Guidance of adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient derived organoids: a single center, open-label, phase II trial.

BACKGROUND: In intermediate-risk non-muscle invasive bladder cancer (NMIBC) clinical guidelines suggest an adjuvant instillation with a chemotherapeutic agent. However, the agent and regimen are not clearly defined. Worldwide, less than 15% of patients receive this adjuvant chemotherapeutic instillation. We recently developed a pipeline for the generation of patient derived organoids (PDO) in NMIBC. In this phase II trial, we aim to use our in vitro pipeline to select the most effective drug for chemotherapeutic instillation in NMIBC patients. METHODS: Patients with first diagnosis of intermediate-risk NMIBC that are directed to transurethral resection of bladder tumor (TURBT) are enrolled. During TURBT, tumor is sampled, and specimens are directed to generate PDO. Once the PDO are formed, drug screens on them for Epirubicin, Mitomycin C, Gemcitabine and Docetaxel are performed. The drug with the highest antitumor activity in vitro will then be selected for 6 adjuvant intravesical instillations once weekly. Thereafter, patients are followed according to clinical guidelines by cystoscopy. DISCUSSION: The aim of this trial is to use drug screens in PDO to precise treatment selection for adjuvant instillation therapies in patients with intermediate-risk NMIBC. The ultimate goal of this trial is to reduce the risk of cancer recurrence. In the future, we aim to conduct clinical multicenter trials with an increased sample size, a broader panel of compounds and a focus on the reduction of cancer recurrence by precision delivery of care. Trial registration NCT05024734.

Which Patients To Consider for Bladder Preservation After a Complete Response to Neoadjuvant Chemotherapy.

The decision on which patients with muscle-invasive bladder cancer to consider for bladder preservation remains controversial. New promising technologies and biomarkers may allow to precise selection of patients for bladder preservation in the future. Currently, bladder preservation should only be considered in highly selected cases and in the setting of clinical trials.

Investigating the mechanisms by which selective attention affects subsequent preferences and choice.

In two experiments, we investigated two untested assumptions regarding the mechanism by which selective attention during search affects subsequent preferences for objects. First, we tested whether an increase in visual competition during search increases preferences for relevant objects and decreases preferences for irrelevant objects subsequent to search. Second, we tested whether searching for objects increases the perceived fluency to process relevant objects and decreases the perceived fluency to process irrelevant objects. Our results show that search can affect relevant and irrelevant objects differently. Selective attention increased preferences for target objects subsequent to search, whereas selective attention did not affect preferences for distractors. Furthermore, our results indicate that searching for a target object increased the perceived fluency for this target object during choice, whereas ignoring a distractor product blocked mere exposure effects. Contrary to assumptions made in previous research, we found no indication that the competition for visual resources during search is linked to preferences for targets or distractors.

Early Switch From Intravenous to Oral Antibiotics in Skin and Soft Tissue Infections: An Algorithm-Based Prospective Multicenter Pilot Trial.

Background: In hospitalized patients with skin and soft tissue infections (SSTIs), intravenous (IV) empiric antibiotic treatment is initiated. The best time point for switching from IV to oral treatment is unknown. We used an algorithm-based decision tree for the switch from IV to oral antibiotics within 48 hours and aimed to investigate the treatment outcome of this concept. Methods: In a nonrandomized trial, we prospectively enrolled 128 patients hospitalized with SSTI from July 2019 to May 2021 at 3 institutions. Clinical and biochemical response data during the first week and at follow-up after 30 days were analyzed. Patients fulfilling criteria for the switch from IV to oral antibiotics were assigned to the intervention group. The primary outcome was a composite definition consisting of the proportion of patients with clinical failure or death of any cause. Results: Ninety-seven (75.8%) patients were assigned to the intervention group. All of them showed signs of clinical improvement (ie, absence of fever or reduction of pain) within 48 hours of IV treatment, irrespective of erythema finding or biochemical response. The median total antibiotic treatment duration was 11 (interquartile range [IQR], 9-13) days in the invention group and 15 (IQR, 11-24) days in the nonintervention group (P < .001). The median duration of hospitalization was 5 (IQR, 4-6) days in the intervention group and 8 (IQR, 6-12) days in the nonintervention group (P < .001). There were 5 (5.2%) failures in the intervention group and 1 (3.2%) in the nonintervention group after a median follow-up of 37 days. Conclusions: In this pilot trial, the proposed decision algorithm for early switch from IV to oral antibiotics for SSTI treatment was successful in 95% of cases. Clinical Trials Registration. ISRCTN15245496.

