Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting.

OBJECTIVES: Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir's pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. METHODS: A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug-drug interactions. RESULTS: A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h-1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. CONCLUSIONS: Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.

30-day mortality after elective colorectal surgery can reasonably be predicted.

BACKGROUND: The aim of the present study was to develop a clinically relevant, accurate and usable risk assessment scoring system solely for colorectal cancer patients undergoing elective resection. METHODS: All colorectal resections for colorectal cancer 2006-2012 were identified from the American College of Surgeons Quality Improvement Program. Independent risk factors for 30-day mortality after elective surgery were identified using univariable and multivariable logistic regression. A points-calculator based on factors most strongly associated with mortality and accurately predicting risk of mortality was developed. RESULTS: Fifty-nine thousand nine hundred eighty-six patients underwent elective colorectal cancer surgery, and 1096 (1.8 %) died within 30 days. On multivariable analysis, the strongest risk factors for mortality were age ≥65 years [odds ratio (OR) 2.17, 95 % confidence interval (CI) 1.61-2.92], American Society of Anesthesiologists score ≥3 (OR 1.77, 95 % CI 1.29-2.42), renal failure (OR 3.15, 95 % CI 1.01-9.77), disseminated cancer (OR 2.56, 95 % CI 1.96-3.35), hypoalbuminemia (OR 2.84, 95 % CI 2.21-3.65), preoperative ascites (OR 3.17, 95 % CI 2.07-4.87), heart failure (OR 2.08, 95 % CI 1.35-3.20) and functional status (OR 2.05, 95 % CI 1.56-2.70). A model that accurately predicted risk of mortality was created using forward stepwise logistic regression and externally validated (area under the curve 0.826). This allowed for development of an eight-factor predictive score; maximum points conferred mortality of 96.1 % (p < 0.0001). CONCLUSIONS: A simple preoperative scoring system predicting 30-day mortality with good capability may allow better preoperative risk assessment, optimization and decision-making.

Molecular-scale simulation of electroluminescence in a multilayer white organic light-emitting diode.

In multilayer white organic light-emitting diodes the electronic processes in the various layers--injection and motion of charges as well as generation, diffusion and radiative decay of excitons--should be concerted such that efficient, stable and colour-balanced electroluminescence can occur. Here we show that it is feasible to carry out Monte Carlo simulations including all of these molecular-scale processes for a hybrid multilayer organic light-emitting diode combining red and green phosphorescent layers with a blue fluorescent layer. The simulated current density and emission profile are shown to agree well with experiment. The experimental emission profile was obtained with nanometre resolution from the measured angle- and polarization-dependent emission spectra. The simulations elucidate the crucial role of exciton transfer from green to red and the efficiency loss due to excitons generated in the interlayer between the green and blue layers. The perpendicular and lateral confinement of the exciton generation to regions of molecular-scale dimensions revealed by this study demonstrate the necessity of molecular-scale instead of conventional continuum simulation.

[Basic standards for a department of cardiac surgery. Quality requirements for the care of cardiac patients in connection with operations on the heart, the heart vessels and thoracic organ transplantation]. / Basisstandards einer Fachabteilung für Herzchirurgie. Qualitätsanforderungen für die Versorgung von herzkranken Patientinnen und Patienten im Zusammenhang mit Operationen/Eingriffen am Herzen, den herznahen Gefäßen und der thorakalen Organtransplantation.

Current evolutions and substantial amendments of the German health care system in combination with distinguished progress in cardiac surgery over the past years require both a reflection of principles in patient-centered care and an update of basic standard requirements for a department of cardiac surgery in Germany. In due consideration of the data from the voluntary registry of the German Society for Thoracic and Cardiovascular Surgery, this article accurately defines core requirements for a cardiac surgical department (cardiac surgery on-site), subdivided into facilities, staff and processes. If based on these standards, one may anticipate that cardiac surgical care is performed under appropriate conditions leading to an intrinsic benefit for patients.

