Moderate Adverse Effects Research Articles

A mediation analysis of the relationship between land use regulation stringency and employment dynamics

ABSTRACT The paper examines the effects of stringent land use regulations, measured using the Wharton Residential Land Use Regulatory Index (WRLURI), on employment growth during the period 2010–2020 in the Retail, Professional, and Information sectors across 878 local jurisdictions in the United States. All the local jurisdictions exist in both (2006 and 2018) waves of the WRLURI surveys and hence constitute unique panel data. We apply a mediation analytical framework to decompose the direct and indirect effects of land use regulation stringency on sectoral employment growth and specialization. Our analysis suggests a fully mediated pattern in the relationship between excessive land use regulations and employment growth, with housing cost burden as the mediator. Specifically, a one standard deviation increase in the WRLURI index is associated with an approximate increase of 0.8 percentage point in the proportion of cost burdened renters. Relatedly, the higher prevalence of cost-burdened renters has moderate adverse effects on employment growth in two sectors. A 1 percentage point increase in the proportion of cost burdened renters is associated with 0.04 and 0.017 percentage point decreases in the Professional and Information sectors, respectively.

Cannabis, cannabinoids and health: a review of evidence on risks and medical benefits

AbstractThe legalization of cannabis for medical and recreational purposes has progressed internationally. Cannabis and cannabinoids are advocated for a plethora of medical indications. An increasing number of medical and nonmedical users regularly consume large doses of delta-9-Tetrahydrocannabinol (THC), the main active component of cannabis. Aim: to summarize the evidence on (1) risks of recreational cannabis use and (2) effectiveness and safety of medicinal cannabis. Findings on recreational use: Cannabis is mostly used to experience its acute rewarding effects. Regular use of high THC products can produce addiction (cannabis use disorder or CUD). Acute consumption of high THC doses (including unintentionally) can cause time-limited mental, gastrointestinal, and cardiovascular problems and motor vehicle accidents. Chronic patterns of cannabis use have been associated with multiple adverse outcomes that are of particular concern among adolescents and young adults, such as, disrupted learning, impaired cognitive performance, reduced educational attainment and an increased risk of CUD, psychosis/schizophrenia, mood and anxiety disorders and suicidal behaviors. There is debate about the extent to which cannabis use is a cause of these adverse outcomes. Physical health risks (e.g., respiratory and cardiovascular, prematurity and restricted fetal growth, hyperemesis syndrome among others) have also been linked with repeated consumption of cannabis with a high THC content. Findings on medical cannabis use: Herbal cannabis, medicines from extracted or synthetized cannabinoids—often used as adjuvants to standard medicines—may produce small to modest benefits. This is primarily the case in treating chronic pain, muscle spasticity, chemotherapy-induced nausea and vomiting, and refractory epilepsy (in the case of cannabidiol, CBD). The evidence is inconclusive on their value in treating mental disorders and other medical conditions. Safety: Cannabis-based medicine is generally well tolerated. There is a risk of mild to moderate adverse effects and CUD.

Side effects of five products largely used by humans and studied on ants as models: a mini review

Here we summarize our recent studies on the physiological and behavior effects of five products widely used by humans, using an ant, having received these substances in their usual diet, as a biological model. Nutmeg is a spice which decrease the activity and movement speed of the ants, leading to further motor-linked impairments, but not impairing other behavioral traits as well as learning and memory. Vortioxetine (Brintellix) is an anti-depressant recently appearing reducing obesity and having moderate adverse effects in humans. It negatively affected the ants’ food intake, general activity, tactile sensitivity, state of stress and cognition. Berberine is a supplementary dietary regulating, in humans, glucosemia and several parameters. In ants, food intake, general activity, tactile sensitivity, were also negatively impacted, but not their state of stress and cognition. Cashew nuts and mangoes may have similar allergenic effects in humans. In ants, cashew consumption induces sinuosity of movement, stress and nervousness while mango consumption reduces their general activity and behaviors related to motor activity. The correspondence between dependence to a substance, short duration of its effect after withdrawal and abrupt loss of its effect is discussed.

