Initial Non-responders Research Articles

Clinicopathological Impact of Gene Polymorphism of Nephrin and Glucocorticoid Receptor Genes in Egyptian Children with Nonfamilial Nephrotic Syndrome.

Idiopathic nephrotic syndrome (NS) is one of the most common primary glomerular diseases in children. In this study, we investigate the association of single-nucleotide polymorphisms of nephrin gene and glucocorticoid receptor gene (NR3C1) and susceptibility to develop NS and the response to steroid therapy in 100 Egyptian children with NS using polymerase chain reaction-restriction fragment length polymorphism. We also analyzed the correlation between the genotypes and clinicopathologic features of the patients. Thirty-four patients (34%) were initial steroid nonresponders, renal biopsy findings of those patients were available, of which 22 (64.7%) showed minimal change NS and 12 (35.3%) had focal segmental glomerulosclerosis. The distribution of the genotypes was comparable between the patient and control groups, allele frequencies showed no significant difference between the patient's group and the control group. The genotypes showed no correlation with the age of onset of NS, initial steroid responsiveness, renal pathologic findings, estimated glomerular filtration rate (eGFR), and serum albumin. However, 24-h protein in urine showed a significant association with the NR3C1 gene. These data suggested that the nephrin gene and NR3C1 gene SNPs do not affect the development of NS, initial steroid responsiveness, renal pathological lesion, eGFR, and serum albumin. However, 24-h protein in urine showed a significant association with the NR3C1 gene in Egyptian children with NS.

Participation in Competing Strategies for Colorectal Cancer Screening: A Randomized Health Services Study (PICCOLINO Study)

Primary colonoscopy and fecal immunochemical testing (FIT) are considered first-tier tests for colorectal cancer (CRC) screening. Although colonoscopy is considered the most efficacious test, FIT might achieve higher participation rates. It is uncertain what the best strategy is for offering population-wide CRC screening. This was a multicenter randomized health services study performed within the framework of the Polish Colonoscopy Screening Program between January 2019 and March 2020 on screening-naïve individuals. Eligible candidates were randomly assigned in a 1:1:1 ratio to participate in 1 of 3 competing invitation strategies: control (invitation to screening colonoscopy only); sequential (invitation to primary colonoscopy and invitation for FIT for initial nonresponders); or choice (invitation offering a choice of colonoscopy or FIT). The primary outcome was participation in CRC screening within 18 weeks after enrollment into the study. The secondary outcome was diagnostic yield for advanced neoplasia. Overall, 12,485 individuals were randomized into the 3 study groups. The participation rate in the control group (17.5%) was significantly lower compared with the sequential (25.8%) and choice strategy (26.5%) groups (P < .001 for both comparisons). The colonoscopy rates for participants with positive FITs were 70.0% for the sequential group and 73.3% for the choice group, despite active call-recall efforts. In the intention-to-screen analysis, advanced neoplasia detection rates were comparable among the control (1.1%), sequential (1.0%), and choice groups(1.1%). Offering a combination of FITand colonoscopy as a sequential or active choice strategy increases participation in CRC screening. Increased participationin strategies with FIT do not translate into higher detection of advanced neoplasia. ClinicalTrials.gov, Number NCT03790475.

Efficacy and Safety of Continued Treatment With Mirikizumab in a Phase 2 Trial of Patients With Ulcerative Colitis