Outcome of patients with double valve surgery between 2009 and 2018 at University Hospital Basel, Switzerland.

BACKGROUND: In isolated mitral valve regurgitation general consensus on surgery is to favor repair over replacement excluding rheumatic etiology or endocarditis. If concomitant aortic valve replacement is performed however, clinical evidence is more ambiguous and no explicit guidelines exist on the choice of mitral valve treatment. Both, double valve replacement (DVR) and aortic valve replacement in combination with concomitant mitral valve repair (AVR + MVP) have been proven to be feasible procedures. In our single-center, retrospective, observational cohort study, we compared the outcome of these two surgical techniques focusing on mortality and morbidity. METHODS: 89 patients underwent DVR (n = 41) or AVR + MVP (n = 48) in our institution between 2009 and 2018. Follow-up data was collected using electronic patient records, by contacting treating physicians and by telephone interviews. We used the Kaplan-Meier method to analyze mortality during follow-up and Cox regression to investigate potential predictors of mortality. RESULTS: During a median follow-up duration of 4.5 [IQR 2.9 to 6.1] years, there was no significant difference in mortality between both cohorts. Thirty days mortality was 6.3% in the DVR and 7% in the AVR + MVP cohort. Overall mortality amounted to 17% for DVR and 23% for AVR + MVP. DVR was the preferred procedure for valve disease of rheumatic etiology and for endocarditis, while in degenerative valves AVR + MVP was predominant. More biological valves were used in the AVR + MVP cohort (p < 0.001) and more mechanical valves were implanted in the DVR cohort. The rate of rehospitalization, deterioration of left ventricular ejection fraction and postoperative complications were equally distributed among the two cohorts. CONCLUSION: Our data analysis showed that both DVR and AVR + MVP are safe and feasible options for double valve surgery. Based on our findings we could not prove superiority of one surgical technique over the other. Choosing the appropriate procedure for the patient should be influenced by valve etiology, patients' comorbidities and the surgeons' experience. TRIAL REGISTRATION: This was a retrospectively registered trial, registered on April 1st 2018, ClinicalTrials.gov Identifier: NCT03667274.

Droplet precautions on-site (DroPS) during the influenza season 2018/2019: a possible alternative to single room isolation for respiratory viral infections.

BACKGROUND: The guideline-driven and widely implemented single room isolation strategy for respiratory viral infections (RVI) such as influenza or respiratory syncytial virus (RSV) can lead to a shortage of available hospital beds. We discuss our experience with the introduction of droplet precautions on-site (DroPS) as a possible alternative. METHODS: During the 2018/19 influenza season we introduced DroPS on several wards of a single tertiary care center, while other wards maintained the traditional single room isolation strategy. On a daily basis, we evaluated patients for the development of respiratory symptoms and screened those with a clinical diagnosis of hospital-acquired respiratory viral infection (HARVI) for influenza/RSV by molecular rapid test. If negative, it was followed by a multiplex respiratory virus PCR. We report the concept of DroPS, the feasibility of the strategy and the rate of microbiologically confirmed HARVI with influenza or RSV infection on the DroPS wards compared to wards using the traditional single room isolation strategy. RESULTS: We evaluated all hospitalised patients at risk for a HARVI, 741 (72%) on the DroPS wards and 293 (28%) on the regular wards. The hospital-acquired infection rate with influenza or RSV was 2/741 (0.3%; 1× influenza A, 1× RSV) on the DroPS wards and 2/293 (0.7%; 2× influenza A) on the regular wards. CONCLUSIONS: Droplet precautions on-site (DroPS) may be a simple and potentially resource-saving alternative to the standard single room isolation strategy for respiratory viral infections. Further studies in a larger clinical context are needed to document its safety.

Droplet precautions on site instead of single room isolation for respiratory tract infections.

We introduced a pragmatic concept of on site droplet precautions instead of single room isolation for rural hospitals in a tiered network. A survey among healthcare workers revealed that this approach was considered comprehensive, safe, and acceptable. This concept could be an alternative for hospitals with few single rooms available for isolation.

Reduction of urinary catheter use and prescription of antibiotics for asymptomatic bacteriuria in hospitalised patients in internal medicine: before-and-after intervention study.

