Triptan non-response in a London tertiary headache centre: What can we learn? A retrospective study.

BACKGROUND: Triptans revolutionized the acute treatment of migraine; however, varied responses to triptans, as a result of poor efficacy and tolerability, are reported. A standardized definition of triptan non-response was recently proposed by the European Headache Federation (EHF). There is currently limited data available on the prevalence of triptan non-response. METHODS: We used clinic letters over a two-year duration to evaluate the triptan response and triptan efficacy or tolerability failure, or both, in a London-based tertiary headache service. RESULTS: In total, 419 adult migraine patients (females: 83.8%, age: 46 ± 18 years, chronic migraine: 88.5%) were included in a service evaluation. In line with the EHF definitions, "triptan non-response" was seen in 63.8% of patients (264/414), whereas 37.7% of patients (156/414) had failed at least two triptans (EHF "triptan resistant") and 4.6% of patients (19/414) had failed at least three triptans, including a subcutaneous formulation (EHF "triptan refractory"). Notably, 21.3% of patients (88/414) had failed at least three triptans inclusive and exclusive of subcutaneous triptan use. Advancing age (p < 0.001) and the presence of medication overuse (p = 0.006) increased the probability of triptan response, whereas an increased number of failed preventives (p < 0.001) and the use of calcitonin gene-related peptide monoclonal antibodies (p = 0.022) increased the probability of triptan non-response. The largest proportion of patients responded to eletriptan (49.5%), followed by nasal zolmitriptan (44.4%) and rizatriptan (35.7%). CONCLUSIONS: Our findings highlight an alarming prevalence of triptan non-response among adult migraineurs receiving treatment in a London-based tertiary headache service. It is imperative for clinicians to explore methods to optimize acute medication efficacy, whether this comprises changing to a triptan with a superior response rate, advocating for early intervention or considering alternative acute medication classes, such as gepants or ditans.

Tighter is better: Can a simple and cost-free parameter predict response to cardiac synchronization therapy?

BACKGROUND: Several studies have evaluated the role of QRS duration (QRSd) or QRS narrowing as a predictor of response to cardiac resynchronization therapy (CRT) to reduce nonresponders. AIM: Our study aimed to determine the correlation between the relative change in QRS index (QI) compared to clinical outcome and prognosis in patients who underwent CRT implantation. METHODS: A three-centers study involving 398 patients with a CRT device was conducted. Clinical, echocardiographic and pharmacological variables, QRSd before and after CRT implantation and QI were measured. RESULTS: In a 6-month follow-up, a significant improvement in left ventricular ejection fraction (LVEF), left ventricular end-diastolic and systolic volumes (LVEDV and LVESV) were observed. QI was related to reverse remodeling (multiple r-squared: 0.48, adjusted r-squared: 0.43, p = .001), and the cut-off value that best predicted LV reverse remodeling after 6 months of CRT was 12.25% (AUC 0.7, p = .001). At 24 months, a statistically significant difference was found between patients with a QI ≤ 12.25% and those with a QI > 12.25% regarding NYHA class worsening (p = .04). The mean of the QI of patients who died from cardiovascular causes was lower than patients who died of other causes (p = .0179). A correlation between pre-CRT QRSd/LVEDV and QI was observed (r = + 0.20; p = .0003). A higher QRSd/LVEDV ratio was associated with an improved LVEF, LVEDV, and LVESV (p < .0001) at follow-up. CONCLUSIONS: QI narrowing after CRT was related to greater echocardiographic reverse remodeling and a lower rate of adverse events (death or cardiovascular hospitalizations). The QI can improve the prediction of adverse events in a population with CRT regardless of comorbidities according to the Charlson Comorbidity Index. QI could be used to predict CRT response.

Modelling inter-individual variability in acute and adaptive responses to interval training: insights into exercise intensity normalisation.

