A low affinity penicillin-binding protein 2x is required for heteroresistance in Streptococcus pneumoniae

Heteroresistance to penicillin in Streptococcus pneumoniae is the ability of subpopulations to grow at a higher antibiotic concentration than expected from the minimal inhibitory concentration (MIC). This may render conventional resistance testing unreliable and lead to therapeutic failure. We investigated the role of the primary β-lactam resistance determinants, penicillin binding proteins PBP2b and PBP2x and secondary resistance determinant PBP1a in heteroresistance to penicillin. Transformants containing PBP genes from heteroresistant strain Spain(23F)2349 in non-heteroresistant strain R6 background were tested for heteroresistance by population analysis profiling (PAP). We found that pbp2x, but not pbp2b or pbp1a alone, conferred heteroresistance to R6. However, a change of pbp2x expression is not observed and therefore expression does not correlate with an increased proportion of resistant subpopulations. Additional ciaR disruption mutants which have been described to mediate PBP-independent β-lactam resistance revealed no heteroresistant phenotype by PAP.We also showed, that the highly resistant subpopulations (HOM*) of transformants containing low affinity pbp2x undergo an increase in resistance upon selection on penicillin plates which partially reverts after passaging on selection-free medium. Shotgun proteomic analysis showed an upregulation of phosphate ABC transporter subunit proteins pstS, phoU, pstB and pstC in these highly resistant subpopulations.In conclusion, the presence of low affinity pbp2x enables certain pneumococcal colonies to survive in the presence of beta lactams. Upregulation of phosphate ABC transporter genes may represent a reversible adaption to antibiotic stress.

The adherence to initial processes of care in elderly patients with acute venous thromboembolism.

BACKGROUND We aimed to assess whether elderly patients with acute venous thromboembolism (VTE) receive recommended initial processes of care and to identify predictors of process adherence. METHODS We prospectively studied in- and outpatients aged ≥65 years with acute symptomatic VTE in a multicenter cohort study from nine Swiss university- and non-university hospitals between September 2009 and March 2011. We systematically assessed whether initial processes of care, which are recommended by the 2008 American College of Chest Physicians guidelines, were performed in each patient. We used multivariable logistic models to identify patient factors independently associated with process adherence. RESULTS Our cohort comprised 950 patients (mean age 76 years). Of these, 86% (645/750) received parenteral anticoagulation for ≥5 days, 54% (405/750) had oral anticoagulation started on the first treatment day, and 37% (274/750) had an international normalized ratio (INR) ≥2 for ≥24 hours before parenteral anticoagulation was discontinued. Overall, 35% (53/153) of patients with cancer received low-molecular-weight heparin monotherapy and 72% (304/423) of patients with symptomatic deep vein thrombosis were prescribed compression stockings. In multivariate analyses, symptomatic pulmonary embolism, hospital-acquired VTE, and concomitant antiplatelet therapy were associated with a significantly lower anticoagulation-related process adherence. CONCLUSIONS Adherence to several recommended processes of care was suboptimal in elderly patients with VTE. Quality of care interventions should particularly focus on processes with low adherence, such as the prescription of continued low-molecular-weight heparin therapy in patients with cancer and the achievement of an INR ≥2 for ≥24 hours before parenteral anticoagulants are stopped.

Global phylogenomic analysis of nonencapsulated Streptococcus pneumoniae reveals a deep-branching classic lineage that is distinct from multiple sporadic lineages.

The surrounding capsule of Streptococcus pneumoniae has been identified as a major virulence factor and is targeted by pneumococcal conjugate vaccines (PCV). However, nonencapsulated Streptococcus pneumoniae (Non-Ec-Sp) have also been isolated globally, mainly in carriage studies. It is unknown if Non-Ec-Sp evolve sporadically, if they have high antibiotic non-susceptiblity rates and a unique, specific gene content. Here, whole genome sequencing of 131 Non-Ec-Sp isolates sourced from 17 different locations around the world was performed. Results revealed a deep-branching classic lineage that is distinct from multiple sporadic lineages. The sporadic lineages clustered with a previously sequenced, global collection of encapsulated S. pneumoniae (Ec-Sp) isolates while the classic lineage is comprised mainly of the frequently identified multi-locus sequences types ST344 (n=39) and ST448 (n=40). All ST344 and nine ST448 isolates had high non-susceptiblity rates to β-lactams and other antimicrobials. Analysis of the accessory genome reveals that the classic Non-Ec-Sp contained an increased number of mobile elements, than Ec-Sp and sporadic Non-Ec-Sp. Performing adherence assays to human epithelial cells for selected classic and sporadic Non-Ec-Sp revealed that the presence of a integrative conjugative element (ICE) results in increased adherence to human epithelial cells (P=0.005). In contrast, sporadic Non-Ec-Sp lacking the ICE had greater growth in vitro possibly resulting in improved fitness. In conclusion, Non-Ec-Sp isolates from the classic lineage have evolved separately. They have spread globally, are well adapted to nasopharyngeal carriage and are able to coexist with Ec-Sp. Due to continued use of pneumococcal conjugate vaccines, Non-Ec-Sp may become more prevalent.

