Intolerable Side Effects Research Articles

Dapsone Ameliorates Colitis through TLR4/NF-kB Pathway in TNBS Induced Colitis Model in Rat

Crohn's disease (CD), a type of inflammatory bowel disease (IBD), emerges with severe gastrointestinal (GI) tract inflammation, sometimes known as hostile abdomen. Conventional treatment of CD has several limitations such as insufficient response to treatment, and intolerable side effects of drugs. In addition, the high cost of biologic drugs prevents patients from continuing their treatment. Dapsone showed vigorous anti-inflammatory effects on the skin diseases, lung diseases and inflammatory diseases of the nervous system. Hence, we decided to investigate the effect of dapsone on animal model of CD. In this study, colitis was induced by instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) 100 mg/kg. Rats were treated with daily gavage of dapsone (10, 12.5 and 20 mg/kg). Seven days after induction of colitis, specimens were collected for pathological and molecular assessments. Dapsone (12.5 and 20 mg/kg) preserved the histologic architecture of the colon and prevented crypts irregularity. Additionally, it decreased tissue edema and hindered inflammatory cells infiltration. Besides, all doses of dapsone decreased tissue concentration of tumor necrosis factor α (TNF-α) and interferon γ (INFγ). Western blot revealed that dapsone could attenuate inflammation via downregulation of toll-like receptor 4 (TLR4) and dephosphorylation of nuclear factor kB (NF-kB). Based on these findings, dapsone attenuates inflammation and decreases TNF-α and INF-γ in animal model of CD. It acts through TLR4/NF-kB pathway to exert these effects.

Personalized ECT: Much ado about nothing?

The discussion about whether or not to focus our attention on the ‘average’ ECT-treatment technique that suits the majority of our patients or tailor the treatment to the needs of individual patients is ongoing. The question is, however, whether the available evidence permits us to to offer treatment ‘à la tête du client’. The start of a treatment course can be personalized by choosing electrodeplacement (EP) (e.g. bilateral in case of a severe or life-threatening condition, when fast improvement prevails over cognitive impact), parameter selection (e.g. a shorter pulse-width in order to avoid cognitive side-effects), and a dosing strategy. A fixed-dose will lead to overdosing in some patients (causing side-effects) and under-dosing in others (delaying/decreasing response) (1) Adjusting an ongoing treatment-technique can be based on response, side-effects or on the quality of the elicited seizure (EEG). In case of inadequate response, the clinician can decide to switch EP or to increase dose. There is no consensus as to the number of sessions after which technique should be changed. In case of intolerable side-effects, parameter selection and/or EP can be adjusted. The evidence that is available to guide these steps is limited. There is some evidence for a relation between several EEG-characteristics and outcome. Thus, in the event of an inadequate seizure, changing the anesthetic regimen, optimizing ventilation, lengthening the anesthetic-ECT time-interval or increasing the stimulus dose, can be of help. 1. Sackeim et al. Treatment of the modal patient: does one size fit nearly all? J ECT 2001;17:219-222.DisclosureNo significant relationships.

Tolerability of cariprazine in the early stage of schizophrenia: A pooled, post-hoc analysis of 4 phase ii/iii double-blind placebo-controlled trials

IntroductionIn the early stage of schizophrenia (first 5 years), the most important clinical target besides symptom control is relapse prevention as each relapse significantly decreases the possibility of preferable long-term outcomes. Early discontinuation of antipsychotic medication due to intolerable side-effects is one of the most common causes of relapse.ObjectivesThis poster aims to present cariprazine’s tolerability in the early stage of schizophrenia.MethodsData from 4 randomized, double-blind, placebo-controlled trials (NCT00404573, NCT01104766, NCT01104779, NCT00694707) with similar design (1 week of wash out period, 6 weeks of treatment and 2-4 weeks of follow-up) were pooled. For the post-hoc analysis, patients with early stage of schizophrenia (defined as having a disease duration of less than 5 years) were extracted from the whole safety population, and approved doses of cariprazine (1.5-6.0 mg/day) were combined. Treatment-emergent adverse events (TEAEs) and discontinuation rates were analysed versus placebo.ResultsOverall, 169 placebo- (PBO) and 322 cariprazine-treated (CAR) patients were identified as having schizophrenia for less than 5 years. 67.7% cariprazine- and 56.2% placebo-treated patients reported at least one TEAE; most frequently insomnia (10.9 % CAR; 12.4% PBO), akathisia (9.6% CAR; 2.4% PBO) and extrapyramidal symptoms (9.3% CAR; 1.8% PBO). Discontinuation due to adverse events was reported in only 8.4% of cariprazine- and 14.8% of placebo-treated patients. Relapse occurred in 3.1% of cariprazine- and 5.3% of placebo-treated patients.ConclusionsCariprazine was generally well-tolerated in the early stage of schizophrenia; given the limitations of this analysis, additional research is warranted.Conflict of interestStudies were funded by Gedeon Richter Plc. and Allergan Plc (prior to its acquisition by AbbVie). Dombi, Acsai, Dr. Barabássy, Dr. Sebe, Dr. Laszlovszky, Dr Vass, Dr. Szatmári and Dr. Németh are employees of Gedeon Richter Plc., Dr. Earley and Dr. Patel a

