Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly.

BCG vaccination in children protects against heterologous infections and improves survival independently of tuberculosis prevention. The phase III ACTIVATE trial assessed whether BCG has similar effects in the elderly. In this double-blind, randomized trial, elderly patients (n = 198) received BCG or placebo vaccine at hospital discharge and were followed for 12 months for new infections. At interim analysis, BCG vaccination significantly increased the time to first infection (median 16 weeks compared to 11 weeks after placebo). The incidence of new infections was 42.3% (95% CIs 31.9%-53.4%) after placebo vaccination and 25.0% (95% CIs 16.4%-36.1%) after BCG vaccination; most of the protection was against respiratory tract infections of probable viral origin (hazard ratio 0.21, p = 0.013). No difference in the frequency of adverse effects was found. Data show that BCG vaccination is safe and can protect the elderly against infections. Larger studies are needed to assess protection against respiratory infections, including COVID-19 (ClinicalTrials.gov NCT03296423).

HIV treatment strategies across Central, Eastern and Southeastern Europe: New times, old problems.

INTRODUCTION: In the last decade, substantial differences in the epidemiology of, antiretroviral therapy (ART) for, cascade of care in and support to people with HIV in vulnerable populations have been observed between countries in Western Europe, Central Europe (CE) and Eastern Europe (EE). The aim of this study was to use a survey to explore whether ART availability and therapies have evolved in CE and EE according to European guidelines. METHODS: The Euroguidelines in Central and Eastern Europe (ECEE) Network Group conducted two identical multicentre cross-sectional online surveys in 2019 and 2021 concerning the availability and use of antiretroviral drugs (boosted protease inhibitors [bPIs], integrase inhibitors [INSTIs] and nucleoside reverse transcriptase inhibitors [NRTIs]), the introduction of a rapid ART start strategy and the use of two-drug regimens (2DRs) for starting or switching ART. We also investigated barriers to the implementation of these strategies in each region. RESULTS: In total, 18 centres participated in the study: four from CE, six from EE and eight from Southeastern Europe (SEE). Between those 2 years, older PIs were less frequently used and darunavir-based regimens were the main PIs (83%); bictegravir-based and tenofovir alafenamide-based regimens were introduced in CE and SEE but not in EE. The COVID-19 pandemic did not significantly interrupt delivery of ART in most centres. Two-thirds of centres adopted a rapid ART start strategy, mainly in pregnant women and to improve linkage of care in vulnerable populations. The main obstacle to rapid ART start was that national guidelines in several countries from all three regions did not support such as strategy or required laboratory tests first; an INSTI/NRTI combination was the most commonly prescribed regimen (75%) and was exclusively prescribed in SEE. 2DRs are increasingly used for starting or switching ART (58%), and an INSTI/NRTI was the preferred regimen (75%) in all regions and exclusively prescribed in SEE, whereas the use of bPIs declined. Metabolic disorders and adverse drug reactions were the main reasons for starting a 2DR; in the second survey, HIV RNA <500 000 c/ml and high cluster of differentiation (CD)-4 count emerged as additional important reasons. CONCLUSIONS: In just 2 years and in spite of the emergence of the COVID-19 pandemic, significant achievements concerning ART availability and strategies have occurred in CE, EE and SEE that facilitate the harmonization of those strategies with the European AIDS Clinical Society guidelines. Few exceptions exist, especially in EE. Continuous effort is needed to overcome various obstacles (administrative, financial, national guideline restrictions) in some countries.

National strategies for vaccination against COVID-19 in people living with HIV in Central and Eastern European region.

