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We read with great interest the manuscript by Marra et al that described the attenuation of syphilis detection in the blood and cerebrospinal fluid (CSF) in subsequent episodes of syphilis. The authors describe how asymptomatic infection significantly increased with the number of prior syphilis episodes, and that the odds of detecting Treponema pallidum DNA in blood or CSF at the index episode were lower in those with prior syphilis. This information validates prior studies we have conducted, which found differences in cytokine expression among individuals with serofast and treated syphilis. In our studies, we identified 20 pairs of cytokines that differed between active and treated syphilis and identified 3 cytokine networks that could potentially be useful for identifying active syphilis...

Purpose. To assess the effectiveness and safety of intravitreal aflibercept injections in clinically significant diabetic macular edema (DME) in a routine clinical practice.Material and methods. This was a prospective, observational, single-center study. During the study, anti-VEGF treatment naïve patients with clinically significant DME received five monthly intravitreal injections of aflibercept 2 mg followed by bimonthly injections. The observation period was 1 year.Results. The study included 11 eyes of 10 patients with clinically significant DME. Use of 8 intravitreal aflibercept injections resulted in central retinal thickness (CRT) reduction by 50 % from the baseline within 1 year of therapy. CRT decreased on average from 446.18 ± 106.88 μm to 226.27 ± 44.56 μm by the end of observational period. In addition, an increase in visual acuity was observed from an average from 0.33 ± 0.22 at the start of therapy to 0.62 ± 0.33 at the end of the observation. Serious adverse events over the entire period of treatment were not observed.Conclusion. Aflibercept showed high efficacy and safety in the treatment of clinically significant DME in routine clinical practice. To obtain optimal functional and morphological results in the treatment of patients with DME, it is necessary to start therapy with 5 loading intravitreal aflibercept injections.

Although apathy is a common psychiatric symptom of Parkinson's disease (PD), there are many unknown aspects of its pathology. This study aimed to investigate the characteristics of apathy in treatment-naïve patients with early-stage PD.Fifty treatment-naïve patients with early-stage PD were divided into 1 of 2 groups-apathetic or non-apathetic-based on Starkstein Apathy Scale (AS) scores. Cognitive function, depressive symptoms, olfactory function, and motor severity were compared between the two groups using validated assessment scales. Multiple linear regression was performed to assess the association between AS scores and clinical parameters.Apathy (AS score ≥16) was observed in 13 (26%) patients. Assessment scale scores (Beck Depression Inventory-Second Edition [p .004]; modified HoehnYahr stage [p = .039]; Unified Parkinson's Disease Rating Scale part III [p .001]) were significantly higher in apathetic patients than in non-apathetic patients. Significant association between these scale scores and AS score was also evident (all p ≤ .001). There were no significant differences in the test scores derived from several other validated scales.Apathy was observed in 26% of treatment-naïve patients with early-stage PD. Significant association between apathy and motor severity was found, suggesting that dysfunction of the dopaminergic pathway is involved in the pathology of apathy.

Background and Aims: The prevalence of People living with human Immunodeficiency virus remains considerably high in Nigeria. Liver disease has emerged as an increasingly significant contributor to mortality among HIV-infected patients. The aim of our study was to compare the difference in the prevalence of liver enzyme abnormalities between treatment naive HIV positive and HIV negative patients. Method: The study was conducted at a teaching hospital. The study population consists of 736 patients (368 cases and 368 controls) that were selected from the hospital. The cases were treatment naive HIV patients and the controls were patients being managed for other diseases. A diagnosis of liver disease was made based on the diagnostic criteria which include; presence of at least one clinical feature of liver disease, two liver chemistry abnormalities and an abnormal hepatic ultrasound report. Result: The mean ages of the cases and controls were 35.97±9.77 and 36.08±9.54 years respectively. Liver disease was seen in 277 (75.3%) of the cases and 54 (14.7%) of the controls, this difference was statistically significant (pConclusion: The use of abnormal liver enzymes and clinical features in resource poor settings are valuable screening tools to indicate the presence of liver diseases particularly in HIV – infected patients.

To compare the detection rate of choroidal neovascularization (CNV) in treatment-naive neovascular age-related macular degeneration by swept source optical coherence tomography angiography (SS-OCTA, Topcon's DRI Triton) working at 1,050 nm wavelength versus fluorescence angiography.Cross-sectional analysis of 156 eyes (107 neovascular age-related macular degeneration and 49 dry AMD) in 98 patients, previously diagnosed by multimodal imaging using fluorescein (FA) and indocyanine green angiography (Heidelberg's Spectralis) in a tertiary retina center, evaluated by SS-OCTA 4.5 mm × 4.5 mm and 6 mm × 6 mm macular cubes. Main outcome measures were sensitivity and specificity of SS-OCTA in AMD. Potential factors influencing CNV detection rate were analyzed.Swept source optical coherence tomography angiography detected CNV in 81 of 107 eyes, resulting in a sensitivity of 75.7%. In 49 eyes with dry AMD, no CNV could be identified (specificity 100%). A statistical significance was calculated for nondetection of treatment-naive CNV by SS-OCTA in pigment epithelial detachment over 400 μm (P = 0.0238).Topcon's SS-OCTA was not able to detect all CNV lesions. Large pigment epithelial detachments were associated with signal loss. Fluorescence angiography still remains the gold standard, but the tested SS-OCTA device can be considered as a feasible additional diagnostic tool in AMD.

Background: Severe complications of chronic hepatitis C – i.e. cirrhosis and hepatocellular carcinoma – are important causes of morbidity and mortality worldwide. Despite the overwhelming rates of sustained virologic response achieved after therapy with different combinations of direct-acting antiviral drugs (DAAs), treatment failure is still recorded, and is due to the mutations harboured by hepatitis C virus (HCV) resistance associated variants (RAVs) selected during therapy. Baseline RAVs testing was found significant for guiding treatment in the cases of treatment failure and, sometimes, in naïve patients. Methods: Romanian chronic hepatitis C patients unexposed to DAAs and infected with subtype 1b HCV were studied. Serum samples were used for Sanger population sequencing of a fragment containing NS3 viral protease, known to harbour resistance mutation against protease inhibitors (PIs). Results: Catalytic triad and zinc-binding site in the studied sequences were conserved. Low-intermediate resistance mutations to first generation PIs were detected either alone or in conjunction with resistance substitutions associated with second generation PIs. Cross-resistance and reduced susceptibility to certain DAAs were observed. Discussion: This study focused on HCV patients infected with subtype 1b strains, the most prevalent in Romania. The rate of RAVs found in this work is consistent with the results reported by similar studies from other countries. Noticeably, numerous polymorphisms of unknown significance to DAAs resistance, but reflecting the high genetic variability of HCV, were found in the studied sequences. Testing for RAVs can be a useful method for guiding treatment in a cost-efficient manner in developing countries where access to DAAs is limited.

