Chronic Effects Research Articles

Pharmacovigilance for the Unani Medicine: Present Scenario and Future Prospects

Treatment is the noblest, as well as the most challenging art. The safe and effective use of medicinal products and procedures is always the core concern of healthcare treatment. In the present scenario, there is an organized adverse event reporting system called pharmacovigilance, has developed to improve patient care and safety regarding the use of medicinal products. The Unani is an ancient system of medicine and is deeply rooted in Asian civilization. It is a popular belief that the Unani medicinal products and procedures are safe, but it is not always true. The acute and chronic adverse drug effects, adverse interactions of drugs with other substances, abuse, and misuse of drugs are discussed in the text of the Unani medicine. Hence, pharmacovigilance is a pressing priority to establish the safety and efficacy of Unani medicinal products to make them more precise. Keywords: Pharmacovigilance, Unani medicine, Traditional Medicine, AYUSH

Noise accelerates embryonic development in a key crab species: Morphological and physiological carryover effects on early life stages

Anthropogenic noise is considered one important global pollutant. The impact of noise on marine invertebrates has been less assessed. The present study evaluated the chronic effect of the motorboat noise obtained from a lagoon's soundscape, the natural habitat of the key crab Neohelice granulata, on its whole embryonic development, considering morphological and physiological carryover effects on embryos and hatched larvae. Results demonstrated that embryonic development was shortened under noise exposure. The effects on advanced embryos, larvae and adult females were: increased heartbeats and non-viable eggs, and decreased fecundity. Biochemical responses showed lipid peroxidation in embryos while antioxidant enzymes were activated in larvae and adults, indicating a counteracting effect related to the life stage. The negative effects on fitness offspring may imply ecological consequences at the population level. Results are discussed in terms of the ecosystem engineer species studied and the habitat, a MAB UNESCO Reserve lagoon, suggesting the urgent need to develop mitigation plans.

The cardiovascular implications for exercise intolerance and dyspnoea in electronic cigarette users

Background: Electronic cigarettes (EC) have been proposed as a safe alternative to tobacco smoking, however, several studies have shown adverse health effects of EC. The chronic implications of EC on cardiorespiratory response and exertional dyspnoea are unknown. Aim: To examine the chronic effects of electronic cigarettes (EC) and tobacco cigarettes (TC) on resting vascular function, inflammatory markers, cardiorespiratory responses during exercise and exertional dyspnoea. Methodology: Three groups of young adults (16 each) with normal spirometry (EC users, TC smokers, and never-smokers [NS]) consented to participate in this study following institutional ethics approval. Participants performed spirometry and an incremental cardiopulmonary exercise test (CPET) 20W/2mins on an electronically braked cycle ergometer with blood lactate (BLa) measurements. Flow-mediated dilation (FMD%) of the brachial artery was assessed using Doppler ultrasonography. Venous blood samples were collected to assess inflammatory biomarkers associated with vascular function. Results: EC and TC groups had a lower peak work rate compared to NS controls (184 ± 30; 185 ± 35 vs. 228 ± 44 W, respectively; P < 0.05). During submaximal exercise, EC and TC groups displayed higher ventilation (VE), higher ratings of dyspnoea and more intense leg fatigue compared to NS controls (e.g. 140 W, VE: 62 ± 10; 64 ± 12 vs. 54 ± 7 L/min, Dyspnoea: 5.0 ± 1.9; 6.1 ± 1.9 vs. 3.4 ± 1.7 Borg units, 6.1 ± 2.05; 7.0 ± 1.9 vs. 4.1 ± 2.1 Borg units, respectively; all P < 0.05). The TC group displayed lower ventilatory efficiency (higher V̇E/V̇CO2) and higher blood lactate compared to NS during submaximal exercise (e.g. 140 W, V̇E/V̇CO2: 31.8 ± 5.6 vs. 28.2 ± 2.41, Blood lactate: 6.5 ± 2.4 vs. 4.3 ± 2.5 mmol/L, respectively; P < 0.05 for both). Like the TC group, the EC group showed a trend for lower ventilatory efficiency and higher BLa during submaximal exercise, but they did not reach statistically significant differences compared to NS controls (P = 0.07 for both). FMD was significantly lower in EC and TC groups compared with NS controls (5.4 ± 2.4; 4.6 ± 2.9 vs. 7.9 ± 3.4%, respectively; P < 0.05) and that was associated with elevated Thrombospondin-1 levels. Conclusion: EC and TC impair vascular function and cardiorespiratory responses to exercise and exertional dyspnoea similarly. EC has a detrimental impact on vascular function and exercise capacity and should not be recommended as a ‘healthier’ alternative to TC.