Gastric cancer prevention by community eradication of Helicobacter pylori: a cluster-randomized controlled trial.

Gastric cancer is a leading cause of cancer-related deaths in China. Affecting more than 40% of the world's population, Helicobacter pylori is a major risk factor for gastric cancer. While previous clinical trials indicated that eradication of H. pylori could reduce gastric cancer risk, this remains to be shown using a population-based approach. We conducted a community-based, cluster-randomized, controlled, superiority intervention trial in Linqu County, China, with individuals who tested positive for H. pylori using a 13C-urea breath test randomly assigned to receiving either (1) a 10-day, quadruple anti-H. pylori treatment (comprising 20 mg of omeprazole, 750 mg of tetracycline, 400 mg of metronidazole and 300 mg of bismuth citrate) or (2) symptom alleviation treatment with a single daily dosage of omeprazole and bismuth citrate. H. pylori-negative individuals did not receive any treatment. We examined the incidence of gastric cancer as the primary outcome. A total of 180,284 eligible participants from 980 villages were enrolled over 11.8 years of follow-up, and a total of 1,035 cases of incident gastric cancer were documented. Individuals receiving anti-H. pylori therapy showed a modest reduction in gastric cancer incidence in intention-to-treat analyses (hazard ratio 0.86, 95% confidence interval 0.74-0.99), with a stronger effect observed for those having successful H. pylori eradication (hazard ratio 0.81, 95% confidence interval 0.69-0.96) than for those who failed treatment. Moderate adverse effects were reported in 1,345 participants during the 10-day treatment. We observed no severe intolerable adverse events during either treatment or follow-up. The findings suggest the potential for H. pylori mass screening and eradication as a public health policy for gastric cancer prevention. Chinese Clinical Trial Registry identifier: ChiCTR-TRC-10000979 .

Oral Supplementation with l-Cystine, Serenoa repens, Cucurbita pepo, and Pygeum africanum in Chronic Telogen Effluvium and Androgenetic Alopecia: A Double-Blind, Placebo-Controlled, Randomized Clinical Study

Plain Language SummaryChronic telogen effluvium and androgenetic alopecia are two common types of hair loss that can have a significant impact on individuals’ quality of life. Research suggests that deficiencies in essential micronutrients may play a role in hair loss. To investigate this further, a study was conducted to assess the effectiveness and safety of an oral supplement containing l-Cystine, Serenoa repens, Cucurbita pepo, Pygeum africanum, as well as vitamins and micronutrients, in treating these conditions. The study involved 80 participants aged 18 to 60, both male and female, who were diagnosed with these types of hair loss. They were randomly assigned to take either the oral supplement or a placebo daily for 6 months. Throughout the study period, participants underwent dermatological evaluations, clinical photography, and phototrichograms to monitor changes in their hair. They also completed standardized questionnaires to assess their subjective experience of hair growth and appearance. Results showed that participants who took the oral supplement experienced a significant increase in hair density compared to those who took the placebo, with improvements observed as early as 3 months into the study. Additionally, the overall volume and appearance of their hair showed noticeable enhancement. Importantly, the oral supplement was well-tolerated, with no reports of moderate or severe adverse effects. In conclusion, the findings suggest that this oral supplement could be a safe and effective treatment option for individuals with chronic telogen effluvium or androgenetic alopecia, offering improvements in hair density and overall appearance.

Transcranial photobiomodulation in children aged 2-6 years: a randomized sham-controlled clinical trial assessing safety, efficacy, and impact on autism spectrum disorder symptoms and brain electrophysiology.