Pulsed versus continuous wave CO2 laser excisions of 100 oral fibrous hyperplasias: a randomized controlled clinical and histopathological study

BACKGROUND In experimental animal studies, pulsing the CO2 laser beam has been shown to reduce the thermal damage zone of excised oral mucosal tissue. However, there is still controversy over whether this is borne out under clinical conditions. OBJECTIVE To compare the outcome following excisional biopsies of fibrous hyperplasias using a pulsed (cf) versus a continuous wave (cw) CO2 laser mode regarding the thermal damage zone, duration of surgeries, intra- and postoperative complications, postoperative pain sensation, scarring and/or relapse during the initial 6 months. MATERIALS AND METHODS One hundred Swiss-resident patients with a fibrous hyperplasia in their buccal mucosa were randomly assigned to the cw mode (5 W) or the cf mode (140 Hz, 400 microseconds, 33 mJ, 4.62 W) group. All excisions were performed by one single oral surgeon. Postoperative pain (2 weeks) was recorded by visual analogue scale (VAS; ranging from 0 to 100). Intake of analgesics and postoperative complications were recorded in a standardized study form. The maximum width of the collateral thermal damage zone was measured (µm) in excision specimens by one pathologist. Intraoral photographs at 6-month follow-up examinations were evaluated regarding scarring (yes/no). RESULTS Median duration of the excision was 65 seconds in the cw and 81 seconds in the cf group (P = 0.13). Intraoperative bleeding occurred in 16.3% of the patients in the cw and 17.7% of the cf group. The median value of the thermal damage zone was 161(±228) μm in the cw and 152(± 105) μm in the cf group (P = 0.68). The reported postoperative complications included swelling in 19% and minor bleeding in 6% without significant differences between the two laser modes. When comparing each day separately or the combined mean VAS scores of both groups between Days 1-3, 1-7, and 1-15, there were no significant differences. However, more patients of the cw group (25%) took analgesics than patients of the cf group (9.8%) resulting in a borderline significance (P = 0.04). Scarring at the excision site was found in 50.6% of 77 patients after 6 months, and more scars were identified in cases treated with the cf mode (P = 0.03). CONCLUSIONS Excision of fibrous hyperplasias performed with a CO2 laser demonstrated a good clinical outcome and long-term predictability with a low risk of recurrence regardless of the laser mode (cf or cw) used. Scarring after 6 months was only seen in 50.6% of the cases and was slightly more frequent in the cf mode group. Based on the findings of the present study, a safety border of 1 mm appears sufficient for both laser modes especially when performing a biopsy of a suspicious soft tissue lesion to ensure a proper histopathological examination.

Bilateral necrotizing sialometaplasia of the hard palate in a patient with bulimia: a case report and review of the literature.

Necrotizing sialometaplasia (NS) is a rare and benign lesion that mostly affects the posterior hard palate. Its importance resides in its clinical and microscopic characteristics, which can closely mimic malignant neoplasias, in particular oral squamous cell carcinoma and mucoepidermoid carcinoma. Accurate histopathologic evaluation of an incisional biopsy is considered as the diagnostic gold standard. NS lesions heal spontaneously within weeks, and no further treatment is necessary. We report a case of a bilateral palatal NS in a 22-yearold woman with bulimia, where an incisional biopsy confirmed the clinical diagnosis. The different clinical stages of the lesions from onset to resolution and the possible etiologic factors are described in detail, as well as a discussion of the differential diagnoses of palatal ulcers. When taking a biopsy from suspicious oral lesions, care has to be taken that an appropriate tissue sample is harvested, and the histopathologic analysis is performed by an experienced pathologist to establish a correct diagnosis.

Polypharmacy is Associated with an Increased Risk of Bleeding in Elderly Patients with Venous Thromboembolism.

