Vitamin B12 Deficiency in Patients Taking Metformin: Pathogenesis and Recommendations.

Metformin is a cornerstone therapy for type 2 diabetes mellitus due to its glucose-lowering efficacy and additional benefits such as reducing cardiovascular mortality. However, accumulating evidence suggests an association between long-term metformin use and vitamin B12 deficiency, which can lead to serious clinical consequences. This review aims to synthesize current knowledge on the pathogenesis, prevalence, clinical implications, and management of metformin-induced vitamin B12 deficiency. Given the significant clinical implications, it is crucial to monitor and manage vitamin B12 levels in patients using metformin. This review emphasizes the importance of early detection and supplementation to prevent adverse outcomes. By analyzing the current evidence, the review aims to inform healthcare professionals about best practices for managing vitamin B12 deficiency in patients on metformin, offering insights to guide future clinical practices and research directions.

Parasomnias and sleep-related movement disorders induced by drugs in the adult population: a review about iatrogenic medication effects.

Parasomnias and sleep-related movement disorders (SRMD) are major causes of sleep disorders and may be drug induced. The objective of this study was to conduct a systematic review of the literature to examine the association between drug use and the occurrence of parasomnias and SRMD. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews, we searched PubMed databases between January 2020 and June 2023. The searches retrieved 937 records, of which 174 publications were selected for full-text screening and 73 drugs were identified. The most common drug-induced parasomnias were nightmares and rapid eye movement (REM) sleep behaviour disorders and sleepwalking. In terms of drug-induced SRMD, restless legs syndrome, periodic limb movement disorders (PLMD), and sleep-related bruxism were most frequent. Medications that inhibit noradrenergic, serotonergic, or orexin transmission could induce REM sleep (e.g., nightmares). Regarding sleepwalking, dysregulation of serotoninergic neurone activity is implicated. Antipsychotics are mentioned, as well as medications involved in the gamma-aminobutyric acid (GABA) pathway. A mechanism of desensitisation-autoregulation of GABA receptors on serotoninergic neurones is a hypothesis. SRMD and PLMD could involve medications disrupting the dopamine pathway (e.g., antipsychotics or opioids). Opioids would act on mu receptors and increase dopamine release. The role of adenosine and iron is also hypothesised. Regarding bruxism, the hypotheses raised involve dysregulation of mesocortical pathway or a downregulation of nigrostriatal pathway, related to medications involving dopamine or serotonin. Parasomnias are rarely identified in drug product labels, likely due to the recent classification of their diagnoses. An analysis of pharmacovigilance data could be valuable to supplement existing literature data.

Reducing Radiation Dermatitis for PBS Proton Therapy Breast Cancer Patients Using SpotDelete.

Purpose: The purpose of this work was to reduce the severity of radiation dermatitis for breast cancer patients receiving pencil beam scanning proton therapy. The hypothesis was that eliminating proton spots (SpotDelete) in the 0.5 cm skin rind would reduce the potentially higher relative biological effectiveness (RBE) known to occur at the Bragg Peak. Patients and Methods: Our center has been using an in-house developed Python script in RayStation since 2021 to remove spots from the skin rind of breast patients. In this work, we retrospectively reviewed the on-treatment visit data from a cohort of breast patients treated with hypofractionation (16 fractions) before this technique (MinDepth) and after (SpotDelete) to acquire the physician-reported radiation dermatitis scores. We evaluated the delivered treatment plans, calculating the linear energy transfer (LET) and applying 3 variable RBE models, Carabe-Fernandez, Wedenberg, and McNamara. An α/ß of 10 was assumed for the skin. Results: In the MinDepth cohort (n = 28), grade 1, 2, and 3 dermatitis accounted for 57%, 36%, and 7% of the cases, respectively. For SpotDelete (n = 27), the incidence rate of grade 1 and 2 acute radiation dermatitis was 67% and 37%, respectively. There were 0 instances of grade 3 dermatitis observed in the SpotDelete cohort. The onset of radiation dermatitis in the SpotDelete cohort was delayed compared to MinDepth, occurring 1 week later in the course of treatment. There was no significant difference in LET or in any of the variable RBE models when analyzing the 0.5 cm skin rind between the cohorts. Conclusion: Despite the lack of correlation in LET or RBE, SpotDelete has been shown to reduce the severity and onset of radiation dermatitis. Possibly, more research into the α/ß for skin and RBE models based on skin cell lines could provide insight into the efficacy of the SpotDelete technique.

