Cumulative Adverse Effects Research Articles

Efficacy of cumulative cisplatin dose on survival in patients with locally advanced cervical cancer treated with definitive chemoradiotherapy: multicenter study by Turkish Oncology Group

ObjectiveTo investigate the impact of cumulative cisplatin dose on clinical outcomes in locally advanced cervical cancer patients undergoing definitive chemoradiotherapy.MethodsA retrospective analysis was conducted on 654 patients with stage IB3–IVA...

The efficacy of cumulative cisplatin dose on survival in patients with locally advanced cervical cancer treated with definitive chemoradiotherapy: A multicenter study by the Turkish Oncology Group (TOG).

e17534 Background: This multicentric study aimed to investigate the impact of cumulative cisplatin dose on clinical outcomes in locally advanced cervical cancer patients undergoing definitive chemoradiotherapy (CRT). Methods: A retrospective analysis was conducted on 654 patients with stage IB3-IVA disease treated with definitive CRT. Radiotherapy (RT) was applied as external beam pelvic with or without para-aortic RT and brachytherapy. Concomitant chemotherapy was in the form of weekly or 3-weekly cisplatin. Data on demographics, treatment protocols, cumulative cisplatin dose, adverse effects, and survival outcomes were collected. Statistical analyses, including univariate and multivariate Cox regression models, were employed to assess factors influencing progression-free survival (PFS) and overall survival (OS). Results: The median cumulative cisplatin dose was 210 mg (range, 40-320 mg), and it was ≥200 mg in 503 (76.9%) patients. Median follow-up was 35 months. The 5-year PFS and OS rates were 66.9% and 77.1%, respectively. Multivariate analysis (MVA) identified poor performance status, non-squamous cell histology, presence of lymph node metastasis and hemoglobin <10 g/dl before CRT were poor prognostic factors for both PFS and OS in the whole group. When stage III cases were evaluated separately, the cumulative cisplatin dose below 200 mg was also found to be a significant poor prognostic factor in OS (HR 1.79, 95% CI, 1.1 to 3.0, p=0.031). Conclusions: The study revealed that a cumulative cisplatin dose exceeding 200 mg, particularly in patients with lymph node metastasis, significantly improved OS. Factors such as anemia, toxicity-related challenges, and comorbidities were identified as critical considerations in treatment planning. These findings emphasize the delicate balance between maximizing therapeutic efficacy and managing toxicity, guiding personalized treatment approaches for locally advanced cervical cancer. [Table: see text]

Polymyalgia rheumatica - an up-to-date review on diagnosis and management

Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease in those over the age of 50 years. Previously it was considered to be a benign clinical syndrome characterised by subacute onset bilateral shoulder and pelvic girdle pain and stiffness, with a corresponding rise in acute phase reactants, and distinctive rapid resolution of symptoms with the instigation of moderate doses of glucocorticoids. However, over the past decade, with the advancements and, indeed, wider application of imaging modalities in PMR, we have garnered an increased understanding of the anatomic predilection of inflammation and, subsequently, disease pathogenesis. Moreover, our appreciation of the relationship between PMR and giant cell arteritis (GCA) has strengthened. Glucocorticoids have formed the cornerstone of the management of PMR for decades, with often protracted treatment durations and associated high cumulative steroid burden and adverse effects. However, we are now on the cusp of a new era in the management of PMR, with our therapeutic armamentarium expanding with the recent FDA approval of the interleukin -6 antagonist sarilumab for the management of refractory disease. It is an exciting time for PMR, and this review aims to explore the recent advancements in both diagnosis and management, while also providing an updated perspective on the relationship between PMR and GCA.

Neurosarcoidosis: The Presentation, Diagnosis and Treatment Review of Two Cases.

Sarcoidosis is a chronic granulomatous disease of unknown cause characterized by the presence of non-caseating granulomas. The disease can affect any organ including the nervous system. Neurosarcoidosis occurs in about 5% patients with sarcoidosis. The clinical presentation of neurosarcoidosis is varied, and it can involve the brain, spinal cord and peripheral nervous system, separately or in different combinations. The diagnosis of neurosarcoidosis is challenging, as biopsies from the nervous system are not readily available. Anti-TNFα agents are becoming one of the cornerstone treatments for neurosarcoidosis. In this case-based review, we discuss two cases of neurosarcoidosis with different clinical presentations. The first patient presented with confusion, while the second presented with walking difficulty and neurogenic bladder. Both patients were treated with methylprednisolone pulse therapy with rapid, but non-complete, improvement. Therefore, infliximab was initiated in both cases with subsequent improvement in the clinical manifestations and imaging findings, emphasizing the effectiveness and safety of infliximab in cases of severe neurosarcoidosis. In conclusion, the goal of neurosarcoidosis management is to prevent organ system damage and minimize the toxic cumulative adverse effects of glucocorticoid use. In this case-based review we discuss the various presentations, the diagnosis and the treatment of neurosarcoidosis.