INTRODUCTION: People living with HIV (PLWH) are at higher risk of poorer COVID-19 outcomes. Vaccination is a safe and effective method of prevention against many infectious diseases, including COVID-19. Here we investigate the strategies for national COVID-19 vaccination programmes across central and eastern Europe and the inclusion of PLWH in vaccination programmes. METHODS: The Euroguidelines in Central and Eastern Europe Network Group consists of experts in the field of infectious diseases from 24 countries in the region. Between 1 November 2020 and 19 March 2021 the group proceeded an on-line survey consisting of 20 questions. RESULTS: Twenty-two countries (out of 24 invited) participated in the survey and 20/22 countries in the period between December 2020 and March 2021 had already started their COVID-19 vaccination programme. In total, seven different vaccines were used by participating countries. In 17/21 countries (81%), vaccinated persons were centralized within the national registry. In 8/21 countries (38%) PLWH were prioritized for vaccination (the Czech Republic, Greece, Hungary, Lithuania, Montenegro, Romania, Slovakia, Slovenia) and the Czech Republic, Greece and Serbia had put in place national guidelines for vaccination of PLWH. In 14/20 countries (70%) vaccination was only provided by designated centres. Eighteen respondents (18/21; 85.7%) reported that they planned to follow up HIV patients vaccinated against COVID-19, mainly by measuring antibody levels and checking COVID-19 incidence (11/21; 52.3%). CONCLUSIONS: This survey-based study suggests that there are significant differences in terms of prioritizing PLWH, the types of vaccines used, vaccination coverage, and the development and implementation of a vaccination programmes within the region. Regardless of heterogenicity and existing barriers within the region, systematic vaccination in PLWH should have the highest priority, especially in those with severe immunodeficiency, risk factors, and in the elderly, aiming for prompt and high vaccination coverage.

Estimation of the determinants for HIV late presentation using the traditional definition and molecular clock-inferred dates: Evidence that older age, heterosexual risk group and more recent diagnosis are prognostic factors.

OBJECTIVES: HIV late presentation (LP) has been increasing in recent years in Europe. Our aim was to investigate the characteristics of LP in Greece using in addition to the traditional definition for LP, the time interval between HIV infection and diagnosis. METHODS: Our nationwide sample included HIV-1 sequences generated from 6166 people living with HIV (PLWH) in Greece during the period 1999-2015. Our analysis was based on the molecularly inferred HIV-1 infection dates for PLWH infected within local molecular transmission clusters of subtypes A1 and B. RESULTS: Analysis of the determinants of LP was conducted using either CD4 counts or AIDS-defining condition at diagnosis or the time from infection to diagnosis. Older age, heterosexual transmission risk group and more recent diagnosis were associated with increased risk for LP. In contrast to previous studies, people who inject drugs (PWID) had a shorter median time to diagnosis (0.63 years) compared to men who have sex with men (MSM) (1.72 years) and heterosexuals (2.43 years). Using HIV infection dates that provide an unbiased marker for LP compared to CD4 counts at diagnosis, which are age-dependent, we estimated that the time to diagnosis increased gradually with age. Migrants infected regionally do not differ with respect to LP status compared to native Greeks. CONCLUSIONS: We demonstrate that older people and heterosexuals are among those at higher risk for LP; and given the growing number of older people among newly diagnosed cases, tailored interventions are needed in these populations.

Earlier treatment initiation is associated with a decreased number of HIV-1 subtype A1 transmissions in Greece.

OBJECTIVES: Subtypes A1 and B are the most prevalent HIV-1 clades in Greece. Subtype A1 epidemic is highly monophyletic and corresponds to transmissions that occurred locally. Our aim in this molecular epidemiology analysis was to investigate the role of early treatment in preventing new HIV-1 transmissions. METHODS: Our analysis focused on 791 subtype A1 sequences from treatment-naïve individuals in Greece. Estimation of infection dates was performed by molecular clock calculations using Bayesian methods. We estimated the time interval between (1) the infection and sampling dates (linkage to care window), (2) the sampling dates and antiretroviral therapy (ART) initiation (treatment window), and (3) the infection dates and ART initiation (transmissibility window) for the study population. We also inferred the putative source of HIV infections between individuals of different groups divided according to the length of treatment, linkage to care or transmissibility window. RESULTS: A significant decline was detected for the treatment window during 2014-2015 versus the 2 previous years (p=0.0273), while the linkage to care interval remained unchanged during the study period. Inference of the putative source of HIV infections suggested that individuals with a recent diagnosis or narrow transmissibility window (time period between HIV infection and ART initiation) were not sources of HIV infections to other groups. Contrarily, a significant number of HIV infections originated from individuals with longer transmissibility window interval. CONCLUSIONS: Our findings showed that the treatment window is decreasing over time, presumably due to the updated treatment guidelines. Our study also demonstrates that people treated earlier after infection do not transmit at high rates, thus documenting the benefits of early ART initiation in preventing ongoing HIV-1 transmission.