Ellagic acid can mitigate chronic ammonia stress-induced adverse effects through the augmentation of liver autophagy in yellow catfish (Pelteobagrus fulvidraco)

The toxicity of ammonia to the majority of fish species is well-known, however, its harmful impact can be mitigated through nutritional intervention. The aim of this study was to investigate whether dietary supplementation of ellagic acid (EA) can mitigate the toxicity of chronic ammonia stress on yellow catfish. Three groups of yellow catfish were fed diets containing different concentrations of EA (0.00, 0.02, and 0.20%) for a duration of 56 days. Additionally, the fish were exposed to three different levels of ammonia (0.00, 2.50, and 25.00 mg/L total ammonia nitrogen) in order to assess any potential interactions. The results showed that ammonia toxicity could affect growth (weight gain rate and specific growth rate were decreased but feed conversion ratio declined), leads to oxidative stress (total antioxidant capacity, superoxide dismutase, and catalase decreased but H2O2 content increased), and physiological function damage (total cholesterol, total protein, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acid phosphatase increased). Additionally, autophagy (becn1, atg3, atg4a, atg7, lc3a, and sqstm1), apoptosis (tgf-β, smad 2, caspase 3, caspase 9, and baxa), inflammation (TNF-α, IL-1β, and Myd88) related genes were up-regulated while myogenic regulatory factors (myod, myf5, myog, and igf) were down-regulated by ammonia. The inclusion of dietary EA supplementation has the potential to alleviate the detrimental impact of ammonia poisoning on fish growth, oxidative damage, physiological function impairment, and apoptotic processes by activating autophagy.

Effect of artificial gravity on neurocognitive performance during head-down tilt bedrest

This study evaluated the acute and chronic effects of intermittent and continuous Artificial Gravity (AG) on cognitive performance during 60 days of Head-down tilt bedrest (HDTBR), a well-established ground-based spaceflight analogue method. Participants were randomly assigned to three groups: intermittent AG, continuous AG, and HDTBR control group without AG exposure. Task performance and electrophysiological measures of attention and working memory were investigated during Simple and Complex tasks in the Visual and the Auditory modality. Compared to baseline, faster reaction time and better accuracy was present during HDTBR regarding the Complex tasks, however, the practice effect was diminished in the three HDTBR groups compared to an ambulatory control group. Brain potentials showed a modality-specific decrease, as P3a was decreased only in the Auditory, while P3b decreased in the Visual modality. No evidence for acute or chronic AG-related cognitive impairments during HDTBR was found.

Chronic Lead Exposure in Adult Mice: Associations with miR-671/CDR1as Regulation, NF-κB Signaling, and Alzheimer's Disease-like Pathology.

Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), β-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-β (Aβ), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis.

Lambda-Cyhalothrin induced behavioural, neurotoxic and oxidative stress on vertebrate model Danio rerio (Hamilton-Buchanan 1822).

λ-cyhalothrin, a synthetic type II pyrethroid, has become increasingly popular for control of aphids, butterfly larvae, and beetles, replacing other agricultural chemicals. As a result of which, residues of this synthetic pesticide are being reported across the globe in natural water, which poses a serious threat to aquatic life. Therefore, the present study was designed to understand the toxicity effects of λ-cyhalothrin on behaviour, oxidative stress and neurotoxicity in a vertebrate aquatic model, zebrafish (Danio rerio). The fish were exposed to 0.129, 0.194 and 0.388 µg/L corresponding to 5%, 10% and 20% of 96hLC50 (1.94 µg/L) for 28 days. Upon exposure to the highest concentration (0.388 µg/L), the test animal exhibited significant alterations in behavioural patterns like number of entries to the top zone (n), decrease in average speed (m/s) and decrease in time spent in top zone (s). Moreover, the shoaling test demonstrated a significant decrease (p < 0.05) in the relative time spent by the tested fish (%) near the stimulus fish. The change in behavioural alterations might be linked to a significant decrease (p < 0.05) in the brain acetylcholine esterase activity. Furthermore, the present study also illustrates oxidative stress exerted by λ-cyhalothrin through an increase in the production of reactive oxygen species, which is again clearly depicted by a significant increase (p < 0.05) in Superoxide dismutase, Catalase and Glutathione peroxidase activities. Overall, the present study systematically demonstrates the chronic effects of λ-cyhalothrin on adult fish behaviour and physiology, which will contribute to assessing the risks of λ-cyhalothrin to organismal health.

