ratios for events. RESULTS: Overall, 327,615 patients on hemodialysis were included. Mean (SD) age was 61.8 (15.0) years old, 52.7% were white, and 55.0% were men. During 716,962 person-years of follow-up, 44,014 fractures and tendon ruptures occurred, the latter being only 0.3% of overall events. Event rates ranged from 5.36 to 7.83 per 100 person-years, a 1.5-fold rate difference across regions. Unadjusted region-level rate ratios varied from 0.83 (95% confidence interval, 0.81 to 0.85) to 1.20 (95% confidence interval, 1.18 to 1.23), a 1.45-fold rate difference. After adjustment for a wide range of case mix variables, a 1.33-fold variation in rates remained. Rates were higher in north and middle bands than the south (north rate ratio, 1.18; 95% confidence interval, 1.13 to 1.23; middle rate ratio, 1.13; 95% confidence interval, 1.10 to 1.17). Latitude explained 11% of variation, independent of region. A complementary analysis of 87,013 patients from a large dialysis organization further adjusted for circulating mineral metabolic parameters and protein energy wasting yielded similar results. CONCLUSIONS: Rates of fractures vary geographically in the United States dialysis population, even after adjustment for known patient characteristics. Latitude seems to contribute to this phenomenon, but additional analyses exploring whether other factors might influence variation are warranted.

Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings.

BACKGROUND: There is currently no pharmacological treatment approved for cannabis dependence. In this proof of concept study, we assessed the feasibility/effects of fixed and self-titrated dosages of Sativex (1:1, Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD)) on craving and withdrawal from cannabis among nine community-recruited cannabis-dependent subjects. METHODS: Participants underwent an 8-week double-blind placebo-controlled trial (an ABACADAE design), with four smoke as usual conditions (SAU) (A) separated by four cannabis abstinence conditions (B-E), with administration of either self-titrated/fixed doses of placebo or Sativex (up to 108 mg THC/100 mg CBD). The order of medication administration during abstinence conditions was randomized and counterbalanced. Withdrawal symptoms and craving were assessed using the Cannabis Withdrawal Scale (CWS), Marijuana Withdrawal Checklist (MWC) and Marijuana Craving Questionnaire (MCQ). Medication use was assessed during the study by means of self-reports, vial weight control, toxicology and metabolite analysis. Cannabis use was assessed by means of self-reports. RESULTS: High fixed doses of Sativex were well tolerated and significantly reduced cannabis withdrawal during abstinence, but not craving, as compared to placebo. Self-titrated doses were lower and showed limited efficacy as compared to high fixed doses. Participants reported a significantly lower "high" following Sativex or placebo as compared to SAU conditions. Cannabis/medication use along the study, as per self-reports, suggests compliance with the study conditions. CONCLUSIONS: The results found in this proof of concept study warrant further systematic exploration of Sativex as a treatment option for cannabis withdrawal and dependence.

Changes in secondary hyperparathyroidism-related biochemical parameters and medication use following parathyroidectomy.

BACKGROUND: Little is known about changes in parathyroid hormone (PTH), calcium and phosphorous levels after parathyroidectomy in hemodialysis patients. We studied the effects of parathyroidectomy on these biochemical values in a large cohort of patients receiving maintenance hemodialysis. METHODS: This retrospective cohort study included patients identified in both the United States Renal Data System and the database of a large dialysis organization who underwent parathyroidectomy in 2007-09, were aged ≥ 18 years, had Medicare Parts A and B as primary payer and had received hemodialysis for ≥ 1 year pre-parathyroidectomy. Descriptive statistics were calculated for continuous variables; categorical variables were used to characterize the population and evaluate monthly laboratory and medication use; median values were calculated for laboratory measures. RESULTS: Among 1402 parathyroidectomy patients, mean age was 48.9 years, 52.4% were males, 58.8% were African American and mean dialysis duration was 7.5 years. Median PTH levels increased over the year before parathyroidectomy from 1039 to 1661 pg/mL and decreased afterward to 98 pg/mL at 1 month; levels remained ≥ 897 pg/mL for 10% of patients. Median calcium levels fell from 9.6 mg/dL before to 7.9 mg/dL 1 month after parathyroidectomy; levels were ≤ 7.1 mg/dL for 25% and remained ≤ 7.2 mg/dL for the lowest 25% at 3 months. Median phosphorous level was 6.8 mg/dL immediately before parathyroidectomy, decreased to 3.8 mg/dL immediately after and reached 5.8 mg/dL at 1 year. CONCLUSIONS: While PTH levels dropped after parathyroidectomy for most patients, surgery was sometimes ineffective in reducing levels and sometimes led to over-suppression. Hypocalcemia could be profound and long lasting, suggesting the need for prolonged vigilance.

In vitro antimicrobial activity of solution blow spun poly(lactic acid)/polyvinylpyrrolidone nanofibers loaded with Copaiba (Copaifera sp.) oil.

In this study poly(lactic acid) (PLA) and polyvinylpyrrolidone (PVP) micro- and nanofiber mats loaded with Copaiba (Copaifera sp.) oil were produced by solution blow spinning (SBS). The Copaiba (Copaifera sp.) oil was characterized by gas chromatography (GC). Neat PLA and four PLA/PVP blends containing 20% (wt.%) oil were spun and characterized by scanning electron microscopy (SEM) and by studying the surface contact angle, in vitro release rate, and antimicrobial activity. All compositions evaluated were able to produce continuous and smooth fibers by SBS. The addition of PVP increased fiber diameter, and decreased the surface contact angle. GC analysis demonstrated that the main component of the Copaiba oil was ß-caryophyllene, a known antimicrobial agent. In vitro release tests of Copaiba oil volatiles demonstrated a higher release rate in fibers containing PVP. Fiber mats made from blends containing higher amounts of PVP had greater antimicrobial action against Staphylococcus aureus. The results confirm the potential of the fiber mats for use in controlled drug release and could lead to promising applications in the biomedical field.

Quantification of 11-nor-9-carboxy-δ9-tetrahydrocannabinol in human oral fluid by gas chromatography-tandem mass spectrometry.

A sensitive and specific method for the quantification of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) in oral fluid collected with the Quantisal and Oral-Eze devices was developed and fully validated. Extracted analytes were derivatized with hexafluoroisopropanol and trifluoroacetic anhydride and quantified by gas chromatography-tandem mass spectrometry with negative chemical ionization. Standard curves, using linear least-squares regression with 1/x weighting were linear from 10 to 1000 ng/L with coefficients of determination >0.998 for both collection devices. Bias was 89.2%-112.6%, total imprecision 4.0%-5.1% coefficient of variation, and extraction efficiency >79.8% across the linear range for Quantisal-collected specimens. Bias was 84.6%-109.3%, total imprecision 3.6%-7.3% coefficient of variation, and extraction efficiency >92.6% for specimens collected with the Oral-Eze device at all 3 quality control concentrations (10, 120, and 750 ng/L). This effective high-throughput method reduces analysis time by 9 minutes per sample compared with our current 2-dimensional gas chromatography-mass spectrometry method and extends the capability of quantifying this important oral fluid analyte to gas chromatography-tandem mass spectrometry. This method was applied to the analysis of oral fluid specimens collected from individuals participating in controlled cannabis studies and will be effective for distinguishing passive environmental contamination from active cannabis smoking.