PURPOSE: To investigate the influence of exercise intensity normalisation on intra- and inter-individual acute and adaptive responses to an interval training programme. METHODS: Nineteen cyclists were split in two groups differing (only) in how exercise intensity was normalised: 80% of the maximal work rate achieved in an incremental test (% W ˙ max) vs. maximal sustainable work rate in a self-paced interval training session (% W ˙ max-SP). Testing duplicates were conducted before and after an initial control phase, during the training intervention, and at the end, enabling the estimation of inter-individual variability in adaptive responses devoid of intra-individual variability. RESULTS: Due to premature exhaustion, the median training completion rate was 88.8% for the % W ˙ max group, but 100% for the % W ˙ max-SP the group. Ratings of perceived exertion and heart rates were not sensitive to how intensity was normalised, manifesting similar inter-individual variability, although intra-individual variability was minimised for the % W ˙ max-SP group. Amongst six adaptive response variables, there was evidence of individual response for only maximal oxygen uptake (standard deviation: 0.027 L·min-1·week-1) and self-paced interval training performance (standard deviation: 1.451 W·week-1). However, inter-individual variability magnitudes were similar between groups. Average adaptive responses were also similar between groups across all variables. CONCLUSIONS: To normalise completion rates of interval training, % W ˙ max-SP should be used to prescribe relative intensity. However, the variability in adaptive responses to training may not reflect how exercise intensity is normalised, underlining the complexity of the exercise dose-adaptation relationship. True inter-individual variability in adaptive responses cannot always be identified when intra-individual variability is accounted for.

Clinicopathological features and outcome of secondary steroid resistant nephrotic syndrome: A retrospective analysis.

Objective: To determine the clinico-pathological features and long-term outcome of secondary steroid-resistant nephrotic syndrome treated with steroids and calcineurin inhibitors. METHODS: The retrospective cohort study was conducted at the Sindh Institute of Urology and Transplant, Karachi, in June and July 2023, and comprised data from January 1, 2008, to December 31, 2020, of children aged 1-18 years who developed steroid resistance after initial sensitivity to steroids with at least 1-year of follow-up. Demographics as well as time taken to secondary steroid response were documented. Renal biopsy of all patients with secondary steroid resistance had been performed. Eventual outcomes after treatment with calcineurin inhibitors based on the degree of proteinuria and serum albumin levels were used to categorise complete remission, partial remission and no response. Kidney function, as determined by estimated glomerular filtration rate, was recorded. Data was analysed using SPSS 22. RESULTS: Of the 1,000 patients who underwent renal biopsy for steroid resistance, 48(4.8%) had idiopathic steroid-resistant nephrotic syndrome; 32(66.7%) males, 16(33.3%) females and median age of 5 years (interquartile range: 4-7.3 years). Median age at diagnosis of nephrotic syndrome was 5 years (interquartile range: 3.6-7.3 years). The median time from nephrotic syndrome to secondary steroid-resistant nephrotic syndrome was 23 months (interquartile range: 8.75-44.5 months). Biopsy results at diagnosis showed that 27(56.3%) had minimal change disease. The mean follow-up time was 6.1±3.2 years. Of the 43(89.5%) patients who received cyclosporin for 1 year, 29(67%) obtained complete remission, 5(12%) attained partial remission and no response was seen in 9(21%) patients. Conclusion: Majority of the children had minimal change disease at the time of diagnosis of secondary steroid-resistant nephrotic syndrome. The long-term response with calcineurin inhibitors was favourable at 1 year.

The role of T cells and myeloid-derived suppressor cells in refractory immune thrombocytopenia.

Immune thrombocytopenia (ITP) is characterized by a dysregulated immune response against platelets, affecting both their destruction and production. A role for an abnormal T-cell compartment has been established in ITP pathogenesis and treatments that increase platelet counts in patients with ITP have shown improvements in T-cell profiles. On the other hand, patients who were refractory to treatment appear to retain the T-cell abnormalities as before. Myeloid-derived suppressive cells (MDSCs) are also emerging as key contributors to the immune pathology of ITP and response to treatment. In this review, we will discuss how various treatments affect the T-cell and MDSC compartments in ITP. The review will focus on studies that have examined the underlying mechanisms and/or genetic basis responsible for refractoriness to a given treatment and highlight remaining challenges in identifying factors and mechanisms to predict response to treatment.

