PEPDar: A randomized prospective noninferiority study of ritonavir-boosted darunavir for HIV post-exposure prophylaxis.

OBJECTIVES: PEPDar compared the tolerability and safety of ritonavir-boosted darunavir (DRV/r)-based post-exposure prophylaxis (PEP) with the tolerability and safety of standard of care (SOC). The primary endpoint was the early discontinuation rate among the per-protocol population. METHODS: PEPDar was an open-label, randomized, multicentre, prospective, noninferiority safety study. Subjects were stratified by type of event (occupational vs. nonoccupational, i.e. sexual) and were randomized to receive DRV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) or SOC PEP. Twenty-two private or university HIV clinics in Germany participated. Subjects were ≥ 18 years old and had documented or potential HIV exposure and indication for HIV PEP. They initiated PEP not later than 72 h after the event and were HIV negative. RESULTS: A total of 324 subjects were screened, the per-protocol population was 305, and 273 subjects completed the study. One hundred and fifty-five subjects received DRV/r-based PEP and 150 subjects received ritonavir-boosted lopinavir (LPV/r)-based PEP for 28-30 days; 298 subjects also received tenofovir/emtricitabine. The early discontinuation rate in the DRV/r arm was 6.5% compared with 10.0% in the SOC arm (P = 0.243). Adverse drug reactions (ADRs) were reported in 68% of DRV/r subjects and 75% of SOC subjects (P = 0.169). Fewer DRV/r subjects (16.1%) had at least one grade 2 or 3 ADR compared with SOC subjects (29.3%) (P = 0.006). All grades of diarrhoea, nausea, and sleep disorders were significantly less frequent with DRV/r, while headache was significantly more frequent. No HIV seroconversion was reported during follow-up. CONCLUSIONS: Noninferiority of DRV/r to SOC was demonstrated. DRV/r should be included as a standard component of recommended regimens in PEP guidelines.

[Clinical decision making with regard to the granting of escorted leave for forensic patients detained by court order in a Dutch psychiatric clinic. Role of gender, disorder and the type of offence in the procedure]. / Behandelduur tot eerste toekenning tbs-verlof in een Nederlandse forensische psychiatrische kliniek; dossieronderzoek naar invloed van patiëntkenmerken en delict.

BACKGROUND: An increase in the length of time until the first escorted leave is granted to a patient detained by court order (tbs) results in a longer period of treatment. Physicians involved in the treatment and clinic managers are striving to reduce, in a responsible manner, the length of the period of treatment preceding the patient's first escorted leave.
AIM: Forensic Psychiatric Clinic (fpk) 'De Woenselse Poort' aims to find out to what extent gender, pathology and the type of offence committed by the detainee influence the length of time that elapses before the patient's first leave is granted. METHOD: We conducted a retrospective study based on patients' records. RESULTS: Although men use physical aggression more often than women, we found that gender, pathology and the type of offence had no influence on the length of the treatment period that preceded the granting of the patient's first escorted leave. CONCLUSION: Partly on the basis of risk management scales, clinicians judge whether the patient has adopted a more positive or a more negative attitude to risk factors relating to his or her offence. If the risk factors have become more positive, one would expect the application for leave to be made earlier. Surprisingly, this was not the case. In order to speed up the decision-making process regarding the application for leave, a clinical method for evaluating risk related treatment needs to be developed in which offence related risk factors are identified and the patient's positive or negative attitude to these risks are measured and monitored. At each treatment evaluation practitioners should be required to produce arguments that determine whether or not the patient is to be granted permission to go on leave at a particular moment.

High rates of quinolone-resistant strains of Shigella sonnei in HIV-infected MSM.

