Evidence Of Rebound Research Articles

Efficacy in myopia control-The impact of rebound.

When myopia control treatment is discontinued, progression will increase, but does it revert to expected values based on the age and race of the child or does it accelerate further? The latter scenario is considered a rebound. A PubMed search was conducted with the words 'rebound' and 'myopia control', identifying further papers from reviews. Inclusion was limited to prospective studies with ≥6 months of treatment, ≥3 months of data following cessation and with axial length data, which allowed calculation of rebound. Nineteen studies were identified, comprising 24 treatment groups. In 10 studies, untreated control children were followed both throughout the treatment and cessation periods, allowing for a concurrent comparison group. In three studies, a control group was followed for 1 or 2 years and thereafter received the treatment under evaluation. Later, treatment ceased in the originally treated children. Finally, six studies were cross-over designs. For these latter two study designs, initial axial elongation and myopia progression in the control group were extrapolated to the cessation period, accounting for annual slowing. Values from durations of <1 year were annualised. The mean annualised rebound was +0.05 ± 0.10 mm and -0.09 ± 0.24 D for axial length and myopia progression, respectively, and these were correlated (r2 = 0.59, p < 0.001). Rebound was associated with 1-year treatment efficacy (r2 = 0.43, p < 0.001). The mean annualised rebound with optical corrections was -0.01 ± 0.03 mm. Five of the six highest rebound values (≥0.14 mm) were from red light therapy and atropine studies. Rebound ranged from +0.03 to +0.14 mm for overnight orthokeratology. Consistent with previous statements, no evidence for rebound was found for myopia control spectacles and soft contact lenses. Future research should explore the influence of age and magnitude of treatment efficacy on rebound.

Ocrelizumab exposure in relapsing-remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension.

Open-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing-remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000mg or 600mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000mg or 600mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600mg every 24weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound.

SAT680 Mounjaro: A Side Effect

Abstract Disclosure: K. Rao: None. E. Kyei Nimako: None. Mounjaro : A Side Effect Dr K Rao, Dr Evans-Nimako, Internal Medicine, North Alabama Medical Center Introduction: Mounjaro has been heralded as a new miracle drug both in the world of diabetes management and weight loss with its pending FDA approval in the latter category. Although common contraindications are known the wider spectrum and prevalence of side effects including diabetic retinopathy, acute kidney injury and gallbladder disease are still being identified. In this case we present a patient with Mounjaro induced AKI and ileus. Case Presentation: We present the case of a 64year-old diabetic, hypertensive male presenting with a 3-day history of nausea vomiting indigestion and excessive burping one day after taking his first dose of Mounjaro. The Patient was started at a walk-in clinic on 2.5 mg subcutaneously however on the very next day he noticed the onset of cramping abdominal pain with multiple episodes of vomiting and watery diarrhea. The patient has not had any other new foods, sick contacts or preceding illnesses. He had a history of previous hernia surgery, cholecystectomy and exploratory laparotomy some 18 years ago due to concerns for nonresolving small bowel obstruction. On examination he was afebrile but tachycardic and in mild distress. His abdomen was soft and nondistended. Bowel sounds were faint but present. He had generalized tenderness without evidence of rebound or guarding. Initial investigations demonstrated a white cell count of 14.7(10E3/ul), creatinine 1.7mg/dl, potassium 4.5mmol/L, blood glucose 176mg/dl and lactate of 2mmol/L. His urine analysis showed small volume ketones, glucosuria and trace leukocyte esterase with 3-5 white blood cells. CT of the abdomen and pelvis with contrast showed distended small and large bowel loops with fluid air levels but no transition point indicative of underlying ileus. The patient was hospitalized in total for approximately six days post the onset of his symptoms and treated with supportive measures including antiemetics, IV fluids and antacids. He never had any fevers or leukocytosis during his stay. His electrolytes remained within normal limits. Conclusion: Due to the impending widespread use and increasing popularity of Mounjaro this case presentation is aimed at raising awareness of potential side effects and their severity. We also hope to contribute towards further knowledge about specific subset of patients who may be more susceptible to the gastrointestinal side effects of Mounjaro. Particularly those patients who have had previous colonic or multiple abdominal surgeries or history of bowel obstruction. In this case the patient received the medication at a walk-in clinic this also highlights the dangers of lack of established care and monitoring of Mounjaro. Presentation: Saturday, June 17, 2023