Exploring toxicological interactions in a changing sea: The case of the alkaloids caffeine and caulerpin

The bisindolic alkaloid caulerpin (CAU) is a bioactive compound isolated from green algae of the genus Caulerpa that are highly invasive in the Mediterranean Sea. On the other side, the purine alkaloid caffeine (CAF) is one of the most globally consumed psychoactive substances and a widespread anthropogenic water pollutant. Both compounds display a large panel of biological properties and are well known to accumulate in the tissues of aquatic organisms and, in certain circumstances, co-occur in the human diet. On this premise, the present study aimed to investigate possible synergistic interactions between CAU and CAF by using the bivalve Mytilus galloprovincialis as a model organism. Mussels were exposed to CAF via medium while they were fed with food enriched with CAU. After treatments, biochemical analysis confirmed the toxic potential of CAF, with increased AChE activity and lipid peroxidation. Also, histopathological alterations were observed in the gills and digestive tubules. The NMR-based metabolomics analysis detected higher levels of free amino acids under CAF treatments. Conversely, the food administration of CAU did not affect the above toxicological biomarkers. In addition, we did not observe any cumulative effect between CAF and CAU toward increased cellular damage and neurotoxicity. On the other hand, a possible action of CAU in decreasing CAF toxicity could be hypothesized based on our results. This hypothesis is supported by the activity of CAU as an agonist of peroxisome proliferator-activated receptors (PPARs). PPARs mediate xenobiotic detoxification via cytochromes P450, which is involved in CAF metabolism. Overall, the results obtained not only rule out any cumulative adverse effects of CAF and CAU but also encourage further research to evaluate the possible use of CAU, a compound easily obtained through the valorization of biomass from invasive species, as a food additive to improve the clearance of xenobiotics.

Prognostic significance of echocardiographic abnormalities in patients with heart failure with preserved ejection fraction

Abstract Funding Acknowledgements Type of funding sources: None. Background Heart failure with preserved ejection fraction (HFpEF) is recognised as a highly heterogenous condition (1). This extends to its echocardiographic phenotype, which according to the latest ESC diagnostic criteria, can include the presence of left ventricular hypertrophy (LVH), left atrial (LA) enlargement and elevated pulmonary artery systolic pressure (PASP) amongst others (2). The relative prognostic significance of these abnormalities however has not been well-described. Purpose The aim of this study was to evaluate the relative prognostic significance of echocardiographic abnormalities in a community-based cohort of patients with HFpEF and elevated NT-proBNP. Methods We analysed the echocardiograms of patients referred from the community with clinical signs of HF and elevated NTproBNP. We specifically evaluated the presence of LVH, LA enlargement and elevated PASP according to EACVI criteria. We excluded patients with NT-proBNP <125 pg/ml. The primary outcome was time to all-cause mortality or cardiovascular hospitalisation. Results The total cohort included 473 patients (mean age 78 years, 66% female, median NT-proBNP 587 pg/ml). Median follow-up was 27 months. 88 individuals had an occurrence of the primary outcome (18.6%). LA enlargement was the commonest abnormality (48.2%), then LVH (37.2%) and elevated PASP (18.4%). After adjustment for age, sex and NTproBNP, LA enlargement was significantly associated with the primary outcome in patients in sinus rhythm but not atrial fibrillation (sinus: hazard ratio 2.02, 95% CI 1.09–3.73, p = 0.025; AF: hazard ratio 0.68, 95% CI 0.31–1.48, p = 0.20; interaction p value 0.013). Neither elevated PASP (HR 1.50, 95% CI 0.94–2.39, p = 0.09) or LVH (HR 0.99, 95% CI 0.64–1.55, p = 0.98) were independently associated with the primary outcome. There did however appear to be a stepwise increase in risk based on the number of echocardiographic abnormalities present, with individuals with 2 or more abnormalities being significantly more likely to have an incidence of the primary outcome than those with fewer (Figure). Conclusion There may be differences in prognosis of HFpEF patients based on echocardiographic structural and functional parameters. These may therefore require different therapeutic approaches. The number of abnormalities appear to have a cumulative adverse effect on prognosis.

