Implementation of Enhanced Recovery (ERAS) in Colorectal Surgery Has a Positive Impact on Non-ERAS Liver Surgery Patients.

BACKGROUND: Enhanced recovery after surgery (ERAS) reduces complications and hospital stay in colorectal surgery. Thereafter, ERAS principles were extended to liver surgery. Previous implementation of an ERAS program in colorectal surgery may influence patients undergoing liver surgery in a non-ERAS setting, on the same ward. This study aimed to test this hypothesis. METHODS: Retrospective analysis based on prospective data of the adherence to the institutional ERAS-liver protocol (compliance) in three cohorts of consecutive patients undergoing elective liver surgery, between June 2010 and July 2014: before any ERAS implementation (pre-ERAS n = 50), after implementation of ERAS in colorectal (intermediate n = 50), and after implementation of ERAS in liver surgery (ERAS-liver n = 74). Outcomes were functional recovery, postoperative complications, hospital stay, and readmissions. RESULTS: The three groups were comparable for demographics; laparoscopy was more frequent in ERAS-liver (p = 0.009). Compliance with the enhanced recovery protocol increased along the three periods (pre-ERAS, intermediate, and ERAS-liver), regardless of the perioperative phase (pre-, intra-, or postoperative). ERAS-liver group displayed the highest overall compliance rate with 73.8 %, compared to 39.9 and 57.4 % for pre-ERAS and intermediate groups (p = 0.072/0.056). Overall complications were unchanged (p = 0.185), whereas intermediate and ERAS-liver groups showed decreased major complications (p = 0.034). Consistently, hospital stay was reduced by 2 days (p = 0.005) without increased readmissions (p = 0.158). CONCLUSIONS: The previous implementation of an ERAS protocol in colorectal surgery may induce a positive impact on patients undergoing non-ERAS-liver surgery on the same ward. These results suggest that ERAS is safely applicable in liver surgery and associated with benefits

Photorefractive keratectomy associated with lamellar keratotomy (LASIK) for correction of myopia, with or without drying the stroma