Mirikizumab is an antibody against the p19 subunit of interleukin 23 that has demonstrated clinical efficacy and was well tolerated following 12 weeks of induction treatment in a phase 2 trial of patients with moderate to severe ulcerative colitis. We present results of the open-label extended induction period in patients who did not initially respond to treatment with mirikizumab. This study was a continuation of I6T-MC-AMAC, a double-blind trial, performed at 75 sites in 14 countries, in which patients with moderate to severe ulcerative colitis were randomly assigned to 12 weeks induction therapy with 50 mg, 200 mg, or 600 mg mirikizumab or placebo. Patients without a clinical response (a 9-point decrease in Mayo subscore of ≥2 points and ≥35% from baseline and either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 were offered the opportunity to participate in an open-label, extended induction study for another 12 weeks, in which they received either 600 mg intravenous mirikizumab (n = 20) or, following a protocol amendment, 1000 mg intravenous mirikizumab (n = 64) every 4 weeks. At week 24, patients with a clinical response continued the extension maintenance period and received 200 mg subcutaneous mirikizumab. Endpoints included clinical remission (Mayo subscores of 0 for rectal bleeding, 0 or 1 with a 1-point decrease from baseline), clinical response, endoscopic remission (Mayo endoscopic subscore of 0), or endoscopic improvement (endoscopic subscore of 0 or 1), at study weeks 24 and 52. Data were analysed for patients who received mirikizumab or placebo during the induction phase of the study. Among participants who did not respond to induction mirikizumab, 50.0% of those who received the 12-week extension of 600 mg mirikizumab and 43.8% who received the extension of 1000 mg mirikizumab achieved a clinical response; 15.0% and 9.4% achieved clinical remission, respectively. Endoscopic improvement was achieved by 20.0% of subjects in the 600 mg mirikizumab group and 15.6% subjects in the 1000 mg mirikizumab group. Among initial nonresponders to mirikizumab who had clinical response at study week 24 and continued into maintenance therapy, 65.8% maintained the clinical response, 26.3% achieved clinical remission, and 34.2% had endoscopic improvement at week 52. No new safety concerns were identified. Extended doses of mirikizumab (600 mg and 1000 mg) for an additional 12 weeks produce a clinical response in up to 50% of patients who did not have a clinical response to 12 weeks of induction doses (50 mg, 200 mg, or 600 mg). Most of the responders to the extended doses maintained clinical response for up to 52 weeks. Clinicaltrials.gov no: NCT02589665.

Loss to follow-up: initial non-responders do not differ from responders in terms of 2-year outcome in a hip arthroscopy registry.

Loss to follow-up in registry studies is a problem due to potential selection bias. There is no consensus on the effect of response rate. The aim of this study was to compare patient-reported outcome measures (PROMs) between responders and initial non-responders (INR) in a hip arthroscopy registry and to examine whether demographics affect the response rate. Data from hip arthroscopies performed at two centres in Gothenburg were collected and the patients were followed up with PROMs. The follow-up was a minimum of 2 years after surgery. All 536 patients who underwent primary hip arthroscopies during 2015 and 2016 and had recorded pre-operative PROMs were included. A total of 396 patients completed the follow-up and were labelled ‘Responders’ (R) and 107 patients responded after reminders were sent and labelled ‘Initial non-responders’ (INR). The mean time of follow-up was 24.7 ± 2.9 and 42.5 ± 7.0 months for the R- and INR-group, respectively. There were no differences between the two groups at the follow-up for the Copenhagen Hip and Groin Outcome Score, European Quality of life 5 dimensions questionnaire, EQ-VAS, International Hip Outcome Tool or a visual analogue scale for hip function. A larger proportion of R was satisfied after hip arthroscopy compared with INR (86% versus 70%, P = 0.0003). INR were younger than responders (31.5 ± 12.5 versus 35.6 ± 12.7 years of age). The conclusion of the study was that there were no differences between R and INR at the follow-up across the PROMs except patient satisfaction, where responders were more satisfied.

The timed barium swallow and its relationship to symptoms in achalasia: Analysis of surface area and emptying rate.

Timed barium swallow (TBS) is used to objectively measure response following achalasia therapy; however, findings can be discordant with symptoms. We hypothesized that measurement of surface area of the residual barium column would improve its utility in measuring outcome. In a single-center cohort, achalasia patients undergoing therapy between September 2015-2016 who had TBS were included. Four metrics of emptying were studied: Post-therapy residual barium (a) absolute height and (b) surface area and percentage reduction in (c) residual height (%H) and (d) surface area (%SA) compared to pretherapy. Metrics were evaluated against symptom response (Eckardt score). Twenty-four achalasics (median age 43year; 13 males) were included; 14 received pneumatic dilatation, and 10 had peroral endoscopic myotomy. Treatment resulted in significant reduction in median Eckardt score (7 to 1; P=.03), mean residual barium column height (14.7±8.7 to 7.9±6.0cm; P=.01) and surface area (52.7±43.5 to 24.5±23.6cm2 ; P=.02). There were 4 (17%) initial non-responders (Eckardt>3). % SA was best at discriminating between responders and non-responders (area under curve 0.85±0.08; sensitivity 100%, specificity 80%). Concordance with symptomatic response following therapy was 83% when using 45% as the cutoff for surface area reduction compared to pretherapy. Eight patients whose static barium height was discordant with symptoms became concordant when % SA was used as a measure of response. Change in barium surface area is a superior measure of esophageal emptying and better correlates with treatment response than the conventional 5-minute barium height in defining objective response to achalasia therapy.