Assessment of Initial Depressive State and Pain Relief With Ketamine in Patients With Chronic Refractory Pain

Repeated ketamine administration is common in treatment-refractory chronic pain, but ketamine analgesic and antidepressant effects are poorly understood in patients with chronic pain with depression symptoms. To determine clinical pain trajectories with repeated ketamine administrations, exploring whether ketamine dose and/or pretreatment depressive and/or anxiety symptoms may mediate pain relief. This nationwide, multicenter, prospective cohort study included patients in France with treatment-refractory chronic pain who received repeated ketamine administration, over 1 year, according to ketamine use in their pain clinic. Data were collected from July 7, 2016, through September 21, 2017. Linear mixed models for repeated data, trajectory analysis, and mediation analysis were performed from November 15 to December 31, 2022. Ketamine administration in cumulative dose (milligrams) over 1 year. Primary outcome was mean pain intensity (0-10 on the Numerical Pain Rating Scale [NPRS]), assessed every month for 1 year by telephone, after inclusion in the hospital. Depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), quality of life (12-item Short Form Health Survey [SF-12]), cumulative ketamine dose, adverse effects, and concomitant treatments were secondary outcomes. A total of 329 patients (mean [SD] age, 51.4 [11.0] years; 249 women [75.7%] and 80 men [24.3%]) were enrolled. Repeated ketamine administration was associated with a decrease of NPRS (effect size = -0.52 [95% CI, -0.62 to -0.41]; P < .001) and an increase of SF-12 mental health (39.7 [10.9] to 42.2 [11.1]; P < .001) and physical health (28.5 [7.9] to 29.5 [9.2]; P = .02) dimension scores over 1 year. Adverse effects were in the normal range. There was a significant difference between patients without and with depressive symptoms in pain diminution (regression coefficient, -0.04 [95% CI, -0.06 to -0.01]; omnibus P = .002 for interaction of time × baseline depression [HADS score ≤7 or >7]). The mediation model showed that ketamine dose was not associated with pain diminution (r = 0.01; P = .61) and not correlated with depression (r = -0.06; P = .32), and that depression was associated with pain diminution (regression coefficient, 0.03 [95% CI, 0.01-0.04]; P < .001), whereas ketamine dose was not (regression coefficient, 0.00 [95% CI, -0.01 to 0.01]; P = .67). The proportion of reduction of pain mediated by baseline depression was 64.6%. The findings of this cohort study on chronic refractory pain suggest that depression (and not ketamine dose or anxiety) was the mediator of the association of ketamine with pain diminution. This finding provides radically new insights on how ketamine reduces pain primarily by dampening depression. This reinforces the need for systematic holistic assessment of patients with chronic pain to diagnose severe depressive symptoms where ketamine would be a very valuable therapeutic option.

Re-treatment with [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE of patients with progressive neuroendocrine neoplasm.

Neuroendocrine neoplasms (NENs) are heterogeneous groups of tumours derived from neuroendocrine cells of the ectoderm or endoderm. They are considered rare, with an estimated incidence and prevalence of 6/100,000 and 35/100,000 respectively, and a noticeable upward trend. Radioligand therapy (RLT) using beta-radiation-emitters combined with somatostatin analogues is an effective and relatively safe treatment method. It is usually used as a second-line therapy in case of progressive disease. In retrospective analysis covering eight years of observation (2015-2023) of patients treated in a single highest-reference NEN centre, a subgroup of 13 who received RLT re-treatment (¹⁷⁷Lu or ¹⁷⁷Lu/⁹⁰Y-mixture) was identified. Epidemiological aspects, renal, hepatic, haematological parameters and chromogranin A serum concentration were analysed. The median PFS after the first cycle of RLT was 53.8 months (IQR = 19.3). Directly after the second cycle of RLT disease stabilization and progression was observed in 11/13 (84.6%) and 2/13 (15.4%) patients respectively. After the second cycle of RLT median observation time for the study group was 16.2 months. Eight out of 13 patients were reachable for long-term observation and stabilization was confirmed in 62.5 % (5/8), progression in 12.5% (1/8) and death in 25% (2/8) patients. Median survival time in patients with confirmed death was 7 months. During observation, an increase in creatinine concentration with a decrease in glomerular filtration rate (GFR) was noticed, however, the values were at a statistical trend level (p = 0.056; p = 0.071). The increase of liver parameters was statistically, but not clinically significant. The decrease in albumin concentration and fasting glucose concentration were not significant. An increase in chromogranin A concentration correlated, although not statistically, with the progression of the disease. A statistically significant decrease in the number of all bone marrow cell lines was observed. The first RLT cycle caused a higher decrease in blood parameters than the second. There were no differences in PFS or laboratory parameters depending on the radioligand ([¹⁷⁷Lu]Lu-DOTA-TATE vs. [¹⁷⁷Lu]Lu-DOTA-TATE/[⁹⁰Y]Y-DOTA-TATE). In follow-up after RLT re-treatment stabilization was observed in 62.5%, progression in 12.5% and death in 25% of patients. Decrease of glomerular filtration, and bone marrow parameters resulted from the cumulative adverse effect of RLT, the natural ageing process, and the progression of the disease. Side effects were mainly caused by the first treatment cycle. There was no significant influence on the measured parameters, depending on the radioisotope used. Re-treatment of RLT seems to be a reliable and relatively safe method, thus should be considered in patients who underwent one cycle of RLT and responded to the treatment.