Long-term myopia control effect and safety in children wearing DIMS spectacle lenses for 6 years

This study evaluated the long-term myopia control effect and safety in children wearing Defocus Incorporated Multiple Segments (DIMS) spectacle lenses. Participants who completed the 2-year RCT were followed for a total of 6 years; their cycloplegic refractions and axial length were measured. Group 1 (n = 36) wore DIMS spectacles for 6 years; Group 2 (n = 14) wore DIMS lens for the first 3.5 years and SV spectacles afterwards; Group 3 (n = 22) wore SV spectacles in the first 2 years and switched to DIMS; Group 4 (n = 18) wore SV spectacles in the first 2 years, switched to DIMS for 1.5 years and then SV spectacles again. Group 1 showed no significant differences in myopia progression (− 0.52 ± 0.66 vs. − 0.40 ± 0.72D) and axial elongation (0.32 ± 0.26 vs. 0.28 ± 0.28 mm, both p > 0.05) between the first and the later 3 years. In the last 2.5 years, DIMS lens groups (Groups 1 and 3) had less myopia progression and axial elongation than the single vision groups (Groups 2 and 4). There was no evidence of rebound after stopping the treatment. Post-wear visual functions in all groups were within norms. The results supported that DIMS lenses provided sustained myopia control without adverse effects over the 6-year study period.Trial registration: clinicaltrials.gov; NCT02206217.

Immune Checkpoint Inhibitor-Induced Hypophysitis and Patterns of Loss of Pituitary Function.

BackgroundImmune checkpoint inhibitors (ICI) are clinically active across multiple tumor types but the associated immune-related adverse events (irAEs) lead to treatment delays or discontinuation and negatively impact quality-of-life. Hypophysitis is often a permanent irAE that may affect multiple pituitary hormonal axes. Here we comprehensively characterize our institution’s clinical experience with ICI-induced hypophysitis and the associated patterns of pituitary function loss.MethodsPatients with solid tumors, mostly melanoma and renal cell carcinoma (RCC), treated with ICI at Yale Cancer Center were prospectively enrolled from October 2016-May 2021. Demographics and clinical data were obtained from the medical record including type and timing of irAEs. Patients were included in this cohort if hypophysitis was diagnosed by pre-specified biochemical and clinical parameters.ResultsThe overall incidence of hypophysitis was 69/490 (14%) in patients with melanoma (n=58, 84%), RCC (n=10,14%), and merkel cell carcinoma (n=1, 1%) who received ipilimumab plus nivolumab (77%; 53/69), anti-PD-(L)1 (17%; 12/69), or ipilimumab monotherapy (6%; 4/69). Of the 69 patients analyzed, median time to hypophysitis on combination ICI versus anti-PD-1 was 2.8 vs. 4.1 months. The incidence of hypophysitis in patients with melanoma was 25% (46/187) with ipilimumab plus nivolumab and 5% (7/129) with anti-PD-(L)1 compared to 9% (7/77) and 8% (3/37), respectively, in patients with RCC. Patients who developed hypophysitis on combination ICI had a higher rate of headache (p=0.05) and co-occurring irAEs (p=0.01) compared anti-PD-(L1)1 monotherapy. At a median follow-up of 2.2 years, 77% of patients were alive. Objective response rates to ICI in melanoma patients were higher than previously reported for unselected populations. Central hypothyroidism and hypogonadism were the most common pituitary axes affected after the adrenal axis. In select cases, there was evidence of spontaneous rebound in free testosterone levels after an initial decline.ConclusionsWe demonstrate a higher rate of ICI-induced hypophysitis than previously reported, which may be reflective of real-world practice due to increased awareness as experience with ICI has grown. In select cases, there was evidence of rebound in free testosterone and/or gonadotropins but not in adrenal axis hormones.

Economy-wide rebound makes UK’s electric car subsidy fall short of expectations

Environmental policies often underperform due to so-called rebound effects, namely behavioural and systemic responses to technical change leading to additional consumption and environmental damage. While evidence of rebound is abundant, studies generally focus on technical changes that are neither associated with specific technologies nor their production costs, making it difficult to connect these changes with the policies governing them. To overcome this limitation, this study proposes to combine a technology-rich model based on life cycle assessment and a behaviour-optimising model for the global economy based on computable general equilibrium modelling. This approach allows to quantify policy-induced economy-wide rebound effects for four relevant environmental impacts: climate change, acidification, photochemical ozone formation, and particulate matter. We apply this approach to evaluate the effectiveness of the United Kingdom’s subsidy on electric cars. The results show notable economy-wide rebound effects associated with this subsidy: over or close to 100% (no environmental benefits) for acidification and particulate matter impacts, and a lower, yet notable, magnitude for climate change (~20–50%) and photochemical ozone formation (~30–80%) impacts. The results also show the important role of macro-economic effects from price changes, particularly how the shift from petrol to electricity triggered additional demand for cheaper petrol.