Lumbar Radicular Pain Response to First Injection with Non-particulate Steroid.

IntroductionRecent studies on the use of transforaminal epidural steroid injection (TFESI) to treat lumbar radicular pain have highlighted controversies pertaining to the choice of corticosteroid agent utilized in lumbosacral TFESI, in terms of both safety and efficacy. The primary objective was to characterize the radicular pain response after a first transforaminal injection with dexamethasone. The secondary objective was to document the response of those who failed to respond to a dexamethasone injection when particulate steroid was utilized for a second injection.MethodsIt was a retrospective study of 94 consecutive patients undergoing transforaminal injection for lumbosacral radicular pain. At two-week follow-up, patients rated their pain response on a clinically oriented five-point survey. First injection non-responders were given a second injection with particulate steroid and again completed the survey.ResultsApproximately one-third (N = 31/94) of patients received no meaningful relief from a single injection with dexamethasone. No patients achieved lasting and complete pain relief after a single injection. Of initial non-particulate steroid non-responders, approximately two-thirds (N = 19/28) demonstrated a notable or complete response to a second injection with particulate steroid.ConclusionsWe are now able to better inform patients with regard to their anticipated pain response to an initial dexamethasone injection. Only one-third of patients realized more significant and lasting relief after a single injection. Of those who did not demonstrate a more meaningful response, a second injection with particulate steroid resulted in more pronounced pain relief in two-thirds of patients.

798 Predictors of Delayed Response to Tofacitinib: Results of the OCTAVE Open Study for Delayed Responders

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib efficacy and safety were shown in 3 Phase 3 trials in patients (pts) with UC. 1 Pts who received tofacitinib 10 mg twice daily (BID) for 8 weeks in OCTAVE Induction 1/2 (NCT01465763/NCT01458951) and did not achieve clinical response could receive tofacitinib 10 mg BID in a Phase 3, open-label, long-term extension (OLE) study (NCT01470612). 2 OLE data (up to 3 years) for pts achieving clinical response with an additional 8 weeks of tofacitinib (delayed responders) have been reported. 3 METHODS: We evaluated potential predictors of delayed response (clinical response [≥3-point and ≥30% decrease from induction study baseline (BL) total Mayo score, and ≥1-point decrease in rectal bleeding subscore (RBS) or absolute RBS ≤1] after 16 weeks of 10 mg BID [8 weeks induction, 8 weeks in OLE]). Characteristics at OCTAVE Induction 1/2 BL and BL and Month 1 of the OLE study were evaluated in induction responders (clinical response to 8 weeks of 10 mg BID), delayed responders, or complete non-responders (non-response to 16 weeks of 10 mg BID). RESULTS: Characteristics at OCTAVE Induction 1/2 BL were generally similar between subgroups (Table 1). The proportion of pts with prior tumor necrosis factor inhibitor (TNFi) failure was numerically higher in complete non-responders vs delayed responders (Table 1). Induction study BL mean C-reactive protein was numerically higher in complete non-responders vs induction responders and delayed responders with a similar trend at OLE BL (Table 1). At OLE Month 1, stool frequency subscore (SFS) and RBS were numerically lower in delayed responders vs complete non-responders, and partial Mayo score (PMS) reduction from OLE BL was greater for delayed responders vs complete non-responders (Table 1). CONCLUSION: Numerically higher proportions of complete non-responders and delayed responders had prior TNFi failure vs induction responders. In pts with UC, early improvement at Month 1 during extended induction in SFS, RBS, and PMS may indicate likelihood of response to extended induction. The post-hoc data suggest tofacitinib 10 mg BID treatment beyond 8-week induction may be associated with clinical response in initial non-responders. Further evaluation with a larger sample size is needed.