Evaluation of US/UV/SO40‒ Advanced Oxidation Process on the Removal of Amoxicillin from Aqueous Solutions

Introduction: Pharmaceuticals, especially antibiotics, are new contaminants that have created a major environmental concern because of their cumulative nature, adverse effects, and drug resistance. Their existence in domestic wastewater will pollute water resources. This study aimed to determine the performance of US/UV/SO40‒ processes in the removal of Amoxicillin (AMX). Method: The current experimental study used ultrasonic waves (US), ultraviolet rays (UV), and sulfate radicals (SO40‒). To detect the effect of variables, including contact time (0-120 min), the antibiotic concentration (5-50 mg/l), pH (3-9), persulfate concentration (1-7 mM), and the input power (550 W), the reactor has been sampled in different intervals, and the residue concentration was detected using a spectrophotometer in 294 nm length wave. Results: The results showed that the separate use of US and UV had no high operation with the best removal percentages of 33.3% and 13.29%, respectively. Simultaneous use of US/UV/SO40‒ showed a more high reduction in AMX concentration and the best removal percentage was 94.12% that took place in pH=6, the antibiotic concentration of 5 mg/L, persulfate concentration of 5 mM, and contact time of 120 min. Conclusion: The result showed that the US/UV/SO40‒ process can be used as an operational process to remove the AMX from an aqueous environment.

The role of extreme high humidex in depression in chongqing, China: A time series-analysis

As global climate change intensifies, people are paying increasing attention to the impact of temperature changes on adverse mental health outcomes, especially depression. While increasing attention has been paid to the effect of temperature, there is little research on the effect of humidity. We aimed to investigate the association between humidex, an index combining temperature and humidity to reflect perceived temperature, and outpatient visits for depression from 2014 to 2019 in Chongqing, the largest and one of the most hot and humid cities of China. We also aimed to further identify susceptible subgroups. A distributed lag non-linear model (DLNM) was used to explore the concentration-response relationship between humidex and depression outpatient visits. Hierarchical analysis was carried out by age and gender. A total of 155,436 visits for depression were collected from 2014 to 2019 (2191 days). We found that depression outpatient visits were significantly associated with extremely high humidex (≥40). The significant positive single-lag day effect existed at lag 0 (RR = 1.029, 95%CI: 1.000–1.059) to lag 2 (RR = 1.01, 95%CI: 1.004–1.028), and lag 12 (RR = 1.013, 95%CI: 1.002–1.024). The significant cumulative adverse effects lasted from lag 01 to lag 014. Hierarchical analyses showed that females and the elderly (≥60 years) appeared to be more susceptible to extremely high humidex. The attributable numbers (AN) and fraction (AF) of extremely high humidex on depression outpatients were 1709 and 1.10%, respectively. Extremely high humidex can potentially increase the risk of depression, especially in females and the elderly. More protective measures should be taken in vulnerable populations.

The Role of Stem Cells Derived From the Mesenchyme of the Umbilical Cord in Reducing Immunosuppressive Drug Doses Used in Allogenic Transplantations.