Seroprotection rates of vaccine-preventable diseases among newly arrived Eritrean asylum seekers in Switzerland: a cross-sectional study.

BACKGROUND: According to 2016 World Health Organization and United Nations Children's Fund country estimates, Eritrea has overall high vaccination coverage with immunization rates for three doses of diphtheria/tetanus/pertussis and polio vaccine of 95%, for two doses measles vaccine of 85% and for three doses hepatitis B vaccine of 85%. If confirmed, this could imply that routine basic vaccination of newly arrived Eritreans could be safely omitted. METHODS: We used stored serum samples from two cross-sectional studies that screened newly arrived Eritrean refugees for infectious diseases. Consenting refugees aged 16 years and older who registered in one of three neighbouring cantons in northwestern Switzerland were enrolled between January 2016 and December 2017. Antibody titers against the following vaccine-preventable diseases were measured (applied thresholds for seroprotection in brackets): diphtheria (>0.1 IU/ml), tetanus (>0.1 IU/ml), measles (>150 mIU/ml), rubella (only for women, >11 IU/ml), varicella (>50 mIU/ml), hepatitis B [hepatitis B surface antigen (HBsAg) Index >0.9, Hepatitis B core antibody (anti-HBc) Index >0.9 and antibodies to HBsAg (anti-HBs) >10 IE/L]. Differences between sex and age groups (≤25 and >25 years) were measured by Fisher's exact test. RESULTS: We analysed samples of 133 study participants (20 women, 15%) with a median age of 25 years (range 16-61). Rates of seropositivity were as follows for women/men, respectively: diphtheria 57.9%/74.8% (difference non-significant), tetanus 94.8%/41.1% (P < 0.001), measles 73.7%/76.6% (non-significant), rubella in women 78.9%, varicella 89.5%/95.3% (non-significant), anti-HBc 15.8%/26.2% (non-significant) and anti-HBs 15.8%/17.8% (non-significant). CONCLUSION: Seroprevalence for vaccine-preventable infections did not meet levels required to confer herd immunity in any of the human-to-human transmissible diseases that were studied. In general, the strategy proposed by the Federal Office of Public Health to offer basic immunization to all newly arrived refugees, including newly arriving Eritrean refugees, is justified.

Scoring system to assess disease severity in children.

A scoring system to assess disease severity in children, based on therapeutic and diagnostic interventions, is suggested. The charts of 475 consecutive admissions to a multidisciplinary pediatric intensive care unit (PICU) were reviewed and therapeutic and diagnostic interventions (TDI) associated with more than 20% mortality identified. These were scored: TDI associated with 20-30% mortality - 1 point; 31-40% - 2 points; 41-50% - 3 points and more than 51% - 4 points. According to these values, a Pediatric Therapeutic and Diagnostic Intervention Score (PTDIS) was calculated for each patient. The study population may be divided, according to PTDIS and mortality, into three groups: moderately severe disease associated with up to 2.7% mortality and PTDIS less than 20; severe disease associated with up to 25% mortality and PTDIS less than 35; critically ill patients with more than 50% mortality and PTDIS greater than 36. PTDIS in survivors was 15.2 +/- 0.6 (mean +/- SE) and 43.6 +/- 1.1 in non-survivors. Pearson's correlation between PTDIS and mortality was R = 0.7162 at a significance level of p less than 0.0001. PTDIS and mortality were not found to be significantly correlated with sex, age or duration of hospitalization in the Unit. Sepsis, central nervous system infections and burns were the primary diseases, and shock, coma and patients after cardiopulmonary resuscitation the indications for admission to the Unit, associated with the highest mortality and PTDIS. This study demonstrates the efficacy of the suggested PTDIS system in accurately assessing severity of disease in a PICU patient population.

Percutaneously adjustable pulmonary artery band.