Small pilot studies have suggested that transcranial photobiomodulation (tPBM) could help reduce symptoms of neurological conditions, such as depression, traumatic brain injury, and autism spectrum disorder (ASD). To examine the impact of tPBM on the symptoms of ASD in children aged two to six years. We conducted a randomized, sham-controlled clinical trial involving thirty children aged two to six years with a prior diagnosis of ASD. We delivered pulses of near-infrared light (40 Hz, 850 nm) noninvasively to selected brain areas twice a week for eight weeks, using an investigational medical device designed for this purpose (Cognilum™, JelikaLite Corp., New York, United States). We used the Childhood Autism Rating Scale (CARS, 2nd Edition) to assess and compare the ASD symptoms of participants before and after the treatment course. We collected electroencephalogram (EEG) data during each session from those participants who tolerated wearing the EEG cap. The difference in the change in CARS scores between the two groups was 7.23 (95% CI 2.357 to 12.107, p = 0.011). Seventeen of the thirty participants completed at least two EEGs and time-dependent trends were detected. In addition, an interaction between Active versus Sham and Scaled Time was observed in delta power (Coefficient = 7.521, 95% CI -0.517 to 15.559, p = 0.07) and theta power (Coefficient = -8.287, 95% CI -17.199 to 0.626, p = 0.07), indicating a potential trend towards a greater reduction in delta power and an increase in theta power over time with treatment in the Active group, compared to the Sham group. Furthermore, there was a significant difference in the condition (Treatment vs. Sham) in the power of theta waves (net_theta) (Coefficient = 9.547, 95% CI 0.027 to 19.067, p = 0.049). No moderate or severe side effects or adverse effects were reported or observed during the trial. These results indicate that tPBM may be a safe and effective treatment for ASD and should be studied in more depth in larger studies.Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04660552, identifier NCT04660552.

Evaluating the impact of efpeglenatide on cardiometabolic and safety outcomes in individuals with diabetes: a systematic review and meta-analysis.

Efpeglenatide, a novel GLP-1 receptor agonist, has shown promise in improving glycemic control and inducing weight loss in individuals with type 2 diabetes (T2DM). This meta-analysis assessed its therapeutic potential and safety profile. A literature search was conducted on PubMed, SCOPUS, and Cochrane Central from inception until September 2023. We selected patients with T2DM and identified and compared those receiving efpeglenatide to placebo. Outcomes assessed included fasting plasma glucose (FPG), HbA1c, body weight, BMI, and cardiometabolic parameters. Data were analyzed using a random-effects model, with results presented as mean differences (MD) for continuous outcomes and risk ratios (RR) for safety analysis, along with their respective 95% confidence intervals. Quality assessment was conducted using the Cochrane risk of bias tool. We included 11 studies in our analysis. Efpeglenatide demonstrated significant reductions in FPG (MD = -1.53 mmol/L, 95% CI = [-2.86, -0.66], p < 0.01), HbA1c (MD = -0.84, 95% CI= [-1.08, -0.60], p < 0.01), body weight (MD = -2.24kg, 95% CI = [-4.20, -2.00], p < 0.01), and BMI (MD = -1.61kg/m2, 95% CI= [-2.12, -1.09], p < 0.01). However, efpeglenatide was associated with a moderate increase in the risk of gastrointestinal adverse events, nausea, diarrhea, and vomiting. There was a non-significant elevated risk of hypoglycemia. Efpeglenatide significantly improves glycemic outcomes and promotes weight loss in individuals with diabetes. However, it is associated with moderate adverse effects related to the gastrointestinal system. Thus, further trials are warranted to comprehensively assess its safety and efficacy to derive a robust conclusion. The online version contains supplementary material available at 10.1007/s40200-024-01409-3.

Trial of zuranolone for depression finds mild to moderate adverse effects

Trial of zuranolone for depression finds mild to moderate adverse effects

Safety and efficacy of fecal microbiota transplantation (FMT) as a modern adjuvant therapy in various diseases and disorders: a comprehensive literature review.