Epidemiological characteristics and access to end-stage liver disease care for HIV-positive patients with HCV and/or HBV coinfections in Central/Eastern European and neighboring countries ­ data from the ECEE network

OBJECTIVES: There is currently an urgent need to harmonize hepatitis standards of care for HIV-positive patients across Europe. The HIV epidemic in Central and Eastern Europe has often been driven by injecting drug use, therefore a higher rate of co-infection with HCV and HBV is expected in this region. We have investigated the epidemiological prevalence and treatment availability for end-stage liver disease in HIV/HCV/HBV coinfections in countries represented in the ECEE Network Group. METHODS: The Euroguidelines in Central and Eastern Europe (ECEE) Network Group was initiated in February 2016 to compare standards of care regarding HIV infection in the region. Information about HIV/HCV/HBV co-infections and the availability for end-stage liver disease treatment for HIV-positive patients were collected through on-line surveys. The respondents were ECEE members from 16 countries of the region. The information on co-infection prevalence was sourced from WHO, national HIV programmes, articles published in international journals, single clinic reports, and personal information in ten of the participating countries (62.5%). RESULTS: The HIV/HCV co-infection rate was from 3% to 99%. The range of reported of HIV/HBV coinfection percentages was 2.3% to 40%. HIV/HCV/HBV co-infection ranged from 0% to 9%. Regarding treatment for end-stage liver disease, liver transplantation was an available option for HIV-positive patients in only three countries (19%). CONCLUSION: Our findings revealed only a limited number of treatment options for the end-stage liver disease in HIV-positive patients for the vast majority of Central and Eastern European countries. There are gaps in epidemiological surveillance in this region. It appears there are many differences in the number of co-infected patients among Central and Eastern European and neighboring countries, but there is no unification of information sources.

Increases in inflammatory and CD14dim/CD16pos/CD45pos patrolling monocytes in sepsis: correlation with final outcome.

BACKGROUND: Evidence on the changes in the absolute counts of monocyte subpopulations in sepsis is missing. METHODS: Firstly, absolute counts of circulating CD14pos/HLA-DRpos/CD45pos monocytes were measured by flow cytometry in 70 patients with Gram-negative sepsis and in 10 healthy volunteers. In the second phase, immunophenotyping was performed and the absolute count of circulating inflammatory monocytes and of circulating CD14dim/CD16pos/CD45pos patrolling monocytes were measured in another 55 patients and 10 healthy volunteers. Measurements were repeated on days 3, 7, and 10. Results were correlated with survival after 28 days. RESULTS: Greater numbers of CD14pos/HLA-DRpos/CD45pos monocytes were found on day 1 in survivors compared to nonsurvivors (p = 0.030). Receiver operating characteristic (ROC) analysis showed that a cutoff higher than 337 cells/mm3 on day 1 could discriminate between survivors and nonsurvivors with a positive predictive value (PPV) of 91.1%. Logistic regression including Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE) II score showed that an absolute count greater than 337 cells/mm3 was independently associated with unfavorable outcome (odds ratio (OR) 0.19, p = 0.050). The absolute counts of inflammatory and of CD14dim/CD16pos/CD45pos monocytes were greater in patients than healthy controls during the entire 10 days of follow-up. The absolute counts on day 3 of CD14dim/CD16pos/CD45pos monocytes were greater in survivors than nonsurvivors (p = 0.027). ROC analysis revealed that the cutoff at 27 cells/mm3 could discriminate between survivors and nonsurvivors with PPV of 94.1%. Logistic regression including age, SOFA score, and APACHE II score showed that an absolute count greater than 27 cells/mm3 was independently associated with unfavorable outcome (OR 0.06, p = 0.033). Logistic regression analysis showed that intra-abdominal infection on day 1 was predictive of low CD14dim/ CD16pos/CD45pos count on day 3. CONCLUSION: Circulating counts of inflammatory and patrolling monocytes are greatly increased in Gram-negative sepsis. Absolute counts of CD14pos/HLA-DRpos/CD45pos monocytes on day 1 and CD14dim/CD16pos/CD45pos monocytes on day 3 are independently associated with final outcome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01223690 . Registered retrospectively on 18 October 2010.

When and how to operate on spondylodiscitis: a report of 13 patients.

