Extended Treatment Research Articles

Phase I trial of hydroxychloroquine to enhance palbociclib and letrozole efficacy in ER+/HER2− breast cancer

Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2−negative metastatic breast cancer (ER+/HER2− MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence. The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses. We conducted a phase I trial (NCT03774472 registered in ClinicalTrials.gov on 8/20/2018) of HCQ (400, 600, 800 mg/day) with palbociclib (75 mg/day continuous) and letrozole, using a 3 + 3 design. Primary objectives included safety, tolerability, and determining the recommended phase 2 dose (RP2D) of HCQ. Secondary objectives included tumor response and biomarker analysis. Fourteen ER+/HER2− MBC patients were evaluable [400 mg (n = 4), 600 mg (n = 4), 800 mg (n = 6)]. Grade 3 adverse events (AEs) included hematological (3 at 800 mg), skin rash (2 at 600 mg), and anorexia (1 at 400 mg), with no serious AEs. The best responses were partial (2), stable (11), and progression (1). Tumor reductions ranged from 11% to 30%, with one 55% increase. The two partial responders sustained tumor size reductions of 30% to 55% over an extended treatment period, lasting nearly 300 days. Biomarker analysis in responders demonstrated significant decreases in Ki67, Rb, and nuclear cyclin E levels and increases in autophagy markers p62 and LAMP1, suggesting a correlation between these biomarkers and treatment response. This phase I study demonstrated that HCQ is safe and well-tolerated and the RP2D was established at 800 mg/day with continuous low-dose palbociclib (75 mg/day) and letrozole (2.5 mg/day). These findings suggest that adding HCQ could potentially enhance the efficacy of low-dose palbociclib and standard letrozole therapy, pending verification in larger randomized studies.

1-Year real-world outcomes of faricimab in previously treated neovascular age-related macular degeneration.

Faricimab, a bispecific antibody targeting VEGF-A and angiopoietin-2, has shown promise in treating neovascular age-related macular degeneration (nAMD). This study evaluates 1-year outcomes of faricimab in treatment-experienced nAMD patients. This single-centre retrospective cohort study included patients previously treated for nAMD who switched to faricimab between November 2022 and March 2024. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and treatment intervals were assessed at baseline, 6, and 12 months. One hundred eighty-four patients (215 eyes) were included. Patients had received a median of 18 (interquartile range [IQR] 10-28.5) anti-VEGF injections per eye over an average of 5.02 ± 11.82 years before switch. An average of 8.63 ± 2.2 faricimab injections were administered per eye over an average follow-up of 12.19 ± 2.70 months. Median BCVA decreased from 70 ETDRS letters (IQR 55-76) at baseline to 62 (IQR 47-76) at 12 months (p = 0.0038). Median CMT improved from 259.5 μm (IQR 223-299.75) at baseline to 232 μm (202.0-272.5) at 12 months (p < 0.0001). At the last follow-up, 40.2% of eyes were dry on OCT. The median dosing interval doubled from 4 weeks (IQR 4-4) to 8 weeks (IQR 6-10) with faricimab (p < 0.0001). 47.4% and 16.3% of eyes achieved treatment intervals of ≥8-12 weeks and ≥12 weeks, respectively. Three events of uveitis were noted following the loading phase. This real-world study demonstrates that faricimab maintains vision and achieves significant anatomical improvements in treatment-experienced nAMD patients. The extended treatment intervals could significantly reduce the burden on patients and healthcare resources.

Cancer-associated thrombosis: what is new?

The life expectancy of patients suffering from thrombosis associated with cancer has improved significantly, making them a chronic disease. Patients with thrombosis and cancer are fragile. Treated with anticoagulants, they remain at risk of complications. Consequently, news issues emerge for clinical practice: anticoagulation therapy personalization is required to optimize the benefit ratio, involving patient characteristics and cancer characteristics. During follow-up, prediction score are designed and investigated to help identify and discriminate patients at risk of venous thromboembolism recurrences and major bleedings. Considering the improved prognosis of patients with cancer and cancer-associated thrombosis, the question of extended treatment arises, representing a major unmet need to date. Finally, new strategies, in particular anti-XI agents that appear attractive options, are currently being evaluated in the treatment of thrombosis associated with cancer. The improved prognosis of patients with cancer-associated thrombosis is accompanied by new therapeutic strategies to improve the benefit-risk ratio of anticoagulant treatment in these fragile patients, at risk of both venous thromboembolic recurrence and haemorrhagic complication.