Switching a combination of first- and second-generation antipsychotic polypharmacy to antipsychotic monotherapy in long-term inpatients with schizophrenia and related disorders. The SwAP trial II: Results on side effects.

OBJECTIVE: This study examined the effects of switching antipsychotic polypharmacy (APP) to antipsychotic monotherapy (APM) on various side effects in inpatients with schizophrenia. Side effects of interest included psychic, autonomic, and sexual symptoms, as well as metabolic side effects and movement disorders. METHOD: A 9-month parallel randomized open-label clinical trial was conducted involving 136 chronic inpatients from two psychiatric hospitals in the Netherlands. Participants were randomly assigned to either a STAY or a SWITCH group. The SWITCH group underwent a 3-month tapering-off period in which either first-generation or second-generation antipsychotic medication was discontinued, followed by APM. Patients were assessed at baseline and at follow-up assessments at 3, 6, and 9 months. Psychic, neurological, autonomic, and sexual side effects were evaluated using the UKU Rating Scale, while movement disorders were measured with the St. Hans Rating Scale. Various metabolic parameters were also recorded. RESULTS: In the STAY group, side effects remained generally stable over time, except for a slight reduction in sexual desire. In contrast, the SWITCH group experienced significant reductions in psychic and autonomic symptoms, as well as improvements in akathisia, parkinsonism, and dyskinesia. There were no changes in dystonia, paresthesia, epilepsy, or sexual symptoms for this group. Notably, the SWITCH group also showed significant reductions in BMI and body weight. CONCLUSION: Switching APP to APM in long-term inpatients reduces the severity of various side effects, including movement disorders and metabolic side effects.

Patient-reported outcomes in CodeBreaK 200: Sotorasib versus docetaxel for previously treated advanced NSCLC with KRAS G12C mutation.

BACKGROUND: In the CodeBreaK 200 phase III, open-label trial, sotorasib significantly improved efficacy versus docetaxel in previously treated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Patient-reported outcomes (PROs) for global health status, physical functioning, dyspnea, and cough favored sotorasib over docetaxel. Here, we report sotorasib's additional impact on quality of life (QOL). METHODS: In CodeBreaK 200, 345 patients who had progressed after prior therapy received sotorasib (960 mg orally daily) or docetaxel (75 mg/m2 intravenously every 3 weeks). Validated questionnaires captured patients' perception of their QOL and symptom burden for key secondary and exploratory PRO endpoints, including the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Quality-of-life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), question GP5 from the Functional Assessment of Cancer Therapy Tool General Form (FACT-G GP5), PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 5-level EuroQOL-5 dimensions (EQ-5D-5L) including visual analog scale (EQ-5D VAS). Change from baseline to week 12 was assessed with generalized estimating equations for ordinal outcomes. RESULTS: Patients receiving sotorasib were less bothered by treatment side effects than those receiving docetaxel (odds ratio [OR] 5.7) and experienced symptoms at lower severity (pain: OR 2.9; aching muscles: OR 4.4; aching joints: OR 4.2; mouth or throat sores: OR 4.3). Further, patients' symptoms interfered less with usual/daily activities (pain: OR 3.2; aching muscles: OR 3.9; aching joints: OR 10.7). QOL remained stable with sotorasib but worsened with docetaxel (change from baseline in EQ-5D VAS score: 1.5 vs -8.4 at cycle 1 day 5 and 2.2 vs -5.8 at week 12). CONCLUSIONS: Patients receiving sotorasib reported less severe symptoms than those receiving docetaxel. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel, suggesting sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS G12C-mutated advanced NSCLC.

Safety of remdesivir in the treatment of acute SARS-CoV-2 infection in pediatric patients.