Cognitive-behavioral therapy for binge-eating disorder for non-responders to initial acute treatments: Randomized controlled trial.

OBJECTIVE: Certain treatments have demonstrated acute efficacy for binge-eating disorder (BED) but many patients who receive "evidence-based" interventions do not derive sufficient benefit. Given the dearth of controlled research examining treatments for patients who fail to respond to initial interventions, this study tested the efficacy of cognitive-behavioral therapy (CBT) for patients with BED who do not respond to initial acute treatments. METHODS: Prospective randomized double-blind placebo-controlled single-site trial, conducted August 2017-December 2021, tested 16-weeks of therapist-led CBT for non-responders to initial treatment (naltrexone/bupropion and/or behavioral therapy) for BED with obesity. Thirty-one patients (mean age 46.3 years, 77.4% women, 80.6% White, mean BMI 38.99 kg/m2 ) who were non-responders to initial acute treatments were randomized to CBT (N = 18) or no-CBT (N = 13), in addition to continuing double-blinded pharmacotherapy. Independent assessments were performed at baseline, throughout treatment, and posttreatment; 83.9% completed posttreatment assessments. RESULTS: Intention-to-treat remission rates were significantly higher for CBT (61.1%; N = 11/18) than no-CBT (7.7%; N = 1/13). Mixed models of binge-eating frequency (assessed using complementary methods) converged revealing a significant interaction between CBT and time and a significant main effect of CBT. Binge-eating frequency decreased significantly with CBT but did not change significantly with no-CBT. Since only four patients received behavioral treatment during the acute treatments, we performed "sensitivity-type" analyses restricted to the 27 patients who received pharmacotherapy during the acute treatment and found the same pattern of findings for CBT versus no-CBT. CONCLUSIONS: Adult patients with BED who fail to respond to initial pharmacological treatments should be offered CBT. PUBLIC SIGNIFICANCE: Even with leading evidence-based treatments for binge-eating disorder, many patients do not derive sufficient benefit. Almost no controlled research has examined treatments for patients who fail to respond to initial interventions. This study found that that cognitive-behavioral therapy was effective for patients with binge-eating disorder who did not respond to initial interventions, with 61% achieving abstinence.

Weight recurrence after Sleeve Gastrectomy versus Roux-en-Y gastric bypass: a propensity score matched nationwide analysis.

BACKGROUND: Literature remains scarce on patients experiencing weight recurrence after initial adequate weight loss following primary bariatric surgery. Therefore, this study compared the extent of weight recurrence between patients who received a Sleeve Gastrectomy (SG) versus Roux-en-Y gastric bypass (RYGB) after adequate weight loss at 1-year follow-up. METHODS: All patients undergoing primary RYGB or SG between 2015 and 2018 were selected from the Dutch Audit for Treatment of Obesity. Inclusion criteria were achieving ≥ 20% total weight loss (TWL) at 1-year and having at least one subsequent follow-up visit. The primary outcome was ≥ 10% weight recurrence (WR) at the last recorded follow-up between 2 and 5 years, after ≥ 20% TWL at 1-year follow-up. Secondary outcomes included remission of comorbidities at last recorded follow-up. A propensity score matched logistic regression analysis was used to estimate the difference between RYGB and SG. RESULTS: A total of 19.762 patients were included, 14.982 RYGB and 4.780 SG patients. After matching 4.693 patients from each group, patients undergoing SG had a higher likelihood on WR up to 5-year follow-up compared with RYGB [OR 2.07, 95% CI (1.89-2.27), p < 0.01] and less often remission of type 2 diabetes [OR 0.69, 95% CI (0.56-0.86), p < 0.01], hypertension (HTN) [OR 0.75, 95% CI (0.65-0.87), p < 0.01], dyslipidemia [OR 0.44, 95% CI (0.36-0.54), p < 0.01], gastroesophageal reflux [OR 0.25 95% CI (0.18-0.34), p < 0.01], and obstructive sleep apnea syndrome (OSAS) [OR 0.66, 95% CI (0.54-0.8), p < 0.01]. In subgroup analyses, patients who experienced WR after SG but maintained ≥ 20%TWL from starting weight, more often achieved HTN (44.7% vs 29.4%), dyslipidemia (38.3% vs 19.3%), and OSAS (54% vs 20.3%) remission compared with patients not maintaining ≥ 20%TWL. No such differences in comorbidity remission were found within RYGB patients. CONCLUSION: Patients undergoing SG are more likely to experience weight recurrence, and less likely to achieve comorbidity remission than patients undergoing RYGB.