Anti-Candida Activity of Pomegranate Peel Extract in Comparison with Curcumin Extract and their Synergism with Fluconazole and Nystatin

Background: Oropharyngeal candidiasis is an important sign that may reflect a serious systemic disease, especially in immunocompromised patients who face the intolerable side effects of the available antifungal drugs. This necessitates the development of safe and effective natural components. Objectives: to evaluate the in vitro activities of both pomegranate peel and curcumin extracts and to compare them with nystatin and fluconazole drugs against Candida species. As far as we know, this is the first study comparing between the antifungal potency of both extracts. Methodology: Different Candida species were isolated from patients with oropharyngeal candidiasis. The antifungal activities of methanolic extracts of pomegranate peel and curcumin were tested by disc diffusion method. Both extracts were added to each of nystatin and fluconazole discs to measure their synergistic effects. Results: Highly significant synergism was detected between both extracts and each of antifungal drugs. Curcumin extract was more potent than pomegranate extract. Conclusion: When used in combination with nystatin and fluconazole, curcumin and pomegranate peel extracts are promising and effective anti-Candida agents.

Neuromodulation techniques for cancer pain management.

Advanced pain management techniques may be indicated in 5-15% of cancer patients. Despite this, a recent review identified that, over the course of 1 year in England, only 458 patients received a procedure intended to provide analgesia and only 30 patients had intrathecal drug delivery (ITDD) devices implanted. This article describes the emerging evidence for ITDD in cancer pain and provides a narrative review of other neuromodulatory techniques (including spinal cord stimulation, peripheral nerve stimulation and acupuncture), approaches that might be employed to address this area of significant unmet clinical need. Numerous studies have been published within the last year reporting positive outcomes associated with ITDD in cancer pain management. Neuromodulation represents an important strategy in the management of persistent pain. Whilst the nonmalignant pain evidence-base is rapidly growing, it remains sparse for cancer pain management. The growing cohort of cancer survivors may significantly benefit from neuromodulatory techniques. ITDD and other neuromodulatory techniques for cancer pain management appear underutilised in the UK and offer the prospect of better treatment for cancer patients with refractory pain or intolerable side-effects from systemic analgesics.

Practical Aspects of Transitioning from Intravenous to Subcutaneous Immunoglobulin Therapy in Neuromuscular Disorders.

Recent evidence shows that subcutaneous immunoglobulin (SCIG) is as efficacious as intravenous immunoglobulin (IVIG) and has a better safety profile and acceptance rate among patients with neuromuscular disorders who require maintenance IVIG treatment. Awareness of the practical aspects of patient selection, enrollment, dose calculation, administration, and follow-up would help physicians coordinate a smooth and seamless transition from IVIG to SCIG. SCIG is ideally offered to patients having intolerable side effects during IVIG or wearing-off effect and in those keen for treatment autonomy. The weekly dose of SCIG is calculated by multiplying the maintenance dose of IVIG by the dose adjustment factor and dividing by the interval between IVIG in weeks and is initiated 1 week after the last dose of IVIG. The physician places the order for the SCIG and the clinic nurse or the physician refers the patient to the home care nursing program for further education and training. The necessary supplies are dispatched to the patient who would also collect the SCIG from the transfusion center of the nearest hospital. The patient is educated on assembling and administering the infusion, and home visits are continued until the patient or caregiver is confident. Regular follow-up with the patient is maintained to assess treatment response and side effects if any. With a smooth transition, most patients have excellent tolerance to SCIG and in our experience seldom request switching back to IVIG. Transitioning patients from IVIG to SCIG offers several advantages and thus, in general, is preferable for multiple stakeholders.