The human gastrointestinal (GI) tract microbiome is a complex and all-encompassing ecological system of trillions of microorganisms. It plays a vital role in digestion, disease prevention, and overall health. When this delicate balance is disrupted, it can lead to various health issues. Fecal microbiota transplantation (FMT) is an emerging therapeutic intervention used as an adjuvant therapy for many diseases, particularly those with dysbiosis as their underlying cause. Its goal is to restore this balance by transferring fecal material from healthy donors to the recipients. FMT has an impressive reported cure rate between 80% and 90% and has become a favored treatment for many diseases. While FMT may have generally mild to moderate transient adverse effects, rare severe complications underscore the importance of rigorous donor screening and standardized administration. FMT has enormous potential as a practical therapeutic approach; however, additional research is required to further determine its potential for clinical utilization, as well as its safety and efficiency in different patient populations. This comprehensive literature review offers increased confidence in the safety and effectiveness of FMT for several diseases affecting the intestines and other systems, including diabetes, obesity, inflammatory and autoimmune illness, and other conditions.

Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open-label, single-centre, single-arm, dose-finding clinical trial.

Hidradenitis suppurativa (HS) is a disease with an unmet need for treatment. To examine tolerability, safety and efficacy of oral phosphodiesterase-4 (PDE4) inhibitior orismilast 10-40 mg twice daily (BID) in HS. A Phase 2a, single-arm, single-centre, open-label, 16-week trial in HS patients. Adjustments in maximal dose and titration were allowed, to improve tolerability, dividing the study population in two groups who completed and discontinued 16 weeks of treatment. Descriptive statistics were applied to efficacy data from patients who completed treatment and patients who discontinued treatment prematurely. A last-observation-carried-forward (LOCF) approach was used for patients who discontinued treatment. The primary endpoint was percent change in the total number of abscesses and nodules (AN-count) at Week 16, with the HS Clinical Response with a 50% reduction in the AN-count (HiSCR50) as key secondary endpoint. Of the 20 patients included, 9 completed 16 weeks of treatment and 11 discontinued treatment prematurely. The mean AN-count was reduced with 33.1% in patients who completed treatment and with 12.0% in patients who discontinued. HiSCR50 was achieved by 67.0% and 27.0% of patients who completed and discontinued treatment, respectively. Most adverse events were mild to moderate. Oral orismilast demonstrated a dose-dependent tolerability, with mild to moderate adverse effects. Further, the results of this exploratory trial indicate that orismilast may lead to clinical improvements in HS. However, larger trials with tolerable dose ranges are warranted. The Trial is registered at Clinicaltrials.gov (UNI50007201) and EudraCT.ema.europa.eu (2021-000049-42).

Prevalence and Quantification of the Effects of Sexual Harassment Victimization of School-Aged Adolescents.

Sexual harassment has become a serious social and public health problem in adolescents, causing adverse effects on mental health. Nevertheless, some behaviours arise that, due to their characteristics, might be misinterpreted as sexual harassment. A field study using a survey with non-probabilistic accidental sampling was designed in order to estimate the prevalence of sexual harassment victimization in the Spanish adolescent population as well as to quantify the harms. A total of 1028 Spanish adolescents, 54.3% females and 45.7% males aged 13-17 years (M = 15.21, SD = 1.03), responded to a diagnostic measure of sexual harassment victimization and an inventory measure of internalizing and externalizing mental health problems (MHPs). The results showed a significant prevalence of diagnosed sexual harassment victimization of school-aged adolescents, 24.1%, 95% CI [0.215, 0.267], with adverse effects on internalizing and externalizing MHPs. As for the internalizing MHPs, the results exhibited moderate adverse effects on depression, anxiety, somatic burns, posttraumatic symptoms, and obsessive-compulsive symptoms, as well as mild adverse effects on social anxiety. Regarding externalizing MHPs, the results revealed moderate adverse effects on hyperactivity-impulsivity, anger control, and antisocial behaviour, as well as mild adverse effects on attention problems, aggression, and defiant behaviour. In addition, it was confirmed that sexual harassment victimization affects adolescent females to a greater extent, with the effect being significantly greater in internalizing than in externalizing MHPs. The results obtained are discussed and future lines of research and intervention are proposed to promote the implementation of prevention and intervention programs that address this phenomenon and, in turn, improve the physical, psychological, and social well-being of adolescents.

