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Objective: The objective of this research study was to obtain the varietal description of two varieties of manzano chili pepper in Las Montañas region, in central Veracruz, Mexico. Design/methodology/approach: The varietal characterization module was established under greenhouse conditions. The markers recorded were in accordance with the International Plant Genetic Resources Institute for Capsicum and the Graphic Handbook for Variety Description of manzano chili pepper. The plants were characterized from seedling in greenhouse to adult plant. The agronomic management of the crop was carried out in accordance with the manual for the production of manzano chili pepper in Las Montañas, state of Veracruz. Results: All qualitative markers were constant for the two varieties, MEXUVNE1-15-C2 and MEXUVCU1-16-C2, from seedling to fruit setting. In contrast, there were dissimilarities in plant height, and stem, leaf, flower, fruit and seed dimensions. Study limitations/implications: The pandemic caused by COVID-19 was the main limitation, resulting in some markers not being recorded in a timely manner as indicated in the Graphic Handbook. Findings/conclusions: Both varieties are very similar; however, the greatest distinction was in the quantitative markers, such as: plant height, fruit length, fruit diameter and number of seeds.

BACKGROUND: Persistent postural-perceptual dizziness (PPPD) is a chronic balance disorder, which is characterised by subjective unsteadiness or dizziness that is worse on standing and with visual stimulation. The condition was only recently defined and therefore the prevalence is currently unknown. However, it is likely to include a considerable number of people with chronic balance problems. The symptoms can be debilitating and have a profound impact on quality of life. At present, little is known about the optimal way to treat this condition. A variety of medications may be used, as well as other treatments, such as vestibular rehabilitation. OBJECTIVES: To assess the benefits and harms of non-pharmacological interventions for persistent postural-perceptual dizziness (PPPD). SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 21 November 2022.SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults with PPPD, which compared any non-pharmacological intervention with either placebo or no treatment. We excluded studies that did not use the Bárány Society criteria to diagnose PPPD, and studies that followed up participants for less than three months. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vestibular symptoms (assessed as a dichotomous outcome - improved or not improved), 2) change in vestibular symptoms (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) generic health-related quality of life and 6) other adverse effects. We considered outcomes reported at three time points: 3 to < 6 months, 6 to ≤ 12 months and > 12 months. We planned to use GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: Few randomised controlled trials have been conducted to assess the efficacy of different treatments for PPPD compared to no treatment (or placebo). Of the few studies we identified, only one followed up participants for at least three months, therefore most were not eligible for inclusion in this review. We identified one study from South Korea that compared the use of transcranial direct current stimulation to a sham procedure in 24 people with PPPD. This is a technique that involves electrical stimulation of the brain with a weak current, through electrodes that are placed onto the scalp. This study provided some information on the occurrence of adverse effects, and also on disease-specific quality of life at three months of follow-up. The other outcomes of interest in this review were not assessed. As this is a single, small study we cannot draw any meaningful conclusions from the numeric results. AUTHORS' CONCLUSIONS: Further work is necessary to determine whether any non-pharmacological interventions may be effective for the treatment of PPPD and to assess whether they are associated with any potential harms. As this is a chronic disease, future trials should follow up participants for a sufficient period of time to assess whether there is a persisting impact on the severity of the disease, rather than only observing short-term effects.

BACKGROUND: Critically ill patients commonly suffer from infections that require antimicrobial therapy. In previous studies, liver dysfunction was shown to have an essential impact on the dose selection in these patients. This pilot study aims to assess the influence of liver dysfunction, measured by the novel LiMAx test, on clinical outcomes in critically ill patients treated with linezolid. METHODS: Twenty-nine critically ill patients were included and treated with linezolid. Indications for linezolid therapy were secondary or tertiary peritonitis (46.7%), bloodstream infection (6.7%) and 46.7% were other infections with gram-positive bacteria. Linezolid Cmin, maximal liver function capacity (LiMAx test) and plasma samples were collected while linezolid therapy was in a steady-state condition. Furthermore, potential factors for the clinical outcome were investigated using logistic regression analysis. Clinical cure was defined as the resolution or significant improvement of clinical symptoms without using additional antibiotic therapy or intervention. RESULTS: Cured patients presented lower median linezolid Cmin yet a significantly higher mean LiMAx-value compared to the clinical failure group (1.9 mg/L vs. 5.1 mg/L) (349 μg/kg/h vs. 131 μg/kg/h). In the logistic regression model, LiMAx < 178 μg/kg/h was the only independent predictor of clinical failure with a sensitivity of 77% and specificity of 93%. CONCLUSIONS: The LiMAx test predicts clinical failure more precisely than linezolid trough levels in critically ill surgical patients. Therefore liver failure may have a stronger impact on the outcome of critically ill surgical patients than low linezolid Cmin. While linezolid Cmin failed to predict patient’s outcome, LiMAx results were the only independent predictor of clinical failure.

Background: Vestibular rehabilitation (VR) is the preferred treatment for chronic vestibular symptoms such as dizziness and vertigo. We developed internet-based VR to increase uptake. Previously, we reported that internet-based VR resulted in a clinically relevant decrease of vestibular symptoms for up to six months, compared to usual care. Aim: To evaluate long-term outcomes of internet-based VR in patients with chronic vestibular syndrome. Design and setting: We conducted a randomised controlled trial in Dutch general practice. 322 participants aged 50 years and older with chronic vestibular syndrome were randomised to stand-alone VR, blended VR (with physiotherapy support), and usual care. Usual care participants were allowed to cross over to stand-alone VR six months after randomisation. Method: We approached participants 36 months after randomisation. Our primary outcome was the presence of vestibular symptoms as measured by the vertigo symptom scale – short form (VSS-SF). Secondary outcomes were dizziness-related impairment, anxiety, depressive symptoms, and health care utilisation. Results: At 36-month follow-up, 65% of participants filled out the VSS-SF. In the usual care group, 38% of participants had crossed over to VR at six months. We found no differences in vestibular symptoms between VR groups and usual care (mean difference -0.8 points, 95%-confidence interval (CI) -2.8 to 1.2, for stand-alone VR; and -0.3, 95%-CI -2.2 to 1.7, for blended VR). In VR groups, clinically relevant improvement compared to baseline maintained over time. Conclusion: Internet-based VR provides a maintained improvement of vestibular symptoms for up to 36 months in patients with chronic vestibular syndrome.