Moving towards patient-reported outcomes in routine clinical practice: implementation lessons from the BREAST-Q.

PURPOSE: Longitudinal, routine utilization of patient-reported outcome measures (PROMs) in clinical care has been challenging. The purpose of this study is to describe a quality improvement initiative to improve patient engagement with the BREAST-Q, a gold-standard PROM for breast reconstruction. METHODS: In 2011, we implemented the BREAST-Q as part of routine care. In 2018, we began a quality improvement initiative to increase BREAST-Q patient participation. The BREAST-Q was administered at every clinic visit via an institutional patient portal or an in-clinic tablet; digital dashboard technologies were used to improve workflow integration, real-time accountability, and immediate data availability at clinic visits. High clinical staff engagement was encouraged by assigning "BREAST-Q Champions." BREAST-Q completion data and patient characteristics were examined to understand non-response to the assessment. RESULTS: Following quality improvement, the average annual BREAST-Q completion rate increased from 42.8% in 2011-2017 to 87.6% in 2019, the last full year of our study period. High completion rates were maintained January-July 2020; however, a significantly larger proportion of BREAST-Qs were completed at home in 2020 versus the same period in 2019 (49.7 vs. 38.8%, p < 0.001), potentially due to the COVID-19 pandemic. Compared with non-responders, responders were younger (49.7 vs. 52.2 years, p < 0.001), more likely to be white (76.9 vs. 73.6%, p < 0.001), and had private insurance (79.4 vs. 69.8%, p < 0.001). CONCLUSION: Our quality improvement initiative successfully increased routine completion of the BREAST-Q. Similar implementation techniques may prove beneficial at other institutions interested in incorporating PROMs into routine care.

Real-world effectiveness of fremanezumab in patients with migraine switching from another mAb targeting the CGRP pathway: a subgroup analysis of the Finesse Study.