Combined Inhibition of Gαq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma.

All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (Gαq) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gαq have shown promising preclinical results, but their therapeutic activity in distinct Gαq mutational contexts and in vivo have remained elusive. We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used in vitro and in in vivo xenograft studies to assess the efficacy of Gαq inhibition as a single agent and in combination with MEK inhibition. We demonstrate that the Gαq inhibitor YM-254890 inhibited downstream signaling and in vitro growth in all mutants. In vivo, YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrated that the combination caused synergistic growth inhibition in vitro and tumor shrinkage in vivo. These data suggest that the combination of Gαq and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gαq in uveal melanoma.See related commentary by Neelature Sriramareddy and Smalley, p. 1217.

Abstract 3410: Adaptive resistance mechanisms to KRASG12C specific inhibitors

Abstract Covalent inhibitors of KRASG12C mutants allow specific targeting of KRAS driven signaling yet early studies suggest bypass signaling as a mechanism of resistance. Understanding adaptive signaling mechanisms enabling cells to survive KRASG12C inhibition could identify combination therapies and associated predictive biomarkers. We employed KRASG12C mutant lung cancer cell lines and evaluated their sensitivity in 2D cell culture to mimic the resistant state. We combined small molecule targeted agents (N=292 compounds) screens alongside KRASG12C inhibition as well as global mass spectrometry based phosphoproteomics (pY/S/T) to examine adaptive signaling changes. KRASG12C mutant lung cancer cell lines have differential sensitivity to KRASG12C inhibition with ARS-1620. Signaling analysis indicates inhibition of p-ERK and to some degree pAKT after 6 hours with evidence of rebound by 24 hr. To expand our understanding of cell type specific response and pathway reactivation upon KRASG12C inhibition, TMT-based quantitative phosphoproteomics was performed after phosphotyrosine (pY) enrichment in 3 cell lines (H358, Calu1 and H1792) after ARS-1620 treatment (6h and 24h). We identified 2275 human phosphosites in total, corresponding to 1153 proteins in 987 protein groups, out of which 433 phosphosites were differentially expressed (1.5-fold change and p-value &amp;lt; 0.05) between any treatment time point and control. Preliminary analysis revealed some common and cell line specific response to ARS-1620. MAPK1, MAPK3, MET, CTNND1, and VTI1B exhibit the strongest down-regulation, across all time points in all cell lines. We observed 84 phosphosites corresponding to 77 proteins that were more abundant in ARS-1620 treated cells indicating a potential for adaptive resistance signaling. Results from the small molecule screens indicate compounds targeting ERBB/HER family of kinases and PI3K pathway showed better synergistic effects with ARS-1620. Signaling analysis in H358, H23 and H2122 cells revealed more abundant tyrosine phosphorylated and total HER2 and HER3 upon ARS-1620 treatment. Further suppression of pERK and pAKT was observed when afatinib was added to ARS-1620 resulting in more combined effects on cell viability. When compared to more specific EGFR inhibition (erlotinib), afatinib enhanced inhibition of pERK and pAKT by ARS-1620 and had more effects on cell viability. However, in H1792 cells, phosphoproteomics identified increased tyrosine phosphorylation of FGFR1 following ARS-1620 and this correlated with combination effects on cell viability of ARS-1620 with the FGFR inhibitor AZD-4547. Lastly, our results suggest that cells sensitive to combination with either HER TKI or FGFR TKI with ARS-1620 are also demonstrating combination effects with SHP2 inhibition (SHP099). Our combined chemical biology and phosphoproteomics results suggest widespread adaptive signaling changes, some of which are contributing to adaptive resistance. Results suggest a more important role of pan-HER inhibition compared with EGFR inhibition. These data may guide biomarker development strategies, especially those that reflect adaptive signaling responses, to predict clinically effective combination strategies in diverse group of KRASG12C mutant lung cancer. Citation Format: Hitendra Singh Solanki, Bin Fang, Eric A. Welsh, Aik C. Tan, Fumi Kinose, Uwe Rix, Eric B. Haura. Adaptive resistance mechanisms to KRASG12C specific inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3410.