Intradetrusor injection of botulinum toxin A in children: a 10-year single centre experience.

We evaluated the efficacy and safety outcomes of endoscopic intradetrusor botulinum toxin A (BTA) injections for the treatment of children with neuropathic bladder (NB) and non-neuropathic bladder (NNB) with or without detrusor overactivity in a single centre with a retrospective analysis. For the period 2006-2015, children who received BTA in our hospital were analysed. They were divided into group 1, those with underlying NB and group 2, those without a clear neuropathic cause of symptoms (NNB). Data are given as percentages or medians (interquartile range). Over the study period, 52 children (28 boys, 54%) received BTA, 28 in group 1 (54%; 17 (61%) boys) and 24 in group 2 (46%; 11 (46%) boys). Age at first injection was 11.8 (9.5-14.4) years. After initial injection, 40 (77%) reported symptomatic improvement, 17 (43%) becoming dry. There was no significant difference in response to initial injection between groups (p = 0.11). Duration of improvement after first injection was 7 (5.8-14) months. Twenty-five (48%) had further injections, of whom 3 (12%) were initial non-responders. Ongoing improvement was reported in 20 (80%), 11 (44%) of whom were dry. There was no significant difference in overall response to injections between groups (p = 0.11). Of the 11 non-responders, none (0/3) improved after subsequent injection and 3 (27%) subsequently underwent major urological surgery. Of the 40 who responded, 2 (5%) underwent major surgery. BTA injection produced symptomatic improvement in 77% of our study population, with no significant differences in response between NB and NNB groups. In 95% of those who improved, major urinary tract procedures were avoided during the period studied. None of the initial non-responders improved after subsequent BTA injection. BTA injection is effective and reliable in the management of children with NB and NNB refractory to medical therapy.

Early serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC—A retrospective cohort study

ObjectivesTo evaluate serum tumor markers (STM) as biomarkers for treatment monitoring and prognosis in advanced non-small cell lung cancer (NSCLC) treated with single-agent PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy. Materials and MethodsCarcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis, initially elevated markers were used for follow-up. Leading STM change between ICI initiation and first subsequent restaging as well as corresponding computed tomography evaluations according to response evaluation criteria in solid tumors (RECIST) were retrospectively analyzed regarding progression-free (PFS) and overall survival (OS). In uni- and multivariate stepwise Cox-regression analyses, STM and RECIST response were analyzed for their impact on PFS and OS together with other known prognostic patient and tumor characteristics. ResultsAmong 84 patients (61% men, mean age 68 years), median PFS was significantly (p < 0.001) longer, when STM decreased (11 M (7,19) N = 37) than in case of increases (<2-fold: 6 M (3,8) N = 31; ≥2-fold: 2 M (1,2) N = 16). Patients with initial STM decrease had longer (p < 0.001) median OS (not reached) than with STM increase (<2-fold: 14 M (12,26); ≥2-fold: 4 M (3,7)). Patients with stable or progressive disease by RECIST and concomitant STM decrease had longer (p < 0.001) PFS and OS (8 M (4,14) and 18 M (10,n.e.) N = 24) than upon STM increase (PFS: 2 M (2,4); OS: 10 M (6,13) N = 42). Significant impact on PFS was shown for STM response (p < 0.001), RECIST response (p = 0.003) and PD-L1 status (p = 0.003). For OS, STM response (p < 0.001), presence of cerebral metastases (p = 0.036) and therapy line ≥3 (p = 0.001) were identified. ConclusionDecreasing leading STM at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.

Do Clinical Correlates of Knee Osteoarthritis Predict Outcome of Intraarticular Steroid Injections?