Reduced- versus full-dose anticoagulants for the extended treatment of cancer-associated venous thromboembolism in Thai patients

BackgroundReduced dose anticoagulant therapy for the extended treatment of cancer-associated venous thromboembolism (VTE) has been used to avoid bleeding. However, it may increase the risk of recurrent VTE. AimsTo study the rate of recurrent VTE and bleeding complications in Thai patients with cancer-associated VTE who were treated with full-dose or reduced-dose anticoagulants. MethodsA retrospective cohort study was conducted in a single-center academic hospital. Electronic medical records were reviewed from 2016-2023. Patients with cancer-associated VTE who received anticoagulants for at least 3 months were evaluated. Reduced-dose anticoagulant was defined as a dose that was lower than the recommended standard dosage. The primary outcome was recurrent VTE. The secondary outcomes were major bleeding and clinically relevant non-major bleeding. ResultsA total of 229 patients were included. The median age was 65 years (interquartile range [IQR] 54-72). In the reduced-dose group, age and history of previous bleeding were higher than in the full-dose group. There were 169 (74%) patients and 60 (26%) patients who received full- and reduced-dose anticoagulants. The median time to reduce the dose was 3.6 months ([IQR] 0.7 – 5.5). Of a total of 7 (3.1%) recurrent VTE, 4 (2.4%) occurred in the full-dose and 3 (5.0%) in the reduced-dose groups (p=0.4), respectively. The median time to recurrent VTE was 7.2 months ([IQR] 3.5-12.4). There were 8 (3.5%) bleeding events, 7 (4.1%) and 1 (1.7%) in the full and reduced-dose anticoagulant groups (p=0.35), respectively. The median follow-up time was 1.5 years (IQR 1-3.1). ConclusionOlder age and a history of previous bleeding were associated with the use of reduced-dose anticoagulants. Patients with cancer-associated VTE receiving reduced-dose anticoagulants had a numerically higher risk of recurrent VTE and lower bleeding outcomes compared with those receiving full-dose anticoagulants.

Discussion on the Splitting Treatment Technique in Gamma Knife Treatment Plans

Objective: In clinical Gamma Knife treatment, when patients have multiple or large lesions, a single Gamma Knife plan may require extended treatment time, making it difficult for patients to complete the session. This study explores the proper application of the splitting treatment technique in Gamma Knife treatment plans to create segmented plans for patients. Methods: Utilizing the design and output functions of the radiotherapy planning system, this study examines the typical errors in clinical treatment plans designed for the Moonlight Gamma Knife. Different splitting approaches were analyzed by comparing beam-on time for each target and calculating beam-on time error rates. Based on this, the appropriate splitting treatment technique for Gamma Knife treatment plans was discussed. Results: Scenarios where dose curves of multiple lesions intersect were categorized into three types: complete intersection, partial intersection, and no intersection. Complete intersection cases were further divided into Type I and Type II complete intersections. For cases with completely intersecting dose curves, the Gamma Knife plans should be split using the upper-lower segmentation method. For cases with no intersection, plans can be split based on individual lesions. For partial intersection cases, either the upper-lower segmentation or lesion-based segmentation method may be used. However, careful handling of target weighting at the dose curve intersection is necessary to ensure dose accuracy. For large lesions, the upper-lower segmentation method is recommended. Conclusion: To meet clinical treatment requirements, the proper application of the splitting treatment technique in Gamma Knife treatment plans is essential. This ensures dose accuracy in radiotherapy, thereby guaranteeing treatment efficacy and patient safety.