Neoadjuvant chemotherapy with bevacizumab for locally advanced vulvar cancer

ObjectivesExternal beam radiation with sensitizing platinum is the recommended therapy for locally advanced vulvar cancers not amenable to curative surgery and is associated with considerable acute and chronic side effects....

Acute and Chronic Effects of Static Stretching on Intramuscular Hamstring Stiffness.

Passive hamstring stiffness varies proximo-distally, resulting in inhomogeneous tissue strain during stretching that may affect localized adaptations and risk of muscle injuries. The purpose of the present study was to determine the acute and chronic effects of static stretching (SS) on intramuscular hamstring stiffness. Thirty healthy active participants had acute changes in passive biceps femoris (BF), semimembranosus (SM), and semitendinosus (ST) stiffness measured at 25% (proximal), 50% (middle), and 75% (distal) muscle length, using shear-wave elastography, immediately after SS. Participants then completed 4 weeks of either a SS intervention (n = 15) or no intervention (CON, n = 15) with stiffness measured before and after the interventions. The acute and chronic effects of SS were compared between anatomical regions and between regions on the basis of their relative stiffness pre-intervention. Acutely, SS decreased stiffness throughout the BF and SM (p ≤ 0.05) but not the ST (p = 0.326). However, a regional effect of stretching was observed for SM and ST with greater reduction in stiffness occurring in stiffer muscular regions (p = 0.001-0.013). Chronically, SS increased BF and ST (p < 0.05), but not SM (p = 0.422) stiffness compared with CON, but no regional effect of stretching was observed in any muscle (p = 0.361-0.833). SS resulted in contrasting acute and chronic effects, acutely decreasing stiffness in stiffer regions while chronically increasing stiffness. These results indicate that the acute effects of SS vary along the muscle's length on the basis of the relative stiffness of the muscle and that acute changes in stiffness from SS are unrelated to chronic adaptations.

WITHDRAWN: COVID-19: Post infection implications in different age groups, mechanism, diagnosis, effective prevention, treatment, and recommendations

SARS-CoV-2 is a highly contagious pathogen that predominantly caused the COVID-19 pandemic. The persistent effects of COVID-19 are defined as an inflammatory or host response to the virus that begins four weeks after initial infection and persists for an undetermined length of time. Chronic effects are more harmful than acute ones thus, this review explored the long-term effects of the virus on various human organs, including the pulmonary, cardiovascular, and neurological, reproductive, gastrointestinal, musculoskeletal, endocrine, and lymphoid systems and found that SARS-CoV-2 adversely affects these organs of older adults. Regarding diagnosis, the RT-PCR is a gold standard method of diagnosing COVID-19; however, it requires specialized equipment and personnel for performing assays and a long time for results production. Therefore, to overcome these limitations, artificial intelligence employed in imaging and microfluidics technologies is the most promising in diagnosing COVID-19. Pharmacological and non-pharmacological strategies are the most effective treatment for reducing the persistent impacts of COVID-19 by providing immunity to post-COVID-19 patients by reducing cytokine release syndrome, improving the T cell response, and increasing the circulation of activated natural killer and CD8 T cells in blood and tissues, which ultimately reduces fever, nausea, fatigue, and muscle weakness and pain. Vaccines such as inactivated viral, live attenuated viral, protein subunit, viral vectored, mRNA, DNA, or nanoparticle vaccines significantly reduce the adverse long-term virus effects in post-COVID-19 patients; however, no vaccine was reported to provide lifetime protection against COVID-19; consequently, protective measures such as physical separation, mask use, and hand cleansing are promising strategies. This review provides a comprehensive knowledge of the persistent effects of COVID-19 on people of varying ages, as well as diagnosis, treatment, vaccination, and future preventative measures against the spread of SARS-CoV-2.

Medical malpractice litigation and daylight saving time.