Purpose: To evaluate the clinical results of LASIK for moderate and high degrees of myopia, with and without drying the stroma during photoablation. Patient and Methods: Retrospective analysis of 39 eyes of 30 patients submitted to LASIK, without drying the stroma during photoablation, in the period from April 1996 to April 1997 (Group I) and analysis of 42 eyes of 28 patients with drying of the stromal bed at each 80 pulses during photoablation in the period of April of 1997 to September of 1997 (Group II). After lamellar keratotomy with an automated microkeratome (Chiron Corneal Shaper ®), photoablation with fluoride-argon excimer laser, 193 nm, Summit model Apex Plus ® was carried out. In 2 eyes of the Group I, the photoablation was not possible due to compli- cations during the lamellar keratotomy. Results: The average follow-up was 8.7 months in Group I and 7.7 months in Group II. The mean treatment was -10.81D (±2.38) in Group I and -8.73D (±2.82) in Group II. The average variations of the achieved spherical equivalent in relation to the attempted treatment in months 1, 3, 6 and 12 were respectively, -0.96D (±1.19), -1.19D (±1.37), -1.06D (±1.41) and -1.10D (±0.66) in Group I and -0.23D (±1.02), -0.41D (±1.34), -0.75D (±1.16) and -1.03D (±1.31) in Group II. On the last visit 17 eyes (45.9%) of Group I and 31 eyes (73.8%) of Group II showed uncorrected VA of 20/40 or better. Four intraoperative complications occurred in Group I, in 2 of them the photoablations were not performed and one intraoperative complication occurred in Group II. There was a loss of 2 or more lines in 3 eyes (3.7%) ot Group I. Conclusion: Drying of the stroma led to a faster visual recovery due to smaller hypocorrection. No significant differences were observed in the long-term follow-up.Objetivo: Avaliar os resultados clínicos da ceratectomia fotorrefrativa associada à ceratotomia lamelar pediculada (LASIK), para miopia moderada e alta, com ou sem secagem do leito estromal durante a foto-ablação. Pacientes e Métodos: Estudo retrospectivo de 39 olhos de 30 pacientes submetidos a LASIK sem secagem do leito estromal durante a foto-ablação no período de abril de 1996 a abril de 1997 (Grupo I) e 42 olhos de 28 pacientes com secagem do leito estromal durante a foto-ablação a cada 80 pulsos, no período de abril de 1997 a setembro de 1997 (Grupo II). Após a ceratotomia lamelar pediculada corneana com um microcerátomo automatizado (Chiron Corneal Shaper ®), foi realizada a foto-ablação com excimer laser de fluoreto de argônio de 193 nm da Summit modelo Apex Plus®. Em 2 olhos do Grupo I, a foto-ablação não foi realizada, devido a complicações durante a ceratotomia lamelar. Resultados: O tempo médio de seguimento pós-operatório foi de 8,7 meses no Grupo I e 7,7 meses no Grupo II. A média de tratamento foi de -10,81D (±2,38) no grupo I e -8,73D (±2,82) no grupo II. As médias das variações dos equivalentes esféricos obtidos em relação ao tratamento desejado nos meses 1, 3, 6 e 12 foram respectivamente, -0,96D (±1,19), -1,19D (±1,37), -1,06D (±1,41) e -1,10D (±0,66) no Grupo I e -0,23D (±1,02), -0,41D (±1,34), -0,75D (±1,16) e -1,03D (±1,31) no Grupo II. Três olhos do total (3,7%), todos do Grupo I, perderam 2 ou mais linhas de visão. Na visita mais recente, 17 olhos (45,9%) do Grupo I e 31 olhos (73,8%) do Grupo II apresentaram Acuidade Visual sem correção de 20/40 ou melhor. Ocorreram 4 complicações intra-operatórias no grupo I, sendo que 2 casos tiveram a foto-ablação não-efetuada e uma complicação intra-operatória no Grupo II. Conclusão: A secagem do leito estromal possibilitou recuperação visual mais rápida, devido a menor hipocorreção primária. O seguimento a longo prazo não evidenciou diferenças estatisticamente significantes entre os dois tratamentos.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de OftalmologiaUNIFESP, EPM, Depto. de OftalmologiaSciEL

QTc interval and resting heart rate as long-term predictors of mortality in type 1 and type 2 diabetes mellitus: a 23-year follow-up

Aims/hypothesis: We evaluated the association of QT interval corrected for heart rate (QTc) and resting heart rate (rHR) with mortality (all-causes, cardiovascular, cardiac, and ischaemic heart disease) in subjects with type 1 and type 2 diabetes. Methods: We followed 523 diabetic patients (221 with type 1 diabetes, 302 with type 2 diabetes) who were recruited between 1974 and 1977 in Switzerland for the WHO Multinational Study of Vascular Disease in Diabetes. Duration of follow-up was 22.6 ± 0.6years. Causes of death were obtained from death certificates, hospital records, post-mortem reports, and additional information given by treating physicians. Results: In subjects with type 1 diabetes QTc, but not rHR, was associated with an increased risk of: (1) all-cause mortality (hazard ratio [HR] 1.10 per 10ms increase in QTc, 95% CI 1.02-1.20, p = 0.011); (2) mortality due to cardiovascular (HR 1.15, 1.02-1.31, p = 0.024); and (3) mortality due to cardiac disease (HR 1.19, 1.03-1.36, p = 0.016). Findings for subjects with type 2 diabetes were different: rHR, but not QTc was associated with mortality due to: (1) all causes (HR 1.31 per 10 beats per min, 95% CI 1.15-1.50, p < 0.001); (2) cardiovascular disease (HR 1.43, 1.18-1.73, p < 0.001); (3) cardiac disease (HR 1.45, 1.19-1.76, p < 0.001); and (4) ischaemic heart disease (HR 1.52, 1.21-1.90, p < 0.001). Effect modification of QTc by type 1 and rHR by type 2 diabetes was statistically significant (p < 0.05 for all terms of interaction). Conclusions/interpretation: QTc is associated with long-term mortality in subjects with type 1 diabetes, whereas rHR is related to increased mortality risk in subjects with type 2 diabete