PRINCIPLES: Unnecessary treatment of asymptomatic bacteriuria and overuse of urinary catheters in hospitals are of concern regarding antimicrobial resistance and patient safety, respectively. We investigated the effectiveness of a multifaceted intervention in reducing urinary catheter use and unnecessary prescription of antibiotics for asymptomatic bacteriuria in hospitalised patients in a clinic for internal medicine. METHODS: Data were collected retrospectively from all inpatients during a 3-month period both before and after a multifaceted intervention from the Clinic for Internal Medicine of our secondary care hospital. The intervention consisted of implementation of guidelines, establishment of a standard for urinary catheter management, introduction of restricted orders and a reminder of indwelling catheters, as well as lectures and internet-based learning focusing on asymptomatic bacteriuria. RESULTS: The incidence rate of urinary catheter days decreased significantly from 27 to 17 catheter days per 100 patient days (incidence rate ratio 0.61, 95% confidence interval 0.57-0.67). The incidence rate of unnecessary antibiotic treatment days for asymptomatic bacteriuria dropped significantly from 22 to 10 treatment days per 1,000 patient days (incidence rate ratio 0.46, 95% confidence interval 0.33-0.63). CONCLUSIONS: A multifaceted intervention was effective in reducing both urinary catheter days and inappropriate antibiotic use for asymptomatic bacteriuria.

Antiretroviral treatment and osteonecrosis in patients of the Swiss HIV Cohort Study: a nested case-control study.

We examined risk factors for avascular bone necrosis (AVN) particularly focusing o the question of whether antiretroviral treatment (ART) is associated with the emergence of osteonecrosis. After 11 years of following the entire cohort, 26 patients were found to have AVN. Compared to 260 concurrent HIV-infected controls, at risk when cases were diagnosed, patients with AVN had lower CD4 cell count nadirs (median 86.5 versus 137.5 cells/microl, p = 0.010) and suffered significantly more often from Pneumocystis pneumonia, cerebral toxoplasmosis, CMV retinitis, and atypical mycobacteriosis and had a significantly higher body mass index than controls. Duration of ART before AVN was not significantly different between cases and controls (2.92 versus 2.17 years, p = 0.30). In conclusion, AVN could not be attributed to time on antiretroviral treatment, but patients with AVN had histories of more severe immunosuppression and a higher body mass index than controls.

Migrants from Sub-Saharan Africa in the Swiss HIV Cohort Study: access to antiretroviral therapy, disease progression and survival.

OBJECTIVE: To examine the proportion of migrants from Sub-Saharan Africa entering the Swiss HIV Cohort Study (SHCS) and to compare these participants with participants from Northwestern Europe for access to antiretroviral therapy, progression to AIDS and survival. DESIGN: Prospective national cohort study of HIV-1-infected adults from seven HIV centres in Switzerland. METHODS: Trends in the proportion of participants from Sub-Saharan Africa were followed in 11 872 HIV-infected adults entering the SHCS from 1984 to 2001. Survival methods were used to compare uptake of antiretroviral therapy, survival and progression to AIDS in the 2684 participants from Sub-Saharan Africa and Northwest Europe enrolled from 1997-2001. RESULTS: There was a steady increase in the proportion of Sub-Saharan African participants over time, reaching 11.9% in 1997-2001. These participants were more likely to be younger, female, to have been infected by heterosexual intercourse and had lower CD4 cell counts at presentation. There were no differences between Sub-Saharan Africans and Northwest Europeans in uptake of triple antiretroviral therapy, progression to AIDS or survival up to 48 months after starting treatment. Tuberculosis was the most frequent AIDS-defining event in Sub-Saharan African patients. CONCLUSIONS: There is no evidence that access to potent antiretroviral therapy is influenced by geographic origin of participants. The prognosis of Sub-Saharan African patients on triple therapy is equivalent to that of Northwest European patients. Future research should address wider issues about access to specialist health services for HIV-infected people from Sub-Saharan Africa.

A controlled trial of granulocyte macrophage-colony stimulating factor during interruption of HAART.