Acceptability of immediate postpartum and post-abortion long-acting reversible contraception provision to adolescents: A systematic review.

Long-acting reversible contraception (LARC) methods are safe for adolescents and provide the greatest assurance against rapid repeated pregnancy when inserted during the immediate postpartum (IPP) and immediate post-abortion (IPA) period. Despite increasing enthusiasm for IPP/IPA LARC insertion, adolescents' preferences and experiences have seldom been examined. The objective of this review was to examine the attitudes of adolescents (aged 10-19years) towards IPP/IPA LARC, their experiences and perceptions around having an LARC device fitted IPP/IPA and the factors involved in decision-making to use, not use or discontinue IPP/IPA LARC. In January 2021, we searched seven bibliographic databases for original research articles published in English, from the year 2000. Studies of any design focused on IPP/IPA LARC were eligible for inclusion. Three of the authors assessed articles for eligibility and extracted data relevant to the outcomes of the review. Joanna Briggs Institute Critical Appraisal Tools were used to assess methodological quality. Key themes emerging from the data were synthesized and reported narratively. We identified 10 relevant articles, four of which were entirely adolescent-focused. Only three addressed IPA LARC. IPP availability was important for ensuring access to LARC postpartum. Attitudes towards LARC IPP were associated with adolescents' sociodemographic characteristics and positive perceptions related to the long duration of action. Determinants of discontinuation and nonuse included poor-quality contraceptive counseling, intolerable side effects and subsequent distress, misconceptions about LARC safety IPP and the influence of partners and community on autonomy. No factors involved in IPA LARC decision-making were available. Limited evidence demonstrated that adolescents may favor contraceptive implants over intrauterine devices, and in certain contexts may face greater barriers to IPA LARC access than adult women do. Immediate insertion of LARC postpartum appears acceptable to adolescents who do not experience side effects and those with the opportunity to make autonomous contraception decisions. This important topic has been addressed in few studies involving an entirely adolescent population. Very limited evidence is available on IPA LARC. Further research on adolescents' lived experiences of IPP/IPA LARC access and use is necessary to inform the provision of person-centered care when assisting adolescents' contraceptive choice following pregnancy.

Metformin Treatment of Pediatric Obesity.

* Abbreviations: FDA — : US Food and Drug Administration RCT — : randomized controlled trial T2DM — : type 2 diabetes mellitus Childhood obesity has steadily become a contemporary epidemic with serious public health implications.1 Approximately 70% of children with obesity will remain obese in adulthood.2 Obesity is a risk factor for development of atherosclerosis and type 2 diabetes mellitus (T2DM),3 and its prevention and management represents a priority for pediatric primary care providers. This underscores the need for evidence-based interventions for children and adolescents with obesity, including pharmacotherapy.4 Metformin is US Food and Drug Administration (FDA) approved for use in children 10 years of age and older with T2DM and has been used off label to achieve weight loss in children. In the current issue of Pediatrics , Masarwa et al5 present a systematic review of the safety and efficacy of metformin use from randomized controlled trials (RCTs) in children and adolescents. The authors demonstrated that metformin therapy resulted in modest benefits in reduction of BMI in those with obesity. Among the 14 RCTs in which BMI was reported, metformin was modestly efficacious at decreasing BMI (range of mean changes: −2.70 to 1.30) compared with a placebo (−1.12 to 1.90). As pointed out by the authors, the results across the studies were heterogeneous, with 11 RCTs suggesting that it decreased BMI, whereas 3 RCTs revealed an increase in BMI. Among the 7 RCTs in which a BMI z score was reported, metformin consistently resulted in a decrease … Address correspondence to Vandana Raman, MD, Division of Endocrinology, Department of Pediatrics, University of Utah School of Medicine, 81 N Mario Capecchi Dr, Salt Lake City, UT 84113. E-mail: vana.raman{at}hsc.utah.edu

Topical Mastic Oil for Treatment of Functional Dyspepsia: A Randomized , Triple-Blind Controlled Trial