BACKGROUND: Pulmonary artery banding, originally introduced to palliate increased pulmonary blood flow, is now primarily used for complex congenital cardiac defects with a prohibitive risk in the early repair, such as tricuspid atresia, or occasionally to prepare the left ventricle for eventual arterial switch. Conventional banding is, however, often poorly tolerated, and the precise adjustment required to reduced pulmonary blood flow or sufficiently challenge the left ventricle is difficult and can cause life-threatening hemodynamic changes. METHODS: We designed a band that allows accurate tightening and is reversible during the operation and at the bedside with the chest closed, allowing precise gradual adjustment over days, thereby minimizing cardiovascular instability. This design is the extension of previous work done by one of us on an adjustable annuloplasty ring. RESULTS: The band has been used for a 16-month-old child with tricuspid atresia type 1C who had undergone two failed attempts at banding. Hemodynamic measurements after 3 months confirmed achievement of the desired pulmonary pressure. CONCLUSIONS: This design, the simple insertion, and the ability to finely readjust the banding over days, combined with excellent patient tolerance, encourage further use of our adjustable band.

Technical evolution of the Ross operation: midterm results in 186 patients.

BACKGROUND: The Ross operation approaches the ideal aortic valve replacement. Between February 1995 and February 2000 we performed 186 procedures. This article reviews modifications introduced reflecting our experience. METHODS: In all patients the Ross operation was performed as root replacement. Echocardiographic follow-up was complete in 94% of patients. RESULTS: No operative death or early mortality occurred, nor did thromboembolic or hemorrhagic events. One patient died at 25 months from hemoptysis with pulmonary valve vegetations. Three patients required reoperation for autograft insufficiency. In 1 patient a tethered cusp was repairable and in 2 patients progressive autograft dilatation required autograft replacement. After routinely incorporating support into the aortic annulus and replacing all dilated ascending aorta, autograft dilatation did not recur. For the pulmonary homograft, one outflow patch was placed to relieve a symptomatic gradient. Nine patients with elevated gradients were under observation. Echocardiography revealed autograft median peak systolic gradients of 4.6+/-2.8 mm Hg, pulmonary homograft gradients of 14.8+/-9.6 mm Hg, and nil or insignificant regurgitation. CONCLUSIONS: The aortic annulus must be supported and the dilated ascending aorta replaced. Root replacement with a short autograft allows consistent results. Pulmonary homograft dysfunction is rare but unpredictable.

Endaortitis of coarctation of the aorta after invasive diagnostics.

We report the case of a young woman in whom endaortitis developed at the site of a coarctation of the aorta after the invasive investigation of right fossa iliac pain. The organism responsible suggests a causal relationship to the investigations without antibiotic prophylaxis, and we emphasize the need for antibiotic prophylaxis in these cases. Invasive investigation of isolated coarctation in a young adult or adolescent is probably superfluous.

Early and late results of closure of ventricular septal defect in infancy.

Fifty infants ranging in age from 13 days to 18 months (mean age 6 months) and weighing from 1.7 to 8.2 kg (mean weight 4.5 kg) underwent patch closure of a ventricular septal defect (VSD) with use of deep hypothermic circulatory arrest. Seventeen infants were under 3 months of age. The principal indication for operation was intractable chronic congestive heart failure; All infants were below the third percentile for weight preoperatively; Three patients (6%) died postoperatively within the second month of life. There was no late mortality. Seven infants (14%) had seizures; these were associated with a low output state in 2 infants, with hypoxic episodes in 4 infants, and occurred postoperatively in 1 infant. Postoperatively, 8 (17%) of the surviving infants developed right bundle-branch block and left anterior hemiblock, and 16 (32%) developed right bundle-branch block alone. One year postoperatively, catheterization studies in 24 children revealed normal pulmonary artery pressure and pulmonary vascular resistance in all; there were no significant residual ventricular septal defects. Because of these results we continue to be enthusiastic about primary closure of VSD irrespective of age or weightk0

Surgical removal of a lipoma of the heart.