Samenvatting Doel: Het evalueren van het GET READY-terugvalpreventieprogramma voor patiënten met herstelde angst- of depressieve stoornissen in de huisartsenpraktijk. Methode: Er werden semigestructureerde interviews (n = 26) en focusgroepinterviews (n = 2) gehouden met patiënten en praktijkondersteuners huisarts GGZ (POH-GGZ). Patiënten met herstelde angst- of depressieve stoornissen en hun POH-GGZ die deelnamen aan de GET READY-studie werden individueel geïnterviewd. Bevindingen uit de interviews werden getoetst in focusgroepinterviews met patiënten en POH-GGZ. Data werden geanalyseerd door het toepassen van thematische analyse. Resultaat: Patiënten waren positief over het programma omdat het bewustwording creëerde over terugvalrisico’s. Een gebrek aan motivatie, herkenbaarheid en steun van de POH-GGZ, samen met ernst van symptomen waren belemmerend in het gebruik van het programma. POH-GGZ spelen een onmisbare rol in het motiveren en steunen van patiënten bij terugvalpreventie. Opvattingen van patiënten en POH-GGZ kwamen grotendeels overeen, wel hadden zij andere opvattingen over de verantwoordelijkheid qua initiatief nemen. Discussie: De implementatie van het GET READY programma was uitdagend. Begeleiding door de POH-GGZ moet bij terugvalpreventieprogramma’s worden aangeboden op basis van eHealth. Conclusie: Begeleiding door de POH-GGZ moet bij terugvalpreventieprogramma’s, die gebaseerd zijn op eHealth, worden aangeboden.

Extracorporeal membrane oxygenation (ECMO) is utilized to temporarily sustain respiratory and/or cardiac function in critically ill patients. Ciprofloxacin is used to treat nosocomial infections, but data describing the effect of ECMO on its pharmacokinetics is lacking. Therefore, a prospective, observational trial including critically ill adults (n = 17), treated with ciprofloxacin (400 mg 8–12 hourly) during ECMO, was performed. Serial blood samples were collected to determine ciprofloxacin concentrations to assess their pharmacokinetics. The pharmacometric modeling was performed (NONMEM®) and utilized for simulations to evaluate the probability of target attainment (PTA) to achieve an AUC0–24/MIC of 125 mg·h/L for ciprofloxacin. A two-compartment model most adequately described the concentration-time data of ciprofloxacin. Significant covariates on ciprofloxacin clearance (CL) were plasma bicarbonate and the estimated glomerular filtration rate (eGFR). For pathogens with an MIC of ≤0.25 mg/L, a PTA of ≥90% was attained. However, for pathogens with an MIC of ≥0.5 mg/L, plasma bicarbonate ≥ 22 mmol/L or eGFR ≥ 10 mL/min PTA decreased below 90%, steadily declining to 7.3% (plasma bicarbonate 39 mmol/L) and 21.4% (eGFR 150 mL/min), respectively. To reach PTAs of ≥90% for pathogens with MICs ≥ 0.5 mg/L, optimized dosing regimens may be required.

PURPOSE: The prognosis of older patients with dizziness in primary care is unknown. Our objective was to determine the prognosis and survival of patients with different subtypes and causes of dizziness.METHODS: In a primary care prospective cohort study, 417 older adults with dizziness (mean age 79 years) received a full diagnostic workup in 2006-2008. A panel of physicians classified the subtype and primary cause of dizziness. Main outcome measures were mortality and dizziness-related impairment assessed at 10-year follow-up.RESULTS: At 10-year follow-up 169 patients (40.5%) had died. Presyncope was the most common dizziness subtype (69.1%), followed by vertigo (41.0%), disequilibrium (39.8%), and other dizziness (1.7%). The most common primary causes of dizziness were cardiovascular disease (56.8%) and peripheral vestibular disease (14.4%). Multivariable adjusted Cox models showed a lower mortality rate for patients with the subtype vertigo compared with other subtypes (hazard ratio [HR] = 0.62; 95% CI, 0.40-0.96), and for peripheral vestibular disease vs cardiovascular disease as primary cause of dizziness (HR = 0.46; 95% CI, 0.25-0.84). After 10 years, 47.7% of patients who filled out the follow-up measurement experienced substantial dizziness-related impairment. No significant difference in substantial impairment was seen between different subtypes and primary causes of dizziness.CONCLUSIONS: The 10-year mortality rate was lower for the dizziness subtype vertigo compared with other subtypes. Patients with dizziness primarily caused by peripheral vestibular disease had a lower mortality rate than patients with cardiovascular disease. Substantial dizziness-related impairment in older patients with dizziness 10 years later is high, and indicates that current treatment strategies by family physicians may be suboptimal.

Dalbavancin is emerging as a promising alternative in the ambulant treatment of gram-positive infections that require long-term antibiotic treatment such as osteomyelitis, prosthetic joint infections, and endocarditis. The aim of the current study was to develop and validate a simple, rapid, and cost-effective high-performance liquid chromatography–ultraviolet spectrometry (HPLC–UV) method for the quantification of dalbavancin. Sample clean-up included a protein precipitation protocol, followed by chromatographic separation on a reverse phase HPLC column (C-18) with gradient elution of the mobile phase. Quantification was performed with the internal standard (caffeine) method. Linear relationships between peak area responses and drug concentrations were obtained in the range of 12.5–400 mg/L. The variation coefficient of precision and the bias of accuracy (both inter- and intraday) were less than 10%. The limit of quantification (LOQ) was 12.5 mg/L. The simple and reliable HPLC–UV assay described is a powerful tool for routine therapeutic drug monitoring (TDM) of dalbavancin in human serum in clinical laboratories. With a total process time of approximately 20 min, it allows for accurate and selective quantification up to the expected pharmacokinetic peak concentrations. The method was successfully used to analyze subsequent serum samples of three patients and showed good performance in monitoring serum levels.