BACKGROUND: Transaminase and creatinine elevations have been well described in adults treated with remdesivir for COVID-19. It is hypothesized that a similar safety profile exists in children with COVID-19 treated with remdesivir, but available data are limited, especially in children < 12 months. The primary aim of this study was to determine the prevalence and timing of elevations in transaminases and creatinine in children with COVID-19 who were treated with remdesivir. METHODS: This was a retrospective, observational cohort study including all pediatric patients admitted to a single, freestanding children's hospital who were positive for COVID-19 and received at least 1 dose of remdesivir between 1/1/2020 and 5/31/2022. Available baseline and peak transaminase and creatinine concentrations were evaluated. Multivariable logistic regression analysis was performed to identify risk factors for transaminase elevation. RESULTS: A total of 180 patients met inclusion criteria. Creatinine elevation of any grade was noted in 16% and remained elevated only in those with underlying chronic kidney disease. Transaminase elevation of any grade was noted in 58% of patients and remained elevated in only 1%. Older age and critical respiratory disease were associated with higher risk of significant transaminase elevation, whereas non-Hispanic ethnicity was strongly associated with protection against significant transaminase elevation. CONCLUSIONS: In our cohort of hospitalized children with COVID-19 who were treated with remdesivir, most patients experienced only mild transaminitis and normal creatinine concentrations. A limited number of patients experienced laboratory abnormalities which were transient, suggesting a favorable safety profile for remdesivir use in pediatrics.

Brivaracetam use in children with epilepsy: A retrospective multicenter study.

PURPOSE: This retrospective multicenter study aimed to assess the efficacy and safety of brivaracetam (BRV) in pediatric epilepsy. METHODS: Our cohort consisted of 93 children (mean age 11.5 ± 7.5 years) with a wide spectrum of pediatric epilepsy, including epileptic encephalopathy and generalized epilepsy. Of these, 61 (60.4%) were diagnosed with focal epilepsy, 19 (15.8%) with generalized epilepsy, and 16 (15.8%) with combined epilepsy, while 8 patients (7.9%) had an unknown epilepsy type. The cohort included rare epilepsy syndromes: 8 patients with Lennox-Gastaut syndrome, 3 with Dravet syndrome, and 1 with Rasmussen syndrome. Patients had a history of various antiseizure medications (ASMs) (6.42 ± 3.15), and on average, were being treated with more than two (2.57 ± 1.16) drugs at the time of BRV deployment. RESULTS: Retention rates were high, with 80.6% of patients adhering to treatment at 3 months, 66.7% at 6 months, and 45.2% at 12 months. In 29 patients (30.1%), BRV was added in an overnight switch from levetiracetam (LEV), resulting in a reduction of behavioral adverse effects (AEs) in 5 patients (17.2%). The response rate was 25.8% at 3 months, 16.1% at 6 months, and 17.2% at 12 months, with no responders in the epileptic encephalopathy group. Therapy tolerance was notable, with 70 patients (75.3%) reporting no AEs. Transient AEs occurred in 10 patients (10.7%), and in 13 cases (14.0%), the AEs warranted dose adjustment or discontinuation of BRV. CONCLUSION: Approximately one-fifth of pediatric patients with drug-resistant epilepsy responded to BRV, with the best response observed in patients with focal seizures. However, the impact on patients with epileptic encephalopathy was limited.

Wearing the mandibular advancement orthosis and dental movements: Contribution of a digital monitoring protocol.