To determine whether clinical correlates of knee osteoarthritis (OA) affect the outcome of intraarticular steroid injections (IASI) in symptomatic knee OA. Men and women aged ≥ 40 years with painful knee OA who participated in an open-label trial of IASI completed questionnaires and clinical examination. The Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) criteria were used to assess response to therapy in the short term (within 2 weeks). Among those who initially responded, those whose pain had not returned to within 20% of the baseline Knee Injury and Osteoarthritis Outcome Score pain score at 6 months were characterized as longer-term responders. Log-binomial regression was used to examine factors associated with outcome. One hundred ninety-nine participants were included, of whom 146 (73.4%) were short-term and 40 (20.1%) longer-term responders. Compared to short-term nonresponders, participants with these characteristics were more likely to be short-term responders: medial joint line tenderness [relative risk (RR) 1.42, 95% CI 1.10-1.82], medial and lateral joint line tenderness (RR 1.38, 95% CI 1.03-1.84), patellofemoral tenderness (RR 1.27, 95% CI 1.04-1.55), anserine tenderness (RR 1.27, 95% CI 1.06-1.52), and a belief that treatment would be effective [RR/unit increase (range 0-10) = 1.05 (1.01-1.09)]. Aspiration of joint fluid (RR 0.79, 95% CI 0.66-0.95) and previous ligament/meniscus injury (RR 0.63, 95% CI 0.44-0.91) were associated with a reduced risk of being a short-term responder. Compared to initial nonresponders and those whose pain recurred within 6 months, participants with a higher number of pain sites [RR/unit increase (range 0-10) = 0.83, 95% CI 0.72-0.97], chronic widespread pain (RR 0.32, 95% CI 0.10-0.98), perceived chronicity of disease [RR/unit increase (range 0-10) = 0.86, 95% CI 0.78-0.94], and a higher depression score [RR/unit increase (range 0-21) = 0.89, 95% CI 0.81-0.99] were less likely to be longer-term responders. Among patients with symptomatic knee OA, tenderness around the knee was associated with better short-term outcome of IASI. However, clinical-related factors did not predict longer-term response, while those with chronic widespread pain and depressive symptoms were less likely to obtain longer-term benefits.

Second Courses of Transcranial Magnetic Stimulation (TMS) in Major Depressive Episodes for Initial Responders and NonResponders

BackgroundTranscranial Magnetic Stimulation (TMS) is effective in major depressive episodes (MDE). However, MDE may follow a chronic, relapsing course, and some individuals may not satisfactorily respond to a first course of TMS.ObjectiveTo investigate the outcome of second courses of TMS.MethodA naturalistic investigation—we prospectively studied 30 MDE in-patients and routinely collected information, including pre- and post-treatment with Six-item Hamilton Depression Rating Scale (HAMD6), a six-item Visual Analogue Scale (VAS6) and the Clinical Global Impression-Severity (CGI-S). Two categories of patients were considered: i) those who had remitted with a first course, but relapsed, and ii) those who had not remitted with the first course.ResultsThirty individuals received a second TMS course. The mean time to the second course was 27.5 weeks. Based on the HAMD6, 26 (87%) achieved remission after the first course, and 22 (73%) achieved remission after the second course. Furthermore, based on the HAMD6 results, of the four patients who did not achieve remission with a first course, three (75%) did so with a second course.ConclusionIn MDE, a second course of TMS is likely to help those who remitted to a first course and then relapsed, as well as those who did not achieve remission with a first course.

The Effectiveness of Bilateral Repetitive Transcranial Magnetic Stimulation in Anhedonia among Patient with Major Depressive Disorder: A pilot study

High-frequency left-sided repetitive transcranial magnetic stimulation (rTMS) is now commonly used treatment for patients with depression. However, there are several other forms of rTMS (low-frequency right-sided and sequential bilateral rTMS) which have also been shown to be effective. No information has been systematically gathered on the likelihood of response to alternative forms of rTMS in patients who do not improve after an initial course of left-sided treatment.To evaluate whether there are differences in antidepressant response between switching to either low-frequency right sided or sequential bilateral stimulation or continuing high-frequency left-sided TMS following non-response to an initial course of high-frequency left-sided rTMS.113 rTMS naïve patients were provided with an initial three-week course of high-frequency left-sided rTMS. Non-responders were then randomised to receive another three weeks of left-sided treatment (n = 21), right-sided low frequency stimulation (n = 18) or sequential bilateral rTMS (n = 20).Although there was an overall improvement in depressive symptoms in the randomised phase of the study, no significant differences in response was seen between the three treatment groups on Montgomery Asberg Depression Rating Scale or Hamilton Depression Rating Scale scores.The main limitation of the study was the duration of treatment provided in both the lead in and random treatment phases.This study does not provide evidence for differences in response to different forms of rTMS in initial non-responders to left-sided stimulation. However, further studies with longer periods of treatment and a larger sample size are required to definitively establish or exclude between group differences in rTMS response in initial non-responders to treatment.