Causal Deep Neural Network-Based Model for First-Line Hypertension Management

ObjectiveTo develop and validate a machine learning model that predicts the most successful antihypertensive treatment for an individual. Patients and MethodsThe causal, deep neural network-based model was trained on data from 16,917 newly diagnosed hypertensive patients attending Mayo Clinic’s primary care practices from January 1, 2005, to December 31, 2021. Eligibility criteria included a diagnosis of primary hypertension, blood pressure and creatinine measurements before antihypertensive treatment, treatment within 9 months of diagnosis, and at least 1 year of follow up. The primary outcome was model performance in predicting the likelihood of a successful antihypertensive treatment 1 year from the start of treatment. Treatment success was defined as achieving blood pressure control with no moderate or severe adverse effects. Model validation and guideline agreement was assessed on 1000 patients. ResultsIn the training set of 16,917 participants (60.8±14.7 years; 8344 [49.3%] women), 33.8% achieved blood pressure control without moderate or severe adverse effects for at least a year with initial treatment. The most common treatment was angiotensin-converting enzyme inhibitor (39.1% average success), and the most successful was angiotensin-converting enzyme inhibitor-thiazide combination (44.4% average success). Our custom-built causal, deep neural network-based model exhibited the highest accuracy in predicting individualized treatment success with a precision of 51.7%, recall of 44.4%, and F1 score of 47.8%. Compared with actual physician practice on the validation set (77.9% agreement), the algorithm aligned with the Eighth Joint National Committee hypertension guidelines 95.7% of the time. ConclusionA machine learning algorithm can accurately predict the likelihood of antihypertensive treatment success and help personalize hypertension management.

Network-Based In Silico Analysis of New Combinations of Modern Drug Targets with Methotrexate for Response-Based Treatment of Rheumatoid Arthritis.

Methotrexate (MTX), sulfonamides, hydroxychloroquine, and leflunomide have consistently resulted in remission with relatively mild to moderate adverse effects in patients with rheumatoid arthritis (RA). Modern medications outperform traditional treatments in that they target the pathological processes that underlie the development of RA. Following PRISMA guidelines, the authors accomplished a systematic review of the clinical efficacy of RA drugs, including the biologics such as Tumor Necrosis Factor-alpha inhibitors (TNF-α i) like Etanercept, Infliximab, Golimumab, and Adalimumab, kinase inhibitors (JAK inhibitors including Baricitinib and Tofacitanib), SyK inhibitors like Fos-tamatinib, MAPK inhibitors such as Talmapimod, T-cell inhibitors (Abatacept), IL6 blockers (Tocilizumab), and B cells depleters (Rituximab). These drugs have been found to increase remission rates when combined with MTX. A bioinformatics-based network was designed applying STRING-MODEL and the DrugBank database for the aforementioned drugs and MTX and, finally, employed for this systematic review. Current research demonstrates that non-TNF-α inhibitor biologicals are particularly helpful in treating patients who did not respond well to conventional medications and TNF-α inhibitors. Despite being effective, these innovative drugs have a higher chance of producing hazardous side effects. The in silico investigations suggested an uncovered molecular interaction in combining MTX with other biological drugs. The STRING-MODEL showed that DHFR, TYMS, and ATIC, as the receptors of MTX, interact with each other but are not connected to the major interacted receptors. New game-changing drugs including Mavrilimumab, Iguratimod, Upadacitinib, Fenebrutinib, and nanoparticles may be crucial in controlling symptoms in poorly managed RA patients. Emerging therapeutic targets like Toll-like 4 receptors, NLRP3 inflammasome complexes, and mesenchymal stem cells can further transform RA therapy.