Novel Medication Supply Model Guarantees Adequate Management and High Adherence to Polypharmacy in Older Opioid Users – Preliminary Results with Outpatients

Background: Life expectancy of older drug users has increased, primarily thanks to opioid agonist treatment (OAT). Nursing homes are often not adapted to accommodate patients with substance use disorders. Although care and adherence to polypharmacy in older opioid users need considerable resources e.g., daily visits to an outpatient clinic, outpatient treatment and surveillance are provided as long as possible. We developed a novel medication supply model with an electronic dispenser of pre-packed medications located at patient home, after allowing for law requirements concerning the dispensing of opioids, and present preliminary results from three illustrative outpatients. Methods: The community pharmacy provided unit-of-dose pouches with all solid oral medications directly to patient home. Opioids for substitution were obtained at the addiction clinic in at least weekly intervals, otherwise in the pouches. The pouches were loaded into a lockable, remote-controlled medication management aid that was programmed according to the patient’s medication schedule. The dispenser reminds patients with acoustic alerts to take their medication and records dates and times of medication retrievals. It automatically sends an alert if a patient misses to retrieve a dose. Results: Our three outpatients used the electronic dispenser during 659, 118 and 61 days, with a total of 5, 9, and 18 pills to take daily at 1, 3 and 5 intake times, respectively. The majority of the doses were taken on the preset time (94%, 68.2% and 73.7%) or deliberately in advance (pocket dose). Clinical benefits were initiation and maintenance of a therapy for dementia over 18 months and suppression of HIV viral load over 1.8 years (patient 1), prevention of further dose escalation of pain medication (patient 2) and release of prompts to initiate the existential task of cooking (patient 3). Conclusion: Our novel supply model allows adequate implementation and persistence of complex treatments with outpatients. Clinical outcomes improved, patients and caregivers were satisfied, and resources were saved

Fuel metabolism during exercise in euglycaemia and hyperglycaemia in patients with type 1 diabetes mellitus—a prospective single-blinded randomised crossover trial

Aims/hypothesis: We assessed systemic and local muscle fuel metabolism during aerobic exercise in patients with type 1 diabetes at euglycaemia and hyperglycaemia with identical insulin levels. Methods: This was a single-blinded randomised crossover study at a university diabetes unit in Switzerland. We studied seven physically active men with type 1 diabetes (mean ± SEM age 33.5 ± 2.4years, diabetes duration 20.1 ± 3.6years, HbA1c 6.7 ± 0.2% and peak oxygen uptake [ $$\mathop {\text{V}}\limits^{\text{.}} {\text{O}}_{2{\text{peak}}}$$ ] 50.3 ± 4.5ml min−1 kg−1). Men were studied twice while cycling for 120min at 55 to 60% of $$\mathop {\text{V}}\limits^{\text{.}} {\text{O}}_{{\text{2peak}}}$$ , with a blood glucose level randomly set either at 5 or 11mmol/l and identical insulinaemia. The participants were blinded to the glycaemic level; allocation concealment was by opaque, sealed envelopes. Magnetic resonance spectroscopy was used to quantify intramyocellular glycogen and lipids before and after exercise. Indirect calorimetry and measurement of stable isotopes and counter-regulatory hormones complemented the assessment of local and systemic fuel metabolism. Results: The contribution of lipid oxidation to overall energy metabolism was higher in euglycaemia than in hyperglycaemia (49.4 ± 4.8 vs 30.6 ± 4.2%; p < 0.05). Carbohydrate oxidation accounted for 48.2 ± 4.7 and 66.6 ± 4.2% of total energy expenditure in euglycaemia and hyperglycaemia, respectively (p < 0.05). The level of intramyocellular glycogen before exercise was higher in hyperglycaemia than in euglycaemia (3.4 ± 0.3 vs 2.7 ± 0.2 arbitrary units [AU]; p < 0.05). Absolute glycogen consumption tended to be higher in hyperglycaemia than in euglycaemia (1.3 ± 0.3 vs 0.9 ± 0.1 AU). Cortisol and growth hormone increased more strongly in euglycaemia than in hyperglycaemia (levels at the end of exercise 634 ± 52 vs 501 ± 32nmol/l and 15.5 ± 4.5 vs 7.4 ± 2.0ng/ml, respectively; p < 0.05). Conclusions/interpretation: Substrate oxidation in type 1 diabetic patients performing aerobic exercise in euglycaemia is similar to that in healthy individuals revealing a shift towards lipid oxidation during exercise. In hyperglycaemia fuel metabolism in these patients is dominated by carbohydrate oxidation. Intramyocellular glycogen was not spared in hyperglycaemia. Trial registration: ClinicalTrials.Gov NCT00325559 Funding: This study was supported by unrestricted grants from the Oetliker-Stiftung für Physiologie, from the Swiss Diabetes Foundation, from NovoNordisk, Switzerland, and from the Swiss National Science Foundatio