Background The Vertigo Symptom Scale – Short Form (VSS-SF) is a widely used questionnaire to measure vestibular symptoms such as dizziness and vertigo. We aimed to translate and cross-culturally validate the Dutch version of the VSS-SF. Methods We performed a psychometric evaluation study in general practice. First, we followed international guidelines to translate the VSS-SF into Dutch. We assessed the comprehensibility of the Dutch translation by interviewing 20 older adults with dizziness. Next, we used data from patients aged 50 years and older with chronic dizziness who participated in British (n=296) and Dutch (n=322) randomized controlled trials to evaluate measurement invariance. In this cross-cultural validation analysis we used ordinal logistic regression to detect potential differential item functioning (DIF) and differential test functioning (DTF). ResultsAccording to the 20 patients we interviewed, the Dutch translation of the VSS-SF was clear and comprehensible. We detected small DIF on 2 of the 15 items of the questionnaire. However, the effect of these DIFs on the overall scale was negligible. ConclusionsWe developed a comprehensible and cross-culturally valid Dutch translation of the VSS-SF. This questionnaire can be used to assess vestibular symptoms in general practice.

BackgroundPersonal continuity of care is a core value of general practice. It is increasingly threatened by societal and healthcare changes.AimTo investigate the association between personal continuity and both practice and patient characteristics; and to incorporate GPs’ views to enrich and validate the quantitative findings.Design and settingA mixed-methods study based on observational, routinely collected healthcare data from 269 478 patients from 48 Dutch general practices (2013–2018) and interviews with selected GPs.MethodFirst, four different personal continuity outcome measures were calculated relating to eight practice and 12 patient characteristics using multilevel linear regression analyses. Second, a thematic analysis was performed of semi-structured interviews with 10 GPs to include their views on factors contributing to personal (dis) continuity. These GPs worked at the 10 practices with the largest difference between calculated and model-estimated personal continuity.ResultsBoth a larger number of usual GPs working in a practice and a larger percentage of patient contacts with locum GPs were dose-dependently associated with lower personal continuity (highest versus lowest quartile −0.094 and −0.092, respectively,PPConclusionPersonal continuity is associated with practice and patient characteristics. The dose-dependent associations suggest a causal relationship and, complemented by GPs’ views, may provide practical targets to improve personal continuity directly.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the benefits and harms of positive pressure therapy for Ménière's disease.

BackgroundIdentification of community-dwelling older adults at risk of unplanned hospitalizations is of importance to facilitate preventive interventions. Our objective was to review and appraise the methodological quality and predictive performance of prediction models for predicting unplanned hospitalizations in community-dwelling older adultsMethods and findingsWe searched MEDLINE, EMBASE and CINAHL from August 2013 to January 2021. Additionally, we checked references of the identified articles for the inclusion of relevant publications and added studies from two previous reviews that fulfilled the eligibility criteria. We included prospective and retrospective studies with any follow-up period that recruited adults aged 65 and over and developed a prediction model predicting unplanned hospitalizations. We included models with at least one (internal or external) validation cohort. The models had to be intended to be used in a primary care setting. Two authors independently assessed studies for inclusion and undertook data extraction following recommendations of the CHARMS checklist, while quality assessment was performed using the PROBAST tool. A total of 19 studies met the inclusion criteria. Prediction horizon ranged from 4.5 months to 4 years. Most frequently included variables were specific medical diagnoses (n = 11), previous hospital admission (n = 11), age (n = 11), and sex or gender (n = 8). Predictive performance in terms of area under the curve ranged from 0.61 to 0.78. Models developed to predict potentially preventable hospitalizations tended to have better predictive performance than models predicting hospitalizations in general. Overall, risk of bias was high, predominantly in the analysis domain.ConclusionsModels developed to predict preventable hospitalizations tended to have better predictive performance than models to predict all-cause hospitalizations. There is however substantial room for improvement on the reporting and analysis of studies. We recommend better adherence to the TRIPOD guidelines.

Linezolid is a treatment option against multi-drug-resistant Gram-positive pathogens. Continuous infusion of linezolid has been proposed to optimize antimicrobial exposure, although pharmacokinetic data from large patient cohorts are lacking.Population pharmacokinetics and the time-dependent association between linezolid exposure and the occurrence of thrombocytopenia in 120 critically ill patients were described. Monte Carlo simulations evaluated pharmacokinetic/pharmacodynamic/toxicodynamic target attainment in relation to body weight and creatinine clearance for continuously infused doses of 300-2400 mg/day.Linezolid pharmacokinetics were highly variable (interindividual variability of clearance: 52.8% coefficient of variation). Non-linear clearance was quantified, which decreased from 6.82 to 3.82 L/h within 3-6 days in the population. A relationship between linezolid exposure and platelet count over time was established. For standard dosing (1200 mg/day), the model predicted Grade 2, 3 or 4 thrombocytopenia (75 × 10Dosing linezolid by continuous infusion should include considerations of creatinine clearance and body weight to maximize the achievement of therapeutic exposures. However, due to the high variability in individual dose, optimization using TDM seems necessary to optimize linezolid dosing under continuous infusion to avoid toxicity, particularly if longer treatment courses are expected.

Background Accurate identification of older persons at risk of unplanned hospital visits can facilitate preventive interventions. Several risk scores have been developed to identify older adults at risk of unplanned hospital visits. It is unclear whether risk scores developed in one country, perform as well in another. This study validates seven risk scores to predict unplanned hospital admissions and emergency department (ED) visits in older home care recipients from six countries. Methods We used the IBenC sample (n = 2446), a cohort of older home care recipients from six countries (Belgium, Finland, Germany, Iceland, Italy and The Netherlands) to validate four specific risk scores (DIVERT, CARS, EARLI and previous acute admissions) and three frailty indicators (CHESS, Fried Frailty Criteria and Frailty Index). Outcome measures were unplanned hospital admissions, ED visits or any unplanned hospital visits after 6 months. Missing data were handled by multiple imputation. Performance was determined by assessing calibration and discrimination (area under receiver operating characteristic curve (AUC)). Results Risk score performance varied across countries. In Iceland, for any unplanned hospital visits DIVERT and CARS reached a fair predictive value (AUC 0.74 [0.68–0.80] and AUC 0.74 [0.67–0.80]), respectively). In Finland, DIVERT had fair performance predicting ED visits (AUC 0.72 [0.67–0.77]) and any unplanned hospital visits (AUC 0.73 [0.67–0.77]). In other countries, AUCs did not exceed 0.70. Conclusions Geographical validation of risk scores predicting unplanned hospital visits in home care recipients showed substantial variations of poor to fair performance across countries. Unplanned hospital visits seem considerably dependent on healthcare context. Therefore, risk scores should be validated regionally before applied to practice. Future studies should focus on identification of more discriminative predictors in order to develop more accurate risk scores.