OBJECTIVES: Oral appliance (OA) has been increasingly used for the treatment of obstructive sleep apnoea hypopnea syndrome (OSAHS). OAs work by propelling the mandible, increasing the upper airway calibre and reducing collapsibility. While they have shown efficacy in reducing OSAHS, long-term use can lead to adverse effects, such as dental displacement. The present study focuses on the impact on dental displacements of the NARVAL® computer-aided design and manufacturing OA from the ResMed laboratory. MATERIALS AND METHODS: The study included 39 patients aged 18 or older who were treated for OSAHS using OAs initiated between 2019 and 2021 and had initial digital dental impressions. A new digital print was taken for each patient using the TRIOS 4 Wireless intra-oral scanner from 3SHAPE. Dental displacement was measured using a 3D system's GEOMAGIC design X 3D reverse engineering software. The study analysed different blocks of teeth in both the maxillary and mandibular arches. Statistical analysis was conducted to determine the significance of dental displacements. RESULTS: Patients had been wearing the OA for an average of 2.5 years. The study found dental displacements in both the maxillary and mandibular arches. However, these displacements were not statistically significant. Qualitative analysis revealed palatoversion and vestibuloversion, while quantitative analysis showed minor dental displacements. CONCLUSION: This study on patients wearing the NARVAL® OA for an average of 2.5 years found dental displacements in both the maxillary and mandibular arches. However, these displacements were not statistically significant. The results suggest that the OA, designed using a complete digital workflow, did not significantly impact dental positions. To confirm the impact, further investigations with larger sample sizes, an exclusively digital protocol and a control group are required.

Enhanced browning of adipose tissue by mirabegron-microspheres.

Thermogenic brown adipose tissue (BAT) has emerged as an attractive target for combating obesity. However, pharmacological activation of energy expenditure by BAT and/or induction of browning of white adipose tissue (WAT) has been hampered by cardiovascular side effects. To address these concerns, we developed polylactide-co-glycolide acid (PLGA) microspheres loaded with mirabegron (MIR), a selective beta-3 adrenergic receptor (ADRB3) agonist, to achieve sustained local induction and activation of thermogenic adipocytes. MIR-loaded PLGA microspheres (MIR-MS) effectively activated brown adipocytes and enhanced the thermogenic program in white adipocytes. Moreover, treating isolated inguinal WAT (iWAT) with MIR-MS resulted in increased expression of browning markers and elevated lipolysis mainly via ADRB3. In mice, injection of MIR-MS over four weeks induced browning of iWAT at the injection site. Importantly, local MIR-MS injection successfully mitigated unwanted cardiovascular risks, including high systolic blood pressure (SBP) and heart rate, as compared to MIR-treated mice. Finally, injecting MIR-MS into human subcutaneous WAT led to a significant induction of lipolysis and an increase in the expression of thermogenic marker uncoupling protein 1 (UCP1). Taken together, our findings indicate that MIR-MS function as a local drug release system that induces browning of human and murine subcutaneous WAT while mitigating undesirable cardiovascular effects.

2024 KSoLA consensus on secondary dyslipidemia.

Elevated blood cholesterol and triglyceride levels induced by secondary causes are frequently observed. The identification and appropriate handling of these causes are essential for secondary dyslipidemia treatment. Major secondary causes of hypercholesterolemia and hypertriglyceridemia include an unhealthy diet, diseases and metabolic conditions affecting lipid levels, and therapeutic side effects. It is imperative to correct secondary causes prior to initiating conventional lipid-lowering therapy. Guideline-based lipid therapy can then be administered based on the subsequent lipid levels.

Trajectory of associative memory impairment during electroconvulsive therapy in depression.

Memory impairment is a serious cognitive side effect of electroconvulsive therapy (ECT) in the treatment of major depressive episodes (MDEs) and has garnered widespread attention in clinical practice, but its underlying evolution pattern during the course of ECT remains rarely understood in detail. Associative memory (AM) is a core indicator that reflects memory impairment in ECT. This study aimed to identify the dynamic trajectory of AM impairment and explore associated predictive factors. 405 intensive longitudinal AM data from 81 patients with MDE were collected at the baseline, after the first, third, fifth, and eighth ECT using five sets of face-cued word memory paradigms. Changes in AM score over time were analyzed using a linear mixed effects model. Trajectory subgroups and predictive factors were investigated using growth mixture model and logistic regression. AM score during ECT were significantly lower than at baseline, with the lowest scores observed after the eighth ECT session. Two trajectories of rapid (N = 56, 69.14%) and slow (N = 25, 30.86%) AM impairment were differentiated. Older female with lower education level were significant predictors contributing to more rapid memory impairment for ECT. The evolving pattern of associative memory impairment during ECT appears to occur early and worsen with subsequent treatment. This study may provide the important evidence understanding of the number effect of ECT sessions on memory impairment and suggest individual factors for predicting ECT memory outcome.