We evaluated the efficacy and safety of loading phase treatment with intravitreal brolucizumab for neovascular age-related macular degeneration (nAMD) with type 1 choroidal neovascularization (CNV). We analyzed consecutive 42 eyes of 40 patients with treatment-naïve nAMD associated with type 1 CNV. Three monthly injections of brolucizumab were completed in 36 eyes (85.7%). In those cases, best-corrected visual acuity (BCVA) was 0.24 ± 0.27 at baseline and improved significantly to 0.12 ± 0.23 after 3 months (P P P

High-risk cytogenetics and minimal residual disease (MRD) after chemoimmunotherapy (CIT) predict unfavorable outcome in chronic lymphocytic leukemia (CLL). This phase 2 study investigated risk-adapted CIT in treatment-naïve CLL (NCT01145209). Patients with high-risk cytogenetics received induction with fludarabine, cyclophosphamide, and ofatumumab. Those without high-risk cytogenetics received fludarabine and ofatumumab. After induction, MRD positive (MRD+) patients received 4 doses of ofatumumab consolidation. MRD negative (MRD−) patients had no intervention. Of 28 evaluable for response, all responded to induction and 10 (36%) achieved MRD−. Two-year progression-free survival (PFS) was 71.4% (CI(95), 56.5–90.3%). There was no significant difference in median PFS between high-risk and standard-risk group. Ofatumumab consolidation didn’t convert MRD+ to MRD−. In MRD+ group, we saw selective loss of CD20 antigens during therapy. In conclusion, risk-adapted CIT is feasible in treatment-naïve CLL. Ofatumumab consolidation didn’t improve depth of response in MRD+ patients. Loss of targetable CD20 likely reduces efficacy of consolidation therapy.

Prostate cancer is the commonest non-cutaneous cancer in males and frequently metastasizes to nodal and skeletal tissues. Metastases to soft tissue viscera such as lung and liver are associated with decreased overall survival compared to nodal and skeletal metastases despite androgen deprivation and chemotherapy with palliative intent. We present a case with complete resolution of lung metastases after 225Ac-PSMA targeted alpha endoradiotherapy in a treatment naive patient with metastatic prostate cancer. Our case gives preliminary clinical support for the efficacy of 225Ac-PSMA therapy in lung metastases.

Importance Outcome data are limited regarding early experience with brolucizumab, the most recently approved anti–vascular endothelial growth factor (VEGF) agent for the treatment of neovascular age-related macular degeneration (nAMD). Objective To report clinical outcomes after intravitreous injection (IVI) of brolucizumab, 6 mg, for nAMD. Design, Setting, and Participants This retrospective case series conducted at 15 private or academic ophthalmological centers in the United States included all consecutive patients with eyes treated with brolucizumab by 6 retina specialists between October 17, 2019, and April 1, 2020. Exposures Treatment with brolucizumab IVI, 6 mg. Main Outcomes and Measures Change in mean visual acuity (VA) and optical coherence tomography parameters, including mean central subfield thickness and presence or absence of subretinal and/or intraretinal fluid. Secondary outcomes included ocular and systemic safety. Results A total of 172 eyes from 152 patients (87 women [57.2%]; mean [SD] age, 80.0 [8.0] years) were included. Most eyes (166 [96.5%]) were not treatment naive, and 65.7% of these eyes (109 of 166) were switched from the prior anti-VEGF agent because of persistent fluid detected on optical coherence tomography scans. Study eyes received a mean (SD) of 1.46 (0.62) brolucizumab IVIs. The mean (SD) VA prior to starting brolucizumab was a 64.1 (15.9) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (Snellen equivalent, 20/50) and was a 63.3 (17.2) ETDRS letter score (Snellen equivalent, 20/63) at the last study evaluation (mean difference, 0.8; 95% CI, −2.7 to 4.3;P = .65). When analyzed by number of brolucizumab IVIs, the presence or absence of fluid prior to starting brolucizumab, or the presence or absence of intraocular inflammation after receiving brolucizumab, there was no difference in mean VA prior to starting brolucizumab compared with after brolucizumab IVIs or at the final study evaluation. The mean (SD) central subfield thickness in all eyes prior to starting brolucizumab was 296.7 (88.0) μm and was 269.8 (66.5) μm at the last study examination (mean difference, 26.9 µm; 95% CI, 9.0-44.7 µm;P = .003). Intraocular inflammation was reported in 14 eyes (8.1%) and was self-limited and resolved without treatment in almost half those eyes (n = 6). One previously reported eye (0.6%) had occlusive retinal vasculitis and severe loss of vision. Conclusions and Relevance In this analysis of brolucizumab IVI for nAMD, VA remained stable, with a reduction in central subfield thickness. Intraocular inflammation events ranged from mild with spontaneous resolution to severe occlusive retinal vasculitis in 1 eye.

The commercial release of the New Oral Anticoagulants (NOACs) has been the most significant change in anticoagulant therapy in recent years. The work aimed to evaluate the economic and health impact for the Local Health Agency Barletta-Andria-Trani (BT). Through the Regional Information System data about naïve patients on NOAC treatment and patients on anti-vitamin-k (VKA), treatments were extrapolated. We assessed therapeutic continuity, pharmaceutical expenditure, hospitalizations, and deaths in 2017 and 2018. Therapeutic continuity was similar in the two groups. The number and the average cost of hospitalizations for a patient treated with VKAs were almost constant, while those of patients treated with NOACs decreased. The treatment of adult-aged naïve patients with NOACs, compared to VKAs therapy, involves an increase in expenditure of about 100€ for a patient, but the reduced hospitalizations could generate, in the long term, saving for the Health System. Clinical data, according to the Real-World Data, confirmed the safety and effectiveness of these drugs. However, attention to the special population is necessary to improve the safety and effectiveness of NOACs. Innovative formulations for pediatric patients are being developed. The challenge for Health Systems is the appropriate use of available resources through health interventions with transversal competences.

Subclinical human cytomegalovirus (HCMV) replication is associated with immune dysfunction in immuno-suppressed antiretroviral therapy (ART) naive HIV infected individuals. No data is documented in Ethiopia so far concerning HCMV co-infection among HIV infected individuals. Hence, this study was aimed at generating data regarding the prevalence of active HCMV infection among treatment-naive HIV-infected individuals from Ethiopia. For this purpose, we enrolled 97 treatment-naive HIV infected study subjects in Addis Ababa from June to December 2018. ELISA and conventional PCR were performed consecutively to detect HCMV specific IgM antibody and HCMV DNA respectively. Of the 97 study subjects, 12 (12.4%) were positive for anti-CMV IgM antibodies but were not confirmed by PCR. With regard to the PCR positivity, 4/97 (4.1%) samples were positive for HCMV DNA. No statically significant associations were found between the dependent and independent variables. The presence of HCMV DNA in the current study highlights the need for a routine laboratory diagnosis for preventing HCMV disease among HIV-infected individuals early. Besides, the use of anti-CMV therapy for these CMV viremic individuals is also recommended as this can reduce the burden of CMV complications and consecutively prolonging the life of HIV infected individuals.

Leorah Freeman,1 Arianna Kee,2 Marc Tian,2 Rina Mehta2 1Dell Medical School, The University of Texas at Austin, TX, USA; 2Bristol Myers Squibb, Princeton, NJ, USACorrespondence: Leorah FreemanHealth Discovery Building, Dell Medical School, The University of Texas at Austin, 1601 Trinity Street, Austin, TX 78701, USATel + 1-512-495-5355Email leorah.freeman@austin.utexas.eduPurpose: Early diagnosis and treatment of multiple sclerosis (MS) with disease-modifying therapy (DMT) can reduce relapse number and severity, which has cost implications. We describe treatment patterns, healthcare utilization, and cost among MS patients newly initiating DMTs (index).Patients and Methods: DMT-naïve adults with 12 months’ continuous enrollment pre- and post-index and ≥ 2 MS claims (2009‒2018) were identified from the Optum Clinformatics Data Mart database. Treatment adherence and persistence were measured as time on index DMT. Relapses were identified using a validated claims-based algorithm. All-cause and MS-related healthcare expenditures and utilization were captured pre- and post-index. Outcomes were stratified by route of administration. Multivariate analyses assessed differences in outcomes and costs.Results: The analysis included 5906 MS patients (mean age, 46.6 years). The majority initiated injectable (63.5%) followed by oral (28.8%) and infusion (7.7%) DMTs. Post-index, 45.3% of patients were nonadherent and 39.4% were nonpersistent. Relapse rates decreased from pre- to post-index (oral: 24.3%‒16.1%; injectable: 25.0%‒17.1%; infusion: 29.3%‒15.5%). Post-index mean (SD) all-cause total costs were lowest with oral ($70,970 [$36,681]) vs injectable ($82,521 [$58,569]) and infusion ($80,871 [$49,627]) DMTs. MS-related total costs were lowest with oral ($65,149 [$65,133]) vs injectable ($76,197 [$60,204]) and infusion ($72,703 [$47,287]) DMTs. Multivariate analysis showed no differences between oral and injectable DMTs in adherence, persistence, or relapse rate; however, oral DMTs had significantly lower all-cause and MS-related costs.Conclusion: With similar outcomes across DMT administration routes, initiating the least costly DMT may be warranted for many patients. In newly treated MS patients, the need exists to improve adherence and persistence.Keywords: administrative claims, healthcare costs, treatment adherence and compliance, drug administration routes