Revisiting the early history of international law

n/aCambridge Commonwealth, European & International Trus

Salmeterol for the prevention of high-altitude pulmonary edema.

BACKGROUND: Pulmonary edema results from a persistent imbalance between forces that drive water into the air space and the physiologic mechanisms that remove it. Among the latter, the absorption of liquid driven by active alveolar transepithelial sodium transport has an important role; a defect of this mechanism may predispose patients to pulmonary edema. Beta-adrenergic agonists up-regulate the clearance of alveolar fluid and attenuate pulmonary edema in animal models. METHODS: In a double-blind, randomized, placebo-controlled study, we assessed the effects of prophylactic inhalation of the beta-adrenergic agonist salmeterol on the incidence of pulmonary edema during exposure to high altitudes (4559 m, reached in less than 22 hours) in 37 subjects who were susceptible to high-altitude pulmonary edema. We also measured the nasal transepithelial potential difference, a marker of the transepithelial sodium and water transport in the distal airways, in 33 mountaineers who were prone to high-altitude pulmonary edema and 33 mountaineers who were resistant to this condition. RESULTS: Prophylactic inhalation of salmeterol decreased the incidence of high-altitude pulmonary edema in susceptible subjects by more than 50 percent, from 74 percent with placebo to 33 percent (P=0.02). The nasal potential-difference value under low-altitude conditions was more than 30 percent lower in the subjects who were susceptible to high-altitude pulmonary edema than in those who were not susceptible (P&lt;0.001). CONCLUSIONS: Prophylactic inhalation of a beta-adrenergic agonist reduces the risk of high-altitude pulmonary edema. Sodium-dependent absorption of liquid from the airways may be defective in patients who are susceptible to high-altitude pulmonary edema. These findings support the concept that sodium-driven clearance of alveolar fluid may have a pathogenic role in pulmonary edema in humans and therefore represent an appropriate target for therapy

The branchial Hox code and its implications for gene regulation, patterning of the nervous system and head evolution

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Loop Interactions during Catalysis by Dihydrofolate Reductase fromMoritella profunda

Dihydrofolate reductase (DHFR) is often used as a model system to study the relation between protein dynamics and catalysis. We have studied a number of variants of the cold-adapted DHFR from Moritella profunda (MpDHFR), in which the catalytically important M20 and FG loops have been altered, and present a comparison with the corresponding variants of the wellstudied DHFR from Escherichia coli (EcDHFR). Mutations in the M20 loop do not affect the actual chemical step of transfer of hydride from reduced nicotinamide adenine dinucleotide phosphate to the substrate 7,8-dihydrofolate in the catalytic cycle in either enzyme; they affect the steady state turnover rate in EcDHFR but not in MpDHFR. Mutations in the FG loop also have different effects on catalysis by the two DHFRs. Despite the two enzymes most likely sharing a common catalytic cycle at pH 7, motions of these loops, known to be important for progression through the catalytic cycle in EcDHFR, appear not to play a significant role in MpDHFR

Adherence to polypharmacy from a pharmaceutical care perspective : evalution of an electronic medication dispenser and of tailored adherence interventions in primary care