THU277 Deletion Or inhibition Of Ornithine Decarboxylase Protects Islet β-cell Health And Is Associated With Preserved Residual C-peptide In Persons With Recent Onset Type 1 Diabetes

Abstract Disclosure: B. Hammoud: None. L.A. DiMeglio: None. A. Kulkarni: None. A. Hull: None. S. Woerner: None. S. Cabrera: None. L.D. Mastrandrea: None. F. Ouyang: None. S.N. Perkins: None. C. Evans-Molina: None. T.L. Mastracci: None. S.A. Tersey: None. S. Sarkar: None. E. Nakayasu: None. B. Webb-Robertson: None. E. Gerner: None. R.G. Mirmira: None. E.K. Sims: None. Inhibition of polyamine biosynthesis using α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, reduces β cell stress and type 1 diabetes (T1D) incidence in preclinical animal models. However, the cellular and molecular mechanisms by which polyamines promote β-cell stress and the tolerability and effectiveness of their depletion by DFMO in humans with T1D remain unknown. We hypothesized that β-cell protection from stress occurs via cell-autonomous effects of polyamine depletion. To test this hypothesis, we generated β-cell specific knockout of ornithine decarboxylase in mice, performed comprehensive proteomics and transcriptomics on human islets treated with DFMO under inflammatory conditions in vitro, and performed a clinical study of DFMO tolerability, safety, and efficacy in persons with new-onset T1D. β-cell-specific deletion of the gene encoding ornithine decarboxylase in mice demonstrated protection of these animals against toxin (streptozotocin)-induced β-cell loss and hyperglycemia, implicating a cell-autonomous role for ornithine decarboxylase in β-cell stress. RNA sequencing and proteomics analyses of human islets exposed to a cytokine mix (1000 U/mL IFNγ + 50 U/mL IL-1β) +/- 5 mM DFMO identified 130 differentially regulated transcripts and 701 differentially regulated proteins. Pathway analysis implicated endosomal transport, vesicle organization and regulation of exocytosis, mRNA processing, and antigen cross presentation as mechanisms underlying DFMO effects on the islet response. To test DFMO in humans, we performed a 3-site randomized, placebo-controlled, double masked dose-ranging study of 3 months daily oral DFMO in persons with recent-onset T1D (&amp;lt;100 days). Dosing at 125, 250, 500, 750 or 1000 mg/m2/day was tested in 41 persons (12-34 y/o, 59% male, mean HbA1c 7.3%), with 6-10 participants/dosing group. Only mild and moderate adverse effects (AEs) were noted. Possible drug-related AEs included mild-moderate gastrointestinal symptoms, headache, upper respiratory infections, a pump site infection, and anemia. Urinary levels of the ODC product putrescine were decreased (p=0.05) in the 1000 mg/m2 dosing group. Compared to placebo, individuals receiving 750 and 1000 mg/m2 doses had significantly higher mixed-meal C-peptide area under the curve values at the 6-month post-randomization visit (p&amp;lt;0.05 vs. placebo). In conclusion, β-cell ODC inhibition protects β-cell health and function in the context of the proinflammatory T1D milieu. A 3-month course of oral DFMO was well tolerated with a favorable AE profile in persons with recent-onset T1D. Higher doses were associated with greater β-function compared to placebo. DFMO may have utility as a β-cell preservation therapy in recent-onset T1D. Presentation: Thursday, June 15, 2023

Adverse Event Profile in Advance Hepatocellular Carcinoma treated with Sorafenib Presenting to CMH Rawalpindi

&#x0D; Objective: To look for adverse event profiles in advance of hepatocellular carcinoma treated with Sorafenib presenting to CMH Rawalpindi and study associated socio-demographic factors&#x0D; Study Design: Comparative cross-sectional study&#x0D; Place and Duration of Study: Oncology Department, Combined Military Hospital, Rawalpindi Pakistan, from Dec 2020 to Nov 2021.&#x0D; Methodology: Three hundred patients with diagnosed hepatocellular carcinoma in advanced stage taking Sorafenib chemotherapy for more than three months and less than one year were included in the study. Each patient was assessed for relevant adverse effects in the follow-up outpatient visits by a consultant oncologist. &#x0D; Results: Out of 300 cancer patients using Sorafenib for more than three months and less than one year, 212(70.7%) patients had at least one or more adverse effects, while 88(29.3%) did not experience any adverse effects. Diarrhoea 120(40%) was the most common adverse effect, followed by rash/desquamation 110(36.7%). Advancing age was statistically significantly associated (p-value-0.001) with adverse effects among the target population.&#x0D; Conclusion: A significant number of patients suffering from hepatocellular carcinoma using Sorafenib had mild to moderate adverse effects. Physicians should keep an eye on patients with advancing age for adverse effects of this medication.