Remission induction therapies and long-term outcomes in granulomatosis with polyangiitis and microscopic polyangiitis: real-world data from a European cohort

To explore disease characteristics, renal involvement and induction treatment strategies over the last decades and evaluate relapse rates and renal outcomes in ANCA-associated vasculitides (AAV). We retrospectively analyzed remission, relapse rates and the occurrence of the composite endpoint (comprising death and renal failure) in newly diagnosed AAV cases in four tertial referral centers in Germany and Switzerland diagnosed between 1999 and 2022. Hazard ratios were computed by Cox proportional hazard and Kaplan–Meier curves were plotted to compare therapeutic strategies after propensity-matching. In our cohort of 358 AAV patients, 203 (58.1%) were classified as granulomatosis with polyangiitis (GPA) based on the novel 2022 ACR/EULAR criteria, 139 (38.8%) as microscopic polyangiitis (MPA). The proportion of MPA cases among all AAV patients increased from 28.9% between 1999 and 2013 up to 46.7% thereafter. Cyclophosphamide (CYC) was chosen most frequently for remission induction (74.8% before 2013 and 57.3% thereafter), whereas the use of rituximab (RTX) increased from 5 to 26% within these periods. GPA patients had a higher relapse rate as compared to MPA patients (41.3% vs. 25.9%, p = 0.006). However, in AAV patients with renal involvement, renal events (i.e. end-stage kidney disease or a persistent drop in the estimated glomerular filtration rate (eGFR) below 15 ml/min/1.73 m2) occurred more frequently in MPA patients, particularly under RTX treatment as compared to matched CYC counterparts (11.8% vs. 7.5%, p = 0.011). In our cohort, GPA patients exhibited frequent relapses, advocating for a more intense and extended treatment. MPA patients had lower relapse rates, however, RTX was less effective to prevent renal endpoints in MPA as compared to CYC, highlighting the need to further investigate additional treatment strategies.

Emerging clinical evidence of a dual role for Ang-2 and VEGF-A blockade with faricimab in retinal diseases.

Anti-vascular endothelial growth factor (VEGF) therapies have transformed the treatment of retinal diseases. However, VEGF signaling is only one component of the complex, multifactorial pathophysiology of retinal diseases, and many patients have residual disease activity despite ongoing anti-VEGF treatment. The angiopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor receptor-2 (Ang/Tie2) signaling pathway is critical to endothelial cell homeostasis, survival, integrity, and vascular stability. Ang-2 can interfere with Ang-1/Tie2 signaling and is increased in several retinal diseases. Lack of Tie2 signaling due to elevated Ang-2 levels drives vascular instability through pericyte dropout, neovascularization, vascular leakage, inflammation, and fibrosis. Although Ang-2 and VEGF can synergistically promote vascular instability and neovascularization, Ang-2 may also mediate vascular instability independently of VEGF. Faricimab is a bispecific antibody designed for intraocular use that inhibits two distinct pathways via Ang-2 and VEGF-A blockade. Clinical biomarkers of vascular instability are important for evaluating disease control and subsequent treatment decisions. These biomarkers include measurement/evaluation with optical coherence tomography (OCT) of intraretinal fluid, subretinal fluid, central subfield thickness, and pigment epithelial detachments (PEDs), and fluorescein angiography imaging of macular leakage and PEDs. Hyperreflective foci (HRF), thought to be representative of activated microglia, indicating an inflammatory microenvironment, and epiretinal membranes (ERMs), a marker for retinal fibrotic proliferation in diabetic macular edema (DME), are both also identified using OCT. Here we summarize data (secondary endpoint and prespecified exploratory analyses as well as post hoc analyses) from six Phase III trials suggest that dual therapy Ang-2/VEGF-A inhibition with faricimab (6mg) has a greater effect on reducing/resolving biomarkers of vascular instability than aflibercept (2mg), by both controlling neovascularization and vascular leakage (with resultant resolution of exudation associated with DME, neovascular age-related macular degeneration, and retinal vein occlusion), as well as by targeting inflammation (reduction of HRF in DME) and retinal fibrotic proliferation (reducing the risk of ERMs in eyes with DME). Modulation of both the Ang-2 and VEGF-A pathways with faricimab may therefore provide greater disease control than anti-VEGF monotherapy, potentially leading to extended treatment durability and improved long-term outcomes.