OBJECTIVES: To explore the effect of granulocyte macrophage colony stimulating factor (GM-CSF) on viral load and CD4 cell count during interruption of highly active antiretroviral therapy (HAART). METHODS: Patients on effective HAART (CD4 cell count > 400 x 10(6)/l; viral load < 50 HIV RNA copies/ml) were randomized to one of two groups: 12 weeks' treatment interruption plus, during the first 4 weeks, 300 microg GM-CSF (Leucomax-Novartis) by subcutaneous injection three times weekly (GM-CSF group); 12 weeks' scheduled treatment interruption (STI-only group). Viral load, CD4 cell count, clinical events and side effects of treatment were monitored. RESULTS: Thirty-three patients, 15 in the GM-CSF group and 18 in the STI-only group, were evaluated according to the intention-to-treat principle. The two groups were well matched with regard to pre-HAART viral loads and CD4 cell counts. During STI, viraemia was approximately two to three times lower in the group receiving GM-CSF (max 4.97 versus 5.45 in STI-only group; P = 0.03). Fifteen out of 17 patients in the STI-only group showed a decrease in their CD4 cell count between weeks 0 and 4 (median decrease 231 x 10(6) cells/l; P < 0.001); there was no such tendency in the GM-CSF group (P = non-significant when comparing CD4 cell counts at weeks 0 and 4). The median CD4 cell AUC (area under the curve) from week 0 to week 12 was higher in the GM-CSF group (9166 cells.week) than in patients without GM-CSF (7257), P = 0.02. GM-CSF produced local reactions in 88% of patients, and generalized symptoms such as fever, back pain or headache in 82% of patients. Seventy-six percent of patients completed the planned course of 12 injections. CONCLUSIONS: The administration of GM-CSF blunted the viral rebound following interruption of HAART, and largely prevented a decrease of CD4 cell counts during a 12-weeks-treatment interruption. A better understanding of the underlying mechanism(s) may help to identify synergistic treatment targets and improved administration protocols to enhance control of chronic HIV infection.

Low incidence of community-acquired pneumonia among human immunodeficiency virus-infected patients after interruption of Pneumocystis carinii pneumonia prophylaxis.

We compared the incidence of bacterial pneumonia among 336 patients who discontinued trimethoprim-sulfamethoxazole (TMP-SMX) as prophylaxis against Pneumocystis carinii pneumonia (PCP) with that among 75 patients who fulfilled the criteria for discontinuation but continued receiving prophylaxis. The difference in the overall incidence rates for the 2 groups (1.2 events per 100 person-years) was not statistically significant. Discontinuation of TMP-SMX prophylaxis against PCP is not associated with a significant increase in the incidence of bacterial pneumonia among patients with a sustained CD4 cell count increase to >200 cells/microL.

Retinal microangiopathy in human immunodeficiency virus infection is related to higher human immunodeficiency virus-1 load in plasma.

PURPOSE: To evaluate the prevalence of retinal microangiopathy in human immunodeficiency virus (HIV)-1-infected patients and its association with virologic, immunologic, and sociodemographic parameters. DESIGN: Single-center cross-sectional study. PARTICIPANTS: One hundred eighty-eight HIV-1-positive individuals from a single outpatient clinic. METHODS: Human immunodeficiency virus-positive patients were screened for signs of HIV-associated retinal angiopathy. Plasma HIV-1 RNA and CD4-positive cell counts were monitored within 3 months of the ophthalmologic assessment. The absence or presence of angiopathy or of opportunistic viral retinitis was then correlated to data respecting CD4-positive cell count, plasma viral load of HIV-1, and sociodemographic parameters. MAIN OUTCOME MEASURES: Association between CD4-positive cell count, HIV-1 plasma viral load, sociodemographic parameters, and the manifestation of retinal microangiopathy. RESULTS: At the baseline consultation, 130 (69%) patients exhibited no retinal pathologic features, 45 (24%) manifested retinal angiopathy, and 13 (7%) had opportunistic viral retinitis. In univariate analysis, retinal angiopathy was associated with lower CD4-positive cell count and higher HIV-1 plasma viral load. In a multivariate logistic model, the presence of retinal microangiopathy was associated with higher age (P = 0.02) and higher viral load of HIV-1 (P < 0.005), but not with lower CD4 cell counts (P > 0.05). CONCLUSIONS: Human immunodeficiency virus-associated retinal microangiopathy is likely a multifactorial condition. Its presence is associated with higher age and higher replication of HIV-1 as measured by plasma HIV-1 RNA levels. In contrast to opportunistic infectious retinitis, the degree of immunodeficiency does not seem to be independently correlated with retinal angiopathy.