IntroductionSurgical site infections (SSIs) are among the most common complications after abdominal surgery and develop in approximately 20% of patients. These patients suffer a 12% increase in mortality, underlying the need for strategies reducing SSI. Perioperative antibiotic prophylaxis is paramount for SSI prevention in major abdominal surgery. Yet, intraoperative redosing criteria are subjective and whether patients benefit from it remains unclear.Methods and analysisThe REpeat versus SIngle ShoT Antibiotic prophylaxis in major Abdominal Surgery (RESISTAAS I) study is a single-centre, prospective, observational study investigating redosing of antibiotic prophylaxis in 300 patients undergoing major abdominal surgery. Adult patients scheduled for major abdominal surgery will be included. Current practice of redosing regarding number and time period will be recorded. Postoperative SSIs, nosocomial infections, clinically relevant infection-associated bacteria, postoperative antibiotic treatment, in addition to other clinical, pharmacological and economical outcomes will be evaluated. Differences between groups will be analysed with analysis of covariance.Ethics and disseminationRESISTAAS I will be conducted in accordance with the Declaration of Helsinki and internal, national and international standards of GCP. The Medical Ethics Review Board of Heidelberg University has approved the study prior to initiation (S-404/2021). The study has been registered on 7 February 2022 at German Clinical Trials Register, with identifier DRKS00027892. We plan to disseminate the results of the study in a peer-reviewed journal.Trial registrationGerman Clinical Trials Register (DRKS): DRKS00027892.

PURPOSE In critically ill patients, changes in the pharmacokinetics (PK) of β-lactams can lead to significant variations in serum concentrations, with possibly detrimental effects on outcomes. The utilization of individually calculated doses, extended infusion regimens, and therapeutic drug monitoring (TDM)-guided dose adjustments can mitigate the PK changes and help to achieve and attain an individual PK target. METHODS We reviewed relevant literature from 2004-2021 using four search engines (PubMed, Web of Science, Scopus, and Google Scholar). Unpublished clinical data were also examined. RESULTS TDM-guided, individualized dosing strategies facilitated PK target attainment and improved patient outcomes. TDM-guided therapy is a core concept of individualized dosing that increases PK target attainment and monitors possible toxic β-lactam concentrations. CONCLUSION Individualized dosing and TDM facilitate the rational use of β-lactams and are integral for antibiotic stewardship interventions in critical care, affording both the optimal exposure of pathogen and drugs, along with enhanced treatment efficacy and reduced emergence of antimicrobial resistance.

उपचार आर्द्रभूमियााँ ‘जैविक अपमिष्ट जल’ िें सातिाृं खृंड है उपचार श्ृंखर ला, जो सीिेज उपचार के विज्ञान और तकनीक की अत्याधुननक प्रस्तुनत देती है। आर्द्रभूमि प्रणामलयों के प्रिुख प्रकार इस खृंड िें िामिल हैं, नाितः: (i) क्षैनतज प्रिाह आर्द्रभूमि; (ii) ऊध्िारधर प्रिाह आर्द्रभूमि; (iii) फ्रें च ऊध्िारधर प्रिाह आर्द्रभूमि; (iv) सघन आर्द्रभूमि; (v) िुक्त जल सतह आर्द्रभूमि; (vi) उपचार आर्द्रभूमि के अन्य अनुप्रयोि। पुस्तक िुख्य अिधारणाओृं, कािकाजी मसद्धाृंतों, अपेक्षक्षत प्रदिरन, डडजाइन िानदृंड, डडजाइन उदाहरण, ननिारण पहलुओृं और पररचालन द्रदिाननदेिों को स्पष्ट और उपचारात्िक तरीके से प्रस्तुत करती है। पुस्तक को उपचार के क्षेत्र के िीर्र वििेर्ज्ञों की एक अृंतरराष्रीय टीि ने मलखा है। श्ृंखर ला के बारे िें: इस बहुप्रिृंमसत श्ृंखर ला िें सात पाठ्यपुस्तकें िामिल हैं - वप्रटृं िें या िुक्त-अमभिि ई-पुस्तकों के रूप िें उपलब्लध - जो जैविक अपमिष्ट जल उपचार के विज्ञान और तकनीक की एक अत्याधुननक प्रस्तुनत प्रदान करती हैं। विकमसत और विकासिील देिों िें छात्रों, िोधकतारओृं और अभ्यासकों द्िारा श्ृंखर ला के सभी खण्डों का व्यापक रूप से उपयोि क्रकया िया है। जैविक अपमिष्ट जल उपचार श्ृंखर ला िें िीर्कर हैं: खृंड 1: अपमिष्ट जल के लक्षण, उपचार और ननपटानखृंड 2: अपमिष्ट जल उपचार के िूल मसद्धाृंतखृंड 3: अपमिष्ट स्स्िरीकरण तालाबखृंड 4: अिायािीय ररएक्टरखृंड 5: सक्रिय कीचड़ और िायुजीिी बायोक्रिल्ि ररएक्टरखृंड 6: कीचड़ उपचार और ननपटानखृंड 7: उपचार आर्द्रभूमियााँ आईएसबीएन: 9781780408767 (पेपरबैक) आईएसबीएन: 9781789062564 (ई-पुस्तक)