BACKGROUND: Monoclonal antibodies targeting the CGRP pathway are effective and safe for prophylactic treatment of episodic (EM) and chronic migraine (CM). In case of treatment failure of a CGRP pathway targeting mAb, physician has to decide whether using another anti-CGRP pathway mAb is useful. This interim analysis of Finesse Study evaluates effectiveness of the anti-CGRP mAb fremanezumab in patients with a history of other prior anti-CGRP pathway mAb treatments (switch patients). METHODS: FINESSE, a non-interventional, prospective, multicentre, two-country (Germany-Austria) study observing migraine patients receiving fremanezumab in clinical routine. This subgroup analysis presents data on documented effectiveness over 3 months after the first dose of fremanezumab in switch patients. Effectiveness was evaluated based on reduction in average number of migraine days per month (MMDs), MIDAS and HIT-6 scores changes as well as in number of monthly days with acute migraine medication use. RESULTS: One hundred fifty-three out of 867 patients with a history of anti-CGRP pathway mAb treatment prior to initiation of fremanezumab were analysed. Switch to fremanezumab led to ≥ 50% MMD reduction in 42.8% of migraine patients, with higher response rate in EM (48.0%) than in CM patients (36.5%). A ≥ 30% MMD reduction was achieved by 58.7% in CM patients. After three months, monthly number of migraine days decreased by 6.4 ± 5.87 (baseline: 13.6 ± 6.5; p < 0.0001) in all patients, 5.2 ± 4.04 in EM and 7.7 ± 7.45 in CM patients. MIDAS scores decreased from 73.3 ± 56.8 (baseline) to 50.3 ± 52.9 (after 3 months; p = 0.0014), HIT-6 scores decreased from 65.9 ± 5.0 to 60.9 ± 7.2 (p < 0.0001). Concomitant use of acute migraine medication had decreased from 9.7 ± 4.98 (baseline) to 4.9 ± 3.66 (3 months) (p < 0.0001). CONCLUSIONS: Our results show that about 42.8% of anti-CGRP pathway mAb-non-responder benefit from switching to fremanezumab. These results suggest that switching to fremanezumab may be a promising option for patients experiencing poor tolerability or inadequate efficacy with prior other anti-CGRP pathway mAb use. TRIAL REGISTRATION: FINESSE Study is registered on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS44606).

Clinical efficacy of alternative TNF inhibitor and secukinumab between primary non-responder and secondary non-responder of prior TNF inhibitor in ankylosing spondylitis.

OBJECTIVES: To compare the drug retention times and clinical efficacy of alternative tumour necrosis factor inhibitors (TNFi) and secukinumab in primary and secondary non-responders with ankylosing spondylitis (AS). METHODS: AS patients treated with biologics and enrolled in the Korean College of Rheumatology Biologics registry were examined. Patients who did not respond to previous TNFi treatment were defined as primary and secondary non-responders. Data regarding drug discontinuation and clinical efficacy were collected after 1 year. Kaplan-Meier and Cox regression analyses were performed to compare drug survival and associated factors. Logistic regression analyses were conducted to compare the clinical efficacy secukinumab with that of alternative TNFi. RESULTS: In total, 124 patients (83 receiving alternative TNFi and 41 receiving secukinumab) had biologic changes due to clinical inefficacy. Drug retention rates in the alternative TNFi and secukinumab groups were similar (P = 0.096). However, subgroup analyses including only secondary non-responders revealed that secukinumab users showed a higher hazard ratio (HR) for drug discontinuation (HR = 3.77, P = 0.045). In addition, secukinumab was negatively associated with achieving BASDAI50 or a major improvement in the ASDAS. CONCLUSION: Alternative TNFi showed better drug retention and clinical efficacy in AS patients experiencing previous TNFi failure, in secondary non-responders. Therefore, alternative TNFi may be a more suitable treatment for secondary non-responders.

HOW TO IDENTIFY SUBGROUPS IN LONGITUDINAL CLINICAL DATA: TREATMENT RESPONSE PATTERNS IN PATIENTS WITH A SHORTENED DENTAL ARCH.