BACKGROUND Polypharmacy, defined as the concomitant use of multiple medications, is very common in the elderly and may trigger drug-drug interactions and increase the risk of falls in patients receiving vitamin K antagonists. OBJECTIVE To examine whether polypharmacy increases the risk of bleeding in elderly patients who receive vitamin K antagonists for acute venous thromboembolism (VTE). DESIGN We used a prospective cohort study. PARTICIPANTS In a multicenter Swiss cohort, we studied 830 patients aged ≥ 65 years with VTE. MAIN MEASURES We defined polypharmacy as the prescription of more than four different drugs. We assessed the association between polypharmacy and the time to a first major and clinically relevant non-major bleeding, accounting for the competing risk of death. We adjusted for known bleeding risk factors (age, gender, pulmonary embolism, active cancer, arterial hypertension, cardiac disease, cerebrovascular disease, chronic liver and renal disease, diabetes mellitus, history of major bleeding, recent surgery, anemia, thrombocytopenia) and periods of vitamin K antagonist treatment as a time-varying covariate. KEY RESULTS Overall, 413 (49.8 %) patients had polypharmacy. The mean follow-up duration was 17.8 months. Patients with polypharmacy had a significantly higher incidence of major (9.0 vs. 4.1 events/100 patient-years; incidence rate ratio [IRR] 2.18, 95 % confidence interval [CI] 1.32-3.68) and clinically relevant non-major bleeding (14.8 vs. 8.0 events/100 patient-years; IRR 1.85, 95 % CI 1.27-2.71) than patients without polypharmacy. After adjustment, polypharmacy was significantly associated with major (sub-hazard ratio [SHR] 1.83, 95 % CI 1.03-3.25) and clinically relevant non-major bleeding (SHR 1.60, 95 % CI 1.06-2.42). CONCLUSIONS Polypharmacy is associated with an increased risk of both major and clinically relevant non-major bleeding in elderly patients receiving vitamin K antagonists for VTE.

Physical Activity and Risk of Bleeding in Elderly Patients Taking Anticoagulants.

BACKGROUND Although the possibility of bleeding during anticoagulant treatment may limit patients from taking part in physical activity, the association between physical activity and anticoagulation-related bleeding is uncertain. OBJECTIVES To determine whether physical activity is associated with bleeding in elderly patients taking anticoagulants. PATIENTS/METHODS In a prospective multicenter cohort study of 988 patients aged ≥65 years receiving anticoagulants for venous thromboembolism, we assessed patients' self-reported physical activity level. The primary outcome was the time to a first major bleeding, defined as fatal bleeding, symptomatic bleeding in a critical site, or bleeding causing a fall in hemoglobin or leading to transfusions. The secondary outcome was the time to a first clinically-relevant non-major bleeding. We examined the association between physical activity level and time to a first bleeding using competing risk regression, accounting for death as a competing event. We adjusted for known bleeding risk factors and anticoagulation as a time-varying covariate. RESULTS During a mean follow-up of 22 months, patients with a low, moderate, and high physical activity level had an incidence of major bleeding of 11.6, 6.3, and 3.1 events per 100 patient-years, and an incidence of clinically relevant non-major bleeding of 14.0, 10.3, and 7.7 events per 100 patient-years, respectively. A high physical activity level was significantly associated with a lower risk of major bleeding (adjusted sub-hazard ratio 0.40, 95%-CI 0.22-0.72). There was no association between physical activity and non-major bleeding. CONCLUSIONS A high level of physical activity is associated with a decreased risk of major bleeding in elderly patients receiving anticoagulant therapy. This article is protected by copyright. All rights reserved.

OSCAR – ein internetbasiertes Unterstützungsprogramm für Angehörige von Menschen mit einer Hirnverletzung: Pilotstudie

Erhöhte Depressivität und Ängstlichkeit sowie ein erhöhtes subjektives Belastungserleben sind bei Angehörigen von Menschen mit einer Hirnverletzung häufig. Die vorliegende Pilotuntersuchung widmet sich der Evaluation einer neuartigen Intervention, dem OSCAR Online-Coaching, einer internetbasierten Mehrkomponentenintervention. In einer randomisierten, kontrollierten Pilotstudie mit 35 TeilnehmerInnen wurde ein 16-wöchiges therapeutengeleitetes Selbsthilfeprogramm mit einer Wartekontrollgruppe verglichen. Als primäre Ergebnismasse wurde der Perceived Stress Questionnaire und das Zarit Burden Interview eingesetzt. Intention-to-treat-Analysen der unmittelbaren Effekte direkt nach der Intervention zeigten keine signifikanten Gruppenunterschiede auf den primären und auf sekundären Ergebnismassen. Im 6-Monate Follow-up, nach Zugang der Kontrollgruppe zur Intervention, wurde in der Gesamtstichprobe eine signifikante Reduktion des Caregiver Burden, depressiver Symptome, der Angst, sowie eine Zunahme positiver Emotionen gefunden. Die Zufriedenheit mit dem Programm war gut.