Background: The main goal of the present study was to evaluate the effect of topical mastic oil, compared to placebo on treatment of functional dyspepsia (FD). Materials and Methods: Sixty-three patients with FD were included. Thirty-two subjects received the topical mastic oil (10 drops/TDS after meal) with massage and 31 patients received topical sesame oil with massage. Both groups received pantoprazole (40 mg daily) along with oil and massage. The severity of early satiation, postprandial fullness, epigastric pain and epigastric burning was assessed after 4 weeks using the Visual Analogue Scale (VAS) as well as frequency of symptoms. Satisfaction with the treatment was also assessed using a researcher-made questionnaire. Changes in the severity of symptoms were evaluated by Friedman’s test. Results: Mean and standard deviation of age of the subjects were equal to 36.95±13.64 and 50 (79.4%) patients were female. Both groups experienced a significant decrease in the severity of all the four symptoms (P<0.001). The percentage of decrease in the severity of early satiation was significantly higher in the mastic group than the control group (76.03±34.91% vs. 37.24±38.86%, P=0.003). No significant differences were found in the percentage of decrease in the severity of postprandial fullness, epigastric pain and burning between the study groups (P=0.05, 0.06, and 0.13, respectively). The frequency of symptoms was decreased similarly in both groups. Satisfaction with the treatment was reported to be significantly higher in the mastic group than the sesame group (P=0.01). There were no intolerable side effects in both groups. Conclusion: Mastic oil reduced early satiation better than the placebo. In addition, satisfaction with the treatment was higher in the mastic group than the sesame group. [GMJ.2021;10:e1965]

Topical Mastic Oil for Treatment of Functional Dyspepsia: A Randomized , Triple-Blind Controlled Trial

Background: The main goal of the present study was to evaluate the effect of topical mastic oil, compared to placebo on treatment of functional dyspepsia (FD). Materials and Methods: Sixty-three patients with FD were included. Thirty-two subjects received the topical mastic oil (10 drops/TDS after meal) with massage and 31 patients received topical sesame oil with massage. Both groups received pantoprazole (40 mg daily) along with oil and massage. The severity of early satiation, postprandial fullness, epigastric pain and epigastric burning was assessed after 4 weeks using the Visual Analogue Scale (VAS) as well as frequency of symptoms. Satisfaction with the treatment was also assessed using a researcher-made questionnaire. Changes in the severity of symptoms were evaluated by Friedman’s test. Results: Mean and standard deviation of age of the subjects were equal to 36.95±13.64 and 50 (79.4%) patients were female. Both groups experienced a significant decrease in the severity of all the four symptoms (P<0.001). The percentage of decrease in the severity of early satiation was significantly higher in the mastic group than the control group (76.03±34.91% vs. 37.24±38.86%, P=0.003). No significant differences were found in the percentage of decrease in the severity of postprandial fullness, epigastric pain and burning between the study groups (P=0.05, 0.06, and 0.13, respectively). The frequency of symptoms was decreased similarly in both groups. Satisfaction with the treatment was reported to be significantly higher in the mastic group than the sesame group (P=0.01). There were no intolerable side effects in both groups. Conclusion: Mastic oil reduced early satiation better than the placebo. In addition, satisfaction with the treatment was higher in the mastic group than the sesame group. [GMJ.2021;10:e1965]

Patients with abrupt early-onset OCD due to PANS tolerate lower doses of antidepressants and antipsychotics

ObjectiveTo characterize drug tolerability in pediatric patients with an abrupt-onset of obsessive-compulsive disorder (OCD) meeting criteria for pediatric acute-onset neuropsychiatric syndrome (PANS). MethodsWe reviewed charts of 188 consecutive patients with PANS seen in the PANS clinic, collecting starting, side effect, and tolerated doses, as well as side effect profile for each antidepressant and antipsychotic trial. ResultsOf 188 included patients: 57% had trials of antidepressants and/or antipsychotics. Patients prescribed psychotropics were older at PANS onset (mean 9.5 vs 7.1 years, p < 0.01) and had had a longer delay before presenting to clinic (median 1.4 vs 0.5 years, p < 0.01). Antidepressant indications (n = 146) were OCD (48%), anxiety (44%), and depression (32%). Antipsychotic indications (n = 119) were aggression (34%), psychotic symptoms (28%), and OCD (24%). Side effects requiring medication change occurred in 54% of patients: in 38% of antidepressant trials and 49% of antipsychotic trials. Antidepressants' most common side effects were anxiety, agitation, aggression, and akathisia. Antipsychotics’ most common side effects were dystonia, aggression, self-injurious behavior, and movement abnormality. Side effects were common at doses lower than the suggested starting doses for these medications. Patients tolerated antidepressants and antipsychotics when doses were low. ConclusionWhen antidepressants and antipsychotics are prescribed to patients with PANS, intolerable side effects were noted at doses lower than or equal to suggested starting doses. Patients with PANS can benefit from these therapies. However, when treating these patients, clinicians are advised to start with significantly lower doses than they might use in other disorders.

Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosis.

Tuberculosis is a highly prevalent infectious disease with more than 1.5 million fatalities each year. Antibiotic treatment is available, but intolerable side effects and an increasing rate of drug-resistant strains of Mycobacterium tuberculosis (Mtb) may hamper successful outcomes. Antimicrobial peptides (AMPs) offer an alternative strategy for treatment of infectious diseases in which conventional antibiotic treatment fails. Human serum is a rich resource for endogenous AMPs. Therefore, we screened a library generated from hemofiltrate for activity against Mtb. Taking this unbiased approach, we identified Angiogenin as the single compound in an active fraction. The antimicrobial activity of endogenous Angiogenin against extracellular Mtb could be reproduced by synthetic Angiogenin. Using computational analysis, we identified the hypothetical active site and optimized the lytic activity by amino acid exchanges. The resulting peptide-Angie1-limited the growth of extra‐ and intracellular Mtb and the fast-growing pathogens Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Toward our long-term goal of evaluating Angie1 for therapeutic efficacy in vivo, we demonstrate that the peptide can be efficiently delivered into human macrophages via liposomes and is not toxic for zebrafish embryos. Taken together, we define Angiogenin as a novel endogenous AMP and derive the small, bioactive fragment Angie1, which is ready to be tested for therapeutic activity in animal models of tuberculosis and infections with fast-growing bacterial pathogens.

Erenumab Versus Topiramate for the Prevention of Migraine – A Randomised, Double-Blind, Active-Controlled Phase 4 Trial

Background: Migraine prophylaxis with oral medications is often compromised by intolerable side effects. We compared the tolerability and efficacy of erenumab, a monoclonal antibody binding to the calcitonin gene-related peptide (CGRP) receptor, to topiramate for migraine prophylaxis in adults. Methods: HER-MES was a 24-week, randomised, double-blind, double-dummy, controlled trial conducted in 82 sites in Germany. Patients with ≥ 4 migraine days per month who were naive to study drugs were randomly assigned (1:1) to either subcutaneous erenumab (70 or 140 mg/month) or oral topiramate at highest tolerated dose (50–100 mg/day). Randomisation and allocation were done via an interactive response system. Randomisation was stratified by monthly migraine days (MMD: 4–7, 8–14, ≥ 15). Masking was achieved by administration of matching placebo. Patients, investigators, and the sponsor were blinded to treatment.The primary endpoint was the proportion of patients who discontinued study medication due to an adverse event during the double-blind phase. Secondary efficacy endpoints included the proportion of patients that achieved at least a 50% reduction from baseline in MMD. The full analysis set (FAS) included all participants who received at least one dose of study drug. The HER-MES study is registered with ClinicalTrials.gov (NCT03828539). Findings: The study was conducted from February 22, 2019 to July 29, 2020. 777 patients were randomised and 95·1% completed the study. The FAS comprised 776 patients (388 in each group) of which 59·1% were naive to prophylaxis. In the erenumab group, 10·6% discontinued medication due to adverse events compared to 38·9% in the topiramate group (odds ratio, 0·19; 95% confidence interval [CI] 0·13 to 0·27; p<0·001). Significantly more patients achieved a ≥ 50% reduction in MMD from baseline with erenumab (55·4% vs. 31·2%). No new safety signals occurred. Interpretation: Erenumab demonstrated a favourable tolerability and efficacy profile compared to topiramate. Trial Registration: NCT03828539 Funding: Novartis. Declaration of Interests: Dr. Reuter reports other from Novartis, during the conduct of the study; personal fees and non-financial support from Amgen, personal fees from Abbvie, personal fees, non-financial support and other from Allergan, other from Alder, personal fees, non-financial support and other from Eli Lilly, personal fees and non-financial support from Medscape, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from StreaMedUp, personal fees and non-financial support from Teva Pharmaceutical, outside the submitted work; Ch. Sieder is an employee of Novartis Pharma; Dr. Ehrlich reports other from Novartis Pharma GmbH, during the conduct of the study; Dr. Gendolla reports, other from Novartis, during the conduct of the study; personal fees and non financial support from Allergan, personal fees and non-financial support and other from Eli Lilly, personal fees from Esanum , personal fees and non-financial support from Novartis, personal fees and non-financial support from Teva Pharmaceutical, Grunenthal ,Mundipharma and DGS outside the submitted work; Dr. Heinze reports personal fees from Novartis, during the conduct of the study; personal fees from Teva, personal fees from Ely Lilly, personal fees from Novartis, outside the submitted work; Ch. Sieder is an employee of Novartis Pharma; Dr. Hentschke reports other from Novartis Pharma , during the conduct of the study; Dr. Reuter reports other from Novartis, during the conduct of the study; personal fees and non-financial support from Amgen, personal fees from Abbvie, personal fees, non-financial support and other from Allergan, other from Alder, personal fees, non-financial support and other from Eli Lilly, personal fees and non-financial support from Medscape, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from StreaMedUp, personal fees and non-financial support from Teva Pharmaceutical, outside the submitted work; Dr. Ehrlich reports other from Novartis Pharma GmbH, during the conduct of the study. Ethics Approval Statement: Independent ethics committees at each trial centre approved the study protocol and its amendments.