RBP-6000, referred to as BUP-XR (extended-release buprenorphine), is a subcutaneously injected, monthly buprenorphine treatment for opioid use disorder. BUP-XR provides sustained buprenorphine plasma concentrations to block drug-liking of abused opioids over the entire monthly dosing period, while controlling withdrawal and craving symptoms. Administration of BUP-XR in a health-care setting also mitigates abuse, misuse, diversion, and unintentional exposure. We aimed to investigate the efficacy of different BUP-XR dosing regimens in participants with opioid use disorder.This randomised, double-blind, placebo-controlled, phase 3 trial was done at 36 treatment centres in the USA. Treatment-seeking adults aged 18-65 years who had moderate or severe opioid use disorder (as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders) entered an open-label run-in phase of up to 2 weeks' treatment with buprenorphine-naloxone sublingual film. Eligible participants were then randomly assigned (4:4:1:1) with an interactive voice/web-response system to receive BUP-XR 300 mg/300 mg (six injections of 300 mg), BUP-XR 300 mg/100 mg (two injections of 300 mg plus four injections of 100 mg), or volume-matched placebo every 28 days, and received weekly individual drug counselling. No supplemental buprenorphine was allowed. The primary efficacy endpoint was participants' percentage abstinence from opioid use, defined as the percentage of each participant's negative urine samples and self-reports of illicit opioid use from week 5 to week 24, analysed in the full analysis set. Safety was assessed in all participants who received at least one dose of BUP-XR or placebo. This study is registered with ClinicalTrials.gov, number NCT02357901.From Jan 28, 2015, to Nov 12, 2015, 1187 potential participants were screened, 665 entered run-in, and 504 received BUP-XR 300 mg/300 mg (n=201), BUP-XR 300 mg/100 mg (n=203), or placebo (n=100). Mean participants' percentage abstinence was 41·3% (SD 39·7) for BUP-XR 300 mg/300 mg and 42·7% (38·5) for 300 mg/100 mg, compared with 5·0% (17·0) for placebo (p0·0001 for both BUP-XR regimens). No compensatory non-opioid drug use was observed during BUP-XR treatment. The most common adverse events were headache (17 [8%] participants in the BUP-XR 300 mg/300 mg group vs 19 [9%] participants in the BUP-XR 300 mg/100 mg group vs six [6%] participants in the placebo group), constipation (16 [8%] vs 19 [9%] vs 0), nausea (16 [8%] vs 18 [9%] vs five [5%]), and injection-site pruritis (19 [9%] vs 13 [6%] vs four [4%]). The BUP-XR safety profile was consistent with other buprenorphine products for treatment of opioid use disorder, except for injection-site reactions, which were reported in more than 5% of all participants who received BUP-XR, but were mostly mild and not treatment-limiting.Participants' percentage abstinence was significantly higher in both BUP-XR groups than in the placebo group. Treatment with BUP-XR was also well tolerated. The availability of this monthly formulation, delivered by health-care providers, represents an advance in treatment for opioid use disorder that enhances the benefits of buprenorphine by delivering sustained, optimal exposure, while reducing risks of current buprenorphine products.Indivior.

Objectives: The aim of this study is to describe the in vitro adsorption of anti-infective drugs onto an extracorporeal cytokine adsorber. Methods: Various anti-infective drugs (β-lactams, quinolones, aminoglycosides, glycopeptides, azole antimycotics) were prepared in normal saline 0.9% and human albumin 5%, and pumped through a cytokine cartridge (CytoSorb®; CytoSorbents Corporation, Monmouth Junction, NJ, USA) at a flow rate of 1.2 L/h for 1.5 h. In addition, meropenem and ciprofloxacin were dissolved in reconstituted blood and run through a CytoSorb cartridge, which was integrated into a continuous renal replacement therapy circuit with a flow rate of 2 L/h for 18 h. Samples from the solution, pre- and post-filter, were quantified by high-performance liquid chromatography with ultraviolet detection and fluorescence polarisation immunoassay. Results: Observed mean clearance of the drugs in normal saline was 1.22 ± 0.07 L/h. In human albumin, clearance was 1.29 ± 0.08 L/h. In reconstituted blood, clearance of meropenem decreased from 5.4 to 1.4 L/h and for ciprofloxacin from 6.3 to 4.3 L/h within the first 1.5 h because of early drug adsorption. Continuous renal replacement therapy clearance measured without CytoSorb was stable at 2 and 1.7 L/h, respectively. Approximately 400 mg of meropenem and 300 mg of ciprofloxacin had been adsorbed by CytoSorb, suggesting that these amounts are the maximum adsorptive capacity for these drugs. Conclusion: In these settings, all tested drugs were adsorbed by the cartridge in relevant amounts. The identified maximum adsorptive capacity and the rapid decline in concentration during the first 1.5 h of CytoSorb use suggest that the administration of an additional dose within the first hours of CytoSorb treatment may be reasonable. In addition, early therapeutic drug monitoring should be considered.

Objective: To analyze the genetic uniformity of MSXJ hybrid papaya in vitro plants, obtained by direct organogenesis.Design/Methodology/Approach: The MSXJ papaya hybrid demonstrates quality characteristics for the national and exports market. In vitro culture of plant tissues represents a useful tool for their multiplication and conservation, but somaclonal variation can diminish their genetic and agronomic uniformity. In order to analyze the genetic uniformity of in vitro plants of this hybrid, ten ISSR primers were used for in vitro plants micropropagated during nine subcultures. DNA was extracted using the CTAB method. Data were analyzed using the program PopGene v 1.3.1.Results: Eighty-five loci of 200 to up to 2000 pb were generated, with 37 polymorphic loci. In the cluster analysis, three groups were observed which separate subculture one, subcultures two to eight, and subculture nine; the Gst value of 0.87 indicated genetic uniformity as far as subculture eight.Study Limitations/Implications: Papaya is one of the most important tropical fruits worldwide; however, these plants need to be healthy and genetically uniform to guarantee commercial success. In vitro propagation allows obtaining healthy and uniform plants, but it is necessary to study genetic uniformity during their micropropagation.Findings/Conclusions: The in vitro multiplication of the MSXJ papaya hybrid permitted the regeneration of vigorous plants in 30 d. Molecular profiles indicate that as far as subculture eight, there is genetic uniformity. As such, no more thaneight subcultures are recommended during micropropagation.