PURPOSE: Conflicting reports exist regarding the surgical indications, timing, approach, staged or not operation, and spinal instrumentation for patients with spondylodiscitis. Therefore, we performed this study to evaluate the outcome of a series of patients with spondylodiscitis aiming to answer when and how to operate on these patients. MATERIALS AND METHODS: We retrospectively studied the files of 153 patients with spondylodiscitis treated at our institution from 2002 to 2012. The approach included MR imaging of the infected spine, isolation of the pathogen with blood cultures and/or biopsy, and further conservative or surgical treatment. The mean follow-up was 6 years (range 1-13 years). We evaluated the indications, timing (when), and methods (how) for surgical treatment, and the clinical outcome of these patients. RESULTS: Orthopedic surgical treatment was necessary for 13 of the 153 patients (8.5 %). These were patients with low access to healthcare systems because of low socioeconomic status, third-country migrants, prisoners or intravenous drug use, patients in whom a bacterial isolate documentation was necessary, and patients with previous spinal operations. The most common pathogen was Mycobacterium tuberculosis. The surgical indications included deterioration of the neurological status (11 patients), need for bacterial isolate (10 patients), septicemia due to no response to antibiotics (five patients), and/or spinal instability (three patients). An anterior vertebral approach was more commonly used. Nine of the 13 patients had spinal instrumentation in the same setting. Improvement or recovery of the neurological status was observed postoperatively in all patients with preoperative neurological deficits. Postoperatively, two patients deceased from pulmonary infection and septicemia, and heart infarction. At the last follow-up, patients who were alive were asymptomatic; ten patients were neurologically intact, and one patient experienced paraparesis. Imaging showed spinal fusion, without evidence of recurrent spondylodiscitis. Complications related to the spinal instrumentation were not observed in the respective patients. CONCLUSIONS: Conservative treatment is the standard for spondylodiscitis. Physicians should be alert for Mycobacterium tuberculosis spondylitis because of the low access to healthcare systems of patients with low social and economic status. Surgical indications include obtaining tissue sample for diagnosis, occurrence or progression of neurological symptoms, failure of conservative treatment, large anterior abscesses, and very extensive disease. Thorough debridement of infected tissue and spinal stability is paramount. The anterior approach provides direct access and improved exposure to the most commonly affected part of the spine. Spinal instrumentation is generally recommended for optimum spinal stability and fusion, without any implant-related complications.

Bloodstream infections and sepsis in Greece: over-time change of epidemiology and impact of de-escalation on final outcome.

BACKGROUND: Choice of empirically prescribed antimicrobials for sepsis management depends on epidemiological factors. The epidemiology of sepsis in Greece was studied in two large-periods. METHODS: Sepsis due to bloodstream infections (BSI) from July 2006 until March 2013 was recorded in a multicenter study in 46 departments. Patients were divided into sepsis admitted in the emergencies and hospitalized in the general ward (GW) and sepsis developing after admission in the Intensive Care Unit (ICU). The primary endpoints were the changes of epidemiology and the factors related with BSIs by multidrug-resistant (MDR) pathogens; the secondary endpoint was the impact of de-escalation on antimicrobial therapy. RESULTS: 754 patients were studied; 378 from 2006-2009 and 376 from 2010-2013. Major differences were recorded between periods in the GW. They involved increase of: sepsis severity; the incidence of underlying diseases; the incidence of polymicrobial infections; the emergence of Klebsiella pneumoniae as a pathogen; and mortality. Factors independently related with BSI by MDR pathogens were chronic hemofiltration, intake of antibiotics the last three months and residence into long-term care facilities. De-escalation in BSIs by fully susceptible Gram-negatives did not affect final outcome. Similar epidemiological differences were not found in the ICU; MDR Gram-negatives predominated in both periods. CONCLUSIONS: The epidemiology of sepsis in Greece differs in the GW and in the ICU. De-escalation in the GW is a safe strategy.

Promoting prudent use of antibiotics: the experience from a multifaceted regional campaign in Greece.

BACKGROUND: Antibiotic resistance, a major public health problem, has been linked to antibiotic consumption. In Greece both consumption and resistance rates are among the highest in Europe. A multifaceted campaign targeting both physicians and parents of school children was implemented for the first time in order to educate the public and update doctors, aiming to promote judicious use of antibiotics and hopefully decrease its consumption. METHODS: The programme consisted of a public education campaign and academic detailing of primary care physicians in the district of Corinth in Peloponnese. The experience and perceptions of parents were recorded in the meetings in the form of course evaluation and assessment, anonymous questionnaires. The use of Rapid Antigen Detection Test (RADT) for streptococcal pharyngitis by primary care physicians was also assessed by use of anonymous questionnaires. Antibiotic consumption was compared before and after the programme between the district of Corinth and the other districts of Peloponnese, as well as at a national level. RESULTS: Antibiotic consumption remained unaltered at 26 Defined daily doses per 1000 Inhabitants per Day (DID) in accordance with the trend in other regions and at a national level. However, the utilization of Amoxycillin and Penicillin was increased by 34.3%, while the use of other antimicrobial classes including macrolides, cephalosporins and fluoroquinolones decreased by 6.4-21.9%. The use of RADT did not lead to a significantly decreased antimicrobial consumption. CONCLUSIONS: A multifaceted educational programme targeting both the general public and primary care physicians was associated with rationalization in the choice of antimicrobial. A reduction in the total antimicrobial consumption was not achieved.