Background Dexamethasone (DEX) implant has been shown to improve visual and anatomic function in patients with diabetic macular edema (DME). The purpose of this study was to investigate the efficacy and safety of DEX implant between refractory and naive eyes with DME. Methods We retrospectively reviewed data from pseudophakic patients with center-involved DME who received DEX implant (1 + as needed retreatment) from May 2015 to May 2017. Baseline clinical characteristics, changes in best-corrected visual acuity (BCVA) and central foveal thickness (CFT) were analyzed and compared between the two groups. Adverse events were recorded. Results Thirty-four eyes of 31 patients refractory to anti-vascular endothelial growth factor agents and 41 eyes of 38 treatment-naive patients were reviewed. Baseline characteristics were comparable between the two groups (p > 0.05). In the refractory eyes, significant improvements in both BCVA and CFT were observed at 1 month post DEX implant and sustained throughout 6 months. Mean change from baseline in BCVA at 6 months was -0.17 ± 0.35 logMAR (7.29 ± 16.22 letters) and 155.44 ± 112.67 μm in CFT. Similar trends of improvement were seen in treatment-naive eyes; however, the visual improvement (-0.30 ± 0.29 logMAR [16.42 ± 14.38 letters]) was significantly better than the refractory group, with significantly less injections (1.54 ± 0.49 versus 1.82 ± 0.38, p = 0.007). Between-group changes in CFT were comparable. No serious ocular complications occurred, and about a quarter of the patients had elevated intraocular pressures that were manageable with topical medications. Conclusion To our knowledge, this was the first study comparing DEX implant between treatment-naive and refractory Asian patients with DME. Intravitreal DEX implant can effectively treat refractory and treatment-naive patients with DME. In addition, superior visual outcomes were observed in the naive group comparing to the refractory group following DEX implant treatment in Taiwanese pseudophakic eyes with DME.

Purpose To investigate the visual and anatomical outcomes associated with treat-and-extend (TAE) regimen of intravitreal (IVT) aflibercept in eyes with treatment naïve neovascular age-related macular degeneration (nvAMD). Methods A retrospective chart review of eyes that underwent IVT aflibercept injections for nvAMD between May 2014 and March 2018 was performed. The primary outcome was the change in best corrected visual acuity (BCVA) at 12 months. Secondary outcomes included the change in central retinal thickness (CRT), subretinal fluid (SRF) and intraretinal fluid (IRF). Results Data from 213 eyes of 213 patients (138 female, 65%) met the inclusion criteria. The mean (SD) age of the patients was 80.4 (± 9.2) years. The mean baseline BCVA (0.92 ± 0.50 logMAR, improved by 0.20 (± 0.40) logMAR units at 12 months (p < 0.001). Seventy-two (34%) eyes gained ≥ 0.3 logMAR and 47 (22%) eyes achieved BCVA ≤ 0.3 logMAR at 12 months. Baseline BCVA, patient age, and the number of aflibercept injections received were predictors of the change in BCVA at 12 months. Mean CRT improved from 347 (± 117) µm at baseline to 246 (± 55) µm at 12 months (p < 0.001). The percentage of eyes with SRF and IRF on SD-OCT declined from 63 to 21% and from 60 to 26% at 12 months, respectively. Conclusion A TAE regimen of IVT aflibercept in treatment naïve nvAMD is associated with good visual and anatomical outcomes in routine clinical practice. Resolution of exudation occurred in about half of nvAMD cases at 12 months. Individualized administration of IVT aflibercept may reduce injection burden.

During SARS-CoV-2 pandemic, we adopted a personalized delayed protocol for ocrelizumab infusions in Relapsing Remitting Multiple Sclerosis (RRMS) patients according to the national recommendations. Out of the 83 RRMS patients whose infusion was scheduled between March and December 2020, 56 patients experienced a delay in treatment based on MS severity and SARS-CoV2 infection risk profile. In most cases, the immunophenotype was performed monthly to guide re-infusions. Specifically, B CD19 + cells repopulation rate was monitored. Mean infusion delay was 103,1 [SD 40,6] days, and none of the patients presented relapses or active disease at MRI at the end of the observation period. Treatment naïve status and the interval between immunophenotyping and the last ocrelizumab infusion were predictors of earlier B CD19 + cells repopulation. Two patients contracted SARS-CoV2 with complete recovery. Definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking. Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine.

Introduction: Renal cell carcinoma (RCC), an immunogenic tumor, is the most common form of kidney cancer worldwide. Immune checkpoint inhibitors (ICIs) play an important role in the treatment of metastatic RCC. Programmed death-ligand (PD-L1) has already been proposed as a possible prognosticator for ICIs effectiveness. To elucidate the feasible role of ICIs in neoadjuvant settings, we have assessed the most common PD-L1 expression modalities [tumor proportion score (TPS), combined positivity score (CPS) and inflammatory cell (IC) score] in primary tumors (PTs) and venous tumor thrombi (VTT) in first diagnosed, previously untreated RCC patients with accompanying VTT. Methods: Between January 1999 and December 2016, 71 patients with a first diagnosed, untreated, locally advanced RCC (aRCC) (≥ pT3a) underwent surgery in Hanover Medical School (MHH). PD-L1 expression was examined separately in PTs and VTT using the CPS, IC score and TPS. We also considered the age at the time of the initial surgery and gender as probable influencing factors. By using a cutoff value of 1 (1%), PD-L1 expression levels in PTs and VTT were assessed to enable the determination of any frequency differences. Results: Positive scores for PTs were shown by 54 (CPS), 53 (IC score) and 34 (TPS) patients, whereas in VTT, positive scores were evaluated for a total of 50 (CPS), 47 (IC-score) and 36 (TPS) patients. No statistically significant differences were obtained between the PD-L1 expression immunoscores for PTs and VTT. The covariates age at the time of the initial surgery and gender could not be statistically proven to influence the differences in PD-L1 expression between the VTT and PTs. Conclusion: To the best of our knowledge, this research is the largest study to investigate PD-L1 expression in PTs and VTT in 71 cases. It could have relevance for the future development of neoadjuvant immunotherapy options, particularly in aRCC with VTT.