Deprescribing antidepressants for depression - what is the evidence for and against?

OBJECTIVE: Recent guidelines suggest that the overall quantity and duration of antidepressant prescriptions should be reduced. In this paper, we comment on the evidence both for and against this view. METHODS: We critically review the arguments proposed by proponents of antidepressant deprescribing in the context of the evidence-base for the treatment of depression. RESULTS: Proponents of deprescribing do not address the substantive issues of whether inappropriate prescribing has been demonstrated, and when prescribing is needed. Their arguments for deprescribing are rebutted in this context. CONCLUSIONS: Whether or not to deprescribe antidepressant medication needs to take into consideration the risk-benefit profile of the decision, the responsibility for which needs to be shared and based on the context of the patient's depression, their preferences, experiences and perspectives.

Pacing lead thrombus in patient with recent COVID-19 infection and subsequent vaccination: a case report.

Background: The association between acute coronavirus disease-19 (COVID-19) infection and a hypercoagulable state has been exhaustively described throughout the pandemic. The presence of external devices, such as intracardiac leads, could predispose to higher thrombotic risk in this setting. We present a clinical case of intracardiac thrombosis on right ventricle device that occurred after COVID-19 infection and subsequent vaccination. Case summary: A 56-year-old man, suffering from usual interstitial pneumonia-pattern fibrosis, was admitted to our hospital because of worsening of his clinical status. About 10 days earlier, he had got vaccinated for COVID-19. Three months earlier, the patient had been reported to have severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. A chest computed tomography scan showed thrombus partially occluding the left pulmonary artery. A transthoracic echocardiography and later a transoesophageal echocardiogram showed a mass adhered to the lead in the right ventricle, compatible with thrombosis, confirmed on a cardiac computed tomography scan. Blood tests showed no major changes except for a slight increase in D-dimer and fibrinogen. Therefore, the subject was treated with anticoagulants. Discussion: COVID-19 infection results in a hypercoagulable state with risk of developing thrombus diffusely, including intracardiac thrombosis. The presence of external devices, such as the intracardiac leads, may increase thrombotic risk since the presence of an external device in the bloodstream could trigger coagulation cascade. This case report highlights the need for special care in this patient setting, using specific imaging techniques for early and rapid diagnosis to optimize therapy.

Clozapine may consistently protect from suicidal behaviors while other antipsychotics may lack a specific protective effect: a comprehensive VigiBase study interpreted in the context of the prior literature.

BACKGROUND: In the United States, clozapine was first approved for treatment-resistant schizophrenia and then for suicidality in schizophrenia psychoses. Systematic reviews support clozapine's anti-suicidal effect, but the forensic literature stresses its lethality during overdoses. RESEARCH DESIGN AND METHODS: Clozapine reports to the international pharmacovigilance database (VigiBase) were analyzed for suicidal ideation, suicide attempts, intentional overdose, and completed suicides from introduction to 1 January 2024. VigiBase uses the information component (IC) as a disproportionality analysis. RESULTS: The clozapine ICs (range: other antipsychotics) were: 1) suicidal ideation IC = 0.570 with IC025 = 0.454 to IC975 = 0.680 (IC = 3.568 for aripiprazole and 1.729 for risperidone), 2) suicide attempt IC = 1.428 with IC025 = 1.323 to IC975 = 1.529 (IC = 4.150 for quetiapine and 2.968 for risperidone), 3) intentional overdose: IC = 0.995 with IC025 = 0.864 to IC975 = 1.120 (IC = 4.080 for quetiapine and 1.957 for aripiprazole), and 4) completed suicide IC = 1.133 with IC025 = 1.026 to IC975 = 1.235 (IC = 4.648 for quetiapine and 2.160 for risperidone). In summary, all clozapine ICs were significantly lower. We found 2391 clozapine-treated patients on the suicidality spectrum (627 cases with suicidal ideation, 752 with suicide attempt, 488 with intentional overdose, and 731 with completed suicide) but many were taking other antipsychotics. The most frequent reporting countries were the United States, the United Kingdom, and Croatia. CONCLUSION: This pharmacovigilance study, with all its inherent limitations, provides independent proof, not overlapping with prior literature, that clozapine may have specific strong anti-suicidal effects that do not appear to be present in other antipsychotics. Further VigiBase studies are needed to compare the lethality of an intentional overdose of clozapine (14.3%) with other antipsychotics.