0768 Time Course Of Improvement In Excessive Daytime Sleepiness And Cataplexy During Treatment With Pitolisant In Patients With Narcolepsy

Abstract Introduction This analysis evaluated the efficacy of pitolisant over time in three 7- to 8-week, randomized, placebo-controlled studies of adults with narcolepsy. Methods Patients in all 3 studies (HARMONY-1, HARMONY-1bis, HARMONY-CTP) experienced excessive daytime sleepiness (EDS) at study baseline; patients in HARMONY-CTP also experienced ≥3 cataplexy attacks/week. Pitolisant was titrated to a maximum dose of 35.6 mg/day (HARMONY-1, HARMONY-CTP) or 17.8 mg/day (HARMONY-1bis). Change from baseline in mean Epworth Sleepiness Scale (ESS) score (3 studies) and mean weekly rate of cataplexy (WRC; 1 study) was compared for pitolisant versus placebo. Results In the higher-dose HARMONY-1 (pitolisant, n=31; placebo, n=30) and HARMONY-CTP (pitolisant, n=54; placebo, n=51) studies, ESS score improvement was significantly greater with pitolisant versus placebo beginning at Week 2 (LS mean difference, -2.8; P=0.015) and Week 3 (LS mean difference, -2.0; P=0.005), respectively. In the lower-dose HARMONY-1bis study (pitolisant, n=66; placebo, n=32), significant separation from placebo was first observed at Week 7 (LS mean difference, -2.3; P=0.044). At end-of-treatment, LS mean difference in ESS score change from baseline was -3.1 (P=0.022) in HARMONY-1, -3.4 (P&amp;lt;0.001) in HARMONY-CTP, and -2.2 (P=0.030) in HARMONY-1bis. In HARMONY-CTP, LS mean WRC with pitolisant was 11.7 at baseline, 4.6 at end-of-treatment, and 5.1 after a 1-week, placebo-washout period. Improvement in WRC was significantly greater with pitolisant versus placebo beginning at Week 2 (LS mean difference, -5.3; P=0.004) and continued through end-of-treatment (LS mean difference, -6.2; P&amp;lt;0.001); there was no evidence of rebound cataplexy after placebo-washout (LS mean difference, -4.9; P=0.027). Conclusion During pitolisant treatment, improvement in EDS occurred sooner (within first few weeks) and was more robust in studies that permitted titration to the maximum recommended dose (35.6 mg/day). The rate of cataplexy attacks decreased early during treatment, with no evidence of rebound when pitolisant was withdrawn. Support Bioprojet Pharma and Harmony Biosciences, LLC.

Aortic and superior mesenteric artery embolectomy after paradoxical embolism

After recent revisional surgery for lumbosacral fusion, a 49-year-old woman presented to the emergency department with sudden-onset epigastric pain with nausea and vomiting. The patient's abdomen was soft, with mild diffuse tenderness without distention or evidence of rebound or guarding.

Relationships between play and responses to tickling in male juvenile rats

Play is a putatively positive experience and of key interest to the study of affective state in animals. Rats produce 50 kHz ultrasonic vocalisation (USVs) during positive experiences, including social play and tickling. The tickling paradigm is intended to mimic social play resulting in positively valanced ultrasonic vocalisation (USV) production. We tested two hypotheses on the relationship between tickling and play: that tickling would increase play behaviour or that play behaviour would increase in anticipation of tickling, and that tickling would share some specific properties of play (rebound and emotional contagion of unexposed cage mates). Male Wistar rats (N = 64, with 32 rats/cohort) of 28 days of age were housed in pairs with one rat assigned to be tickled and one as the non-tickled control. Production of 50 kHz USVs and hand-following behaviour was measured. Prior to handling, solitary and social play was recorded for 5 min in the home cage. A two-day break in tickling was used to assess a potential rebound increase in responses to tickling. Only one rat within each cage was handled to assess emotional contagion through changes in the behaviour of the cage-mate. Solitary but not social play increased prior to tickling relative to controls (p = 0.01). There were marked differences between cohorts; tickled rats in C2 produced less 50 kHz USVs than those in C1 (p = 0.04) and overall, C2 rats played less than rats in C1 (social p = 0.04 and solitary p < 0.001) and had a lighter start weight on arrival (p = 0.009) compared with cohort 1 (C1). In C1, there was evidence of rebound in USV production (p < 0.001) and a contagious effect of tickling reflected by increased hand-following in cage mates (p = 0.02). We found a positive relationship between start weight and USV responses to tickling (Rs = 0.43, p < 0.001), suggesting that the divergence in USV production may be due to developmental differences between cohorts. The results suggest that the relationship between tickling and play is complex in that tickling only affected solitary and not social play, and that tickling responses showed rebound and contagion effects on cage-mates which were specific to cohort responses to tickling.

Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial

Results from a previous phase 3 study showed efficacy of the RTS,S/AS01 vaccine against severe and clinical malaria in children (in 11 sites in Africa) during a 3-4-year follow-up. We aimed to investigate malaria incidence up to 7 years postvaccination in three of the sites of the initial study. In the initial phase 3 study, infants aged 6-12 weeks and children aged 5-17 months were randomly assigned (1:1:1) to receive four RTS,S/AS01 doses (four-dose group), three RTS,S/AS01 doses and a comparator dose (three-dose group), or four comparator doses (control group). In this open-label extension study in Korogwe (Tanzania), Kombewa (Kenya), and Nanoro (Burkina Faso), we assessed severe malaria incidences as the primary outcome for 3 additional years (January, 2014, to December, 2016), up to 6 years (younger children) or 7 years (older children) postprimary vaccination in the modified intention-to-treat population (ie, participants who received at least one dose of the study vaccine). As secondary outcomes, we evaluated clinical malaria incidences and serious adverse events. This trial is registered with ClinicalTrials.gov, number NCT02207816. We enrolled 1739 older children (aged 5-7 years) and 1345 younger children (aged 3-5 years). During the 3-year extension, 66 severe malaria cases were reported, resulting in severe malaria incidence of 0·004 cases per person-years at risk (PPY; 95% CI 0-0·033) in the four-dose group, 0·007 PPY (0·001-0·052) in the three-dose group, and 0·009 PPY (0·001-0·066) in the control group in the older children category and a vaccine efficacy against severe malaria that did not contribute significantly to the overall efficacy (four-dose group 53·7% [95% CI -13·7 to 81·1], p=0·093; three-dose group 23·3% [-67·1 to 64·8], p=0·50). In younger children, severe malaria incidences were 0·007 PPY (0·001-0·058) in the four-dose group, 0·007 PPY (0·001-0·054) in the three-dose group, and 0·011 PPY (0·001-0·083) in the control group. Vaccine efficacy against severe malaria also did not contribute significantly to the overall efficacy (four-dose group 32·1% [-53·1 to 69·9], p=0·35; three-dose group 37·6% [-44·4 to 73·0], p=0·27). Malaria transmission was still occurring as evidenced by an incidence of clinical malaria ranging from 0·165 PPY to 3·124 PPY across all study groups and sites. In older children, clinical malaria incidence was 1·079 PPY (95% CI 0·152-7·662) in the four-dose group, 1·108 PPY (0·156-7·868) in the three-dose group, and 1·016 PPY (0·14-7·213) in the control group. In younger children, malaria incidence was 1·632 PPY (0·23-11·59), 1·563 PPY (0·22-11·104), and 1·686 PPY (0·237-11·974), respectively. In the older age category in Nanoro, clinical malaria incidence was higher in the four-dose (2·444 PPY; p=0·011) and three-dose (2·411 PPY; p=0·034) groups compared with the control group (1·998 PPY). Three cerebral malaria episodes and five meningitis cases, but no vaccine-related severe adverse events, were reported. Overall, severe malaria incidence was low in all groups, with no evidence of rebound in RTS,S/AS01 recipients, despite an increased incidence of clinical malaria in older children who received RTS,S/AS01 compared with the comparator group in Nanoro. No safety signal was identified. GlaxoSmithKline Biologicals SA.