Eco-Friendly and High-Performance Bio-Polyurethane Adhesives from Vegetable Oils: A Review.

Current petrochemical-based adhesives adversely affect the environment through substantial volatile organic compound (VOC) emissions during production, contributing to air pollution and climate change. In contrast, vegetable oils extracted from bio-resources provide a compelling alternative owing to their renewability, abundance, and compatibility with adhesive formulation chemistry. This review aimed to critically examine and synthesize the existing scholarly literature on environmentally friendly, sustainable, and high-performance polyurethane adhesives (PUAs) developed from vegetable oils. The use of PUAs derived from vegetable oils promises to provide a long-term replacement while simultaneously maintaining or improving adhesive properties. This quality renders these adhesives appropriate for widespread use in various sectors, including construction, automotive manufacturing, packaging, textile, and footwear industries. This review intended to perform a comprehensive assessment and integration of the existing research, thereby identifying the raw materials, strengths, weaknesses, and gaps in knowledge concerning vegetable oil-based PUAs. In doing so, it responded to these gaps and proposes potential avenues for future research. Therefore, this review accomplishes more than merely evaluating the existing research; it fosters the advancement of greener PUA technologies by identifying areas for improvement and innovation towards more sustainable industrial practices by showcasing vegetable oil-based PUAs as viable, high-performance alternatives to their petroleum-based counterparts.

Multimodal Approach to Neurocognitive Function in People Living with HIV in the cART Era: A Comprehensive Review.

Combination antiretroviral treatment (cART) has revolutionized the management of human immunodeficiency virus (HIV) and has markedly improved the disease burden and life expectancy of people living with HIV. HIV enters the central nervous system (CNS) early in the course of infection, establishes latency, and produces a pro-inflammatory milieu that may affect cognitive functions, even in the cART era. Whereas severe forms of neurocognitive impairment (NCI) such as HIV-associated dementia have declined over the last decades, milder forms have become more prevalent, are commonly multifactorial, and are associated with comorbidity burdens, mental health, cART neurotoxicity, and ageing. Since 2007, the Frascati criteria have been used to characterize and classify HIV-associated neurocognitive disorders (HAND) into three stages, namely asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). These criteria are based on a comprehensive neuropsychological assessment that presupposes the availability of validated, demographically adjusted, and normative population data. Novel neuroimaging modalities and biomarkers have been proposed in order to complement NCI assessments, elucidate neuropathogenic mechanisms, and support HIV-associated NCI diagnosis, monitoring, and prognosis. By integrating neuropsychological assessments with biomarkers and neuroimaging into a holistic care approach, clinicians can enhance diagnostic accuracy, prognosis, and patient outcomes. This review interrogates the value of these modes of assessment and proposes a unified approach to NCI diagnosis.

Immunogenicity of a seasonal influenza and a pneumococcal polysaccharide vaccine in multiple sclerosis patients under disease modifying therapies: A single-center prospective study.