Predictors for pain and functioning in patients with plantar fasciopathy one year after inclusion in a treatment trial in specialist care

BackgroundPlantar fasciopathy is common, is characterized by heel pain and is associated with decreased functioning and health-related quality of life. While many recover from this condition, a considerable number of people experience persistent heel pain. This study seeks to evaluate predictors for pain and function twelve months after inclusion in a treatment trial in specialist care.MethodsSecondary analysis was conducted on 200 patients with plantar fasciopathy included in a randomized controlled trial and followed for twelve months. Baseline demographics and clinical characteristics were included as possible predictors. Univariate and multivariable linear regression models were applied to identify predictors for foot pain (Numeric rating scale) and function (Foot Function Index revised short form) at 12-month follow-up.ResultsUnilateral heel pain, lower physical activity level and higher number of repetitions in the clinical heel-rise test were identified as statistically significant predictors for reduced pain. Unilateral heel pain, shorter duration of heel pain and being married/cohabitating were predictors for better functioning.ConclusionsUnilateral heel pain as opposed to bilateral heel pain, was the most consistent positive predictor for the outcomes pain and function in plantar fasciopathy at 12-month follow-up. Hence, patients with bilateral PF may need extended assessment and treatment. Other predictors varied among outcomes. These findings may be used to improve clinical management of patients with persistent PF.Trial registrationClinicalTrials.gov NCT03472989. Date of registration 2018-03-20.

Extended treatment-dose antibiotic therapy versus low-dose prophylaxis for the management of recurrent uncomplicated urinary tract infections in peri- and postmenopausal women.

To assess treatment efficacy over one year in women with recurrent urinary tract infection (UTI) receiving extended treatment-strength antibiotics compared to standard low-dose prophylactic antibiotic regimens. A retrospective cohort study of adult women presenting with acute uncomplicated UTI between January 1, 2018 and October 1, 2020 meeting recurrent UTI criteria (≥2 in 6 months or ≥3 in one year). Women were offered either: 1) treatment-strength antibiotic therapy for 1 month; or 2) up to 7 days of treatment-strength antibiotics followed by ≥3-months of low-dose prophylactic antibiotics. We excluded those with complicated UTI. The primary outcome was one or more symptomatic, culture-proven UTIs within 12 months. Multivariable logistic regression assessed differences in the primary outcome while controlling for potential confounders. Among the 246 patients, women receiving extended treatment dose antibiotics (n=43) had a significantly lower risk of experiencing subsequent UTI within 1 year when compared to those receiving standard prophylactic dosing for ≥3-months(n=203) (rate 34.9% vs 59.6%; P<0.01). This significant risk reduction was maintained in logistic regression analyses while controlling for potentially confounding variables (aOR 0.42; 95% CI 0.20,0.89). Women treated with a 1-month course of treatment-strength antibiotics had a significantly lower risk of subsequent UTI within 12 months compared to women receiving ≥3-months of prophylactic antibiotics. These retrospective data preliminarily suggest that extended treatment-strength antibiotic dosing may provide therapeutic benefit while reducing overall cumulative antibiotic dose and duration. This innovative approach warrants further evaluation in randomized trials.

Extended versus standard corticosteroid treatment in primary nephrotic syndrome onset.

Introduction. The standard treatment for the onset of primary nephrotic syndrome (PNS) consists of 8 weeks of prednisone. Alternatively, it was postulated that extending treatment to 12 weeks is associated with fewer relapses. We aimed to evaluate whether relapses' cumulative incidence (CI) at 2 years was lower with extended treatment. Population and methods. This is a retrospective cohort study of patients with PNS who were followed for 2 years and grouped according to the initial treatment received. Results. Thirty-seven patients were included per regimen. The time to first relapse was similar (p = 0.63), and the CI of relapses at 2 years was 75.6% with standard treatment and 72.9% (p = 0.79) with extended treatment; relative risk was 0.96 (95%CI 0.73-1.26). Relapse-free survival in the 2 years of follow-up was also similar (log-rank test = 0.51). Conclusion. Relapse CI at 2 years was similar with both treatment regimens.

The Role of Transcranial Ultrasound Imaging in Intensive Care Treatment of Decompressive Hemicraniectomy Patients: A Retrospective Single-Center Analysis.