Objectives Clinical trials demonstrated that golimumab is effective in anti-TNF naive patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. Materials and methods This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore >= 2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by >= 3 points or 30% from baseline) and remission (defined as a Mayo score of 1). Results Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6-9) at baseline to 1 (0-5) at 52 weeks (p < .01) and the faecal calprotectin decreased from 862 (335-1759) mu g/g to 90 (34-169) mu g/g (p < .01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5-1188.9). Conclusions The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis. Funding Agencies|MSD; Swedish governments agreement on medical training and research [OLL-836791, OLL-929900]

BACKGROUND: We aimed to assess the detection rate of overall PCa and csPCa, and the clinical impact of MRI/TRUS fusion targeted biopsy (FUSION-TB) compared to TRUS guided systematic biopsy (SB) in patients with different biopsy settings. METHODS: Three hundred and five patients were submitted to FUSION-TB, divided into three groups: biopsy naïve patients, previous negative biopsies and patients under active surveillance (AS). All patients had a single suspicious index lesion at mpMRI. Within these groups, we enrolled men underwent both to FUSION-TB and SB in the same session. Overall detection rate of PCa and csPCa for the two biopsy methods were compared separately between the three groups of patients. RESULTS: No differences were observed between the three groups concerning clinical and radiological characteristics. We found no differences in terms of overall PCa detection (66% vs. 63.8%, P=0.617) and csPCa detection (56.4% vs. 51.1%; P=0.225) concerning biopsy naïve patients. In patients previously submitted to a negative biopsy, FUSION-TB showed higher detection rate of csPCa compared to SB alone (41,3% vs. 27% respectively, P=0.038). In patients under AS, no differences were observed between FUSION-TB and SB in terms of overall PCa (50% vs. 73.1%) and csPCa (30.8% vs. 26.9%, respectively; P=0.705) detection. CONCLUSIONS: Our results suggest that in men with previously negative biopsy, FUSION-TB showed significantly higher diagnostic performance for clinically significant PCa as compared to SB. Combination of FUSION-TB and SB should be recommended in AS population to offer higher chance of csPCa diagnosis.

Background and Aims. Flexible endoscopic treatment plays an important role in the treatment of Zenker’s diverticulum (ZD). This study analyzes long-term symptom control and the rate of adverse events in treatment-naïve patients and patients with recurrence, using the stag beetle knife junior (sb knife jr). Methods. From August 2013 to May 2019, 100 patients with symptomatic ZD were treated with flexible endoscopy using the sb knife jr. Before treatment, as well as 1 and 6 months afterwards, symptoms were obtained by a nine-point questionnaire, with symptoms weighted from 0 to 4. Results. Overall, 126 interventions were performed. The median follow-up period was 41 months (range 7-74). For the three most frequent symptoms, regurgitation, dysphagia, and dry cough, a significant reduction of the mean score could be achieved, from 2.85/3.45/2.85 before the initial treatment to 0.56/1.09/0.98 6 months later. 17 patients were retreated because of recurrence. Out of these, 12 patients underwent a 2nd, 4 patients a 3rd, and 1 patient a 4th session, respectively. The mean dysphagia score for successfully treated patients could be reduced from initially 2.34 to 0.49/0.33/0.67 after the 1st/2nd/3rd session, the frequency of dysphagia from 3.45 to 0.92/1.00/1.33, and the score for regurgitations from 2.85 to 0.35/1.00/0.67. In first-line treatment, as well as in retreatment, no severe adverse event occurred. Conclusion. Patients with ZD can be treated safely and effectively with the sb knife jr. Retreatment leads to equal symptom relief as compared to a successful first-line treatment and is not associated with a higher rate of adverse events.

Background & aims Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Non-invasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis at disease presentation in PBC. Approach & results We collected data from 167 consecutive treatment-naive PBC patients who underwent liver biopsy(LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves(AUROCs) for advanced fibrosis (Ludwig stage≥III). The effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. Derivation cohort consisted of 126 patients with valid LSM and LB, VCTE identified patients with advanced fibrosis with AUROC of 0.89. LSM cut-offs ≤6.5kPa and >11.0kPa enabled to exclude and confirm, respectively, advanced fibrosis (negative predictive value[NPV]=0.94, positive predictive value[PPV]=0.89, error rate=5.6%). These values were externally validated in an independent cohort of 91 PBC patients(NPV=0.93, PPV=0.89, error rate=8.6%). Multivariable analysis found the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. Conclusions In a multicenter study of treatment-naive PBC patients, we identified two cut-offs (LSM≤6.5kPa and>11.0kPa) able to discriminate at diagnosis the presence or the absence, respectively, of advanced fibrosis in PBC patients, with external validation. In patients with LSM between these two cut-offs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

Background/aim: A proliferation-inducing ligand (APRIL) has been investigated as a prognostic marker in chronic lymphocytic leukemia (CLL) patients. However, there is no cut-off level for serum APRIL (sAPRIL) levels that predict time to treatment in CLL patients. Materials and methods: Between May and December 2012, 94 consecutive CLL patients and 25 healthy controls were assessed. sAPRIL levels were measured by ELISA. Demographic data and prognostic markers were obtained from the patients' files. Treatment-naive patients were followed up for 6.5 years for any treatment need. Results: Patients were divided into 3 groups: Treatment-naive (n = 47), chemotherapy receiving (n = 25), and those who had received chemotherapy previously (n = 22). There was no difference in median sAPRIL levels of patients who were receiving chemotherapy at the sampling time and the healthy controls, which indicates that sAPRIL levels might be influenced by treatment. For treatment-naive patients, the best cut-off in predicting time to treatment was found at the sAPRIL level of 2.04 ng/mL, with 78% sensitivity and 63% specificity. Time to treatment was significantly earlier in the APRIL high group (n = 27) than in the APRIL low group (n = 20) (P = 0.010, log-rank test). Conclusion: sAPRIL, a simple, promising blood test which can be measured by ELISA, will likely obtain a place in the wide range of prognostic markers in CLL. Prospective large-scale studies are required to validate and confirm the feasibility of the proposed cut-off level of 2.04 ng/mL as a predictor of time to treatment in treatment-naive CLL patients. Scientific Research Projects Coordination Unit of stanbul University [19694] Acknowledgments/Disclaimers/Conflict of interest The study was supported by an unrestricted grant by Scientific Research Projects Coordination Unit of stanbul University (Project No.: 19694) .

Purpose To compare the 12 months visual and anatomical outcomes of treatment-naive neovascular age-related macular degeneration (nAMD) patients diagnosed by optical coherence tomography angiography (OCT-A) compared with fluorescein angiography (FA)/indocyanine green angiography (ICGA), after anti-VEGF treatment in a real-world setting. Methods Monocentric, observational, parallel-group study of nAMD patients diagnosed with either FA/ICGA or non-invasive OCT-A methods. Patients were treated with a fixed dosing regimen of intravitreal ranibizumab or aflibercept and followed up for 12 months. Primary outcomes were the 12 months functional (BCVA) and anatomical (CST reduction) gains between the two groups. The stratification of BCVA and CST gains by type of neovascular lesion and by anti-VEGF treatment was also assessed. Results Seventy-two patients received FA/ICGA for the initial diagnosis of nAMD, while 73 received OCT-A. Overall, the mean BCVA gain at 12 months was 11.5 ± 9.6 letters. There were no statistically significant differences between the invasive and non-invasive imaging groups in BCVA gain (p = 0.87) or CST reduction (p = 0.76). No statistically significant outcome differences between different lesion types and the two drugs were observed. Conclusion In a real-world setting, nAMD patients diagnosed with OCT-A showed meaningful improvements in visual and anatomical parameters during 12 months of treatment, without significant differences with those diagnosed by invasive modalities.