PURPOSE: There is increasing evidence that shigellosis is a predominantly sexually transmitted disease among men who have sex with men (MSM) and that infection with the human immunodeficiency virus (HIV) is a risk factor for shigellosis. METHODS: Retrospective analysis of antibiotic resistance profiles of Shigella species isolated from stool specimens of patients presenting with diarrhea from January 2010 to July 2012 in three German outpatient clinics specialized in HIV care. RESULTS: Among 79 cases of Shigella sonnei, 56 occurred in HIV-infected MSM, while 23 were observed in HIV-negative MSM. High resistance rates (>90%) were found for doxycycline, tetracycline, aminoglycosides, all cephalosporins of first and second generations tested, and trimethoprim/sulfamethoxazole. In total, 54% of cases were resistant to ciprofloxacin. Compared to negative subjects, HIV-infected MSM had a significantly higher rate of quinolone resistance. For ciprofloxacin, the resistance rates were 66 versus 24%, respectively (p = 0.0016). Individual resistance patterns did not indicate that this was due to a limited outbreak. Rates of resistance to other antibiotics than quinolones showed no differences between HIV-infected and HIV-negative cases. No resistance was found for carbapenems or newer cephalosporins such as ceftriaxone. CONCLUSIONS: The high rates of S. sonnei isolates resistant to quinolones and other traditional antibiotics are of concern. Innovative prevention efforts are urgently needed. The empirical use of quinolones in HIV-infected patients presenting with S. sonnei infection is no longer recommended.

Sports behaviour among HIV-infected versus non-infected individuals in a Berlin cohort.

Physical activity has been recommended based on beneficial effects described in HIV-infected patients. However, such guidelines do not take into account actual sport behaviours and general attitudes towards physical activity. To evaluate actual sport activity and attitudes towards sport in HIV-infected versus non-infected individuals we conducted an anonymous questionnaire investigating the prevalence, as well as possible changes, in sports engagement and the overall attitude to physical activity. A total of 283 patients of a general care facility specialized in the treatment of HIV/AIDS in Berlin, Germany, participated; 124 were HIV infected and 159 were non-infected, mostly men who have sex with men (MSM) (88%), with a median age of 35 years. The HIV-infected participants had a median CD4+ count of 554 cells/µL and 48.8% of them were using antiretroviral therapy (ART) at the time of survey. The proportion of patients actually performing physical activity was significantly lower (P = 0.028) within the HIV-infected group (61.3%) than within the non-infected group (74.2%). This difference remained significant after accounting for possible confounders such as age, gender, injecting drug use and sexual preferences. Previously reported sport activity prevalence was similar in both groups on leaving school. From our data we could not identify an association between the time of HIV diagnosis and changes in sports activity. In conclusion, fewer HIV-infected individuals report physical activity than non-infected individuals. Sociodemographic studies to evaluate potential differences in sports behaviour are required in order to inform exercise guidelines for HIV-infected patients.

A Multicenter, Open Labeled, Randomized, Phase III Study Comparing Lopinavir/Ritonavir Plus Atazanavir to Lopinavir/Ritonavir Plus Zidovudine and Lamivudine in Naive HIV-1-Infected Patients: 48-Week Analysis of the LORAN Trial.

OBJECTIVE: The primary aim of the study was to compare the metabolic side effects of a nucleoside analogue-containing regimen with a nucleoside analogue-sparing double protease inhibitor regimen. A secondary goal was to test for efficacy of a double-PI regimen. DESIGN: Multicenter, randomized, open-label, phase III clinical trial. SUBJECTS: Adult HIV-1-infected individuals naïve to antiretroviral therapy with viral load above 400 HIV-RNA copies/ml were randomized (1:1) to either 400 mg lopinavir /100 mg ritonavir (LPV/r) BID plus 150 mg lamivudine/300 mg zidovudine (CBV) BID versus LPV/r BID plus 300 mg atazanavir (ATV) QD. Main outcome measure was the virologic failure in both groups, defined as viral load ≥50 copies/ml at week 48. RESULTS: In the CBV/LPV/r-arm, 29 out of 35 patients [(83%; 95% confidence interval (CI) 66.9-92.2%] and 18 out of 40 patients (45%; 95% CI 29.7-61.5%) in the ATV/LPV/r-arm had a HIV-RNA level <50 copies/ml at week 48. The intent-to-treat analysis revealed inferior virologic response in the ATV/LPV/r arm (Chi-Q and Fisher´s Exact Test p<0.001) and resulted in premature termination of the trial. Eleven patients in the ATV/LPV/r-arm discontinued therapy because of virological failure. These failures mostly presented with low level replication (<1,000 copies/ml). Increases in CD4 cell counts was significantly more rapid in the ATV/LPV/r arm (p=0.02), but comparable at week 48. CONCLUSIONS: ATV/LPV/r had less virologic efficacy than the conventional RTI-based regimen and resulted in a high virological failure rate with low level replication.