In a 29-year-old woman echocardiography revealed a tumour originating from the anterior wall of the right ventricle. Noninvasive findings aroused suspicion of a lipoma. The tumour was removed under cardiopulmonary bypass, the resulting defect in the right ventricular wall being covered with a Goretex patch. Histological examination classified the tumour as a rhabdomyolipoma.

The ross operation in 225 patients: a five-year experience in aortic root replacement.

BACKGROUND AND AIM OF THE STUDY: The Ross operation, introduced more than 30 years ago, has recently undergone several modifications to improve both technical feasibility and results. At the authors' institution, the Ross operation, performed as root replacement in all cases, was commenced in February 1995. METHODS: A total of 225 patients (177 males, 48 females; mean age 39+/-15 years; range: 2 to 67 years) were operated on up to December 2000. Aortic regurgitation was present in 80 patients, stenosis in 69, and combined disease in 73; prostheses were replaced in three patients. Combined procedures were performed in 51 patients. Nine patients had active endocarditis. Follow up was 98% complete and totaled 471 patient-years. RESULTS: There was no early mortality, and no thromboembolic or hemorrhagic events. Complications included prolonged ventilation in two patients, perioperative myocardial infarction in three, pacemaker implants in three and perioperative bleeding in six. One patient died at 25 months from hemoptysis, and one at five months of unknown cause. In the long term, four patients required reoperation due to autograft regurgitation (one autograft repair, three autograft replacements). Routine aortic annulus support, a lowered threshold in replacing all dilated ascending aorta and keeping the autograft short to the level of the sinotubular junction seems to have prevented further autograft failure. Pulmonary homograft stenosis led to reoperation in one patient. Six patients with elevated gradients are currently under observation. Echocardiography revealed autograft median peak gradients of 5.1+/-2.8 mmHg, pulmonary homograft gradients of 14.2+/-11.5 mmHg, and no significant regurgitation, except in one additional patient with recently diagnosed aortic insufficiency (grade >2). CONCLUSION: Mid-term excellent hemodynamic results, low morbidity and reoperation requirement support the evolved root replacement technique and justify its further utilization.

The influence of geometric mismatch between the native aortic, native pulmonary and homograft pulmonary valve on the results of the pulmonary autograft operation.

BACKGROUND: The pulmonary autograft operation has achieved broad acceptance and may be the ideal aortic valve substitute. Both the pulmonary autograft and the aortic homograft are more complicated procedures than prosthetic valve replacement. The trend to insert the pulmonary autograft as a root replacement rather than in the subcoronary position has achieved greater uniformity in the results, but there is still confusing diversity in opinions on technical details and anatomical dimensions. The importance of both size and shape mismatches between the three valves involved has received little attention. The valves often differ in diameter and in the shape of the recipient aortic annulus. This uncertainty and the diversity of opinions on essential technical details was disconcerting when we proceeded from aortic homograft-to-pulmonary autograft operations, this was compounded by only a single homograft being available for every operation as we have no homograft bank. METHODS: We compared the hemodynamic results regarding various geometric mismatches. All operative details were the same and patients were studied at regular intervals. Comparisons were made in patients with mismatch between recipient aortic annulus and pulmonary autograft. Patients with a normal tricuspid aortic annulus were compared to those with either a circular redo prosthetic valve annulus or a bicuspid recipient annulus. Thirdly we compared the patients with plication of the aortic annulus to those with remodeling of the distal aorta. Lastly we compared mismatch between donor homograft and pulmonary autograft. RESULTS: No influence of geometric mismatch between the three valves could be found on the results of the pulmonary autograft operation. CONCLUSIONS: Good results are obtainable without a painful learning curve if one keeps to certain surgical principles. It need not be a complicated operation and geometric mismatches between the three valves involved may be compensated for adequately.

A standardized letter of recommendation for residency application.