Purpose: To investigate whether the coronavirus disease 2019 (COVID-19) pandemic-associated postponement in care had effects on the baseline clinical presentation of patients with newly diagnosed treatment-naïve exudative neovascular age-related macular degeneration (AMD). Methods: We included the first 50 consecutive patients referred within the COVID-19 pandemic with a diagnosis of treatment-naïve exudative neovascular AMD. Two groups of fifty consecutive patients with newly diagnosed neovascular exudative AMD presenting in 2018 and 2019 (control periods) were also included for comparisons. Results: Baseline visual acuity was statistically worse in patients referred during the COVID-19 pandemic period (0.87 ± 0.51 logarithm of the minimum angle of resolution (LogMAR)) as compared with both the “2019” (0.67 ± 0.48 LogMAR, p = 0.001) and “2018” (0.69 ± 0.54 LogMAR, p = 0.012) control periods. Data on the visual function after a loading dose of anti-vascular endothelial growth factor (VEGF) was available in a subset of patients (43 subjects in 2020, 45 in 2019 and 46 in 2018, respectively). Mean ± SD best corrected visual acuity (BCVA) at the 1-month follow-up visit after the third anti-VEGF injection was still worse in patients referred during the COVID-19 pandemic (0.82 ± 0.66 LogMAR) as compared with both the “2019” (0.60 ± 0.45 LogMAR, p = 0.021) and “2018” (0.55 ± 0.53 LogMAR, p = 0.001) control periods. On structural optical coherence tomography (OCT), the maximum subretinal hyperreflective material (SHRM) height and width were significantly greater in the COVID-19 pandemic patients. Conclusions: We demonstrated that patients with newly diagnosed treatment-naïve exudative neovascular AMD referred during the COVID-19 pandemic had worse clinical characteristics at presentation and short-term visual outcomes.

The ZIPANGU study assessed the efficacy and safety of ranibizumab as a one loading dose + pro re nata (one + PRN) regimen with/without focal/grid laser among treatment-naïve patients suffering from macular edema (ME) following branch retinal vein occlusion (BRVO). ZIPANGU was a phase IV, prospective, randomized, open-label, active-controlled, 12-month, two-arm, multicenter study. Treatment-naïve patients with visual impairment (19-73 letters) caused by ME, defined as central subfield thickness (CSFT) 300 µm, due to BRVO were randomly assigned to ranibizumab monotherapy (n = 29) or combination therapy (ranibizumab + focal/grid short-pulse laser, n = 30). The primary endpoint was the number of ranibizumab injections. Secondary endpoints were mean changes in best-corrected visual acuity (BCVA) and CSFT, and safety. There were no statistically significant differences in the mean number of ranibizumab injections between monotherapy (4.3 injections) vs. combination (4.1 injections) therapy, or in CSFT. BCVA improvement in the monotherapy arm (22.0 letters) was better than the combination therapy arm (15.0 letters) (p = 0.035). Overall, both regimens appeared to be safe and well tolerated. One + PRN ranibizumab is safe and efficacious in treatment-naïve patients with ME secondary to BRVO. A conjunctive laser treatment did not lead to better functional outcomes or fewer ranibizumab injections.

Background. Tuberculosis (TB) constitutes a global emergency as it affects one-third of the world’s inhabitants. Although pulmonary Tuberculosis (PTB) is curable, immunological responses to the infection induce several haematological derangements. This study evaluated the effect of PTB on Protein C, Protein S, Antithrombin-III, and blood count parameters. Methods. Ninety adults with ages ≥18 years were purposively recruited: 60 PTB patients and 30 non-TB controls. All patients were diagnosed with sputum GeneXpert MTB/Rif assay. Blood specimens were collected from each participant for Protein C, S, Antithrombin-III and complete blood count. Results. Pulmonary TB was associated with significantly reduced Protein C activity (101.46 [87.61-128.3] vs 121.44 [99.50-149.8] IU/L, p=0.038), RBC (3.88±0.91 vs 4.80±0.55, pp=0.0019), HCT (32.21±7.79 vs 42.05±4.97, pp=0.0133) and PDW (12.95 [10.73-15.00] vs 15.30 [14.18-15.93], pp=0.0086), TWBC (7.76 [6.06-9.78] vs 6.50 [4.85-7.50], p=0.0047), Abs. GRAN (5.27 [3.30-6.71] vs 3.75 [2.48-4.75], p=0.0226), RDW-CV (13.70 [13.20-15.43] vs 12.95 [12.50-13.65], ppp=0.0027) compared to controls. The PTB patients were disproportionately affected with anaemia (91.7%, p=0.001), erythrocytopenia (75.0%; p≤0.001) and reduced HCT (80.0%, p≤0.001). The frequency of thrombocytosis, leucocytosis, and granulocytosis (50.0%, p=0.013; 23.3%, p=0.013; 18.3%, p=0.025; respectively) in PTB patients were significantly higher than in controls. Conclusion. Our findings suggest that PTB predisposes patients to hypercoagulability, with a significant reduction in Protein C activity but not Protein S and antithrombin-III. The condition causes derangements in erythrocytes, leucocytes, and thrombocytes, and disproportionately causes anaemia. Protein C activity and complete blood count are useful in the management of PTB and should be included in the routine workup for patients.

This study aimed to determine the relation of best corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) in proliferative diabetic retinopathy (PDR) following treatment with either aflibercept or pan-retinal photocoagulation (PRP). The study was conducted as a post-hoc analysis of the CLARITY trial in which na&iuml, ve and PRP treated PDR patients were randomised to receive either aflibercept or PRP. BCVA and LLVA were assessed at baseline and at week 52. Our analyses showed that the BCVA and LLVA correlate well in treatment na&iuml, ve PDR with an average low luminance deficit of 11.79 Early Treatment Diabetic Retinopathy Score (ETDRS) letters. However, LLVA at lower levels of BCVA showed more variance. Post aflibercept therapy, the mean change in BCVA and LLVA at 52 weeks after aflibercept was +2.1 (SD 6.05) letters and +0.39 (SD 5.6) letters, respectively. Similarly, after PRP, it was &minus, 2.5 (SD 4.9) letters and &minus, 1.9 (SD 8.7) letters, respectively. When comparing treatment arms, BCVA change was found to be statistically significant (p &lt, 0.001) whereas LLVA was not (p = 0.11). These findings show that LLVA does not respond as well as BCVA following any treatment for PDR, even though BCVA and LLVA both test foveal function.

Background: For detection of the nucleus(t)ide analog resistance (NAr) mutants among Hepatitis B virus (HBV) quasispecies, the selection of appropriate methodologies is necessary. Here, we aimed to investigate the role of different methods for the detection of NAr mutations among treatment-naïve patients with chronic HBV (CHB) infection.Methods: In this systematic review and meta-analysis study, five databases were searched. Desired data were extracted from the selected studies. The I2 was used as an indicator of heterogeneity. The NAr mutations rate was investigated with a 95% confidence interval (CI).Results: The overall ratio of occurrence of NAr within treatment-naïve CHB patients (14653) from 128 studies was 0.085 (95% CI, 0.069-0.103, p-value < 0.0001). Direct sequencing was the most prevalent method of DNA sequencing (56.25%). The rates of NAr mutations in the different methodologies, including the direct sequencing, InnoLipa, NGS, and PASS, were 0.079 (0.037-0.160, p < 0.0001), 0.058 (0.021-0.152, p < 0.0001), 0.729 (0.441-0.902, p = 0.114), and 0.448 (0.281-0.628, p = 0.001), respectively.Conclusions: Drug-resistant quasispecies of HBV exist in treatment-naïve patients in relatively high abundance. More sensitive methodologies like NGS should be used for detecting NAr fractions of the viral population. Replacement of current therapy with novel anti-HBV candidates also should be considered.