Objective: To identify the sex of in vitro plants of papaya (Carica papaya L.) MSXJhybrid obtained via somatic organogenesis, through SCAR type molecular markers. Design/Methodology/Approach: Eight-month old MSXJ papaya hybrid plants in thefructification stage were collected in Cotaxtla, Veracruz, Mexico. They weresuperficially disinfected with abundant running water, detergent during 30 min, andthen alcohol at 70% was added for one minute, commercial chlorine at 30% for 30min, and they were rinsed with sterile distilled water; then the meristems werecultivated in MS medium and after 30 d a subculture was made. The DNA extractionwas made with the CTAB method, and the DNA PCR was done with the Deputy et al.(2002) method, and the primers T1, T12 and W11 were used.Results: The T1 primer was the positive control and the T12 and W11 primersallowed the amplification of fragments that identify hermaphrodite, feminine and maleplants, while the T12 and W11 primers were specific for hermaphrodite plants.Study Limitations/Implications: It is required to standardize the method for it to beinexpensive.Findings/Conclusions: The sexuality of papaya plants can be differentiated until thestage of flowering, which is why the implementation of molecular markers wouldfacilitate plant selection if it is implemented at a large scale. Costs, maintenance timeand elimination of plants of unwanted sex are reduced this way.

Background Existing studies have yet to investigate the perspectives of patients and professionals concerning relapse prevention programs for patients with remitted anxiety or depressive disorders in primary care. User opinions should be considered when optimizing the use and implementation of interventions. Objective This study aimed to evaluate the GET READY relapse prevention programs for patients with remitted anxiety or depressive disorders in general practice. Methods Semistructured interviews (N=26) and focus group interviews (N=2) with patients and mental health professionals (MHPs) in the Netherlands were performed. Patients with remitted anxiety or depressive disorders and their MHPs who participated in the GET READY study were interviewed individually. Findings from the interviews were tested in focus group interviews with patients and MHPs. Data were analyzed using thematic analysis. Results Participants were positive about the program because it created awareness of relapse risks. Lack of motivation, lack of recognizability, lack of support from the MHP, and symptom severity (too low or too high) appeared to be limiting factors in the use of the program. MHPs play a crucial role in motivating and supporting patients in relapse prevention. The perspectives of patients and MHPs were largely in accordance, although they had different perspectives concerning responsibilities for taking initiative. Conclusions The implementation of the GET READY program was challenging. Guidance from MHPs should be offered for relapse prevention programs based on eHealth. Both MHPs and patients should align their expectations concerning responsibilities in advance to ensure optimal usage. Usage of blended relapse prevention programs may be further enhanced by diagnosis-specific programs and easily accessible support from MHPs. International Registered Report Identifier (IRRID) RR2-10.1186/s12888-019-2034-6

Additional file 2. : Comprehensive description of risk scores. This file elaborates on how the risk scores assessed in this article were developed.

Additional file 3. : Baseline characteristics of the IBenC data. This table provides information on the baseline characteristics of each country subcohort within the IBenC study

Additional file 3. Description of the determinants for implementation of healthcare innovations.

Additional file 1. Royal College of General Practitioners Continuity of Care Toolkit.

Additional file 6. : Calibration plots. Calibration plots of the risk scores for each country, provided this could be assessed.

Additional file 4. Data management plan.

Additional file 5. : Distribution of the risk scores. Descriptive statistics of each of the seven risk scores per country

Additional file 1. : Loss to follow-up and elaboration on multiple imputation methodology. This file shows the flow of the IBenC cohort for this article and how missing data was handled. It also elaborates on the MI method, such as the methods used for imputation and selected key variables.

Additional file 2. Unpublished observations by van Stippend and Schers (2016). The Usual Provider Continuity index (UPC) was calculated among 9 general practices in the Nijmegen area (the Netherlands). The UPC is used to measure personal continuity and is calculated as the number of contacts with the own GP divided by the total number of general practice contacts during the study period. The score of the UPC index varies between 0 (low personal continuity) and 1 (high personal continuity)

Background We aimed to compare different methods to treat lower leg soft tissue defects with tibia fracture using free flaps and pedicled flaps. We also highlighted the aesthetic outcome after using 1-stage secondary debulking procedure for tibia area. Patients and methods From December 2000 to March 2017, 83 patients with lower leg defects and tibia fractures were reconstructed using 71 free flaps and 12 pedicled flaps. One-stage secondary debulking procedures were performed for 39 patients after flap reconstruction. Infection control and aesthetic outcomes using 5-point Likert scale were reviewed after a 16-month follow-up. Results Twenty-five myocutaneous free flaps, 45 fasciocutaneous free flaps, 1 fibula free flap, 12 pedicled flaps of which 8 were distally based sural artery flaps, and 4 medial gastrocnemius flaps were used. The flap survival rate was 100%. There was no recurrence of osteomyelitis in any patient after reconstruction with any of these flaps. Using a 5-point Likert scale, performance of a 1-stage secondary debulking procedure showed statistically significant difference in terms of contour, color, and texture compared with the group without debulking procedure. Conclusions The use of free flaps and pedicled flaps in the reconstruction of lower leg defects with tibia fracture is reliable and results in good infection control. A 1-stage secondary debulking procedure delivers excellent long-term aesthetic outcome after reconstruction of the tibia area.

BACKGROUND Given that relapse is common in patients in remission from anxiety and depressive disorders, relapse prevention is needed in the maintenance phase. Although existing psychological relapse prevention interventions have proven to be effective, they are not explicitly based on patients’ preferences. Hence, we developed a blended relapse prevention program based on patients’ preferences, which was delivered in primary care practices by mental health professionals (MHPs). This program comprises contact with MHPs, completion of core and optional online modules (including a relapse prevention plan), and keeping a mood and anxiety diary in which patients can monitor their symptoms. OBJECTIVE The aims of this study were to provide insight into (1) usage intensity of the program (over time), (2) the course of symptoms during the 9 months of the study, and (3) the association between usage intensity and the course of symptoms. METHODS The Guided E-healTh for RElapse prevention in Anxiety and Depression (GET READY) program was guided by 54 MHPs working in primary care practices. Patients in remission from anxiety and depressive disorders were included. Demographic and clinical characteristics, including anxiety and depressive symptoms, were collected via questionnaires at baseline and after 3, 6, and 9 months. Log data were collected to assess the usage intensity of the program. RESULTS A total of 113 patients participated in the study. Twenty-seven patients (23.9%) met the criteria for the minimal usage intensity measure. The core modules were used by ≥70% of the patients, while the optional modules were used by CONCLUSIONS Although the core modules of the GET READY program were used by most of the patients and all patients saw an MHP at least once, usage decreased quickly over time. Most patients remained stable while participating in the study. The significant association between the frequency of contact and the course of symptoms most likely indicates that those who received more support had more symptoms, and thus, it is questionable whether the support offered by the program was sufficient to prevent these patients from relapsing. INTERNATIONAL REGISTERED REPORT RR2-10.1186/s12888-019-2034-6