Assessing Therapeutic Value and Side Effects of Key Botanical Compounds for Optimized Medical Treatments.

Due to the significance of variable chemical groups across a wide spectrum of modern medicine, it is imperative to determine what is the most widely used group in medical applications with the fewest side effects. Ten compounds from ten chemical groups that are most commonly known for their medical uses were compared in terms of their therapeutic potential and side effects. The comparison among the selected compounds indicated the superiority of the flavonoids over other groups in the multitude of their utilizations and the lower side effects. Kaempferol and quercetin showed higher medical utilization with lower side effects. Whereas alkaloid compounds showed the lowest levels of medical use and the highest levels of side effects. Based on the comparison conducted, it is concluded to give priority to flavonoid compounds being used in medical applications because they exhibit the highest medical uses with the lowest side effects. Within flavonoids, kaempferol and quercetin are the two compounds that are highly recommended to be used in the widest range of medical applications. Serious caution should be considered before applying alkaloids to any medical service. Understanding the characteristics of these compounds can aid in developing safer and more effective treatments for medicinal plants.

Quality of Life Outcomes in Breast Cancer Patients Receiving Chemotherapy With or Without Radiation Therapy.

PURPOSE: Understanding quality of life (QOL) implications of individual components of breast cancer treatment is important as systemic therapies continue to improve oncologic outcomes. We hypothesized that adjuvant radiation therapy does not significantly impact QOL domains in breast cancer patients undergoing chemotherapy. METHODS: Data was drawn from three prospective studies in women with localized breast cancer being treated with chemotherapy from March 2014 to December 2019. Patient-reported measures were collected at baseline (pretreatment) and post-treatment using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) measure, which consists of 5 subscales. Changes in mean QOL scores in patients who received radiotherapy were compared to those who did not using a one-sided noninferiority method. Statistical significance was determined below 0.05 to meet noninferiority. RESULTS: In a sample of 175 patients, 131 were treated with radiation and 44 had no radiation. The sample consisted mostly of stage I-II breast cancer (78%) with hormone receptor positive (59%) disease, receiving either neoadjuvant (36%) or adjuvant chemotherapy (64%). Mean change in QOL for the group treated with radiation compared to no radiation was noninferior with respect to Physical Well-Being (P = .0027), Social/Family Well-Being (P = .0002), Emotional Well-Being (P = .0203), FACIT-Fatigue Subscale (P = .0072), and the Total FACIT-F score (P = .0005); however, mean change in QOL did not meet noninferiority for Functional Well-Being (P = .0594). CONCLUSION: Patient-reported QOL from baseline to post-treatment, using the Total FACIT-F score, was noninferior in patients treated with versus without radiation therapy. This finding, in addition to individualized QOL subscales, provides important information in the informed decision-making process when discussing the effects of locoregional radiation on QOL in localized breast cancer patients treated with chemotherapy.

Sex-dependent responses to acute sodium bicarbonate different dose treatment: A randomized double-blind crossover study.