Modern medicine offers a multitude of evidence-based treatments for many chronic diseases. Polypharmacy, the prescription of multiple medications to treat one or more conditions in the same patient, has become increasingly common. Non-adherence to medication may be the principal reason for gaps between efficacy and effectiveness of treatments. Medication adherence is not a stable personality trait but a complex behavior influenced by discrete factors. Pharmacists as suppliers of medications with frequent patient contact are in a unique position to interview patients about barriers to treatment and to offer individual support to enhance their adherence. The management of polypharmacy and medication adherence represent important aspects of pharmaceutical care (PhC). Interventions to improve adherence are diverse, often complex, and show inconsistent results. Research about interventions addressing barriers associated with polypharmacy is scarce. Medication management aids (MMA) are widely used tools to overcome challenges with complex regimens. Apart from the visual cue to take their medication, more advanced electronic MMAs (e-MMAs) may offer more explicit reminders, such as visual or audible alerts. Electronic monitoring can be used to provide customized feedback. Various e-MMAs for polypharmacy exist, but only few studies using these devices have been published. The goal of this thesis was to investigate adherence to polypharmacy from a pharmaceutical care perspective. PROJECT A aimed to review existing definitions of PhC and to describe the process of developing a redefined definition. A literature search identified 19 definitions that were paraphrased using a standardized syntax. Twenty-four experts defined PhC during a moderated workshop as “the pharmacist’s contribution to the care of individuals in order to optimize medicines use and improve health outcomes.” PROJECT B aimed to analyze the prescription patterns of split tablets in general and of quetiapine in particular. Out of 4,784,999 tablets that were repacked in 2012 in unit-of-use pouch blisters for 1,321 patients residing in 53 retirement homes in northwestern Switzerland, 8.5% were fragmented. The patients were on average 81.5 years old and obtained 1.7 fragments. A total of 43.7% of patients received two or more fragments. The fragments concerned 132 different active substances, and 50% of them were psycholeptics or psychoanaleptics. Prescription of half quetiapine tablets appeared to be constricted to the region of Basel. For PROJECT C, we investigated an e-MMA for pharmacy-filled blister pouches. PROJECT C1 aimed to collect opinions on MMAs in general and on the abovementioned e-MMA in particular. Six participants completed the 14-day trial and participated in a focus group. Participants rated ten of 17 general attributes as clearly applicable to the e-MMA and five as unsuitable. Attributes pertained to three interrelated themes: product design, patient support, and living conditions. Envisaged target groups were patients with time-sensitive medication regimens, patients with dementia, the visually impaired, and several patients living together to prevent accidental intake of the wrong medication. In PROJECTS C2 – C5, we evaluated the e-MMA in older patients with opioid-assisted treatment (OAT), who often suffer from chronic diseases and disability in addition to their opioid dependence. As a result, they often need to deal with polypharmacy and complex regimens and are at high risk for medication non-adherence. PROJECT C2 confirmed the increasing age and use of polypharmacy for opioid-dependent patients from an Outpatient Addiction Service (OAS) in Basel, Switzerland. In PROJECT C3, we report the first long-term experiences with a novel supply model with the e-MMA for two opioid-dependent patients with HIV. During the entire observation period of 1.7 and 2.6 years, respectively, both patients retrieved over 90% of the pouches within 75 minutes of the scheduled time. Viral loads fell below detection limits during the entire observation period. PROJECT C4 aimed to evaluate for the first time a quantitative and qualitative (mixed-method) single-case study design to investigate the use of the e-MMA in other patients on OAT with polypharmacy. Five patients from the OAS participated in a sequential multiple-baseline single subject study. Between November 2014 and August 2015, 3 women and 2 men (mean age 48 years), taking in addition to OAT a median of 7 medications during 3 dosing times per day were included in the study. An intervention phase with intake reminder was implemented for two participants. For both patients completing the intervention phase, taking adherence increased by more than 25% and no missed doses were observed when audible and visual reminders were introduced. Participants generally accepted the e-MMA, especially for the security of having enough medication at home, the possibility to pre-dispense pocket-doses, and the assurance of regular intakes. Finally, in PROJECT C5, we estimated yearly cost-of-illness (COI) of 109‘611 Swiss Francs (SFr) per patient for patients receiving OAT and polypharmacy, with direct costs accounting for 30% of