Physicochemical and Polycyclic Aromatic Hydrocarbons (PAHs) Analysis in Soil and Sediment from Vicinity of Ikot Akpaden, Akwa Ibom State, Nigeria

The study was undertaken to determine the levels of 16 priority PAHs in soil and sediments from some vicinities of Ikot Akpaden, Mkpat Enin. The soils were prepared using standard procedure in the laboratory and analyzed for 16 US EPA priority PAHs using Gas Chromatography-Mass Spectrophotometer (GC-MS). The soil samples were obtained from two sampling sites at Ikot Akpaden (Site A and C). Site C showed minimal PAHs concentration while site A recorded PAHs levels ranging from 0.01 to 4.25 mg/kg. According to European commission, the PAHs concentrations in soil samples of this study are moderate, but deleterious over time. The soils were negatively affected more with low molecular weight PAHs than High Molecular Weight PAHs.This study revealed that the sampling sites had low carcinogenic burden, hence would exhibit moderate adverse health effects to plants and animals. It was concluded that automobile repair activities in site A contributed to the soil contamination with PAHs; hence it should be properly sited.

Competitive actions and supply chain relationships: How suppliers' value‐diminishing actions affect buyers' procurement decisions

AbstractWhile greater competitive activity is generally associated with competitive advantage, certain competitive actions by a supplier may have spillover effects that adversely impact buying firms, leading them to reduce future purchases from the supplier. We study the effects of competitive actions in the context of vertical buyer–supplier relationships. Specifically, leveraging insights from screening theory, we examine how a supplier firm's value‐diminishing competitive actions—moves that may negatively impact buyer firms—lead to subsequent reductions in the buyer's procurement allocations and how contextual factors moderate such adverse effects. We test the associated hypotheses using a panel dataset comprising 12,690 dyadic buyer–supplier observations. A series of econometric analyses provide consistent evidence that a supplier's value‐diminishing actions are associated with decreases in the buyer's purchases from the supplier, thus highlighting the “dark side” of competitive actions. Furthermore, we find that the supplier's downstream vertical relatedness and the degree to which rival suppliers pursue value‐diminishing actions moderate this effect. Our findings, thus, add to our understanding of factors that shape the success and continuity of supply chain relationships and help supplier firms evaluate the economic viability of their competitive actions.

Misfolded α-Synuclein Assessment in the Skin and CSF by RT-QuIC in Isolated REM Sleep Behavior Disorder.

Real-time quaking-induced conversion (RT-QuIC) assay detects misfolded α-synuclein (AS) in the skin and CSF of patients with the synucleinopathies Parkinson disease and dementia with Lewy bodies. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of these synucleinopathies. We aimed to compare the ability of RT-QuIC to identify AS in the skin and CSF of patients with IRBD. This was a cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. Three-millimeter skin punch biopsies were obtained bilaterally in the cervical region from dorsal C7 and C8 dermatomes and in distal legs. RT-QuIC assessed AS in these 6 skin sites and the CSF. We recruited 91 patients with IRBD and 41 controls. In the skin, sensitivity to detect AS was 76.9% (95% CI 66.9-85.1), specificity 97.6% (95% CI 87.1-99.9) positive predictive value 98.6% (95% CI 91.0-99.8), negative predictive value 65.6% (95% CI 56.6-73.6), and accuracy 83.3% (95% CI 75.9-89.3). In the CSF, the sensitivity was 75.0% (95% CI 64.6-83.6), the specificity was 97.5% (95% CI 86.8-99.9), the positive predictive value was 98.5% (95% CI 90.5-99.8), the negative predictive value was 63.9% (95% CI 55.2-71.9), and the accuracy was 82.0% (95% CI 74.3-88.3). Results in the skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC AS-positive patients had a higher likelihood ratio of prodromal Parkinson disease (p < 0.001) and showed more frequently hyposmia (p < 0.001), dopamine transporter imaging single-photon emission CT deficit (p = 0.002), and orthostatic hypotension (p = 0.014). No severe or moderate adverse effects were reported. There was no difference between the percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% vs 17.2%; p = 0.053). One hundred and ten (83%) and 104 (80%) participants, respectively, stated they would accept to undergo skin biopsy and lumbar puncture again for research purposes. Our study in IRBD shows that (1) RT-QuIC detects AS in the skin and CSF with similar high sensitivity, specificity, and agreement, (2) AS RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and (3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. RT-QuIC in the skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting AS in IRBD. This study provides Class III evidence that RT-QuIC-detected AS in the skin and CSF distinguishes patients with IRBD from controls.

Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile?

Antibacterial fluoroquinolones (FQs) are frequently used in treating infections. However, the value of FQs is debatable due to their association with severe adverse effects (AEs). The Food and Drug Administration (FDA) issued safety warnings concerning their side-effects in 2008, followed by the European Medicine Agency (EMA) and regulatory authorities from other countries. Severe AEs associated with some FQs have been reported, leading to their withdrawal from the market. New systemic FQs have been recently approved. The FDA and EMA approved delafloxacin. Additionally, lascufloxacin, levonadifloxacin, nemonoxacin, sitafloxacin, and zabofloxacin were approved in their origin countries. The relevant AEs of FQs and their mechanisms of occurrence have been approached. New systemic FQs present potent antibacterial activity against many resistant bacteria (including resistance to FQs). Generally, in clinical studies, the new FQs were well-tolerated with mild or moderate AEs. All the new FQs approved in the origin countries require more clinical studies to meet FDA or EMA requirements. Post-marketing surveillance will confirm or infirm the known safety profile of these new antibacterial drugs. The main AEs of the FQs class were addressed, highlighting the existing data for the recently approved ones. In addition, the general management of AEs when they occur and the rational use and caution of modern FQs were outlined.

A phase Ia dose-escalation trial of Ametumumab (a fully human monoclonal antibody against epidermal growth factor receptor) in patients with advanced solid malignancies.

Epidermal growth factor receptor (EGFR) is a well-known target for cancer treatment. However, the authorized anti-EGFR monoclonal antibodies generally cause several toxic effects, especially severe cutaneous toxicities as well as infusion reactions, and the clinical indications are limited. Here we developed Ametumumab, a fully human recombinant anti-EGFR monoclonal antibody. To assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of Ametumumab. A first-in-human phase Ia dose escalation study of Ametumumab in patients with advanced solid malignancies. An open-label, first-in-human dose escalation study was done in 22 patients with advanced malignancies who received six ascending dosages ranging from 75 to 750 mg/m2. Following a single dosage and a 28-day dose-limiting toxicity (DLT) monitoring period, patients were given repeated doses weekly. Blood samples were taken to determine the PK parameters of Ametumumab and anti-drug antibody concentrations. Every 8 weeks, radiographic tumor evaluations were conducted. In this trial, no DLT was observed, and the maximum tolerated dose was not reached at doses up to 750 mg/m2. There were no severe adverse events but mild and moderate adverse effects, such as headache, proteinuria, and rash. Single-dose PK results demonstrated a straightforward linear relationship with dosage escalation. The medication concentrations accumulated and attained steady-state after four rounds of injections. It was calculated that 10 patients with disease control would be observed in the 22 evaluable patients. The disease control rate was 45.5%. The Ametumumab was well tolerated and safe in patients with advanced solid malignancies, exhibiting minimal immunogenicity, a long half-life, high levels of drug exposure in the blood, and preliminary effectiveness. The trial was registered with CTR20170343 on 10 April 2017, The China Center for Drug Evaluation.