BACKGROUND: When dental patients seek care, treatments are not always successful,that is patients' oral health problems are not always eliminated or substantially reduced. Identifying these patients (treatment non-responders) is essential for clinical decision-making. Group-based trajectory modeling (GBTM) is rarely used in dentistry, but a promising statistical technique to identify non-responders in particular and clinical distinct patient groups in general in longitudinal data sets. AIM: Using group-based trajectory modeling, this study aimed to demonstrate how to identify oral health-related quality of life (OHRQoL) treatment response patterns by the example of patients with a shortened dental arch (SDA). METHODS: This paper is a secondary data analysis of a randomized controlled clinical trial. In this trial SDA patients received partial removable dental prostheses replacing missing teeth up to the first molars (N = 79) either or the dental arch ended with the second premolar that was present or replaced by a cantilever fixed dental prosthesis (N = 71). Up to ten follow-up examinations (1-2, 6, 12, 24, 36, 48, 60, 96, 120, and 180 months post-treatment) continued for 15 years. The outcome OHRQoL was assessed with the 49-item Oral Health Impact Profile (OHIP). Exploratory GBTM was performed to identify treatment response patterns. RESULTS: Two response patterns could be identified - "responders" and "non-responders." Responders' OHRQoL improved substantially and stayed primarily stable over the 15 years. Non-responders' OHRQoL did not improve considerably over time or worsened. While the SDA treatments were not related to the 2 response patterns, higher levels of functional, pain-related, psychological impairment in particular, and severely impaired OHRQoL in general predicted a non-responding OHRQoL pattern after treatment. Supplementary, a 3 pattern approach has been evaluated. CONCLUSIONS: Clustering patients according to certain longitudinal characteristics after treatment is generally important, but specifically identifying treatment in non-responders is central. With the increasing availability of OHRQoL data in clinical research and regular patient care, GBTM has become a powerful tool to investigate which dental treatment works for which patients.

Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis.

BACKGROUND: The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients. METHODS: Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients' peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed. RESULTS: Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment. CONCLUSION: Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.

Lasmiditan efficacy in the acute treatment of migraine was independent of prior response to triptans: Findings from the CENTURION study.

BACKGROUND: A significant proportion of triptan users exhibit an insufficient response or inadequate tolerability to a triptan, and some may develop a contraindication. Lasmiditan, a selective 5-HT1F receptor agonist, may be an option for these individuals. We assessed lasmiditan efficacy in a subgroup of patients in CENTURION (Phase 3 migraine consistency study) who exhibited an insufficient response to triptans, including a subgroup with insufficient response due to efficacy only. METHODS: Patients were randomized to lasmiditan 200 mg for four attacks, lasmiditan 100 mg for four attacks, or placebo for three and lasmiditan 50 mg for one attack. Triptan insufficient responders were pre-defined as patients with insufficient efficacy or tolerability, or who developed a contraindication. RESULTS: In triptan insufficient responders, lasmiditan was superior to placebo (p < 0.05) for pain freedom beginning at 1 h (both doses); pain relief beginning at 0.5 (200 mg) or 1 h (100 mg); migraine-related disability freedom, much/very much better on the Patient Global Impression of Change, and most bothersome symptom freedom at 2 h; sustained pain freedom; and need for rescue medication. Lasmiditan showed benefit for consistency of effect across attacks for 2-h pain freedom and pain relief. Findings were similar in triptan responders and triptan naïve patients and when the triptan insufficient response definition was based on efficacy only. CONCLUSIONS: Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans.Trial Registration: CENTURION (NCT03670810); SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Sensory experiences of one's deceased spouse in older adults: An analysis of predisposing factors.

Objectives This study focuses on pre-disposing factors associated with sensory experiences of the deceased (SED), also called bereavement hallucinations. Even though SED are common among older widowed adults, our knowledge of these experiences is still limited.Method Survey responses were obtained from 310 older widowed participants (M = 70.05 ± 8.39), complemented with data from Danish national registers.Results Hierarchical logistic regression analysis revealed four significant pre-disposing factors: prior experiences of SED in the context of previous significant bereavements (OR = 4.72), a history of interpersonal trauma (OR = 5.8), high pre-death relationship closeness (OR = 2.76) and stronger religious/spiritual worldview (OR = 1.12). No association to registered mental health diagnosis was identified.Conclusion: SED may be considered an interpersonal experience, which may be more likely to occur if the pre-death relationship is described as very close and if the bereaved has previously experienced interpersonal trauma. We argue that SED should not necessarily be considered an indication of neurodegenerative or psychiatric diseases.

Lipoprotein Profile in Immunological Non-Responders PLHIV after Antiretroviral Therapy Initiation.