Comparison of indinavir + ritonavir 600 + 100 mg vs. 400 + 100 mg BID combinations in HIV1-infected patients guided by therapeutic drug monitoring.

OBJECTIVE: To compare two reduced dose indinavir (IDV) + ritonavir (RTV) combinations guided by therapeutic drug monitoring (TDM) in treatment-naive HIV1-infected patients. METHODS: HIV1-infected treatment naive patients were prospectively randomized to treatment with IDV 600 mg or 400 mg BID each in combination with RTV 100 mg BID. Boosted IDV was combined with 2 NRTI, and patients were followed for 48 weeks. IDV-trough levels and initially also peak levels (C2h) were performed to allow dose modification of IDV following a specified protocol. RESULTS: 14 patients were randomized (age 38 +/- 10.4 years; mean +/- SD; 3 female, 11 male). 8 were treated with 600 mg (group 1), 6 with 400 mg IDV BID (group 2). Efficacy of treatment was good: CD4-cell count increased from 198/microl (14-523; median, range) to 371/microl (214-927) after 48 weeks (p<0.01). All but one patient with adherence problems achieved a viral load below the limit of detection. At the beginning two patients had plasma levels below 0.1 mg/l, most likely due to adherence problems. However, in the course of the observation period all patients had adequate plasma levels. 3 patients in group 1 could further reduce their IDV dose to 400 mg BID due to high plasma (peak and trough) levels. Rate of discontinuation was high (1: 4 pat., 2: 2 pat.), but only one discontinuation was possibly associated with IDV (alopecia; group 2). There were no significant changes in laboratory parameters (bilirubin, triglycerides, cholesterol) or suspicious urine results. Incidence and severity of adverse events was lower than in previous studies. CONCLUSION: Despite the low number of patients it seems reasonable to state, that boosted IDV may be used in significantly reduced dose. Efficacy seemed not to be altered, whereas tolerability was improved.

Overexpressed TP73 induces apoptosis in medulloblastoma.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated DeltaNp73 to assess their effects on growth. METHODS: We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of TP73 RNA including the full-length transcript and the 5'-terminal variants that encode the DeltaNp73 isoform, as well as TP53 RNA using quantitative real time-RTPCR. Protein expression of TAp73 and DeltaNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on TP73 RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and DeltaNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods. RESULTS: Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant TP73 RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated DeltaNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or DeltaNp73 induced apoptosis under basal growth conditions in vitro and sensitized them to cell death in response to chemotherapeutic agents. CONCLUSION: These results indicate that primary medulloblastomas express significant levels of TP73 isoforms, and suggest that they can modulate the survival and genotoxic responsiveness of medulloblastomas cells.

The appetite-suppressant effect of nicotine is enhanced by caffeine.