Emergency medicine (EM) program directors have expressed a desire for more evaluative data to be included in application materials. This is consistent with frustrations expressed by program directors of multiple specialties, but mostly by those in specialties with more competitive matches. Some of the concerns about traditional narrative letters of recommendation included lack of uniform information, lack of relative value given for interval grading, and a perception of ambiguity with regard to terminology. The Council of Emergency Medicine Residency Directors established a task force in 1995 that created a standardized letter of recommendation form. This form, to be completed by EM faculty, requests that objective, comparative, and narrative information be reported regarding the residency applicant.

Thromboembolic and bleeding complications after mitral valve replacement.

One thousand six hundred and sixty-eight consecutive patients who underwent isolated mitral valve replacement (MVR) from 1963 to 1984 were evaluated retrospectively. Thromboembolism occurred with a linearised rate of 2.5% +/- 0.2%/patient-year (PY) for Starr-Edwards disc prosthesis Model 6520, 2.4% +/- 0.3%/PY for Bjørk-Shiley plane prosthesis, 3.0% +/- 0.8%/PY for Bjørk-Shiley convexo-concave 60 degrees prosthesis, 3.0% +/- 0.8%/PY for St. Jude Medical prosthesis and 3.4% +/- 0.5%/PY for Carpentier-Edwards tissue valve without the differences reaching significance. In the SJM group, the incidence of thromboembolism was significantly higher (P less than 0.025) in smaller sizes (less than M29) probably due to a more turbulent flow. The linearised rate for major haemorrhage was 1.6% +/- 0.1%/PY. Twenty-three percent of the thromboembolic and 18% of the bleeding events were fatal. Sixty-eight percent of the emboli involved the central nervous system and bleeding apart from fatalities was predominantly non-cerebral (81%). Whereas thromboembolism was a time-related event with more than twice as high a risk in the first postoperative year (4.2% +/- 0.5% vs. 1.7% +/- 0.8%, P less than 0.01), bleeding occurred with a constant rate over time (0.9% +/- 0.4%). Adequacy of anticoagulation was an important risk factor for postoperative embolism with the prothrombin time (PT) exceeding the therapeutic range in 65% of all events. A preoperative history of embolism was the only additional patient-related risk factor for postoperative embolism (18.3% vs. 9.6%, P less than 0.001). In 30% of all haemorrhage, the PT was below 15%.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid mass-spectrometric determination of boron isotopic distribution in boron carbide.

Boron isotopic ratios are measured in boron carbide by thermionic ionization mass spectrometry with no prior chemical separation. A powder blend of boron carbide and sodium hydroxide is prepared, a small portion is transferred to a tantalum filament, the filament is heated to produce sodium borate, and the filament is transferred to the mass spectrometer where the(11)B/(10)B ratio is measured, using the Na(2)BO(2)(+) ion. Variables investigated for their effect on preferential volatilization of (10)B include the sodium hydroxide-boron carbide ratio and the temperature and duration of filament heating. A series of boron carbide pellets containing natural boron, of the type proposed for the control rods of the Fast Flux Test Facility reactor, were analysed with an apparently unbiased result of 4.0560 for the (11)B/(10)B ratio (standard deviation 0.0087). The pellets contained over 3% metal impurities typically found in this material. Time of analysis is 45 min per sample, with one analyst.

Phrase repetition in Alzheimer's disease: effect of meaning and length.

Repetition ability depends in part on the intactness of semantic memory. If the conceptual contents of semantic memory are lost as a function of Alzheimer's disease (AD) pathology, meaningfulness of stimuli should have progressively less effect on the ability to repeat as the disease worsens. This study was designed to evaluate the effects of meaningfulness and length of phrasal stimuli on repetition ability in mild and moderate AD patients and normal elderly subjects. Fifty-seven AD patients and 52 normal subjects were given six- and nine-syllable phrases that were meaningful, improbable in meaning, or meaningless. Cross-sectional and longitudinal data analyses were conducted and results failed to confirm a performance pattern consistent with a semantic memory loss theory. Meaningless nine-syllable phrases were those most difficult to repeat for moderate as well as mild AD patients and normal controls.