Non-invasive cortical stimulation: Transcranial direct current stimulation (tDCS).

Transcranial direct current stimulation (tDCS) is a re-emerging non-invasive brain stimulation technique that has been used in animal models and human trials aimed to elucidate neurophysiology and behavior interactions. It delivers subthreshold electrical currents to neuronal populations that shift resting membrane potential either toward depolarization or hyperpolarization, depending on stimulation parameters and neuronal orientation in relation to the induced electric field (EF). Although the resulting cerebral EFs are not strong enough to induce action potentials, spontaneous neuronal firing in response to inputs from other brain areas is influenced by tDCS. Additionally, tDCS induces plastic synaptic changes resembling long-term potentiation (LTP) or long-term depression (LTD) that outlast the period of stimulation. Such properties place tDCS as an appealing intervention for the treatment of diverse neuropsychiatric disorders. Although findings of clinical trials are preliminary for most studied conditions, there is already convincing evidence regarding its efficacy for unipolar depression. The main advantages of tDCS are the absence of serious or intolerable side effects and the portability of the devices, which might lead in the future to home-use applications and improved patient care. This chapter provides an up-to-date overview of a number tDCS relevant topics such as mechanisms of action, contemporary applications and safety. Furthermore, we propose ways to further develop tDCS research.

Double-binding botulinum molecule with reduced muscle paralysis: Evaluation in in vitro and in vivo models of migraine

With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene–related peptide–targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain—binary toxin-AA (BiTox/AA)—cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.

Axillary Botulinum Toxin Injection for the Treatment of Moderate to Severe Hyperhidrosis

ABSTRACT Primary focal hyperhidrosis can cause lifelong distress in everyday activities. Some patients cannot adequately decrease excessive perspiration with over-the-counter or prescription-strength antiperspirants. Oral glycopyrrolate is an anticholinergic medication that can decrease perspiration but may also lead to intolerable systemic side effects. Botulinum toxin injected into the axilla provides immediate symptomatic relief that lasts for approximately 6 months. Offering patients botulinum toxin as a second-line agent for treatment-resistant axillary hyperhidrosis can markedly improve quality of life with minimal side effects.

“When it comes to time of removal, nothing is straightforward”: A qualitative study of experiences with barriers to removal of long-acting reversible contraception in Western Kenya

ObjectiveBarriers to removal of long-acting reversible contraception (LARC) threaten reproductive self-determination, but their influence on contraceptive behaviors is not well understood. We describe perspectives of women in Western Kenya concerning LARC removal barriers. Study designWe used a qualitative descriptive approach with conventional content analysis to analyze transcripts for content and themes from eight focus group discussions (n = 55 participants) and one client journey mapping workshop (n = 9 participants) with women ages 18–49 in Western Kenya who were currently using or had formerly used contraceptives. FindingsOur primary themes concerned women's experience of LARC removal barriers and the impact on their behaviors and attitudes towards contraception. Women described providers being unwilling to remove LARC, regardless of rationale (including expiration, seeking pregnancy, or experiencing intolerable side effects) or demanding unaffordable fees. Women were reluctant to try LARC for fear of having to use the method for its entire lifespan even if they did not like it. Women saw LARC removal barriers as increasing their risk of unintended pregnancy through non-replacement of expired devices and fostering distrust in the health system. ConclusionBarriers to LARC removal may discourage utilization of LARC and contraceptive services generally, which can undermine women's efforts to achieve reproductive self-determination. ImplicationsOur findings affirm the importance of timely LARC removal to ensure that family planning programs uphold women's reproductive autonomy.

