Modern medicine is facing the spread of biofilm-related infections. Bacterial biofilms are difficult to detect in routine diagnostics and are inherently tolerant to host defenses and antibiotic ...therapies. In addition, biofilms facilitate the spread of antibiotic resistance by promoting horizontal gene transfer. We review current concepts of biofilm tolerance with special emphasis on the role of the biofilm matrix and the physiology of biofilm-embedded cells. The heterogeneity in metabolic and reproductive activity within a biofilm correlates with a non-uniform susceptibility of enclosed bacteria. Recent studies have documented similar heterogeneity in planktonic cultures. Nutritional starvation and high cell density, two key characteristics of biofilm physiology, also mediate antimicrobial tolerance in stationary-phase planktonic cultures. Advances in characterizing the role of stress response genes, quorum sensing and phase variation in stationary-phase planktonic cultures have shed new light on tolerance mechanisms within biofilm communities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To describe admission characteristics, risk factors and outcomes of patients with coronavirus disease 2019 (COVID-19) hospitalised in a tertiary care hospital in Switzerland during the early phase of ...the pandemic.
This retrospective cohort study included adult patients with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction (PCR) testing and hospitalised at the cantonal hospital Aarau (Switzerland) between 26 February 2020 and 30 April 2020. Our primary endpoint was severe COVID-19 progression defined as a composite of transfer to the intensive care unit (ICU) and in-hospital mortality.
A total of 99 patients (median age 67 years interquartile range 56-76, 37% females) were included and 35% developed severe COVID-19 progression (24% needed ICU treatment, 19% died). Patients had a high burden of comorbidities with a median Charlson comorbidity index of 3 points and a high prevalence of hypertension (57%), chronic kidney disease (28%) and obesity (27%). Baseline characteristics with the highest prognostic value for the primary endpoint by means of area under the receiver operating characteristic curve were male gender (0.63) and initial laboratory values including shock markers (lactate on ambient air 0.67; lactate with O2 supply 0.70), markers of inflammation (C-reactive protein 0.72, procalcitonin 0.80) and markers of compromised oxygenation (pO2 0.75 on ambient air), whereas age and comorbidities provided little prognostic information.
This analysis provides insights into the first consecutively hospitalised patients with confirmed COVID-19 at a Swiss tertiary care hospital during the initial period of the pandemic. Markers of disease progression such as inflammatory markers, markers for shock and impaired respiratory function provided the most prognostic information regarding severe COVID-19 progression in our sample.
BackgroundReduced bone mineral density (BMD) is common in adults infected with human immunodeficiency virus (HIV). The role of proximal renal tubular dysfunction (PRTD) and alterations in bone ...metabolism in HIV-related low BMD are incompletely understood MethodsWe quantified BMD (dual-energy x-ray absorptiometry), blood and urinary markers of bone metabolism and renal function, and risk factors for low BMD (hip or spine T score, −1 or less) in an ambulatory care setting. We determined factors associated with low BMD and calculated 10-year fracture risks using the World Health Organization FRAX equation ResultsWe studied 153 adults (98% men; median age, 48 years; median body mass index, 24.5; 67 44% were receiving tenofovir, 81 53% were receiving a boosted protease inhibitor PI). Sixty-five participants (42%) had low BMD, and 11 (7%) had PRTD. PI therapy was associated with low BMD in multivariable analysis (odds ratio, 2.69; 95% confidence interval, 1.09–6.63). Tenofovir use was associated with increased osteoblast and osteoclast activity (P⩽.002). The mean estimated 10-year risks were 1.2% for hip fracture and 5.4% for any major osteoporotic fracture ConclusionsIn this mostly male population, low BMD was significantly associated with PI therapy. Tenofovir recipients showed evidence of increased bone turnover. Measurement of BMD and estimation of fracture risk may be warranted in treated HIV-infected adults
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
With the technical developments in neurosurgery, increasing numbers of neurosurgical implants are used in an increasingly aged population of patients with several comorbidities. Consequently, the ...number of neurosurgical implant-associated infections is continuously raising, resulting in significant morbidity and mortality, including disfiguring skull deformities and lack of brain protection. In this article we review infections associated with craniotomy, cranioplasty, neurostimulators, internal cerebrospinal fluid shunts, and external ventricular and lumbar cerebrospinal fluid drainages. In all implant-associated infections biofilms are involved, which are difficult to eradicate. A low number of microorganisms is sufficient to form a biofilm on the implant surface. In most infections, microorganisms of the skin flora are involved. Microorganisms reach the implant during surgery or immediately thereafter as a result of wound healing disturbances. In about two thirds of patients, implant-associated infections manifest early (within the first month after surgery), whereas the remaining infections present later as a result of low-grade infections or by direct extension from adjacent infections (per continuitatem) to the implants due to soft tissue damage. Except for ventriculo-atrial cerebrospinal fluid shunts, neurosurgical implants are rarely infected by the haematogenous route. In this article we review established and clinically validated concepts for the management of biofilm-associated infections in orthopaedic and trauma surgery, which can be extrapolated to other surgical disciplines that use implants. However, the evidence for the success of this extrapolation to neurosurgical patients is sparse and has not been evaluated in large patient populations. For favourable outcome, an optimised microbiological diagnosis including sonication of removed implants and prolonged incubation of cultures is required. Furthermore, a combined surgical and antimicrobial management strategy is needed. Surgery includes an appropriate debridement with or without implant exchange or removal, depending on the age of the biofilm and the soft tissue condition. Antimicrobial treatment includes a prolonged biofilm-active therapy, typically for 4-12 weeks. This concept is attractive, because in selected patients, implants can be retained or exchanged in a one-stage surgical procedure, which improves not only quality of life, but also decreases morbidity because every additional neurosurgical intervention can lead to secondary complications, including intracerebral bleeding or ischemia.
The opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental evidence exists. Expression of δ-opioid receptors (DORs) correlates with poor prognosis ...for breast cancer patients, but mechanistic insights into oncogenic signaling mechanisms of opioid-triggered cancer progression are lacking. We show that orthotopic transplant models using human or murine breast cancer cells displayed enhanced metastasis upon opioid-induced DOR stimulation. Interestingly, opioid-exposed breast cancer cells showed enhanced migration and strong STAT3 activation, which was efficiently blocked by a DOR-antagonist. Furthermore, opioid treatment resulted in down-regulation of E-Cadherin and increased expression of epithelial-mesenchymal transition markers. Notably, STAT3 knockdown or upstream inhibition through the JAK1/2 kinase inhibitor ruxolitinib prevented opioid-induced breast cancer cell metastasis and migration in vitro and in vivo. We conclude on a novel mechanism whereby opioid-triggered breast cancer metastasis occurs via oncogenic JAK1/2-STAT3 signaling to promote epithelial-mesenchymal transition. These findings emphasize the importance of selective and restricted opioid use, as well as the need for safer pain medication that does not activate these oncogenic pathways.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In opioid agonist therapy (OAT) programmes, chronic hepatitis C is highly prevalent and directly observed therapy guarantees optimal adherence. Since 2017, all patients with chronic hepatitis C in ...Switzerland can be treated with pangenotypic direct-acting antivirals irrespective of liver fibrosis stage. Until the end of 2021, however, prescription was restricted to infectious disease specialists, gastroenterologists and certain addiction specialists. Difficult venous access after long-term intravenous drug use and, in the case of referral to a specialist, difficulties keeping appointments are barriers to HCV diagnosis and treatment.
To assess whether minimally invasive point-of-care tests and a "test-and-treat / vaccinate on-site" approach can improve human immunodeficiency virus (HIV) / hepatitis C virus (HCV) screening, HCV treatment uptake and immunity against hepatitis A/B.
Since September 2018, an infectious disease specialist and a study nurse performed 4-weekly visits in the OAT programme "HAG" (heroin dispensation of the canton Aargau), offering HIV/HCV antibody rapid testing (20 min) and HCV RNA quantification (GeneXpert®, 60 min) from capillary blood, noninvasive liver fibrosis assessment (Fibroscan®, 5-10 min) and HCV treatment prescription on-site. Recommended venous blood draws for HAV/HBV serology and HAV/HBV vaccinations were performed by the staff of the "HAG". Project performance was assessed by annual cross-sectional chart review.
Of the 128 patients registered in April 2018, 79 (62%) were still present in May 2021. With 72 newly registered, a total of 200 patients could be assessed, of whom 129 (65%) were still present in May 2021. Between April 2018 and May 2021, the proportion ever tested for HIV antibodies increased from 79% (101/128) to 91% (117/129), the proportion ever tested for HCV antibodies from 83% (106/128) to 93% (120/129) and the proportion of those HCV antibody positive ever tested for HCV RNA tested from 89% (47/53) to 98% (56/57). The proportion with adequate HCV management (last HCV antibody test ≤1 year ago, if HCV antibody negative or last HCV RNA test ≤1 year ago, if HCV antibody-positive and RNA-negative) improved from 23% (15 + 15/128) to 80% (55 + 48/129). Overall, HCV treatment uptake increased from 60% (21/35) to 92% (55/60) and HCV RNA prevalence among the HCV antibody positives decreased from 38% (18/47) to 7% (6/84). Between 2018 and 2021, 19 non-cirrhotic chronic hepatitis C patients were successfully treated on-site (18 sustained virological responses SVR 12, 1 SVR4), with excellent adherence (≥93%) and, so far, no reinfection. The proportion with known HAV/HBV serostatus increased from 38%/51% to 64%/76%. Immunity against HAV/HBV improved from 19%/23% to 50%/57%.