Long-term follow-up of patients treated with entecavir and peginterferon add-on therapy for HBeAg-positive chronic hepatitis B infection: ARES long-term follow-up.

Addition of peginterferon alpha (PEG-IFN add-on) to entecavir (ETV) treatment after a short lead-in phase results in more response than ETV monotherapy in HBeAg-positive chronic hepatitis B infection (CHB). This study is the first to assess long-term efficacy of this treatment strategy. Patients who received ETV±24weeks of PEG-IFN add-on in a global trial (ARES study) and completed follow-up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200IU/mL) at LTFU. In total, 48 patients treated with PEG-IFN add-on and 48 patients treated with ETV monotherapy were included. The median follow-up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non-responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P=0.81), and 1 log10 HBsAg decline in 59% vs 28% (P=0.02) for PEG-IFN add-on and ETV monotherapy, respectively. In 41 initial non-responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG-IFN add-on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow-up, rates of serological response became comparable between PEG-IFN add-on and ETV monotherapy. Although in this LTFU study initial non-responders were overrepresented in the add-on arm, PEG-IFN add-on possibly leads rather to accelerated HBeAg loss than to increased long-term HBeAg loss rates.

Safety and Efficacy of Budesonide Oral Suspension Maintenance Therapy in Patients With Eosinophilic Esophagitis

We aimed to determine the safety and efficacy of budesonide oral suspension (BOS) maintenancetherapy in patients with eosinophilic esophagitis (EoE). We performed an open-label extension study of a 12-week, multicenter, randomized, double-blind, placebo-controlled trial. Patients with EoE (11-40 years old) who completed double-blind BOS (n = 45) or placebo therapy (n = 37) received 24 weeks' open-label BOS (2.0mg once daily for 12 weeks, with optional dose increase [1.5-2.0 mg twice daily] for 12 weeks thereafter). Predefined efficacy outcomes included: proportion of patients with a histologic response (≤6 eosinophils/high-power field [eos/hpf]) and change in mean peak eosinophil counts after 24 weeks. Analyses were stratified by patients who received placebo (placebo/BOS) or BOS (BOS/BOS) during the double-blind trial. BOS was well tolerated and drug-related adverse events were uncommon (placebo/BOS, 19% [7/37]; BOS/BOS, 4% [2/45]). Incidence of oral candidiasis (1 per group) and esophageal candidiasis (placebo/BOS group, n = 4) remained low. Changes in morning serum cortisol levels were not clinically relevant. A histologic response was observed in 49% (16/33) of patients receiving placebo/BOS and 23% (9/39) receiving BOS/BOS. Mean peak eosinophil counts (baseline vs week 24 or early termination) were: placebo/BOS, 118.8 vs 29.1; P < .001 and BOS/BOS, 38.1 vs 72.4; P = .01. Of the patients who responded to double-blind therapy, 42% maintained a histologic response during the open-label extension; 4% of nonresponders gained response. In an open-label extension study of patients with EoE, BOS was well tolerated and drug-related adverse events were uncommon. BOS maintained a histologic response in some initial responders, but few initial nonresponders had a response. ClinicalTrials.gov no: NCT01642212.