Background Given that relapse is common in patients in remission from anxiety and depressive disorders, relapse prevention is needed in the maintenance phase. Although existing psychological relapse prevention interventions have proven to be effective, they are not explicitly based on patients’ preferences. Hence, we developed a blended relapse prevention program based on patients’ preferences, which was delivered in primary care practices by mental health professionals (MHPs). This program comprises contact with MHPs, completion of core and optional online modules (including a relapse prevention plan), and keeping a mood and anxiety diary in which patients can monitor their symptoms. Objective The aims of this study were to provide insight into (1) usage intensity of the program (over time), (2) the course of symptoms during the 9 months of the study, and (3) the association between usage intensity and the course of symptoms. Methods The Guided E-healTh for RElapse prevention in Anxiety and Depression (GET READY) program was guided by 54 MHPs working in primary care practices. Patients in remission from anxiety and depressive disorders were included. Demographic and clinical characteristics, including anxiety and depressive symptoms, were collected via questionnaires at baseline and after 3, 6, and 9 months. Log data were collected to assess the usage intensity of the program. Results A total of 113 patients participated in the study. Twenty-seven patients (23.9%) met the criteria for the minimal usage intensity measure. The core modules were used by ≥70% of the patients, while the optional modules were used by Conclusions Although the core modules of the GET READY program were used by most of the patients and all patients saw an MHP at least once, usage decreased quickly over time. Most patients remained stable while participating in the study. The significant association between the frequency of contact and the course of symptoms most likely indicates that those who received more support had more symptoms, and thus, it is questionable whether the support offered by the program was sufficient to prevent these patients from relapsing. International Registered Report Identifier (IRRID) RR2-10.1186/s12888-019-2034-6

Background Due to high pharmacokinetic variability, standard doses of meropenem are frequently inadequate in septic patients. Therapeutic drug monitoring of meropenem is not widely available; therefore, improved empiric dosing recommendations are needed. Objectives This study aimed to compare the attainment of pharmacologic targets for two common empirical dosing regimens for meropenem in patients with septic shock. Methods Two empiric dosing schemes for meropenem were compared using extended infusions (120 minutes) in 32 patients with septic shock in the intensive care units at two different hospitals. One regimen was 3 × 2 g meropenem/24 h for two days, followed by 3 × 1 g meropenem/24 h; the other regimen was 4 × 1 g meropenem/24 h. Serum meropenem concentrations were measured for the first 72 h of therapy, and pharmacokinetic modelling was performed to define the percentage of time the free drug concentration was above various target MICs for each regimen (%fT>MIC). Results Both regimens led to a sufficiently high %fT>MIC for pathogens with target MICs MIC of 4 × 1 g meropenem decreased faster than that of 3 × 2 g meropenem. At high MICs of 32 mg/L, both dosing regimens failed to provide appropriate drug concentrations. Renal function was a significant covariate of target attainment. Conclusions The results of this study can guide clinicians in their choice of an empirical dosing regimen for meropenem. If pathogens with low MICs (

BACKGROUND Existing studies have yet to investigate the perspectives of patients and professionals concerning relapse prevention programs for patients with remitted anxiety or depressive disorders in primary care. User opinions should be considered when optimizing the use and implementation of interventions. OBJECTIVE This study aimed to evaluate the GET READY relapse prevention programs for patients with remitted anxiety or depressive disorders in general practice. METHODS Semistructured interviews (N=26) and focus group interviews (N=2) with patients and mental health professionals (MHPs) in the Netherlands were performed. Patients with remitted anxiety or depressive disorders and their MHPs who participated in the GET READY study were interviewed individually. Findings from the interviews were tested in focus group interviews with patients and MHPs. Data were analyzed using thematic analysis. RESULTS Participants were positive about the program because it created awareness of relapse risks. Lack of motivation, lack of recognizability, lack of support from the MHP, and symptom severity (too low or too high) appeared to be limiting factors in the use of the program. MHPs play a crucial role in motivating and supporting patients in relapse prevention. The perspectives of patients and MHPs were largely in accordance, although they had different perspectives concerning responsibilities for taking initiative. CONCLUSIONS The implementation of the GET READY program was challenging. Guidance from MHPs should be offered for relapse prevention programs based on eHealth. Both MHPs and patients should align their expectations concerning responsibilities in advance to ensure optimal usage. Usage of blended relapse prevention programs may be further enhanced by diagnosis-specific programs and easily accessible support from MHPs. INTERNATIONAL REGISTERED REPORT RR2-10.1186/s12888-019-2034-6