BACKGROUND: Immunogenicity of influenza and pneumococcal vaccines varies and requires further elucidation in patients with multiple sclerosis (MS) under treatment with disease-modifying therapies (DMTs). METHODS: Adult MS patients who consented with vaccination after standard-of-care consultation by their treating physicians were enrolled. All received a single dose of an inactivated quadrivalent influenza vaccine and of the 23-valent pneumococcal vaccine. A blood sample was collected before and after four weeks of vaccination for measurement of antibodies against Influenza A, B and S. pneumoniae. Patients were followed-up for adverse events and MS relapse for 12 months. RESULTS: One hundred and seventy-two patients (65.7 % female, mean age 42 ± 13 years old, mean MS duration 7.6 ± 7.2 years, 81.4 % under DMTs) were enrolled from November 2019 to March 2020. Antibody measurements were available for 151 patients. Seropositivity for anti-PPSV23 did not differ between baseline and at 4 weeks of follow-up (n = 56, 37.1 %). There was a significant increase of absolute antibody titers post-vaccination for both influenza A and B (p < 0.001). For Influenza A, seropositivity was evident for 57 (37.7 %) patients at 4 weeks compared to 19 (12.6 %) patients at baseline (pMcNemar < 0.001). For Influenza Β, 110 (72.8 %) seroconverted 4 weeks after vaccination compared to 12 (7.9 %) at baseline (pMcNemar < 0.001). Interferon and fumarate did not affect influenza seroconversion while rituximab was associated with lower titers. Mild local AEs (pain, edema) were observed in 23.8 %; no severe AE was reported. Thirty-four patients (19.8 %) had a relapse during the 12-month follow-up; none was attributed to the vaccination. CONCLUSIONS: Seroconversion in MS patients on treatment was more frequent following influenza compared to PPSV23 vaccination. Rituximab had an effect on the height of the immune response. Better immunization coverage as well as future evaluation of the breadth of immune response elicited by immunization is necessary for these patients.

Mpox across countries from Central and Eastern Europe - 2022 outbreak.

BACKGROUND: The aim of the study was to assess socio-demographical characteristics, clinical presentation, and outcomes in patients diagnosed with mpox. METHODS: A survey on patients diagnosed with mpox was performed in 14 countries from Central and Eastern Europe. Data was compared according to HIV status and country of origin (EU vs. non-EU). Mpox diagnosis was confirmed by RT-PCR from oropharyngeal swabs, skin lesions, and other body fluids. RESULTS: Out of 154 patients confirmed with mpox in 2022, 99.3% were males, with a median age (years) of 35 (IQR 30-39), 90.2% MSM and 48.7% PLWH. Compared to HIV-negative subjects, PLWH had more frequent high-risk behaviours:chemsex (p = 0.015), group sex (p = 0.027), and a history of sexually transmitted infections (STIs) (p = 0.004). Persons from EU were more often PLWH (p = 0.042), MSM (p < 0.0001), had multiple sexual partners (p = 0.025), practiced chemsex (p = 0.008) or group-sex (p = 0.005) and had more often history of STIs (p < 0.0001). The median CD4 cell count/mL at mpox diagnosis was 713 (IQR 486-996) and 73.5% had undetectable HIV VL. The commonest clinical features were fever (108 cases), lymphadenopathy (78), and vesiculo-pustular rash: penile (76), perianal (48), limbs (67). Fifty-one (31%) persons were hospitalized due to complications or epidemiological reasons. Three patients received tecovirimat or cidofovir. The outcome was favorable for all patients, including 4 with severe forms. CONCLUSIONS: Mpox was diagnosed predominantly in young MSM, with high-risk behaviors and history of STIs. Effective contact tracing and vaccination are important strategic pillars to control mpox outbreaks.

Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Addition of macrolide antibiotics to ß-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a ß-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome. METHODS: The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of ß-lactam plus ß-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044). FINDINGS: Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. INTERPRETATION: Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to ß-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. FUNDING: Hellenic Institute for the Study of Sepsis and Abbott Products Operations.

Nanotechnology and Wood Science.

Nanotechnology, in a sense, is not entirely a new concept [...].

Low-Intensity Pulsed Ultrasound Treatment for Non-unions of Long Bone Fractures in a Scottish District General Hospital.

OBJECTIVE: Despite advances in treatment, the management of fracture non-union remains a challenging and complex problem in orthopaedics. Low-intensity pulsed ultrasound (LIPUS) treatment has been shown to be an effective, non-invasive, affordable treatment option. This treatment was evaluated in a Scottish district hospital over a nine-year period, which included the COVID-19 pandemic. MATERIALS AND METHODS: This submission describes a case series at Dr Gray's Hospital in Scotland, 18 patients in whom fracture non-union was treated using LIPUS. RESULTS: An overall healing rate of 94% was achieved. Exogen™ (Bioventus LLC, NC, USA) proved to be most successful in oligotrophic non-union. No observed patient demographic appeared predictive of outcome. LIPUS treatment failed in one case. No significant adverse effects of LIPUS were detected. CONCLUSION: LIPUS represents a useful, cost-effective potential alternative to revision surgery. LIPUS may therefore be the preferred treatment when surgical intervention and face-to-face interactions are to be minimised, as during the COVID-19 pandemic.