Nuclear magnetic resonance (NMR)-based advanced lipoprotein tests have demonstrated that LDL and HDL particle numbers (LDL-P and HDL-P) are more powerful cardiovascular (CV) risk biomarkers than conventional cholesterol markers. Of interest, in people living with HIV (PLHIV), predictors of preclinical atherosclerosis and vascular dysfunction may be associated with impaired immune function. We previously stated that immunological non-responders (INR) were at higher CV risk than immunological responders (IR) before starting antiretroviral therapy (ART). Using Liposcale® tests, we characterized the lipoprotein profile from the same cohort of PLHIV at month 12 and month 36 after starting ART, intending to explore what happened with these indicators of CV risk during viral suppression. ART initiation dissipates the differences in lipoprotein-based CV risk markers between INR and IR, and only an increase in the number of HDL-P was found in INR + IR when compared to controls (p = 0.047). Interestingly, CD4+ T-cell counts negatively correlated with medium HDL-P concentrations at month 12 in all individuals (ρ = -0.335, p = 0.003). Longitudinal analyses showed an important increase in LDL-P and HDL-P at month 36 when compared to baseline values in both IR and INR. A proper balance between a proatherogenic and atherogenic environment may be related to the reconstitution of CD4+ T-cell count in PLHIV.

A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA.

BACKGROUND & AIMS: In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment. METHODS: We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5× upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12-16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury. RESULTS: Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n = 43), the primary histologic endpoint was not met (p >0.05). The proportion of patients with ALP <1.67×ULN, a ≥15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p <0.05, each). In contrast to placebo, budesonide reduced mean ALP and 35% of budesonide-treated patients achieved normalisation of ALP (placebo 9%; p = 0.023). Serious adverse events occurred in 10 patients receiving budesonide and 7 patients receiving placebo. CONCLUSION: Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses. LAY SUMMARY: Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests. CLINICALTRIALS. GOV NUMBER: NCT00746486.

Immunogenicity and safety of HBAI20 Hepatitis B vaccine in non-responders: Double-blinded, randomised, controlled phase 2 trial.

BACKGROUND & AIMS: Approximately 5%-10% of the general population respond inadequately to licensed recombinant hepatitis B vaccines. We assessed the immunogenicity and safety of a new HBAI20 vaccine, consisting of a new AI20 adjuvant (20-µg recombinant human IL-2 attached to 20-µg aluminium hydroxide) in combination with HBVaxPro®-10 µg. METHODS: In a double-blinded, randomised, controlled phase 2 trial, 18- to 59-year-old healthy non-responders (titre <10 mIU/ml after three or more doses of hepatitis B vaccine) were assigned (3:1 ratio) to receive either HBAI20 vaccine or HBVaxPro®-10 µg in a 0, 1 and 2-month schedule. The primary outcome was seroprotection (titre ≥ 10 mIU/ml) measured 1-3 months following the third vaccination. RESULTS: A total of 133 participants were randomised to receive either HBAI20 vaccine (n = 101) or HBVaxPro®-10 µg (n = 32). In the modified intention-to-treat analysis, the seroprotection rate after the third vaccination was 92.0% (80/87) in the HBAI20 group and 79.3% (23/29) in the HBVaxPro®-10-µg group, P = .068. Using a generalised linear mixed model to adjust for stratification factors, a higher odds of seroprotection with HBAI20 vaccine was shown (adjusted odds ratio = 3.48, P = .028). Frequency of mild and moderate local adverse events was greater in the HBAI20 group than in the HBVaxPro®-10 µg. Rates of severe local adverse events and systemic adverse events were low and similar in both groups. CONCLUSIONS: In this group of hepatitis B vaccine non-responders, the HBAI20 vaccine demonstrated a higher seroprotection rate when adjusting for stratification factors and a similar safety profile compared to the licensed recombinant HBVaxPro®-10 µg.

A genome-wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites.