Several months of field work in La Palma (western Canary Islands) yielded a number of interesting new records of non-native vascular plants. Alstroemeria aurea, A. ligtu, Anacyclus radiatus subsp. radiatus, Chenopodium album subsp. borbasii, Cotyledon orbiculata, Cucurbita ficifolia, Cynodon nlemfuensis, Datura stramonium subsp. Tatula, Digitaria ciliaris var. rhachiseta, D. ischaemum, Diplotaxis tenuifolia, Egeria densa, Eugenia uniflora, Galinsoga quadriradiata, Glebionis segetum, Kalanchoe laetivirens, Lemna minuta, Ligustrum lucidum, Lotus broussonetii, Oenothera fallax, Paspalum notatum, Passiflora caerulea, P. manicata × tarminiana, P. tarminiana, Pelargonium capitatum, Phaseolus lunatus, Portulaca trituberculata, Pyracantha angustifolia, Sedum mexicanum, Trifolium lappaceum, Urochloa mutica, U. subquadripara and Volutaria tubuliflora are naturalized or (potentially) invasive xenophytes or of special floristic interest, reported for the first time from either the Canary Islands or La Palma. Three additional, presumably ephemeral taxa are reported for the first time from the Canary Islands, whereas seven ephemeral taxa are new for La Palma. Varios meses de trabajos de campo en La Palma (Islas Canarias occidentales) han posibilitado el descubrimiento de nuevas plantas vasculares no nativas. Alstroemeria aurea, A. ligtu, Anacyclus radiatus subsp. Radiatus, Chenopodium album subsp. borbasii, Cotyledon orbiculata, Cucurbita ficifolia, Cynodon nlemfuensis, Datura stramonium subsp. tatula, Digitaria ciliaris var. rhachiseta, D. ischaemum, Diplotaxis tenuifolia, Egeria densa, Eugenia uniflora, Galinsoga quadriradiata, Glebionis segetum, Kalanchoe laetivirens, Lemna minuta, Ligustrum lucidum, Lotus broussonetii, Oenothera fallax, Paspalum notatum, Passiflora caerulea, P. manicata × tarminiana, P. tarminiana, Pelargonium capitatum, Phaseolus lunatus, Portulaca trituberculata, Pyracantha angustifolia, Sedum mexicanum, Trifolium lappaceum, Urochloa mutica, U. subquadripara y Volutaria tubuliflora son xenófitos naturalizados o (potencialmente) invasores o de especial interés florístico, que se citan por primera vez para las Islas Canarias o para la isla de La Palma. Tres táxones adicionales, probablemente casuales, se dan a conocer por primera vez de las Islas Canarias, y siete táxones de la isla de La Palma.

Pathophysiological changes are important risk factors for critically ill patients with pneumonia manifesting sub-therapeutic antibiotic exposures during empirical treatment. The effect of coronavirus disease 2019 (COVID-19) on antibiotic dosing requirements is uncertain. We aimed to determine the effect of COVID-19 on ß-lactam pharmacokinetics (PK) and PK target attainment in critically ill patients with a personalized dosing strategy. Retrospective, single-center analysis of COVID-19 ± critically ill patients with pneumonia (community-acquired pneumonia or hospital-acquired pneumonia) who received continuous infusion of a ß-lactam antibiotic with dosing personalized through dosing software and therapeutic drug monitoring. A therapeutic exposure was defined as serum concentration between (css) 4 to 8 times the EUCAST non-species related breakpoint). Data from 58 patients with pneumonia was analyzed. Nineteen patients were tested COVID-19-positive before the start of the antibiotic therapy for community-acquired pneumonia or hospital-acquired pneumonia. Therapeutic exposure was achieved in 71% of COVID-19 patients (68% considering all patients). All patients demonstrated css above the non–species-related breakpoint. Twenty percent exceeded css above the target range (24% of all patients). The median ß-lactam clearance was 49% compared to ß-lactam clearance in a standard patient without a significant difference regarding antibiotic, time of sampling or present COVID-19 infection. Median daily doses were 50% lower compared to standard bolus dosing. COVID-19 did not significantly affect ß-lactam pharmacokinetics in critically ill patients. Personalized ß-lactam dosing strategies were safe in critically ill patients and lead to high PK target attainment with less resources.

Patients in the intensive care unit frequently require antibiotic treatment. Liver impairment poses substantial challenges for dose selection in these patients. The aim of the present pilot study was to assess the novel maximal liver function capacity (LiMAx test) in comparison with conventional liver function markers as covariates of drug clearance in liver failure using linezolid as a model drug. A total of 28 patients with different degrees of liver failure were recruited. LiMAx test as well as plasma, dialysate and urine sampling were performed under linezolid steady-state therapy (600 mg twice daily). NONMEM® was used for a pharmacometric analysis in which the different clearance routes of linezolid were elucidated. Linezolid pharmacokinetics was highly variable in patients with liver failure. The LiMAx score displayed the strongest association with non-renal clearance (CLnon-renal) [ = 4.46∙(body weight/57.9) 0.75∙(LiMAx/221.5)0.388 L/h], which reduced interindividual variability in CLnon-renal from 46.6% to 33.6%, thereby being superior to other common markers of liver function (international normalised ratio, gamma-glutaryl transferase, bilirubin, thrombocytes, alanine aminotransferase, aspartate aminotransferase). For LiMAx < 100 µg/kg/h, 64% of linezolid trough concentrations were above the recommended trough concentration of 8 mg/L, indicating the necessity of therapeutic drug monitoring in these patients. This is the first pilot application of the LiMAx test in a pharmacokinetic (PK) study demonstrating its potential to explain PK variability in linezolid clearance. Further studies with a larger patient collective and further drugs are highly warranted to guide dosing in patients with severe liver impairment.

This study’s aim was to establish a protocol for the micropropagation of G. skinneri using temporary immersion system (TIS). Different concentrations of 6-Benzylaminopurine (0, 1, 2, and 3 mg L(−1)), three different systems of cultivate semi-solid (SS) and liquid media under partial (PI) and temporary immersion systems (TIS), different compositions of the inorganic salts, and the number of subcultures were evaluated. The results showed a maximum of 16.56 shoots per explant obtained through TIS, adjusting all the parameters evaluated in our study. One higher number of shoots per explant was observed in the micropropagation of G. skinneri TIS compared to SS and PI. While the use of 3 mg L(−1) of BAP + MS (Murashige and Skoog) media was better than 3 mg L(−1) of BAP VW (Vacint and Went) for the generation of a greater number of shoots per explant, 6.33 and 2.72, respectively. The immersion frequency of 2 min every 4 h allowed the production to be scaled to 8.54 shoots per explant. While it was necessary to perform three subcultures every 30 days, to obtain 16.56 shoots per explant, a rooting phase was not required due to the generation of adventitious roots during the different subcultures. However, a phase of elongation of the regenerated plants with ½ MS + GA3 (gibberellic acid) was needed to guarantee 100% survival in the process of acclimatization. In conclusion, this plant production system can be applied for the commercial micropropagation of this species for ornamental purposes, as well as for its reintroduction in protected natural areas.