A Phase III Skin Cancer Chemoprevention Study of DFMO: Long-term Follow-up of Skin Cancer Events and Toxicity

Decreasing the incidence of nonmelanoma skin cancer (NMSC) is of great importance in regards to future healthcare services. Given the previously reported preventive effects of α-difluoromethylornithine (DFMO) in skin and colon cancer trials, we determined appropriate cause to update the clinical data on the subjects from the recently reported randomized, double-blind, placebo-controlled phase III skin cancer prevention study of DFMO. Our intention was to retrospectively assess the further incidence of skin cancer, other malignancies, and adverse events of patients accrued to our phase III skin cancer prevention study of DFMO. Clinical records of 209 University of Wisconsin (UW) Health subjects were reviewed, and 2,092.7 person years of on study (884.3 person years) and poststudy (1,208.4 person years) follow-up for these patients were assessed for new NMSC events and recurrence rates from the on study period, the poststudy period, and the two study periods combined. No evidence of increased significant diagnoses or serious adverse events was observed in the DFMO participants. The initially observed, marginally significant reduction (P = 0.069) in NMSC rates for DFMO subjects relative to placebo continued without evidence of rebound. Event rates after discontinuation from study for total NMSCs (DFMO 0.236 NMSC/person/year, placebo 0.297, P = 0.48) or the subtypes of basal cell carcinomas (BCC; DFMO 0.179 BCC/person/year, placebo 0.190, P = 0.77) and squamous cell carcinomas (SCC; DFMO 0.057 SCC/person/year, placebo 0.107, P = 0.43) are listed. Follow-up data revealed a persistent but insignificant reduction in new NMSCs occurring in DFMO subjects without evidence of latent or cumulative toxicity relative to placebo subjects.

Assessment of rebound and relapse following ecallantide treatment for acute attacks of hereditary angioedema

Hereditary angioedema (HAE) is a rare genetic disease characterized by unpredictable and recurring attacks of angioedema. This study assessed potential attack rebound and relapse following treatment with ecallantide, a plasma kallikrein inhibitor approved for HAE attack treatment. Results were integrated from 2 double-blind, placebo-controlled studies of ecallantide treatment for HAE: EDEMA3-DB and EDEMA4. Symptoms were assessed by treatment outcome score (TOS), mean symptom complex severity (MSCS) score, and global response. Patients with improvement at 4 h post-dosing in all three measures followed by any sign of worsening at 24 h were considered to show potential rebound if worsening was beyond baseline or potential relapse if not beyond baseline. Likeliness of rebound or relapse was determined by the number of measures showing worsening and the magnitude of worsening. Patients receiving placebo who met the criteria for rebound/relapse were evaluated for descriptive comparison only. Significantly more ecallantide-treated patients (42 of 70) compared to placebo (26 of 71) showed improvement in three measures at 4 h and were thus eligible for rebound/relapse (P = 0.006). Of the nine ecallantide-treated patients with signs of worsening at 24 h, none were likely rebound, one was assessed as possible rebound, one as likely relapse, and two as possible relapse. No patient with potential rebound/relapse experienced new symptoms after dosing. Medical intervention was required in one ecallantide-treated patient. Ecallantide was efficacious for treating acute HAE attacks. Relapse was observed in a small proportion of patients, and there was little evidence of rebound.

Effect of glatiramer acetate on disease reactivation in MS patients discontinuing natalizumab

Multiple sclerosis (MS) patients discontinuing natalizumab are at risk of rebound of disease activity. In the present multi-center, open-label, non-randomized, prospective, pilot study, we tested whether treatment with glatiramer acetate (GA) is safe and effective after natalizumab in MS patients. The study was performed at academic tertiary medical centers. Forty active relapsing-remitting MS patients who never failed GA therapy and who discontinued natalizumab after 12-18months of therapy were enrolled. GA was initiated 4weeks after the last dose of natalizumab. 62.5% of patients were relapse-free 12months after GA initiation. Annualized relapse rate and time to relapse were significantly lower than before natalizumab. Notably, the frequency of relapses was significantly lower amongst those patients who had experienced ≤2 relapses the year before initiation of natalizumab therapy, compared with patients who had had three or more relapses. No evidence of rebound was observed in magnetic resonance imaging scans. Furthermore, Expanded Disability Status Scale and Multiple Sclerosis Functional Composite were stable in our patients, again suggesting that 12months of post-natalizumab-GA therapy is not associated with clinical deterioration. Following discontinuation of natalizumab, 12 months of therapy with GA is safe and well tolerated in MS patients. GA can reduce the risk of early reactivation/rebound of disease activity in this setting.

What happens when natalizumab therapy is stopped?