BACKGROUND & AIMS: Tolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites. METHODS: From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5 kg decrease of BW) were included in the GWAS and replication study. RESULTS: Genome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 × 10-8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P = .003; OR = 1.02, P = .02 and OR = 3.98, P = .000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774. CONCLUSION: SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

MultiPole pacing in non-responders to cardiac resynchronization therapy: Results from the QP ExCELs/MPP sub-study.

BACKGROUND: Multisite LV stimulation therapy allows for stimulation of two different left ventricular pacing vectors within a single LV lead and may improve responsiveness to cardiac resynchronization therapy (CRT). This study prospectively evaluated the safety and efficacy of the MultiPole Pacing (MPP) feature in CRT non-responder patients. METHODS AND RESULTS: CRT non-responders with a standard CRT-D indication were eligible for enrollment into the MPP Sub-Study. Patient status, NYHA classification, Patient Global Assessment (PGA), and adverse events were collected at follow-up. A clinical composite score (CCS) was determined at the 6 month follow-up visit. The primary objective was defined as the proportion of patients with an improved CCS. Safety was evaluated as freedom from MPP system related adverse events requiring additional invasive intervention to resolve. A total of 53 patients were enrolled across 26 U.S. centers. The cumulative follow-up duration was 24.1 years. CCS was improved in 35.6% of patients (p < .0001 when compared to a performance goal of 3%) after 6 months of MPP therapy. When incorporating patient feedback into a modified CCS, 60.0% of patients showed an improvement. Three patients (5.7%) experienced hospitalization for heart failure, and three patient deaths occurred over the follow-up period. No MPP system-related events were reported for an AE-free rate of 100% (95% CI 93.28% to 100.0%). CONCLUSIONS: The results of this small, non-randomized study suggest that the MPP feature is safe, and may be effective at converting a percentage of CRT non-responders to responders. Larger, randomized studies are needed to confirm this result.

Complementary effects on glycaemic and non-glycaemic parameters between responders and non-responders treated with pioglitazone and canagliflozin in drug-naive subjects with type 2 diabetes.

OBJECTIVES: The aim of this study was to investigate the differential regulation of metabolic parameters between pioglitazone and canagliflozin in relation to their glycaemic efficacies. METHODS: Drug-naive subjects with T2DM received pioglitazone 15-30 mg/day or canagliflozin 50-100 mg/day monotherapy for 3 months. Those who had a ≥1% reduction in HbA1c were defined as responders and others who had a <1% reduction were defined as non-responders. RESULTS: In the pioglitazone group, baseline BMI, FFA, HOMA-R or adipo-IR was significantly higher, and HDL-C was significantly lower in responders vs non-responders. In the canagliflozin group, baseline HbA1c or FBG was significantly higher, and HOMA-B or age was significantly lower in responders vs non-responders. In pioglitazone responders, significant decreases in HbA1c (from 10.75% to 8.31%), FBG (-29.7%), FFA (-37.7%), non-HDL-C (-13.4%), TG (-30.1%), HOMA-R (-35.6%) or adipo-IR (-38.7%), and increases in BMI (2.8%) or HDL-C (14.2%) were observed. In pioglitazone non-responders, none of the parameters were regulated. In canagliflozin responders, significant decreases in HbA1c (from 11.31% to 8.60%), FBG (32.1%), BMI (-2%) or HOMA-R (-33.8%), and increases in HOMA-B (50%) were observed. In canagliflozin non-responders, significant decreases in BMI (-2.4%), insulin (-21.8%) or HOMA-R (-33.6%) were observed. CONCLUSIONS: (i) Glycaemic efficacy of pioglitazone is linked to body weight and atherogenic lipids while this is not the case with canagliflozin. (ii) Responders (or non-responders) to pioglitazone have some distinct features from non-responders (or responders) to canagliflozin. Collectively, a combination of pioglitazone and canagliflozin may compensate for each other's metabolic drawbacks or augment their advantages, thereby achieving overall improvements in the metabolic profiles and pathogenic defects of patients with T2DM.