Foot Osteomyelitis Caused by Multidrug- and Extensively Drug-Resistant Gram-Negative Bacteria.

There are scarce data regarding foot osteomyelitis (FO) caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria (GNB). This study investigates the causative organisms, the diagnostic and therapeutic approach and the outcome of these infections. All patients with FO caused by MDR and/or XDR GNB who received treatment in the Department of osseous infectious diseases of the "Attikon" University Hospital of Athens, Greece, were recorded and evaluated during a six-year-period. Seventeen patients, of which 64.7% females, with a mean age of 54.06 years were studied. There were nine cases with diabetic (DFO), and 76.5% of patients reported previous use of antimicrobials. Pathogens were isolated from soft-tissue biopsies or intra-operative tissue samples (n=12) and/or affected bone samples (n=5). In most cases, E. coli and P. aeruginosa were isolated (each 29.4%), followed by P. mirabilis (11.7%), while polymicrobial infection was detected in nine patients (53%). Most cases were given antimicrobial monotherapy (88.2%) with a mean duration of 90.05 days, while surgery significantly promoted cure of the infection. Foot and DFO cases represent a challenging to treat disease, requiring a multidisciplinary approach. Surgical treatment remains the cornerstone of treatment, while it is of utmost importance to isolate the causative organisms. MDR and XDR GNB represent an emerging threat and more data are needed to better understand these infections.

Enterovirus-Rhinovirus-Induced Acute Respiratory Distress Syndrome in Adults: A Case Report and Short Literature Review.

Enteroviruses and rhinoviruses (EV-RV) are small RNA viruses that usually cause the common cold and asthma exacerbations. Although EV-RV-induced acute respiratory distress syndrome (ARDS) is common in children, only scattered reports of ARDS in adults have been published. The diagnosis has been greatly facilitated by the advent of molecular techniques, namely, real-time polymerase chain reaction (RT-PCR). EV-RV can cause ARDS by stimulating a cytokine cascade. No antiviral therapy has yet been approved, and treatment is entirely supportive. Herein, we report a rare case of EV-RV infection in an afebrile adult with dyspnea that rapidly progressed to acute lung injury and ARDS. EV-RV was isolated with multiple real-time PCR in nasopharyngeal and bronchial specimens, while no other pathogen was detected. We also present an up-to-date review of relevant literature, in an attempt to stress the importance of the early identification of viral culprits, which can minimize the use of invasive diagnostic procedures and antibiotic agents.

Switching from Tenofovir Disoproxil to Tenofovir Alafenamide Fumarate: Impact on Cardiovascular Risk and Lipid Profile in People Living with HIV, an Observational Study.

In the era of combination antiretroviral therapy (ART), people living with HIV (PLHIV) still face an increased risk of cardiovascular disease (CVD). Tenofovir alafenamide fumarate (TAF) is superior to its precursor tenofovir disoproxil fumarate (TDF) regarding bone and renal toxicity, but there are concerns about a negative effect on lipid profile. This observational, single-center study investigates the effects on lipid profile and cardiovascular (CVD) risk of the switch from TDF to TAF, in combination with emtricitabine/elvitegravir/cobicistat (FTC/EVG/c), in patients with no exposure to other antiretrovirals. Routine laboratory measurements, somatometric characteristics, and smoking status were analyzed for the assessment of CVD risk changes, using D:A:D and ATP III scores pre- and postswitch. A total of 62 patients with a mean age of 32.9 years were included in this study. Sixty-one patients (98.4%) were men, 38 (61.3%) late presenters, and 39 (62.9%) active smokers. A year after the switch, there was a significant increase in total cholesterol (178 ± 38 to 194 ± 40 mg/dL, p < .001), high-density lipoprotein (45 ± 12 to 48 ± 13 mg/dL, p = .001), and low-density lipoprotein (117 ± 32 to 137 ± 36 mg/dL, p < .001). Mean increase of the 10-year D:A:D score was 1.13% (95% confidence interval, 1.05-1.22, p = .002). Changes were more prominent in nonsmokers. Body mass index and average weight showed an upward trend. Switching from TDF to TAF caused significant changes in lipid profile at 14 months of follow-up, in young, otherwise healthy PLHIV. CVD risk, as measured by D:A:D, showed a statistically significant increase, but more data are needed to determine clinical significance. These results point toward a patient-centered approach when selecting an ART regimen.