Evaluation of: O’Connor PW, Goodman A, Kappos L et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76(22), 1858–1865 (2011).Natalizumab is an α-4 integrin antagonist used for the treatment of relapsing multiple sclerosis (MS). Concerns with the drug have a risen owing to a heightened risk of progressive multifocal leukoencephalopathy, which has caused some physicians to interrupt or stop treatment altogether. The article under review evaluates the safety of natalizumab treatment interruption, including the rate and magnitude of the return of MS disease activity toward baseline levels by clinical and MRI measures. The investigators found that by 4–7 months after natalizumab treatment interruption, MS disease activity began to reach baseline levels, which is consistent with the known elimination kinetics of natalizumab. The duration of prior natalizumab exposure or alternate MS treatments during interruption was demonstrated to not affect return of disease activity. Despite nearly similar disease activity after natalizumab treatment, patients with highly active disease prior to treatment had a return of disease activity that was greater in magnitude when compared with those with less active disease. Most significantly, the study did not show evidence of rebound following natalizumab cessation. We agree with these conclusions, but note that a subgroup of MS patients may demonstrate highly active disease after natalizumab cessation.

Intermittent Preventive Treatment for Malaria Control Administered at the Time of Routine Vaccinations in Mozambican Infants: A Randomized, Placebo‐Controlled Trial

There is an urgent need to deploy and develop new control tools that will reduce the intolerable burden of malaria. Intermittent preventive treatment in infants (IPTi) has the potential to become an effective tool for malaria control. We performed a randomized, double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine (SP) treatment in 1503 Mozambican children. Doses of SP or placebo were given at 3, 4, and 9 months of age. The intervention was administered alongside routine vaccinations delivered through the Expanded Program on Immunization (EPI). Hematological and biochemical tests were done when infants were 5 months old. Morbidity monitoring through a hospital-based passive case-detection system was complemented by cross-sectional surveys when infants were 12 and 24 months old. IPTi was well tolerated, and no adverse events associated with SP were documented. During the first year of life, intermittent SP treatment reduced the incidence of clinical malaria by 22.2% (95% confidence interval [CI], 3.7%-37.0%; P=.020) and the rate of hospital admissions by 19% (95% CI, 4.0%-31.0%; P=.014). Although the incidence of severe anemia (packed cell volume of <25%) did not differ significantly between the 2 groups (protective effect, 12.7% [95% CI, -17.3% to 35.1%]; P=.36), there was a significant reduction in hospital admissions for anemia during the month after dosing for both the first and second dose. The serological responses to EPI vaccines were not modified by the intervention. IPTi with SP has been shown to moderately reduce the incidence of clinical malaria in Mozambican infants without evidence of rebound after stopping the intervention or of interactions with EPI vaccines. Its recommendation as a malaria control strategy in Mozambique needs to be balanced against the scarcity of affordable control tools and the burden of malaria in children.

Government report on third quarter of 2002 offers evidence of rebound from Lackluster 2001

Government report on third quarter of 2002 offers evidence of rebound from Lackluster 2001

Thought Suppression and Obsession-Compulsion

It was argued that obsession-compulsion might affect the consequences of thought suppression. A group of 35 female students who were first submitted to thought suppression and then to an expression instruction were compared with a group of 38 female students submitted twice to an expression instruction. The emotional character of a target story read by subjects was systematically varied between subjects, and obsession-compulsion was included as a third between-subjects factors. No evidence of rebound or of initial enhancement was found when reported story-related thoughts were compared across instructional conditions. There was an interaction between obsession-compulsion and initial instruction on attempts to avoid target thoughts during the first period. Contrary to expectations obsession-compulsion was related to fewer attempts at suppression in the suppression and more in the expression conditions. Similarly, there was a trend for obsession-compulsion to be related to more frequent target thoughts in the expression and less in the suppression conditions. These findings are discussed in relation to the role of perceived responsibility in obsession-compulsion for thought as a determinant of thought processes of obsessive-compulsive people.

Effects of the?-adrenoceptor antagonists acebutolol and metoprolol on sleep pattern in normal subjects

The effects of acute introduction and withdrawal of 2 new beta-adrenergic blockers, acebutolol and metoprolol, on sleep in normal subjects were investigated. Both the subjective effects of the drug and EEG sleep variables were determined during a baseline period with placebo and in relation to the drug. The results showed that neither drug had a significant effect on sleep pattern in normal subjects. However, a transient effect on certain sleep parameters was seen on the first night of drug administration, with complete return to baseline, on the following night without any evidence of rebound. Possible mechanisms to explain the central actions of beta-adrenergic blockers are briefly discussed.