Purpose The occurrence of multiple vertebral fractures was reported after denosumab discontinuation. The use of bisphosphonates following denosumab has been suggested to prevent this bone loss. The aim of our observational trial was to evaluate the ability of risedronate to prevent the bone loss related to denosumab discontinuation in post-menopausal osteoporosis. Methods Eighteen female patients, aged 69.8 years (56–79), were followed. All patients were prescribed 35 mg of risedronate per week for 3 months, starting when the next denosumab injection would have been administered. We measured BMD at denosumab initiation (T0), denosumab withdrawal (T1), and nine months after the discontinuation of risedronate (1 year post-denosumab: T2). Results 1 year after denosumab discontinuation, the mean bone loss at the spine was – 4.6 ± 5.2% for the total population, −0.3 ± 2.3% in patients with prior exposure to bisphosphonates, −6.3 ± 5.7% in patients with prior exposure to teriparatide, and − 7.6 ± 3.5% in naïve patients. Spine BMD loss after the risedronate bridging therapy (T2 vs. T1) was significantly lower in patients who experienced prior exposure to bisphosphonates, when compared to naïve patients (p = .0190) and to patients with prior teriparatide exposure (p = .0176). 1 year after denosumab discontinuation, the mean densitometric loss at the hip was −1.8 ± 3.4% in the total cohort, −0.6 ± 1.8% in the patients previously treated with bisphosphonates, −1.5 ± 4.7% in the patients previously treated with teriparatide, and − 4.2 ± 0.6 in naïve patients. The mean densitometric loss during the off-denosumab period was lower in patients with previous bisphosphonate exposure than in naïve patients (p = .043) and in patients with previous exposure to teriparatide (p = .05). Conclusions Three months of risedronate treatment does not prevent bone loss in patients who have not been treated with bisphosphonates before denosumab., Highlights • Three months of risedronate • Ineffectiveness • Bone loss • discontinuation of denosumab

Background: Peroral endoscopic myotomy (POEM) is an emerging technique in the treatment of Zenker&rsquo, s diverticulum (ZD). This study aimed to analyze the feasibility of Zenker&rsquo, s POEM (Z-POEM) in a multicenter setting and assess its performance using a validated Kothari-Haber Scoring System newly developed for symptom measurement in ZD. Materials and methods: This was a multicenter retrospective study involving three Polish tertiary referral endoscopic units. The data of consecutive patients with symptomatic ZD treated with Z-POEM in Poland between May 2019 and August 2020 were retrieved and analyzed. Primary outcome measures were technical success and clinical success rate (&lt, 3 points in Kothari-Haber Score at 2&ndash, 3 months follow-up). Secondary outcome measures included procedures&rsquo, duration, length of hospital stay, and adverse events. Results: 22 patients with symptomatic ZD were included. The mean age was 67.6 (&plusmn, 10.7) years, and 14 (63.6%) were male. All but two patients were treatment na&iuml, ve. The average size of the ZD was 30 mm (IQR, 24&ndash, 40 mm). Technical success was achieved in all patients (100%), whereas clinical success was 90.9%. The average Kothari-Haber Score was 6.35 before treatment and has dropped to 0.65 after the treatment (p &lt, 0.0001). The mean procedure time was 48.8 (&plusmn, 19.3) minutes, and the median length of hospital stay was 2 days (IQR, 2&ndash, 3). Three patients (13.6%) had post-procedural emphysema, of which two were mild and self-resolving (9.1%), and one was moderate (4.5%) and complicated with laryngeal edema and prolonged intubation. Conclusions: This feasibility study suggests that Z-POEM is a highly effective and safe treatment for ZD, particularly among treatment-na&iuml, ve patients. Comparative studies with other treatment modalities over longer follow-up are warranted.

Multiple sclerosis (MS) treatment with new agents is associated with the risk of the development of progressive multifocal leukoencephalopathy (PML). The seropositivity and a high index of anti-John Cunningham virus (JCV) antibodies are some of the risk factors for PML development. The aim of this study was to assess the seroprevalence of anti-JCVAb and JCVAb index (AI), as well as its correlations with demographic and clinical characteristics in treatment-na&iuml, ve Polish MS patients. This is a multicenter, prospective, and cross-sectional study involving 665 MS patients. The overall prevalence of anti-JCVAb was 65.3%, while 63.1% of seropositive patients had an index level of &gt, 1.5. The seroprevalence was shown to increase along with the patient&rsquo, s age. Except for age, the prevalence of anti-JCVAb was not associated with demographic or clinical data. No correlations between the index levels and the demographic or clinical data were observed. In Poland, the seroprevalence of anti-JCVAb in treatment-na&iuml, ve MS patients is one of the highest in Europe. The majority of seropositive patients had an anti-JCV antibody level denoting a high-risk category. This means that we need further studies to be conducted on the individualization of MS treatment in order to provide patients with an appropriate therapeutic safety level.

Contains fulltext : 251829.pdf (Publisher’s version ) (Open Access) OBJECTIVE: There is a lack of real-life studies on interleukin-17 (IL-17) inhibition in psoriatic arthritis (PsA). We assessed real-life 6- and 12-month effectiveness (i.e., retention, remission, low disease activity [LDA], and response rates) of the IL-17 inhibitor secukinumab in PsA patients overall and across 1) number of prior biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), 2) years since diagnosis, and 3) European registries. METHODS: Thirteen quality registries in rheumatology participating in the European Spondyloarthritis Research Collaboration Network provided longitudinal, observational data collected as part of routine care for secondary use. Data were pooled and analyzed with Kaplan-Meier plots, log rank tests, Cox regression, and multiple linear and logistic regression analyses. RESULTS: A total of 2,017 PsA patients started treatment with secukinumab between 2015 and 2018. Overall secukinumab retention rates were 86% and 76% after 6 and 12 months, respectively. Crude (LUNDEX adjusted) 6-month remission/LDA (LDA including remission) rates for the 28-joint Disease Activity Index for Psoriatic Arthritis, the Disease Activity Score in 28 joints using the C-reactive protein level, and the Simplified Disease Activity Index (SDAI) were 13%/46% (11%/39%), 36%/55% (30%/46%), and 13%/56% (11%/47%), and 12-month rates were 11%/46% (7%/31%), 39%/56% (26%/38%), and 16%/62% (10%/41%), respectively. Clinical Disease Activity Index remission/LDA rates were similar to the SDAI rates. Six-month American College of Rheumatology 20%/50%/70% improvement criteria responses were 34%/19%/11% (29%/16%/9%); 12-month rates were 37%/21%/11% (24%/14%/7%). Secukinumab effectiveness was significantly better for b/tsDMARD-naive patients, similar across time since diagnosis (4 years), and varied significantly across the European registries. CONCLUSION: In this large real-world study on secukinumab treatment in PsA, 6- and 12-month effectiveness was comparable to that in previous observational studies of tumor necrosis factor inhibitors. Retention, remission, LDA, and response rates were significantly better for b/tsDMARD-naive patients, were independent of time since diagnosis, and varied significantly across the European countries.