OBJECTIVES: This study quantified blood bicarbonate (HCO3-) kinetics and gastrointestinal upset to determine the gender-related ergogenic potential of sodium bicarbonate (0.15-, 0.25- and 0.35 gSB·kgFat-free mass (FFM)-1) in high intensity functional training. DESIGN: Double-blind randomized placebo-controlled crossover. METHODS: Thirty female and male athletes performed two bouts of the Wingate Anaerobic Test (WAnTPRE-HIFT and WAnTPOST-HIFT) interspaced with two 3-min bouts of Wall Balls and Burpees 120min after ingestion of three sodium bicarbonate doses. Blood HCO3- was determined pre-ingestion, after supplementation and before/post exercise. Gastrointestinal upset was evaluated 120min post-ingestion. Control (CTRL) measurements were performed. RESULTS: There were significant gender×treatment interactions for: changes in blood HCO3- at 60min post-ingestion (p=0.014; η2p=0.104; at 0.15gSB·kgFFM-1 males experienced higher increase than females); peak power (p=0.015; η2p=0.103) and average power (p=0.005; η2p=0.124) during WAnTPOST-HIFT, and changes in peak power between the Wingate Anaerobic Test bouts (p=0.049; η2p=0.081). Sodium bicarbonate compared to PLA had no significant impact on Wall Balls and Burpees performance. The dose of 0.35gSB·kgFFM-1 resulted in higher less severe gastrointestinal symptoms compared to CTRL and 0.15gSB·kgFFM-1 (p=0.001; W=0.178); and higher total gastrointestinal upset compared to CTRL, PLA and 0.15gSB·kgFFM-1 (p<0.001; W=0.323). CONCLUSIONS: There were dose- and gender-related differences in extracellular buffering capacity and ergogenic potential of sodium bicarbonate. The study suggested a detrimental impact of gastrointestinal upset on performance.

Identifying the psychological effects of nocebo education: results from two pre-registered experiments.

Providing treatment side effect information to patients increases the risk of harm due to the nocebo effect. Nocebo education, in which patients learn about nocebo effects, is a novel strategy that can be used across a variety of situations and individuals to decrease unpleasant treatment side effects. It is currently unclear which psychological changes are induced by nocebo education, which is information required to maximize this intervention. Two pre-registered studies investigated the effects of nocebo education on side effect expectations, side effect control beliefs, feelings toward treatments, intentions to avoid or seek side effect information, and perceptions of treatment efficacy. In Study 1 (N = 220), adult participants either watched or did not watch a nocebo education intervention video prior to reading vignettes about receiving a surgical treatment for pain and a medication for pain. Study 2 (N = 252) was similar to Study 1, with the inclusion of a health behavior video control group and participants only reading about a medication treatment for pain. In both experiments, nocebo education reduced global side effect expectations and increased side effect self-efficacy beliefs. Nocebo education also increased intentions to avoid side effect information and decreased intentions to seek more side effect information. Evidence was inconclusive on whether nocebo education changes affective associations with the treatments. The findings demonstrate that nocebo education has a multi-faceted influence with the potential to change patient behavior. The results can be used to improve the management of adverse treatment side effects.

Conorphin-66 produces peripherally restricted antinociception via the kappa-opioid receptor with limited side effects.

With the current unmet demand for effective pain relief, analgesics without major central adverse effects are highly appealing, such as peripherally restricted kappa-opioid receptor (KOR) agonists. In this study, Conorphin-66, an analog of the selective KOR peptide agonist Conorphin T, was pharmacologically characterized in a series of experiments, with CR845 serving as the reference compound. Firstly, in vitro functional assay indicated that Conorphin-66 selectively activates KOR and exhibits weak ß-arrestin2 signaling bias (-1.54 versus -4.35 for CR845). Additionally, subcutaneous Conorphin-66 produced potent antinociception in mouse pain models with ED50 values ranged from 0.02 to 3.28 µmol/kg, including tail-flick test, post-operative pain, formalin pain, and acetic acid-induced visceral pain. Similarly, CR845 exert potent antinociception in mouse pain models ranged from 0.15 to 1.47 µmol/kg. Notably, antagonism studies revealed that the analgesic effects of Conorphin-66 were mainly mediated by the peripheral KOR. Furthermore, Conorphin-66 produced non-tolerance-forming antinociception over 8 days. Unlike CR845, subcutaneous Conorphin-66 did not promote the sedation, anxiogenic effects, depressive-like effects, but did exhibit diuretic activity. Further study showed that Conorphin-66 does not have apparent antipruritic effects in an acute itch model. Overall, Conorphin-66 emerges as a novel peripherally restricted KOR agonist that produced potent antinociception with reduced side effects.