Effects of depressive symptoms on antecedents of lapses during a smoking cessation attempt: an ecological momentary assessment study

AIMS: To investigate pathways through which momentary negative affect and depressive symptoms affect risk of lapse during smoking cessation attempts. DESIGN: Ecological momentary assessment was carried out during 2 weeks after an unassisted smoking cessation attempt. A 3-month follow-up measured smoking frequency. SETTING: Data were collected via mobile devices in German-speaking Switzerland. PARTICIPANTS: A total of 242 individuals (age 20-40, 67% men) reported 7112 observations. MEASUREMENTS: Online surveys assessed baseline depressive symptoms and nicotine dependence. Real-time data on negative affect, physical withdrawal symptoms, urge to smoke, abstinence-related self-efficacy and lapses. FINDINGS: A two-level structural equation model suggested that on the situational level, negative affect increased the urge to smoke and decreased self-efficacy (β = 0.20; β = -0.12, respectively), but had no direct effect on lapse risk. A higher urge to smoke (β = 0.09) and lower self-efficacy (β = -0.11) were confirmed as situational antecedents of lapses. Depressive symptoms at baseline were a strong predictor of a person's average negative affect (β = 0.35, all P < 0.001). However, the baseline characteristics influenced smoking frequency 3 months later only indirectly, through influences of average states on the number of lapses during the quit attempt. CONCLUSIONS: Controlling for nicotine dependence, higher depressive symptoms at baseline were associated strongly with a worse longer-term outcome. Negative affect experienced during the quit attempt was the only pathway through which the baseline depressive symptoms were associated with a reduced self-efficacy and increased urges to smoke, all leading to the increased probability of lapses.

Zusammenhänge zwischen sozialer Unterstützung und Suizidalität bei homo- und bisexuellen Personen

Der Beitrag untersucht Zusammenhänge zwischen sozialer Unterstützung und Suizidalität bei 615 homo- und bisexuellen Personen in der Schweiz. In einer Internetumfrage wurden dazu Suizidgedanken, Suizidpläne und Suizidversuche, sowie diverse Aspekte sozialer Unterstützung und die soziale Belastung erfragt. Obwohl homo- und bisexuelle Personen hohe Werte sozialer Unterstützung und niedrige Werte sozialer Belastung aufwiesen, zeigten sich hohe 12-Monats- und Lebenszeitprävalenzen bezüglich Suizidgedanken, -plänen und -versuchen. Alle Aspekte sozialer Unterstützung waren mit der Suizidalität in den letzten zwölf Monaten assoziiert, wobei die Zusammenhänge mit der sozialen Integration (r = -.34) und der sozialen Belastung (r = .39) am stärksten ausfielen. Selbst bei Kontrolle der depressiven Stimmung und des Alters teilnehmender Personen blieben die soziale Unterstützung (OR = .61) und die soziale Belastung (OR = 2.13) prädiktiv für die Suizidalität in den letzten zwölf Monaten. Personen, die viel soziale Unterstützung wahrnahmen (> 1 SD über dem Mittelwert) berichteten fünfmal weniger Suizidalität als solche mit geringer sozialer Unterstützung (> 1 SD unter dem Mittelwert). Personen, die viel soziale Belastung in ihrem Umfeld wahrnahmen (> 1 SD über dem Mittelwert), zeigten im vergangenen Jahr 14-mal häufiger Suizidalität als Personen, die geringe soziale Belastung erlebten (> 1 SD unter dem Mittelwert).

Bereavement and Complicated Grief across the Lifespan

Loss can be seen as a normative life event; nevertheless for most individuals, the experience of the loss of a loved one is extremely stressful. The grief reaction is universal but shaped by cultural norms and individual expectations; grief may also become a serious health problem. The aim of this article is to review the consequences of grief as well as explanations and treatment of complicated grief disorder. Five areas are identified to be of importance to clinicians and researchers: (1) grief reactions, (2) models of grief, (3) bereavement across the life span, (4) diagnostic criteria, and (5) treatment for complicated grief.

Longitudinal Measurement Invariance Issues Illustrated by Examples of Marital Satisfaction in Later Life and the Structure of Psychopathology Before and After Psychotherapy

Talk at the Symposium "Opportunities and Challenges of Longitudinal Perspectives"

Longitudinal associations between causal sexual relationships and stressful life events in emerging adults

Findings on the consequences of casual sexual relationships (CSR) are inconsistent and range from positive to negative outcomes. The longitudinal association between stressful live events and CSR was investigated in a random sample of 2844 Swiss emerging adults. Cross-lagged panel models with baseline, two- and five-year follow-up data showed that life events predicted more subsequent CSR across emerging adulthood. In contrast, CSR predicted life events only from the first to the second wave. Results suggest that the link between stressful life events and CSR was mainly explained by romantic breakups as stressful life event. Environment-related life events were not substantially associated with casual sexual relationships. Thus, engaging in CSR did not seem to be a general emotion-focused coping strategy in the context of life events nor can the engagement in casual sex be seen as a result of stressful life events affecting general self-regulation.

Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups

Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.