Little is known about long-term maintenance of virologic suppression in HIV migrants in Italy. The study aims to compare virologic failure rates and associated factors among antiretroviral therapy (ART)-naive migrants and natives enrolled in the ARCA database since 2007 who achieved virologic suppression within 18 months from the beginning of the ART. Kaplan-Meier method assessed the probability of virologic suppression and failure. Cox regression model was used for multivariate analysis. Of 2515 patients, 2020 (80.3%) were Italian, 286 (10.6%) migrants from low-income countries, of whom 201 (75.0%) from Africa, and 227 (9.0%) from high-income-countries. The median follow-up was 4.5 years (IQR 2.5-7). No difference was observed in the time of achievement of virological suppression in the three groups (log-rank: p = 0.5687). Higher probability of virologic failure was observed in Africans compared to Italians, to patients from high-income-countries and from low-income-countries other than Africans (Log-rank = p < 0.001). In the adjusted analysis, a higher virologic failure risk was found in Africans only compared to Italians. [HR 4.01; 95% CI 2.44-6.56, p < 0.001]. In Italy, African migrants are less likely to maintain virologic suppression compared to natives and other migrants. Targeted interventions could be needed for foreigners, especially for Africans.

Objectives: Chronicity could be a serious threat to hepatitis B virus (HBV)-infected children. The necessity of antiviral treatment to HBV-infected children has caused much controversy. The authors aimed to conduct a systematic review and meta-analysis of synthesized evidence regarding the spontaneous loss of chronic HBV infection markers in treatment-naïve children for exploring their long-term management. Methods: Observational cohort studies and non-treatment arms of randomized controlled trials were searched that reported the spontaneous loss of chronic HBV infection markers in untreated children (characterized by the presence of HBsAg ≥6-month), via the rates of hepatitis B surface antigen (HBsAg) loss, hepatitis B e antigen (HBeAg) seroconversion, and HBV DNA suppression with random-effects model. Results: Of 7,427 studies screened, 20 were included in meta-analysis. With cumulative 23,153 person-years of follow-up, the pooled annual incidences of HBsAg and HBeAg loss, HBV DNA suppression were 1, 6, 7%, respectively. Rates within HBeAg loss and HBV DNA suppression did differ by the transmission modes and ALT levels, not in HBsAg. Conclusion: Spontaneous HBsAg loss (function cure) occurs infrequently in treatment-naïve children with chronic HBV infection. Design of practically applicable programs aiming at therapeutics of children may be necessary to support the goal of eliminating HBV infection worldwide.

BACKGROUND Meningioma is the commonest primary brain tumour. 70% of patients are seizure-free at presentation, but approximately 12% will have seizures within 12 months of surgery. Seizures impact quality of life. Neurosurgeons administer prophylactic anti-epileptic drugs (AED) to prevent seizures despite a lack of evidence to support this. A meta-analysis of RCTs in brain tumours suggests that older AED may prevent seizures in the first week after surgery but not thereafter. There are no studies assessing newer AEDs in the prophylactic setting. RESEARCH QUESTION In patients with meningioma who have never had a seizure and are undergoing surgical resection, does prophylactic levetiracetam reduce the risk of developing seizures? DESIGN multi-centre, double-blind RCT in 20 UK centres. 1:1 randomisation of 14 days levetiracetam 500mg bd started one day before surgery compared to placebo. PRIMARY OBJECTIVE Determine whether 2 weeks prophylactic levetiracetam reduces the risk of developing seizures within 12 months of surgery compared to placebo. ECONOMIC OBJECTIVE Estimate cost-effectiveness of prophylactic levetiracetam. SECONDARY OBJECTIVES Determine effect of prophylaxis on time to first seizure and first convulsive seizure, whether prophylaxis affects quality of life and influences return to driving, safety of prophylaxis. POPULATION seizure-naïve meningioma undergoing surgery. SAMPLE SIZE seizure rate at 12 months is 12.3%. A 50% reduction is clinically beneficial. A two-group chi-squared test with 5% two-sided significance level will have 90% power to detect the difference between a Group 1 proportion of 0.12 and a Group 2 proportion of 0.06 when the sample size in each group is 477. Allowing for 5% dropout, 1004 patients will be recruited. FUNDING NIHR (£1.64M) award June 2020. Study opens March 2021. TRANSLATIONAL RESEARCH MRI, blood and tissue will be collected to explore risk factors for seizures. CONCLUSIONS study will provide class I evidence of the role of prophylactic levetiracetam in meningioma surgery.

Objective Liver inflammatory activity staging is critical to guide the treatment of chronic hepatitis B virus (CHB) infection. Here, we aimed to identify practical clinical biomarkers of moderate inflammatory activity in hepatitis B e-antigen (HBeAg)-negative CHB patients. Methods Treatment-naïve HBeAg-negative CHB patients who underwent liver biopsy at our hospital from 1 January 2013 to 31 December 2016 were enrolled. Markers of inflammatory activity were analyzed using binary logistic regression. The area under the receiver operator characteristic curve (AUROCC) was used to assess diagnostic accuracy. Results A total of 106 HBeAg-negative treatment-naive CHB patients were enrolled. According to their METAVIR inflammatory scores, 30.2% of patients were in stage ≥A2. Total triiodothyronine (TT3) and hepatitis B virus (HBV) DNA levels were predictors of moderate inflammatory activity (A ≥ 2). The AUROCCs of TT3 and HBV DNA levels were 0.651 and 0.797, respectively. The optimal cut-off values for TT3 and HBV DNA were 1.755 nmol/L and 4.61 log10 IU/mL, respectively. Conclusions A sizable proportion of treatment-naive HBeAg-negative CHB patients required antiviral treatment (30.2%) after undergoing liver biopsy. TT3 and HBV DNA helps identify patients with moderate inflammatory activity (A ≥ 2), potentially reducing the need for liver biopsies and helping guide treatment of CHB patients.

Background Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue that is widely used to treat chronic hepatitis B infection. This treatment is currently considered to be effective in achieving good virological, serological, and biochemical response with a high barrier of resistance. We reported a case of a virological breakthrough in a patient with chronic hepatitis B and cirrhosis receiving TDF. Methods We presented a case of a 48-year-old male who had been treated with TDF for the last 10 months. Results The patient was diagnosed with decompensated cirrhosis with variceal bleeding and was tested positive for hepatitis B. his initial viral load prior to treatment was 4.38 × 104 IU/mL. Four months after the initiation of the antivirus, his serum HBV DNA level was undetectable, and there were improvements in biochemicals parameters. However, the serum HBV DNA level rebounded to 1.28 × 103 IU/mL at 10 months after treatment. The patient was compliant with the treatment program, was monitored regularly, and took his medication every day. No prior history of other antiviral agents was noted, and he didn’t have any specific comorbidity. He is in otherwise stable clinical condition. We are planning on switching his treatment to entecavir. TDF is one of the only 2 antivirus agents (along with entecavir) that was thought to have a high barrier of resistance. A longitudinal study of TDF therapy demonstrated no resistance development throughout 8 years of treatment, although several case reports have identified resistance cases. Several studies had pointed out possible mutations’ points for TDF resistance, including A181T/V, A194T, M204V/I, Y9H, L91I, S106C, S106G, T118C, T118G, Q267L, I269L, A317S, K333Q, and N337H. Switching treatment to entecavir seemed to show good results in previous reports. Conclusions The virological breakthrough might still occur in patients receiving TDF. Further evaluation of such resistance mechanism was needed.