Background: Post-hemicraniectomy patients often need extended intensive care treatment. While computed tomography (CT) is considered the gold standard for regular imaging, its frequent use could be linked to adverse clinical outcomes. This study aimed to assess bedside transcranial ultrasound (TUS) to capture intracranial anatomical structures and pathologies. Methods: We analyzed 19 patients treated in our neurosurgical ICU from 1 January 2023 to 1 February 2024. Six physicians from our unit (three residents and three attending physicians) conducted a retrospective evaluation. A total of 158 sessions, including multiple freeze frames and video footage, were analyzed, including 7 imaging categories, using a Likert scale. Subsequently, correlation between CT and TUS was evaluated for midline (ML) shift, subdural space, lateral ventricular width (LVW), and extent of intracerebral hematoma using the Pearson's correlation coefficient (r). Results: TUS was performed on average on 8.32/19.53 days (mean inpatient stay). It provided the lowest Likert scores for the imaging categories ventricular system, midline, subdural space, intraventricular catheter placement, and cortical gyration. Residents reported slightly inferior assessability, resulting in higher scores on the Likert scale (0.02-0.93 mean difference compared with attending physicians). A high correlation was shown in terms of ML shift, LVW, and intracerebral hematomas. No relevant correlation was shown in subdural space. Conclusions: TUS is a safe, cost-, and time-efficient method, potentially gaining relevance for imaging post-hemicraniectomy patients. In our setting, the method seemed effective in depicting intraventricular catheter placement, hydrocephalus, ML shift, and space-occupying lesions. Further improvement in image quality could potentially reduce the overall number of indicated CT scans.

Preferences of continuous care service options for patients with venous leg ulcer development of attributes for discrete choice experiments.

Patients suffering from lower extremity venous ulcers typically undergo prolonged dressing changes, entailing extended treatment cycles and significant costs, creating an urgent need for effective continuous care. There is scarce literature reporting on the preferences and requirements for wound care within continuous care services for such conditions. Discrete choice experiments serve as an innovative method to elicit patient preferences, where the development of attributes and levels is a critically important process. To identify attributes and levels patients with venous leg ulcers consider when making decisions about continued care services for venous leg ulcers. In this study, we employed four steps to devise service features (i.e., attributes) and their potential manifestations (i.e., levels). Firstly, we conducted a systematic literature search with articles screened and content compiled by two researchers to identify possible service attributes. Secondly, we conducted in-depth interviews with patients suffering from venous leg ulcers to gather personal experiences and expectations for quality care, and used Nvivo11.0 for data management. Thirdly, focus group discussions were held to assess general viewpoints from various perspectives. Finally, expert meetings were organized to refine our research tools further. To narrow down the attributes to a manageable number for the discrete choice experiment, focus groups and expert meetings performed ranking exercises, calculating the average importance scores by dividing the total score by the number of participants and ranking attributes from highest to lowest average scores. Through literature reviews, qualitative data acquisition, expert meetings, and ranking exercises, a total of six attributes were finalized, each with two to three levels. The attributes included: 1) service cost (Ave score: 4.7); 2) Mode of service delivery (Ave score: 4.5); 3) Service type (Ave score: 4.4); 4) Consistency of caregiver (Ave score: 4.4); 5) Category of service providers (Ave score: 4.3); and 6) Appointment scheduling (Ave score: 4.3). These attributes encompassed key aspects related to wound care in the continuous care services for patients with venous leg ulcers. The mixed-methods approach adopted in this study has proven particularly suitable for identifying, refining, and selecting attributes and levels for discrete choice experiments. By leveraging the advantages and limitations of the four steps, and especially through qualitative data analysis, a more profound and comprehensive understanding of the attributes and levels was achieved. This approach has facilitated the practicality and accuracy in attribute construction, enhancing the overall efficacy of the DCE design.

New Perspectives on Antimicrobial Agents: Rezafungin.

Candidemia and invasive candidiasis persist as significant causes of morbidity and mortality. As fluconazole resistance rates rise, alternative means of treatment are necessary, either via mold-active azoles or extended durations of echinocandins. These come with the potential for undesirable side effects for triazoles or choosing between prolonged hospitalization or outpatient parenteral antimicrobial therapy in the case of echinocandins. Rezafungin offers an opportunity to manage extended treatment durations with shorter hospital stays and no extended parenteral access. Herein, we review the most recent published data pertaining to rezafungin including anti-fungal activity, pharmacokinetics, and clinical data relating to the treatment of invasive candidiasis. Given its prolonged half-life allowing for once-weekly dosing, rezafungin has the potential as an anti-fungal prophylactic agent in high-risk patients, and studies to examine this potential role are ongoing.

The Frequency and Incidence of QT Prolongation with Extended Use of Bedaquiline or Delamanid in a Large, Multi-Country MDR/RR-TB Cohort.