Oral dydrogesterone vs. micronized vaginal progesterone gel for luteal phase support in frozen-thawed single blastocyst transfer in good prognosis patients

ObjectiveTo investigate the efficacy of oral dydrogesterone for luteal phase support (LPS) in modified natural cycle frozen-thawed embryo transfers (mNC-FET) compared to micronized vaginal progesterone (MVP) gel. MethodsThis was a randomized, single-center, parallel controlled trial conducted at an ART and Reproductive Genetics Centre within a private hospital between January and August 2019. A total of 134 women, aged below 38, were assigned randomly to receive oral dydrogesterone (n=67) or MVP (n=67) for LPS in mNC-FET. The primary outcome was ongoing pregnancy rate (OPR) and secondary outcomes were clinical pregnancy and miscarriage rates, patients’ satisfaction and tolerability of oral and vaginal progesterone. A questionnaire was developed to compare patient satisfaction and side effect profiles. ResultsThere was no significant difference in demographic features such as female age, body mass index, AMH levels and fresh cycle characteristics between two groups (p>0.05). When mNC-FET outcomes were compared, OPR was 68.7 % in MVP gel group and 71.6 % in the dydrogesterone group respectively percentage difference, -2.99; 95 % CI: -17.96, 13.10) Biochemical and clinical pregnancy rates and biochemical and clinical miscarriage rates were also similar between two groups. A significantly higher patient tolerability score was present in the dydrogesterone arm (4.09 ± 0.96 vs 3.36 ± 1.23, p=0.001). ConclusionOur results suggest that oral dydrogesterone provides similar ongoing pregnancy rates compared to MVP gel as a LPS in mNC FET. Since dydrogesterone is an effective and easy-to-use option with fewer intolerable side effects including vaginal irritation, vaginal discharge, and preventing sexual intercourse, it can be used as LPS in mNC FET.

Outcomes of Laparoscopic Redo Fundoplication in Patients With Failed Antireflux Surgery: A Systematic Review and Meta-analysis.

The aim of this meta-analysis was to summarize the current available evidence regarding the surgical outcomes of laparoscopic redo fundoplication (LRF). Although antireflux surgery is highly effective, a minority of patients will require a LRF due to recurrent symptoms, mechanical failure, or intolerable side-effects of the primary repair. A systematic electronic search on LRF was conducted in the Medline database and Cochrane Central Register of Controlled Trials. Conversion and postoperative morbidity were used as primary endpoints to determine feasibility and safety. Symptom improvement, QoL improvement, and recurrence rates were used as secondary endpoints to assess efficacy. Heterogeneity across studies was tested with the Chi-square and the proportion of total variation attributable to heterogeneity was estimated by the inconsistency (I2) statistic. A random-effect model was used to generate a pooled proportion with 95% confidence interval (CI) across all studies. A total of 30 studies and 2,095 LRF were included. The mean age at reoperation was 53.3 years. The weighted pooled proportion of conversion was 6.02% (95% CI, 4.16%-8.91%) and the meta-analytic prevalence of major morbidity was 4.98% (95% CI, 3.31%-6.95%). The mean follow-up period was 25 (6-58) months. The weighted pooled proportion of symptom and QoL improvement was 78.50% (95% CI, 74.71%-82.03%) and 80.65% (95% CI, 75.80%-85.08%), respectively. The meta-analytic prevalence estimate of recurrence across the studies was 10.71% (95% CI, 7.74%-14.10%). LRF is a feasible and safe procedure that provides symptom relief and improved QoL to the vast majority of patients. Although heterogeneously assessed, recurrence rates seem to be low. LRF should be considered a valuable treatment modality for patients with failed antireflux surgery.

Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine

With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene–related peptide–targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain—binary toxin-AA (BiTox/AA)—cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.