BACKGROUND: Patients with atrial fibrillation (AF) have a high incidence of cognitive impairment, which may be related to clinically silent microembolism causing cerebral infarctions. OBJECTIVE: To explore the occurrence and timing of silent brain lesions following electrical cardioversion (CV) of recent onset AF in anticoagulant-naïve patients and to study related effects on cognitive function and biomarkers of cerebral damage, S100b. METHODS: Patients with AF duration > 48 hours were prospectively included. Brain magnetic resonance imaging (MRI) and S100b, were obtained prior, after and 7-10 days following CV. Trail making tests (TMT-A and TMT-B) and their difference, ΔΤΜΤ, were assessed prior to CV, 7-10 days and 30 days after CV. RESULTS: Forty-three patients (84% males) with median CHA2DS2-VASc score 1 (interquartile range 0-1) were included. Sequential MRI, including diffusion weighted scans, showed no new brain lesions after CV. Chronic white matter hyperintensities were present at baseline in 21/43 (49%) patients. The S100b (µg/l) levels increased significantly from baseline, (mean ±SD) 0.0472±0.0182 to 0.0551±0.0185 after CV, p=0.001 and then decreased 7-10 days after CV to 0.0450±0.0186, p 1.96). CONCLUSIONS: New brain lesions could not be detected on MRI after CV, but the high incidence of white matter hyperintensities and the transient increase in S100b may indicate transient or minor brain damage undetectable by MRI thus heightening the need to reevaluate thromboembolic risk prior to CV even in low risk patients.

Background The aims of the present study were to determine the alterations in mRNA and miR expressions and their role in signaling pathways, to correlate their levels with the severity of PH, and to investigate the relationship between those alterations and serum levels of apelin, kynurenine, and endocan in PH. Methods The study included 32 treatment-naive patients with precapillary PH and 55 controls. All subjects underwent RHC. Total RNA was isolated and cDNAs for mRNA and miR were synthesized. mRNA expressions of HIF-1α, HIF-2α, STAT 3, FGF-2, FGFR-1, PARP 1 and miR expressions of miR-210, miR-130a, miR-424, miR-204, and miR-223 were determined. Concentrations of kynurenine, apelin, and endocan were analyzed. Results HIF-2α, STAT 3, and FGF-2 were increased; miR-210 and miR-130a were increased; miR-223 and miR-204 were decreased. Apelin and kynurenine concentrations were decreased. There were positive correlations: HIF-2α-miR-424: r=0.474, p=0.011; APLN-miR-424: r=0.385, p=0.030; kynurenine-miR-210: r=0.551, p=0.004; STAT 3- PVR: r=0.478, p=0.006; miR-210- RAP: r=0.536, p=0.07; kynurenine-RAP: r=0.409, p=0.022. There were negative correlations: PARP 1-miR-210: r=−0.561, p=0.007; PARP 1- RAP: r=−0.424, p=0.27. miR-130a (OR= 1.257, p=0.016) and APLN (OR= 0.223, p=0.004) were independent risk factors for PH. Conclusions We report: 1) novel relationship between the kynurenine and PARP 1 signaling pathways that could be mediated by miR-210, 2) relationship between the apelin and HIF-2α signaling pathways that could be mediated by miR-424, 3) reduced levels of apelin and elevated levels of miR-130a are associated with PH, 4) elevated levels of STAT 3, miR-210, and kynurenine, and reduced levels of PARP 1 correlate with more severe hemodynamics. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Pamukkale University Scientific Research Projects Coordination Unit

AIMS Early discharge after transcatheter aortic valve implantation (TAVI) may potentially impact post-procedural safety of the patient. The study aim was to compare safety of TAVI in patients planned for fast track hospital stay with patients planned for standard hospital stay. METHODS AND RESULTS All-comers patients undergoing transfemoral TAVI between 2011 and 2017 were allocated to two matched groups depending whether the procedure was performed before or after transition from standard to fast track course. Data on vital status and hospitalizations were obtained through national registries. Three hundred and nineteen matched pairs were eligible for analysis. The median length of post-procedural stay was 3 days (IQR: 2-4) for patients in the fast track group compared to 6 days (IQR: 4-8) in the standard approach group (p

Introduction Dyslipidemia, especially an increase in the low-density lipoprotein cholesterol (LDL-C) has been established as one of the most important risk factors for atherosclerotic cardiovascular diseases. In contrast, some recent studies have shown that the low LDL-C level was associated with short-term poor prognosis in patients with cardiovascular disease, and this is so-called “cholesterol paradox”. However, there is few data evaluating the effects on long-term outcome of “cholesterol paradox” in patients with acute coronary syndrome (ACS). Purpose The purpose of this study was to examine whether the low LDL-C level on admission affect long-term prognosis in patients with ACS. Methods A total of 434 ACS patients who survived to hospital discharge were enrolled in this study. All patients were statin-naïve on admission, and were received statin therapy after hospitalization. Patients were divided into the low LDL-C (≤114 mg/dl) and high LDL-C (>114 mg/dl) groups using the first tertile of the LDL-C level on admission. The primary endpoint was composite outcomes of all-cause death, myocardial infarction, ischemic stroke, hospitalization for congestive heart failure and unplanned revascularization. Results During a median follow-up period of 5.5 years, primary endpoint occurred in 117 patients. Overall, event-free rates differed significantly between the low and high LDL-C groups, demonstrating the lower event-free rate in patients with the low LDL-C group (38.9% in low LDL-C group versus 20.7% in high LDL-C group, p=0.0002; Figure). Even after adjustment for age, sex, body mass index, and various classical risk factors, the low LDL-C group was significantly at higher risk for primary composite outcomes compared to the high LDL-C group (adjusted hazard ratio 1.65, 95%-confidence interval 1.10–2.49, p=0.02). Conclusion In patients with ACS, the low LDL-C level on admission was significantly associated with long-term worse prognosis, regardless of statin therapy at discharge. In ACS patients with low LDL-C level, it might be necessary for elucidating the residual risk for secondary adverse event to improve their prognosis. Funding Acknowledgement Type of funding source: None

Background : The intestinal bacterial flora of febrile neutropenic patients has been found to be significantly diverse and may play a role in clinical decisions regarding antimicrobial de-escalation with predictive complications. However, there are few reports of microbiota alteration of adult acute myeloid leukemia (AML) patients. Methods : Stool samples of each treatment-naïve AML patient were collected the day before the initiation of induction chemotherapy (pretreatment), on the first date of neutropenic fever and first date of bone marrow recovery. Bacterial DNA was extracted from stool samples and bacterial 16s ribosomal RNA genes were sequenced by next-generation sequencing. Relative abundance, overall richness, Shannon's diversity index and Simpson's diversity index were calculated. Results : Ten AML patients (4 men and 6 women) were included with a median age of 39 years (range: 19-49). Twenty-four stool samples were collected and assigned into three groups: (1) pretreatment (n = 10); (2) first date of febrile neutropenia (n=9); and (3) first date of bone marrow recovery (n=5). All of patients developed febrile neutropenia; three patients had detectable infectious organisms and all of these cases had invasive pulmonary aspergillosis with two being co-infected with Pseudomonas pneumonia and Escherichia coli septicemia. Median absolute neutrophil count was 2.85 x 109/L (range: 1.42-7.67 x 109/L), 0.04 x 109/L (range: 0.01-0.43 x 109/L) and 3.65 x 109/L (range: 2.09-5.78 x 109/L) at pretreatment, first date of febrile neutropenia and first date of bone marrow recovery, respectively. At the phylum level, Firmicutes dominated over the period of neutropenic fever, subsequently declining after bone marrow recovery a pattern in contrast to that shown by Bacteroidetes and Proteobacteria. At the genus level, Enterococcus was more abundant in the febrile neutropenia period compared to pretreatment (mean difference of 20.2, [95%CI (5.9, 34.6)]; P Conclusions : Adult AML patients with a first episode of febrile neutropenia after initial intensive chemotherapy demonstrated a significant decrease in gut microbiota diversity and the level of diversity remained constant despite recovery of bone marrow. Figure Disclosures No relevant conflicts of interest to declare.