The 2022 WHO guidelines on multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) recommend six months of bedaquiline (Bdq) in the all-oral 9-month shorter regimen and six months or longer for Bdq and delamanid (Dlm) in the 18-20-month longer regimen. However, lack of evidence on extended treatment using Bdq or Dlm has limited their use to six months. We examine the frequency and incidence of QT prolongation based on duration of Bdq and/or Dlm use in longer regimens. We analyzed a prospective cohort of MDR/RR-TB patients from 16 countries who initiated treatment with Bdq and/or Dlm containing regimens from 1 April 2015-30 September 2018. Data were systematically collected using a shared protocol. The outcome of interest was the first clinically relevant prolonged QT interval (grade 3 or above) or a Serious Adverse Event (SAE) involving prolonged QT of any grade. Among 2,553 patients, 59% received >6 months of Bdq and/or Dlm. Of these, 579 (20.9%) patients experienced a prolonged QT event, the majority (95.5%) being grade 1 or 2. Sixty-four(2.5%) patients experienced the outcome of interest with only 12 (0.5%) having ≥ 1 QT prolonging drugs permanently suspended. The incidence rate of the first prolonged QT event was highest in the first six months of treatment and lower in subsequent six-month periods. We demonstrate that Bdq and/or Dlm use beyond six months is safe in longer MDR/RR-TB regimens with most clinically relevant QT prolongation events occurring in the first six months. ECG monitoring for early identification of QT prolongating events is possible in programmatic conditions.

The reality of bronchoscopy care in Germany: a survey by the German Respiratory Society

In September 2022, sites where bronchoscopy was carried out were systematically surveyed regarding structural and process quality features in an anonymized DGP survey with 33 questions. The data collected were analyzed descriptively. Of the 196 participating sites, bronchoscopies were performed regularly at 180 sites. The majority were standard secondary care (n=51) and tertiary care (n=43) hospitals (range of services: diagnostic bronchoscopy, predominantly (80%) including endobronchial ultrasound-guided transbronchial needle aspiration, EBUS-TBNA). Extended treatment options were guaranteed for acute cases at >90% of these locations. University hospitals (n=24) and specialist pulmonary hospitals (n=35) also offered more complex diagnostic procedures and therapeutic-interventional techniques. The performance figures were significantly higher in the specialist pulmonary hospital (specialist pulmonary hospitals: 62%: >2000 bronchoscopies/year; university hospitals: 25%: >2000 bronchoscopies/year; p<0.001). In the practice setting (n=21, partly in co-operation with hospitals) , <500 bronchoscopies/year were performed.Intensive care units were available in 97% of the hospitals; 88% of the hospitals had fluoroscopy facilities in the bronchoscopy room. Propofol (91%) and/or midazolam (62%) were the preferred drugs for sedation. At 21% of the sites, >200 bronchoscopies under ventilation/year were performed. BAL and transbronchial forceps biopsies were mainly performed via the nasal or oral approach, EBUS-TBNA via a bronchoscopy tube or the oral approach, the EBUS mini-probe/navigation, cryotechnique or more complex interventions via the rigid tube or a bronchoscopy tube. ASA >2 led to involvement of a second physician at 46% of clinical sites, at 47% of sites at an ASA classification >3. The majority of bronchoscopic examinations are performed in respiratory departments at secondary care centres as well as maximum care hospitals. For more complex procedures, cooperation with hospitals specialized in bronchoscopy (e.g. university hospital or a specialist lung clinic) is advisable.

The integration of dermatology experts into primary care to assess and treat patients with skin lesions is cost-effective: A quasi-experimental study.