Exploring alternative rTMS strategies in non-responders to standard high frequency left-sided treatment: A switching study

BackgroundHigh-frequency left-sided repetitive transcranial magnetic stimulation (rTMS) is now commonly used treatment for patients with depression. However, there are several other forms of rTMS (low-frequency right-sided and sequential bilateral rTMS) which have also been shown to be effective. No information has been systematically gathered on the likelihood of response to alternative forms of rTMS in patients who do not improve after an initial course of left-sided treatment. ObjectiveTo evaluate whether there are differences in antidepressant response between switching to either low-frequency right sided or sequential bilateral stimulation or continuing high-frequency left-sided TMS following non-response to an initial course of high-frequency left-sided rTMS. Methods113 rTMS naïve patients were provided with an initial three-week course of high-frequency left-sided rTMS. Non-responders were then randomised to receive another three weeks of left-sided treatment (n = 21), right-sided low frequency stimulation (n = 18) or sequential bilateral rTMS (n = 20). ResultsAlthough there was an overall improvement in depressive symptoms in the randomised phase of the study, no significant differences in response was seen between the three treatment groups on Montgomery Asberg Depression Rating Scale or Hamilton Depression Rating Scale scores. LimitationsThe main limitation of the study was the duration of treatment provided in both the lead in and random treatment phases. ConclusionThis study does not provide evidence for differences in response to different forms of rTMS in initial non-responders to left-sided stimulation. However, further studies with longer periods of treatment and a larger sample size are required to definitively establish or exclude between group differences in rTMS response in initial non-responders to treatment.

A sequential multiple assignment randomized trial for cocaine cessation and relapse prevention: Tailoring treatment to the individual

Drug addiction is a chronic, devastating, but treatable disorder. A core principle of drug addiction treatment states that no single treatment is appropriate for everyone (NIDA, 2012); treatments need to adjust based on patient characteristics and response in order to be maximally effective. For cocaine use disorders (CUD), specifically, the most potent intervention currently available for initiating abstinence is behavior therapy using contingency management (CM) procedures, with early cessation being a robust predictor of future abstinence. This raises two key questions for treatment development research: First, can we significantly improve initial CM response rates with targeted adjunctive interventions? Second, for individuals who fail to achieve initial abstinence with CM, is pharmacotherapy an effective augmentation strategy? This paper describes how a sequential, multiple assignment, randomized trial (SMART) design has advantages over a fixed-intervention approach when it comes to collecting data needed to answer both questions. The first aim will examine whether Acceptance and Commitment Therapy (ACT) in combination with CM increases initial abstinence response rates (i.e., 2 consecutive weeks of cocaine-negative urine screens). The second aim will examine whether ACT+CM in combination with modafinil promotes abstinence achievement in initial non-responders. Results are expected to inform how we tailor treatment of CUD to maximize outcomes.

Role of glucocorticoids in Kawasaki disease.

Although treatment with intravenous immunoglobulin (IVIg) with aspirin is the standard of care for children with Kawasaki disease (KD), 15-20% of patients fail to respond and experience persistent or recurrent fever after completion of IVIg administration. These IVIg non-responders are at high risk for coronary artery lesions (CAL), and may need alternative or supplemental therapy. Based on retrospective studies (albeit with low evidence levels), glucocorticoid therapy was hitherto thought to worsen CAL. However, subsequent prospective studies have shown that prednisolone or IV methylprednisolone pulse as the initial or rescue therapy is effective in reducing CAL. A clinical trial known as the Randomized controlled trial to Assess Immunoglobulin plus Steroid Efficacy for KD (RAISE) Study, demonstrated the efficacy of prednisolone with initial IVIg, especially in predicted IVIg non-responders. Several meta-analyses have also supported the use of glucocorticoids for patients with severe forms of KD. Glucocorticoids can be considered as pre-emptive therapy for children with severe KD and as rescue therapy for initial non-responders. However, routine use of glucocorticoids in KD remains a contentious issue and would need further study.

Assessment of Bleeding and Thrombosis Based on Aspirin Responsiveness after Continuous-Flow Left Ventricular Assist Device Placement.