Daylight saving time (DST) constitutes a natural quasi-experiment to examine the influence of mild sleep loss and circadian misalignment. We investigated the acute effects of spring transition into DST and the chronic effects of DST (compared to standard time) on medical malpractice claims in the United States over 3 decades. We analyzed 288,432 malpractice claims from the National Practitioner Data Bank. To investigate the acute effects of spring DST transition, we compared medical malpractice incidents/decisions 1 week before spring DST transition, 1 week following spring DST transition, and the rest of the year. To investigate the chronic effects of DST months, we compared medical malpractice incidents/decisions averaged across the 7-8 months of DST vs the 4-5 months of standard time. With regard to acute effects, spring DST transitions were significantly associated with higher payment decisions but not associated with the severity of medical incidents. With regard to chronic effects, the 7-8 DST months were associated with higher average payments and worse severity of incidents than the 4-5 standard time months. The mild sleep loss and circadian misalignment associated with DST may influence the incidence of medical errors and decisions on medical malpractice payments both acutely and chronically. Gao C, Lage C, Scullin MK. Medical malpractice litigation and daylight saving time. J Clin Sleep Med. 2024;20(6):933-940.

Associations between neonicotinoids and liver function measures in US adults: National Health and Nutrition Examination Survey 2015–2016

Background: Toxicological studies indicate that neonicotinoids may be associated with disruptions in liver function due to an increase in oxidative stress. There are scant epidemiological studies investigating the chronic hepatotoxic effects of neonicotinoids. Objective: To examine the association between detectable concentrations of parent neonicotinoids and neonicotinoid metabolites with liver function markers among US adults, and whether sex modifies this association. Methods: National Health and Nutrition Examination Survey 2015–2016 data were used to estimate associations between detectable neonicotinoids and serum alkaline phosphatase (ALP), alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transaminase (GGT), albumin, total bilirubin, total protein, and Hepatic Steatosis Index (HSI) using multiple linear regression. Results: Detectable levels of N-desmethyl-acetamiprid were associated with a decrease in GGT (β = −3.54 unit/l; 95% confidence interval [CI] = −6.48, −0.61) and detectable levels of 5-hydroxy-imidacloprid were associated with a decrease in HSI (β = −1.11; 95% CI = −2.14, −0.07). Sex modified the association between any parent neonicotinoid and ALP (P int = 0.064) and the association between clothianidin and ALP (P int = 0.019), with a pattern of positive associations in males and inverse associations in females, though stratified associations did not reach statistical significance. Sex also modified the association between 5-hydroxy-imidacloprid and total protein (P int = 0.062), with a significant positive association in females (β = 0.14 g/dl; 95% CI = 0.03, 0.25) and a null association in males. Conclusion: Detectable concentrations of neonicotinoid metabolites were inversely associated with GGT and HSI in US adults. Evidence suggests neonicotinoids may influence liver function differently depending on sex. Future research is recommended to replicate the findings as the study was limited in its cross-sectional nature and inability to examine continuous neonicotinoid concentrations with liver function.

Оценка риска здоровью населения, проживающего на территории влияния космодрома «Восточный», в условиях многофакторной многосредовой экспозиции имических веществ

Rocket and space activities occupy an important place among modern sources of impact on the environment. Its results can manifest themselves in an area where a cosmodrome is located, adjacent territories, in areas where separated parts of a launch vehicle fall. This impact has certain specific features that create population health risks. Health risks for population of Tsiolkovsky settlement were assessed upon exposure to chemicals that pollute the environment in accordance with the methodical approaches stipulated in the valid Guide (R 2.1.10.3968-23). Initial data were represented by results of environmental surveillance accomplished within social-hygienic monitoring and in field conditions as well as by data collected for a project aimed at substantiating a sanitary protection zone for the Vostochny Cosmodrome launch sites. Average annual concentrations and their 95 % confidence intervals, which were established based on average daily concentrations, were used to calculate chronic chemical exposures. The 95 % percentile of maximum single concentrations was employed to calculate acute exposures. Ambient air was established to make the greatest contribution (88.99 %) into non-carcinogenic health risks for people residing in Tsiolkovsky settlement. Particulate matter made the greatest contribution (42.4 %) to the risk of chronic non-carcinogenic effects. Alerting chronic non-carcinogenic risks of respiratory diseases (up to 5.9 HI) and the blood system (up to 4.1 HI) were established under combined inhalation chemical exposures. Major contributions to non-carcinogenic risks are made by particulate matter (up to 42.4 %), lead (up to 25.9 %), nitrogen oxide (up to 20.2 %), nitrogen dioxide and carbon oxide (23.1 % each).

Barriers to the use of Methylphenidate in Pediatric Neuro-oncology Services.