AIM: To test whether the anorectic effect of nicotine may be amplified by caffeine. METHODS: Chewing gums with nicotine and caffeine were administered to 12 healthy young men of normal weight. Different combinations of 0, 1 or 2 mg of nicotine and 0, 50 or 100 mg of caffeine were applied during a 2-h period in a randomized, double blind, cross over design. Appetite sensations were measured using visual analogue scales. RESULTS: Hunger and prospective food consumption were negatively associated with the increasing doses of nicotine, whereas satiety and fullness were positively associated with the increasing doses of nicotine (p < 0.05). Caffeine appeared to amplify the effects of nicotine on hunger and fullness as a caffeine x nicotine x time interaction was observed in these scores (p < 0.05). The 2-mg dose of nicotine in combination with the 100-mg dose of caffeine caused nausea in four of the non-smokers. However, the effects of nicotine and the caffeine x nicotine x time interaction persisted after the exclusion of these subjects. CONCLUSION: Caffeine added to nicotine chewing gum appears to amplify its attenuating effects on appetite and the combinations of 1-mg of nicotine with caffeine seem to be well tolerated.

Bioactive food stimulants of sympathetic activity: effect on 24-h energy expenditure and fat oxidation.

OBJECTIVE: Bioactive food ingredients influence energy balance by exerting weak thermogenic effects. We studied whether the thermogenic effect of a combination of capsaicin, green tea extract (catechins and caffeine), tyrosine, and calcium was maintained after 7-day treatment and whether local effects in the gastric mucosa were involved in the efficacy. DESIGN: The present study was designed as a 3-way crossover, randomised, placebo-controlled, double-blinded intervention. SETTING: Department of Human Nutrition, RVAU, Denmark. SUBJECTS: A total of 19 overweight to obese men (BMI: 28.0+/-2.7 kg/m2) were recruited by advertising locally. INTERVENTION: The subjects took the supplements for a period of 7 days. The supplements were administrated as a simple supplement with the bioactive ingredients, a similar enterocoated version, or placebo. In all, 24-h energy expenditure (EE), substrate oxidations, spontaneous physical activity (SPA), and heart rate were measured in respiration chambers on the seventh day of each test period. RESULTS: After adjustment for changes in body weight and SPA, 24-h EE was increased by 160 kJ/day (95% CI: 15-305) by the simple preparation as compared to placebo, whereas the enterocoated preparation had no such effect (53 kJ/day, -92 to 198); simple vs enterocoated versions (P=0.09). The simple preparation produced a deficit in 24-h energy balance of 193 kJ/day (49-338, P=0.03). Fat and carbohydrate oxidation were equally increased by the supplements. CONCLUSION: A supplement containing bioactive food ingredients increased daily EE by approximately 200 kJ or 2%, without raising the heart rate or any observed adverse effects. The lack of effect of the enterocoated preparation suggests that a local action of capsaicin in the gastric mucosa is a prerequisite for exerting the thermogenic effect.

[Mastocytosis]. / Mastocytose.

Mastocytoses are diseases caused by proliferating mast cells infiltrating one or more organs. The spectrum of mastocytosis includes the cutaneous forms urticaria pigmentosa and solitary mastocytoma (about 90% of mastocytoses) and systemic forms affecting other organs. Infiltrates are most often found in the bone marrow, spleen, lymph nodes and liver, but any organ may be affected. Patients with systemic mastocytosis may or may not have urticaria pigmentosa. About 35% of patients without urticaria pigmentosa have an associated malignant haematological disease and a poor prognosis. Symptoms caused by mast cell mediator release are best treated with antihistamines, but several other drugs may be used if the response is unsatisfactory. Many antineoplastic drugs have been tried to combat aggressive mastocytoses and mast cell leukaemia, but the results have been disappointing.

Patient and family perceptions of hospital chaplains.

While most hospitals provide chaplaincy services for patients, families, and staff, these services are seldom studied and their contribution is poorly understood. A questionnaire created by the College of Chaplains of the American Protestant Health Association was mailed by an insurance company to patients recently dismissed from the hospital, requesting evaluation of three non-medical services (social services, chaplaincy, and patient representatives) and how well the spiritual needs for support/counseling, prayer, and sacraments were met. Responses revealed that, in comparison to the other two non-medical services, patients receive more visits from chaplains, evaluate these visits as more important (p less than 0.000), and report that these visits meet their expectations more highly (p less than 0.000). Regression analyses demonstrate that when the chaplain meets the patient's need for support/counseling, the respondent is more likely to select the hospital again (p = 0.04) and recommend it to others (p = 0.05). Similarly, when chaplains meet the family's need for support/counseling, the respondent is likely to choose the hospital again. Since chaplains clearly make an important contribution to patients, their families, and the hospital, administrators should review the adequacy of their chaplaincy services in the light of these data.