The management of patients with skin changes can be challenging in primary healthcare; general practitioners (GPs) often lack the expertise to make accurate assessments and treatment decisions. The standard care pathway for skin changes can result in extended treatment times and costs. This study was designed to evaluate the cost-effectiveness of integrating a dermatologist into the primary care setting to assess and treat patients with skin disorders. The primary outcome was the incremental cost-effectiveness ratio (ICER) for each malignant or pre-malignant skin disease found and treated. The secondary outcomes included ICER for any treated skin finding, number needed to excise to find malignant or pre-malignant skin disease, number of hospital referrals required and changes in quality of life (QoL) in the presence and absence of the integration. This was a quasi-experimental cohort study conducted at three primary healthcare centres in Finland. In the two intervention centres, patients with skin findings visited a dermatologist; in the control centre they visited a GP. Cost-effectiveness was assessed using the incremental cost-effectiveness ratio (ICER). QoL was assessed with the PROMIS v1.2, calculative EQ-5D-3L and PROMIS Anxiety 4a instruments. In total, 186 integration and 176 control patients were included. For an additional patient treated for a (pre-)malignant skin disease, the ICER was €852 lower and with any skin disease €381 lower in the integration group than with standard care. Fewer biopsies were required for each malignant or pre-malignant skin disease in the integration group compared to the control group (2.1 and 6.5 per patient; p < 0.001) and lower proportion of patients were referred to hospital (8.1 vs. 17.1%, p < 0.001). Patient QoL did not differ between groups. The integration of dermatological expertise into primary care settings is cost-effective and can streamline the management of patients with skin conditions without worsening their QoL.

Association Between Neuropsychiatric Event and Systemic Lupus Erythematosus Clinical Manifestation: A Meta-Analysis.

To uncover the clinical characteristics and investigate the underlying causes of psychiatric manifestations in patients with systemic lupus erythematosus (SLE), including its subset, neuropsychiatric systemic lupus erythematosus (NPSLE). Through comprehensive database searches in PubMed, Embase, Medline, and Cochrane, from their inception to August 2023, the study focused on adult SLE and NPSLE cases. From the selected studies, data were synthesised via a random-effects meta-analysis, encompassing a total of 2,997 subjects across six studies. The findings highlighted differences in medical indicators such as discoid rash, hypertension, mean disease duration, and various autoantibodies between SLE and NPSLE patients, indicating a nuanced approach to treatment is necessary, particularly with NPSLE requiring extended treatment periods. The analysis suggests that the causality behind these manifestations is multifactorial, encompassing mental state, autoantibody profiles, and environmental factors, thus providing valuable insights into the clinical management and understanding of SLE and NPSLE. This study emphasises the complexity of SLE, particularly in its neuropsychiatric manifestations, and underscores the importance of targeted treatment strategies. Key Words: Systemic lupus erythematosus, Neuropsychiatric systemic lupus erythematosus, Neuropsychiatric event, Meta-analysis.

Assessment and Treatment of Vaginitis.

Vaginitis is the presenting symptom at millions of office visits each year in the United States. Although treatment of sporadic cases is often straightforward, recurrent cases present both diagnostic and treatment challenges. Molecular diagnostic tests are likely superior to in-office microscopy for most clinicians and most cases. In both recurrent bacterial vaginosis and recurrent vulvovaginal candidiasis, national treatment guidelines recommend an extended treatment duration with one of the first-line agents. In cases in which such treatment is not successful, vaginal boric acid is likely the cheapest and easiest alternative option. New antifungal medications offer additional but limited treatment options. Probiotics are not recommended for prevention of vulvovaginal candidiasis; however, vaginal products containing Lactobacillus crispatus may have promise for recurrent bacterial vaginosis. Trichomoniasis should be treated with a 1-week course of metronidazole; this is the only sexually transmitted infection for which treatment recommendations vary by sex. In cases in which patients do not respond to initial treatment, the diagnosis should be reconsidered, and other potential causes such as desquamative inflammatory vaginitis, genitourinary syndrome of menopause, or vulvodynia should be considered.

Dibutyl phthalate degradation and toxicity assessment based on hydroxyl radicals generated by plasma jet

Phthalate esters such as dibutyl phthalate (DBP) are widely used as plasticizers in various industries and are known to cause water pollution reaching 15.7 mgL-1 in freshwater and 0.01 mgL-1 in seawater. This study investigated the effectiveness of DBP degradation using an atmospheric-pressure plasma jet (APPJ). Variation in the argon (Ar) gas flow rate influenced the spatial distribution of the hydroxyl radicals (∙OH) as it altered the laminar-to-turbulent flow transition. The highest density of ∙OH was recorded to be 3.1 × 1016 cm−3 when the Ar flow rate was maintained at 2 standard liters per minute. Additionally, the ∙OH concentration in plasma-activated water substantially increased to 35.5 μM with prolonged treatment. Similarly, the concentrations of H2O2, which is formed as a result of the recombination of the ∙OH, gradually increased to 34.4 μM over 8 min of treatment time, and subsequently reduced to 32.6 μM after an additional 2 min of treatment. A degradation rate of 96.6 % was achieved within 10 min of treatment, as confirmed by a gas chromatography (GC)-flame ionization detector. GC-mass spectrometry was used to identify the intermediate products, and propose possible degradation pathways. However, a decline in the energy efficiency was observed because of reduced initial concentration over the extended treatment time. Furthermore, a 40 % increase in cell viability and a 45 % decrease in the percentage of the dead cell population were observed during the exposure of MRC5, astrocytes, and PC-3 cell lines to APPJ-treated DBP solution, indicating reduced toxicity of the contaminant. Thus, the proposed approach can effectively reduce the contamination of water resources by DBP.