Capillary blood point-of-care tests and a "test-and-treat / vaccinate on-site" approach remove crucial barriers to diagnosis and treatment, making hepatitis elimination in OAT programmes achievable. A high fluctuation rate requires HIV/HCV/HAV/HBV testing at admission, but also allows more patients to be screened.
Background. We investigated the incidence and outcome of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)–infected individuals before and after the introduction ...of combination antiretroviral therapy (cART) in 1996. Methods. From 1988 through 2007, 226 cases of PML were reported to the Swiss HIV Cohort Study. By chart review, we confirmed 186 cases and recorded all-cause and PML-attributable mortality. For the survival analysis, 25 patients with postmortem diagnosis and 2 without CD4+ T cell counts were excluded, leaving a total of 159 patients (89 before 1996 and 70 during 1996–2007). Results. The incidence rate of PML decreased from 0.24 cases per 100 patient-years (PY; 95% confidence interval CI, 0.20–0.29 cases per 100 PY) before 1996 to 0.06 cases per 100 PY (95% CI, 0.04–0.10 cases per 100 PY) from 1996 onward. Patients who received a diagnosis before 1996 had a higher frequency of prior acquired immunodeficiency syndrome–defining conditions (P=.007) but similar CD4+ T cell counts (60 vs. 71 cells/µL; P=.25), compared with patients who received a diagnosis during 1996 or thereafter. The median time to PML-attributable death was 71 days (interquartile range, 44–140 days), compared with 90 days (interquartile range, 54–313 days) for all-cause mortality. The PML-attributable 1-year mortality rate decreased from 82.3 cases per 100 PY (95% CI, 58.8–115.1 cases per 100 PY) during the pre-cART era to 37.6 cases per 100 PY (95% CI, 23.4.–60.5 cases per 100 PY) during the cART era. In multivariate models, cART was the only factor associated with lower PML-attributable mortality (hazard ratio, 0.18; 95% CI, 0.07–0.50; P<.001), whereas all-cause mortality was associated with baseline CD4+ T cell count (hazard ratio per increase of 100 cells/µL, 0.52; 95% CI, 0.32–0.85; P=.010) and cART use (hazard ratio, 0.37; 95% CI, 0.19–0.75; P=.006). Conclusions. cART reduced the incidence and PML-attributable 1-year mortality, regardless of baseline CD4+ T cell count, whereas overall mortality was dependant on cART use and baseline CD4+ T cell count.
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BFBNIB, NUK, PNG, UL, UM, UPUK
To evaluate the prevalence of 25-hydroxyvitamin D 25(OH)D deficiency in HIV-positive patients, a population at risk for osteoporosis.
Retrospective assessment of vitamin D levels by season and ...initiation of combined antiretroviral therapy (cART).
25(OH)D was measured in 211 HIV-positive patients: samples were taken before initiation of cART from February to April or from August to October as well as 12 (same season) and 18 months (alternate season) after starting cART. 1,25-Dihydroxyvitamin D 1,25(OH)2D was measured in a subset of 74 patients. Multivariable analyses included season, sex, age, ethnicity, BMI, intravenous drug use (IDU), renal function, time since HIV diagnosis, previous AIDS, CD4 cell count and cART, in particular nonnucleoside reverse transcriptase inhibitor (NNRTI) and tenofovir (TDF) use.
At baseline, median 25(OH)D levels were 37 (interquartile range 20-49) nmol/l in spring and 57 (39-74) nmol/l in the fall; 25(OH)D deficiency less than 30 nmol/l was more prevalent in spring (42%) than in fall (14%), but remained unchanged regardless of cART exposure. In multivariable analysis, 25(OH)D levels were higher in white patients and those with a longer time since HIV diagnosis and lower in springtime measurements and in those with active IDU and NNRTI use. 1-Hydroxylation rates were significantly higher in patients with low 25(OH)D. Hepatitis C seropositivity, previous AIDS and higher CD4 cell counts correlated with lower 1,25(OH)2D levels, whereas BMI and TDF use were associated with higher levels. In TDF-treated patients, higher 1,25(OH)2D correlated with increases in serum alkaline phosphatase.
Based on the high rate of vitamin D deficiency in HIV-positive patients, systematic screening with consideration of seasonality is warranted. The impact of NNRTIs on 25(OH)D and TDF on 1,25(OH)2D needs further attention.
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