Survivors of childhood CNS tumors are at a significant risk of chronic and multifaceted neurocognitive late effects. Recent findings indicate the potential utility of methylphenidate in addressing neurocognitive and academic plateauing and improving quality-of-life outcomes in this clinical population. However, the prescription of methylphenidate in neuro-oncology services remains inconsistent. To explore the neurocognitive assessment and rehabilitative interventions (including the use of methylphenidate) offered to survivors of childhood CNS tumors within mainland UK. We used a semi-structured questionnaire to gather qualitative data from clinical psychologists and neuropsychologists within National Health Service pediatric neuro-oncology principal treatment centers (PTCs) during May 2018. Thematic analytical methods were used to explore themes within the collected data. Eleven (58%) of the 19 PTCs returned the completed questionnaire. Respondents reported inadequate resource of psychology in many pediatric neuro-oncology PTCs, which limited the provision of methylphenidate to a restricted proportion of the patient group (i.e., those with the most profound neurocognitive difficulties). Respondents reported an interest in exploring the utility of methylphenidate in their patient group yet described a lack of appropriate evidence of its efficacy. In addition, respondents highlighted the need for the provision of accessible research summaries and treatment protocols addressing the use of methylphenidate. We anticipate that national collaboration between clinicians and researchers working in the cancer survivorship field will support the advancement of interventions such as methylphenidate for the growing clinical population of survivors of childhood CNS tumors.

Assessment of the health risk for people residing on the territory influenced by the vostochny cosmodrome under multi-factor and multi-environment exposure to chemicals

Rocket and space activities occupy an important place among modern sources of impact on the environment. Its results can manifest themselves in an area where a cosmodrome is located, adjacent territories, in areas where separated parts of a launch vehicle fall. This impact has certain specific features that create population health risks. Health risks for population of Tsiolkovsky settlement were assessed upon exposure to chemicals that pollute the environment in accordance with the methodical approaches stipulated in the valid Guide (R 2.1.10.3968-23). Initial data were represented by results of environmental surveillance accomplished within social-hygienic monitoring and in field conditions as well as by data collected for a project aimed at substantiating a sanitary protection zone for the Vostochny Cosmodrome launch sites. Average annual concentrations and their 95 % confidence intervals, which were established based on average daily concentrations, were used to calculate chronic chemical exposures. The 95 % percentile of maximum single concentrations was employed to calculate acute exposures. Ambient air was established to make the greatest contribution (88.99 %) into non-carcinogenic health risks for people residing in Tsiolkovsky settlement. Particulate matter made the greatest contribution (42.4 %) to the risk of chronic non-carcinogenic effects. Alerting chronic non-carcinogenic risks of respiratory diseases (up to 5.9 HI) and the blood system (up to 4.1 HI) were established under combined inhalation chemical exposures. Major contributions to non-carcinogenic risks are made by particulate matter (up to 42.4 %), lead (up to 25.9 %), nitrogen oxide (up to 20.2 %), nitrogen dioxide and carbon oxide (23.1 % each).

Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability.

6561 Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, Cmax and AUC0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]

Evolving Standards of Care in the Management of Localized Colorectal Cancer.

The treatment of patients with localized rectal cancer is complex and requires input from a multidisciplinary team. Baseline local staging and mismatch repair protein testing are vital to develop individualized treatment plans. There are multiple options in terms of treatment modalities and sequencing, including transanal excision, short-course radiation, long-course chemoradiation, chemotherapy doublet or triplet, nonoperative management, and immune checkpoint blockade for patients with mismatch repair deficient tumors. While localized colon cancer is typically treated with surgical resection and consideration of adjuvant chemotherapy, emerging data suggest that neoadjuvant chemotherapy may be beneficial in patients with higher-risk disease. Quality-of-life considerations are imperative to prevent potential chronic effects on psychosocial health, neuropathy, fertility, and bowel, bladder, and sexual function. The omission of radiation or surgery can mitigate these toxicities without diminishing oncologic outcomes. The optimal treatment plan and sequence is not a one-size-fits-all approach but rather should be personalized to the patient's disease burden, tumor location, comorbidities, and preferences.