Parental knowledge and views of pediatric congenital heart disease.

BACKGROUND: Parental knowledge of their child's heart disease, while often overlooked, contributes to compliance and reduces anxiety. Prior studies have shown that 36% of parental diagnostic descriptions are incorrect. OBJECTIVES: To assess parental knowledge and attitudes among outpatients at a hospital pediatric cardiology clinic. METHODS: Seventy-four families completed a questionnaire in which they described their child's condition and stated their attitude towards dental hygiene and future prenatal diagnosis. RESULTS: Eighteen percent of the parents failed to describe their child's malformation correctly. We found that parental understanding of the heart defect correlated with parental education. Future prenatal diagnosis was considered by 88% of families, and termination of pregnancy by 40%. Only 40% of children were aware of their heart problem. Children of parents who were ignorant about the condition tended to lack knowledge themselves. An additional finding was that 68% of Jewish families turn to non-medical personnel for medical advice--an interesting finding not hitherto addressed. CONCLUSIONS: Ignorance of their child's problem did not correlate with its severity or complexity but rather with parental background: the less educated the parent, the more likely was the problem perceived incorrectly.

Use of adjunctive modalities in occupational therapy.

This article reminds us that as practice evolves, we must revisit and reaffirm the fundamental philosophy and precepts in which our profession is grounded. The face of practice is fluid. Its superficial appearance is molded by external forces and stresses. These include the changes in the needs of the persons we serve, the emergence of new and different treatment modalities, and the realities of the socioeconomic environment in which we work. Beneath the surface, however, are the basic structures that all of us hold in common. These are our philosophical beliefs that are articulated both in the professional literature and in the ethical principles that we espouse.

Initial experience with a modified left atrial maze procedure concomitant to cardiac surgery.

BACKGROUND: The excellent results of the Cox-Maze-III operation showed that a surgical treatment of atrial fibrillation is possible. The maze operation is surgically demanding and time-consuming. This fact led to the development of simplified modifications. Due to the good results of an exclusive left atrial maze procedure in combination with mitral valve surgery and new technologies of ablation, it seems reasonable to perform these techniques concomitant to cardiac surgery on a large number of patients.¶ METHODS: From November 1999 until June 2000 a modified maze procedure concomitant to a cardiac surgical intervention was performed on 42 patients, with a mean age of 62.2 years, suffering from chronic or intermittent atrial fibrillation. Primary cardiac disease was mainly cardiac valve disease (mitral valve disease 19 patients, aortic valve disease 10 patients) or coronary heart disease (8 patients). After left atriotomy and with the use of the Thermaline probe (Boston Scientific, Corporation, San Jose, California, USA) a bilateral pulmonary veins isolation was carried out by radiofrequency ablation. An additional ablation line was directed from the left pulmonary veins to the posterior mitral valve anulus. Finally, the left atrial appendage was resected. An evaluation of the therapeutic success was carried out in the immediate postoperative course and 3 months after surgery, at that point of time operation-related influences on the refractory period of the atrial myocardium were negligible.¶ RESULTS: At the time of discharge 32 patients (76.2%) showed a regular supraventricular rhythm. Twenty-one patients have already undergone the 3-month follow-up examination. At the time of discharge 13 out of these 21 patients (61.9%) were in sinus rhythm and at 3 months after surgery 18 out of these 21 patients (85.7%) showed a sinus rhythm with a restoration of atrial transport function echocardiographically determined. Three patients were still receiving antiarrhythmic medication.¶ CONCLUSION: The modified maze procedure in combination with cardiac surgical interventions proved to be easy, quick and reliable to perform. The early results suggest a high success rate of this technique. The long-term results have to be verified with further, regular follow-up examinations of the patients.