[Bladder leukoplakia]. / Blaereleukoplaki.

Leukoplakia of the bladder is a rare condition. It is characterized by squamous metaplasia of the transitional epithelium and keratinization. The etiology and possible pathogenetic factors are discussed. Up to 42% develop carcinoma which makes early diagnosis important. The clinical diagnosis is difficult. The patients present with symptoms of vesical irritation and the passage of flakes is pathognomonic. Diagnosis is made by cystoscopy with biopsies. Characteristic cystoscopic findings are described. Treatment and a follow-up programme are outlined. As conservative treatment remains unsatisfactory radical extirpation or cystectomy is recommended for extensive lesions.

The value of hospital chaplains: patient perspectives.

Reports the results of a questionnaire mailed to insurance claimants (N = 2480) recently discharged from a hospital. Analyzes the results and concludes from the data that patients place high value on pastoral services. Suggests that both hospital administrators and chaplains make sure that adequate attention be given to serving patient families, long-stay and repeated admission patients, and to the patients' demonstrated need for frequent visits, particularly in these times of rapid changes in condensing hospital stays.

[Hemolysis, elevated liver enzymes and thrombocytopenia: the HELLP syndrome--a manifestation of severe pre-eclampsia]. / Haemolyse, et forhøjet leverenzymtal og trombocytopeni: HELLP-syndromet--en manifestation af svaer praeeklampsi?

On the basis of a review of the literature and five case histories, the pathophysiological and clinical features in pregnant women with haemolysis, elevated liver enzymes and thrombocytopenia which together constitute the HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count) are illustrated. This syndrome describes a complicated obstetric course with greatly increased neonatal and maternal morbidities. Hypertension/proteinuria are common but are not obligatory. The condition should be suspected in pregnant women with pain under the right rib margin and unexplained jaundice. The diagnosis is verified by the blood picture, liver enzyme count and a blood smear. Women with verified HELLP syndrome and gestational age greater than 34 weeks should be delivered immediately. Women with the same syndrome and gestational age less than 32 weeks should be delivered if the condition cannot be rapidly controlled. In exceptional cases cesarean section may be necessary. On the basis of the coagulation status, the defective plasma components may be supplied (e.g. fresh frozen plasma and antithrombin-III). Plasmapheresis and specific pharmacological intervention must be considered as experimental at present, although these present promising therapeutic possibilities.

A case of vesical leukoplakia.

A 54-year-old woman who had earlier been treated for cervical dysplasia complained of recurrent cystitis, urgency and frequency, but without signs of genital prolapse. At cystoscopy with biopsies, leukoplakia of the bladder was diagnosed. We describe how the condition is distinguished from squamous metaplasia of the trigone as seen in normal premenopausal women. An association between leukoplakia and cancer is widely accepted. Against this background, a follow-up program is outlined. The possibility of leukoplakia as a multicentric disorder of the genito-urinary tract is briefly discussed.

[The cryopathies]. / Kryopatier.

The term cryopathies includes conditions in which abnormal sensitivity to cold is a prominent feature and includes the cold agglutinin syndrome, the cold hemolysin syndrome, the cold urticarias, the cryoglobulinemias, and cryofibrinogenemia. The cryopathies may be secondary to lymphoproliferative, autoimmune, and infectious diseases, but in many patients no underlying disease can be found (essential cryopathy). Avoidance of cold is of prime importance in all patients. Underlying disease should be treated, if possible. Severe therapeutic problems may arise in patients with essential cryopathies.