the total costs. With the novel supply model, total yearly costs per patient increased by SFr 2’509 for repackaging of medication, leasing of the e-MMA, and time spent for travel, refill, and support. Sensitivity analysis showed that the results were robust and overall costs did not substantially change with various estimations. Despite much research, interventions aimed at improving medication adherence report disappointing and inconsistent results. We aimed to assess congruence between patient characteristics and adherence interventions in PROJECT D. In PROJECT D1, we extracted 42 determinants of non-adherence (26 modifiable and 16 unmodifiable) and 103 interventions from published literature, match the modifiable determinants to interventions like locks and keys, and categorized them into 11 domains. In Project D2, we applied the results from Project D1 to a Cochrane database with 190 randomized controlled trials on adherence-enhancing interventions. We correlated a congruence score consisting of 6 features related to inclusion criteria, patient characteristics at baseline, and intervention design with intervention effects regarding adherence and clinical outcomes. The inclusion of non-adherent patients was the single feature significantly associated with effective adherence interventions. However, neither the overall congruence score, nor any other individual feature were significantly associated with intervention effects. Conclusions: - It was possible to paraphrase definitions of PhC using a standardized syntax focusing on the provider, recipient, subject, outcomes, and activities of PhC practice. During a one-day workshop, experts in PhC research agreed on a definition, intended to be applicable for the present time, representative for various work settings, and valid for countries in- and outside of Europe. - Tablet splitting is a pharmaceutical care issue with potential consequences on adherence, which plays a major role in dosage adjustments for geriatric patients and is sometimes prescribed against the recommendations from the manufacturer. - The appearance of MMAs, but also its functionality and the whole medication supply process play an important role with regards to the design and targeting of MMAs. Patients’ living conditions like mobility remain the key determinants for their acceptance of the e-MMA. - The increase in the number of substances and medications for older drug users might lead to an increased risk for drug-drug interactions, adverse events, and non-adherence. Alternative supply models to assist patients with their medication management and to support medication adherence are needed in particular for older patients with OAT and polypharmacy. - A novel supply model with an e-MMA may be feasible to simultaneously monitor and improve implementation of dosing regimens for opioid-dependent patients with polypharmacy. - The use of a mixed-method single-subject design showed promising results for the evaluation of an e-MMA for polypharmacy. Our pilot study showed that the e-MMA may ensure correct implementation of dosing regimens for opioid-substituted patients with polypharmacy when certain prerequisites are considered. Overall, the flexibility of single-subject research designs offers considerable advantages for the evaluation of adherence interventions. - Cost-of-illness for older patients with OAT and polypharmacy is high, especially when considering indirect costs, such as productivity loss due to disability. According to our cost comparison model, the novel electronic medication supply model increases overall costs marginally, but might offset the costs of more expensive alternatives such as nursing homes. - In published trials on medication adherence, the congruence between interventions and determinants can be assessed with matching interventions to determinants. To be successful, interventions in medication adherence should target current modifiable patient determinants and be tailored to the unmodifiable patient determinants. - A 6-item score to assess congruence between patient characteristics and adherence interventions was not significantly associated with intervention effects in 190 RCTs included in a Cochrane review. The presence of only six studies that included non-adherent patients and the inter-dependency of this item with the remaining five precluded a conclusive assessment of congruence between patient characteristics and adherence interventions. Future research about the e-MMA should aim at: - developing and implementing robust care models for older patients with polypharmacy and opioid-assisted therapy. - evaluating the effectiveness of the e-MMA in terms of clinical, humanistic and economic outcomes. - evaluating the long-term benefits and cost-effectiveness of the novel supply model. Future research to improve adherence to polypharmacy should aim at: - providing guidelines for the appropriate design and analyses of single-subject trials in adherence research, including recommendations for statistical analysis. - developing instruments to reliably assess modifiable and unmodifiable determinants of non-adherence and to select appropriate interventions in research and practice