A dynamic energy budget (DEB) model to assess the sublethal effects of imidacloprid toward Gammarus pulex at different temperatures

Environmental ambient temperature significantly impacts the metabolic activities of aquatic ectotherm organisms and influences the fate of various chemicals. Although numerous studies have shown that the acute lethal toxicity of most chemicals increases with increasing temperature, the impact of temperature on chronic effects — encompassing both lethal and sublethal endpoints — has received limited attention. Furthermore, the mechanisms linking temperature and toxicity, potentially unveiled by toxicokinetic-toxicodynamic models (TKTD), remains inadequately explored. This study investigated the effects of environmentally relevant concentrations of the insecticide imidacloprid (IMI) on the growth and survival of the freshwater amphipod Gammarus pulex at two different temperatures. Our experimental design was tailored to fit a TKTD model, specifically the Dynamic Energy Budget (DEB) model. We conducted experiments spanning three and six months, utilizing small G. pulex juveniles. We observed effects endpoints at least five times, employing both destructive and non-destructive methods, crucial for accurate model fittings. Our findings reveal that IMI at environmental concentrations (up to 0.3 μg/L) affects the growth and survival of G. pulex, albeit with limited effects, showing a 10% inhibition compared to the control group. These limited effects, observed in both lethal and sublethal aspects, suggest a different mode of action at low, environmentally-relevant concentrations in long-term exposure (3 months), in contrast to previous studies which applied higher concentrations and found that sublethal effects occurred at significantly lower levels than lethal effects in an acute test setting (4 days). Moreover, after parameterizing the DEB model for various temperatures, we identified a lower threshold for both lethal and sublethal effects at higher temperatures, indicating increased intrinsic sensitivity. Overall, this study contributes to future risk assessments considering temperature as a crucial factor and exemplifies the integration of the DEB model into experimental design for comprehensive toxicity evaluations.

Chronic Mexiletine Administration Increases Sodium Current in Non-Diseased Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

A sodium current (INa) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia risks. The sodium channel blocker mexiletine has been shown to restore the trafficking of mutant sodium channels to the membrane. However, these studies were mostly performed in heterologous expression systems using high mexiletine concentrations. Moreover, the chronic effects on INa in a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated the chronic and acute effects of a therapeutic dose of mexiletine on INa and the action potential (AP) characteristics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of a healthy individual. Control hiPSC-CMs were incubated for 48 h with 10 µM mexiletine or vehicle. Following the wash-out of mexiletine, patch clamp analysis and immunocytochemistry experiments were performed. The incubation of hiPSC-CMs for 48 h with mexiletine (followed by wash-out) induced a significant increase in peak INa of ~75%, without any significant change in the voltage dependence of (in)activation. This was accompanied by a significant increase in AP upstroke velocity, without changes in other AP parameters. The immunocytochemistry experiments showed a significant increase in membrane Nav1.5 fluorescence following a 48 h incubation with mexiletine. The acute re-exposure of hiPSC-CMs to 10 µM mexiletine resulted in a small but significant increase in AP duration, without changes in AP upstroke velocity, peak INa density, or the INa voltage dependence of (in)activation. Importantly, the increase in the peak INa density and resulting AP upstroke velocity induced by chronic mexiletine incubation was not counteracted by the acute re-administration of the drug. In conclusion, the chronic administration of a clinically relevant concentration of mexiletine increases INa density in non-diseased hiPSC-CMs, likely by enhancing the membrane trafficking of sodium channels. Our findings identify mexiletine as a potential therapeutic strategy to enhance and/or restore INa and cardiac conduction.

Differential Roles of Key Brain Regions: Ventral Tegmental Area, Locus Coeruleus, Dorsal Raphe, Nucleus Accumbens, Caudate Nucleus, and Prefrontal Cortex in Regulating Response to Methylphenidate: Insights from Neuronal and Behavioral Studies in Freely Behaving Rats.

A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in neuronal and behavioral activity in dose-response characteristics. The response to chronic MPD exposure, as compared to acute 0.6, 2.5, or 10.0 mg/kg MPD administration, elicits electrophysiological and behavioral sensitization in some animals and electrophysiological and behavioral tolerance in others when the neuronal recording evaluations were performed based on the animals' behavioral responses, or amount of locomotor activity, to chronic MPD exposure. The majority of neurons recorded from those expressing behavioral sensitization responded to chronic MPD with further increases in firing rate as compared to the initial MPD responses. The majority of neurons recorded from animals expressing behavioral tolerance responded to chronic MPD with decreases in their firing rate as compared to the initial MPD exposures. Each of the six brain areas studied-the ventral tegmental area, locus coeruleus, dorsal raphe, nucleus accumbens, prefrontal cortex, and caudate nucleus (VTA, LC, DR, NAc, PFC, and CN)-responds significantly (p < 0.001) differently to MPD, suggesting that each one of the above brain areas exhibits different roles in the response to MPD. Moreover, this study demonstrates that it is essential to evaluate neuronal activity responses to psychostimulants based on the animals' behavioral responses to acute and chronic effects of the drug from several brain areas simultaneously to obtain accurate information on each area's role in response to the drug.