Pump thrombosis (PT) is a severe complication of left ventricular assist device (LVAD) support. This study evaluated PT and bleeding after LVAD placement in patients responsive to a standard aspirin dose of 81 mg using platelet inhibition monitoring compared with initial nonresponders who were then titrated upward to achieve therapeutic response. Patients ≥ 18 years of age with initial placement of HeartMate II LVAD at our institution and at least one VerifyNow Aspirin test performed during initial hospitalization were included. The primary endpoints were bleeding and PT compared between initial aspirin responders and nonresponders. Of 85 patients, 19 (22%) were nonresponsive to initial aspirin therapy. Responders and nonresponders showed similar survival (p = 0.082), freedom from suspected/confirmed PT (p = 0.941), confirmed PT (p = 0.273), bleeding (p = 0.401), and incidence rates in PT and bleeding. Among the initial responders (<500 vs. 500-549 aspirin reaction units), there were no significant differences in survival (p = 0.177), freedom from suspected/confirmed PT (p = 0.542), confirmed PT (p = 0.159), bleeding (p = 0.879), and incidence of PT and bleeding. Platelet function testing may detect resistance to standard aspirin regimens used in LVAD patients. Dose escalation in initially nonresponsive patients to achieve responsiveness may confer a similar PT risk to patients initially responsive to standard aspirin dosing without increased bleeding risk.

Long-term protection after hepatitis B vaccination in people living with HIV

BackgroundHepatitis B vaccine is important in people living with HIV (PLHIV) since both viruses have the same transmission routes and co-infection has greater morbidity.PLHIV usually have poor response to hepatitis B vaccine. The duration of immunity in PLHIV is unknown.The objective of this study is to evaluate the duration of serological response and clinical protection provided by hepatitis B vaccination in PLHIV. MethodsRetrospective study of a PLHIV cohort primarily vaccinated for hepatitis B virus (HBV) from 2001 to 2002. Markers of infection and protection from HBV were investigated in those individuals who were still attending the outpatient clinic, in São Paulo, Brazil from 2012 to 2014. Three groups were analyzed. Group 1: adults who responded to primary vaccine series. Group 2: non-responders to primary vaccine series. Group 3: subjects from both Groups 1 and 2 who did not receive any booster doses after seroconversion. ResultsA cohort of 121 PLHIV was analyzed for seroconversion and persistence of anti-HBs. The majority were female (54.5%) and mean age was 50.1years.After 11years, none of the patients had serologic evidence of HBV infection.Overall, 41/58 (70.7%) of the initial responders (Group 1) had maintained anti-HBs≥10mIU/mL. Greater CD4+ values and anti-HBs>100mIU/mL at the time of first vaccine series were associated with persistence of anti-HBs.During the time of evaluation, 35/63 (55.6%) of the initial non-responders (Group 2) successfully seroconverted (anti-HBs≥10mIU/mL) in response to one or more booster doses.From the time of their seroconversion, 70 of the patients did not receive any further booster doses (Group 3). After 10years, 54/70 (77.1%) of these individuals has maintained anti-HBs≥10mIU/mL. ConclusionsEvaluation of long-term immunity for hepatitis B in PLHIV following vaccination showed a strong persistence of anti-HBs and no serologic evidence of HBV infection. Boosters may be effective in PLHIV non-responders to primary vaccination.

Double-blind switch study of vilazodone in the treatment of major depressive disorder.

Approximately 40% of patients treated for depression do not respond to a trial of an antidepressant. The aim of the proposed study was to evaluate the efficacy and safety of switching to vilazodone in patients with major depressive disorder who are unresponsive or only partially responsive to a trial of citalopram. Seventy-nine adults with major depressive disorder were enrolled in an open-label study of citalopram (20 mg/day) for 6 weeks. Those still symptomatic after 6-weeks of citalopram were randomly assigned to either a higher dose of citalopram (40 mg/day) or to vilazodone in a double-blind trial for 6 weeks. Of those who received citalopram 20 mg/day for 6 weeks, 20.3% were 'responders' (defined as ≥50% reduction on the Montgomery-Åsberg Depression Rating Scale). Of the 42 who did not respond, 23 were assigned to citalopram 40 mg/day and 19 were randomized to 40 mg/day of vilazodone. Both groups showed decreases in all outcome measures, but there were no significant differences between groups. Initial nonresponders to a low dose of citalopram seem equally likely to respond to a higher dose of citalopram or to vilazodone. Whether to increase an selective serotonin reuptake inhibitor or switch to a different antidepressant may be best determined on the basis of their adverse event profile.