Extended Treatment of Venous Thromboembolism with Reduced- Vs Full-Dose Direct Oral Anticoagulants in Patients at High Risk of Recurrence

BACKGROUNDVenous thromboembolism is a common, potentially fatal disease. Beyond the first 3 months of anticoagulation treatment, extending anticoagulation up to 12 or 24 months reduces the risk of recurrence by at least 80% in patients at high risk of recurrence, but this benefit is lost after stopping anticoagulation. Consequently, guidelines recommend indefinite anticoagulation in such patients. However, continued anticoagulation exposes patients to a linear increase in bleeding risk, which is expected to ultimately exceed the risk of recurrent venous thromboembolism after stopping anticoagulation.To address this issue, lower-dose anticoagulation may reduce bleeding risk while maintaining similar efficacy in preventing recurrent venous thromboembolism. In the EINSTEIN-CHOICE and AMPLIFY-EXT studies, extended reduced-dose anticoagulation appeared as effective as and safer than full-dose. However, with the inclusion of a placebo or aspirin control group, both studies enrolled patients in whom physicians were uncertain about continuing anticoagulation. Consequently, robust evidence for recommending reduced- over full-dose anticoagulation in patients with a strong indication for extended treatment is lacking. METHODSThe Reduced Dose Versus Full-Dose of Direct Oral Anticoagulant After Unprovoked Venous Thromboembolism (RENOVE) trial (ClinicalTrials.gov Identifier: NCT03285438) is an academic, multicenter, prospective, randomized, open, blinded end-point (PROBE) trial. In this study, we compared, using hierarchical sequential testing, extended anticoagulation with reduced-dose versus full-dose direct oral anticoagulants in patients with venous thromboembolism at high risk of recurrence initially treated for 6 to 24 months. Primary outcome was recurrent symptomatic venous thromboembolism (noninferiority hypothesis). Key secondary outcomes were clinically relevant bleeding and the composite of recurrent venous thromboembolism and clinically relevant bleeding (superiority hypotheses). Critical events were adjudicated by an independent committee blinded to treatment allocation. RESULTSDuring the 36-month median follow-up, recurrent venous thromboembolism occurred in 19 of 1383 patients in the reduced-dose group versus 15 of 1385 patients in the full-dose group (5-year cumulative incidence 2.2%; 95% confidence interval [CI], 1.1 to 3.3 versus 1.8%; 95% CI, 0.8 to 2.7; hazard ratio, 1.32; 95% CI, 0.67 to 2.60; P=0.23 for noninferiority). Clinically relevant bleeding occurred in 96 and 154 patients in the reduced- and full-dose groups, respectively (5-year cumulative incidence 9.9%; 95% CI, 7.7 to 12.1 versus 15.2%; 95% CI, 12.8 to 17.6). The composite outcome occurred in 113 and 166 patients in the reduced- and full dose groups, respectively (5-year cumulative incidence 11.8%; 95% CI, 9.4 to 14.3 versus 16.5%; 95% CI, 14.0 to 19.0). All-cause death occurred in 35 (4.3%) and 54 (6.1%) patients in the reduced- and full-dose groups, respectively. CONCLUSIONSIn patients with venous thromboembolism who need extended anticoagulation, the noninferiority of a reduced-dose versus a full-dose of direct anticoagulants to prevent recurrent venous thromboembolism could not be proven. In the reduced-dose group, clinically relevant bleeding and the composite of recurrent venous thromboembolism or clinically relevant bleeding were lower than in the full-dose group and did not appear to be offset by an increased risk of death or arterial thromboembolic events.