This study evaluated the potential of Wharton's jelly mesenchymal stem cells with high tolerogenic properties in reducing immunosuppressive dosage and related adverse effects. A 4- to 6-week-old, 30-40 g weight, male inbred CD57BL/6 mice were used as skin allograft donors, whereas Balb/c mice with similar characteristics were used as recipients. Wharton's jelly stem cells were obtained from a commercial kit sourced from human umbilical cord. Skin allografts were performed from CD57Bl6 to Balb/c mice (day 0). Group 1 (control) received no treatment. Group 2 received 15 mg/kg cyclosporin A on days 0 to 30. Group 3 received 5.7 × 10 6 and 10.3 × 10 6 cell/kg Wharton's jelly stem cells on days 0 and 3, respectively. Groups 4, 5, and 6 received a combination of 15, 10, and 5 mg/kg per day cyclosporine A (days 0 to 30) with the same stem cell dose with group 3, respectively. Graft rejection was evaluated with digital photography and thermal imaging, histopathology (Banff grading, epithelialization scores, dermoepidermal dissociation), immunochemistry (Ki-67 and Bcl-2), and biochemical methods (interleukin 10, interleukin 2, interferon γ, tumor necrosis factor α) (day 10). Cumulative adverse effects of cyclosporin A occurring in the groups were revealed by histopathological evaluation of kidney and liver (a modified semiquantitative method of infiltration of inflammatory cells around the portal area and lobular region in liver; modification of the Banff rating of proximal tubules and hypertrophia of juxtaglomerular apparatus cells in kidney) (day 30). There was no rejection in groups 2, 4, and 5 until the end of study. These were statistically different versus groups 1 (day 10 ± 0.71), 3 (day 11 ± 0.82), and 6 (day 11 ± 0.58) (all P 's < 0.05). Groups 4 and 5 have exhibited statistically similar findings in histopathological (4 epithelization score: 3.7 ± 1.3; 5 epithelization score: 3.5 ± 0.5; 4 Banff grading score: 0.8 ± 0.6; 5 Banff grading score: 1.0 ± 0.5; both P 's = 1.00), immunohistochemical (4 Bcl-2 score: 3.5 ± 0.5, P = 0.618; 5 Bcl-2 score: 3.4 ± 0.5, P = 1.00; 4 Ki-67 score: 3.7 ± 0.4, P = 1.00; 5 Ki-67 score: 3.5 ± 0.5, both P 's = 1.00), and levels of cytokines (both P 's = 1.00) versus group 2. Adverse effects on kidneys and liver were lowest and statistically similar in groups 3, 5, and 6 (all P 's = 00) versus group 1. Wharton's jelly mesenchymal stem cells alter bioavailability of cyclosporine, albeit at much lower doses and with fewer systemic adverse effects.

Constraints in Adoption of Clean and Safe Milking Techniques by Dairy Farmers in Kerala: An Assessment

Aim: The constraints involved in the adoption of clean and safe milk production practices were identified from a sample of 210 farmers covering three major districts of Kerala i.e. Kollam, Thiruvananthapuram, and Palakkad randomly. Average adoption score of 65 out of 95 practices indicated the need to sensitize the farmers for adoption of clean and safe milk production practices.&#x0D; Methodology: The constraints faced by the farmers in adopting clean and safe milk production practices were identified and ranked using Garrett’s ranking technique. Kendall rank correlation was used to estimate the ordinal association of the ranks given to constraints by the farmers.&#x0D; Results: Inadequate information about clean and safe milk production practices was identified to be the major constraint faced by the farmers followed by high cost of inputs, lack of finance, lack of infrastructure and constraints on the availability of land. Lack of finance, high cost of inputs and constraints on the availability of land were found to be strongly correlated to each other, having a cumulative adverse effect on the adoption of clean and safe milking practices.

Cumulative life course adversity, mental health, and cognition in the UK biobank

The association between adversity and cognition varies according to the specific adversity, when the adversity was experienced, and the cognitive domains investigated. Disentangling the effect of adversity and the underlying mechanistic pathway is therefore difficult. The association between adversity (i.e., maltreatment) accumulated over the life course and cognitive flexibility, as well as two potential mediators (i.e., intra-individual variability in reaction time and depression) of this association, were investigated. Data stem from the baseline population of the UK Biobank study (N = 73,489, Mdnage = 56, SDage = 7.628, 55.740% of women). Cumulative life course adversity (specifically maltreatment) was measured with items based on the Childhood Trauma Questionnaire (CTS-5) and items adapted from the British Crime Survey. Depression was assessed with the Patient Health Questionnaire-9 (PHQ-9). Intra-individual variability in reaction time was measured with a reaction time test “snap game” and the Trail Making Test A and B were used as a measure of cognitive flexibility. A path analysis was performed on these data. Higher cumulative adverse experiences were associated with lower performance in cognitive flexibility (β = .016, p < .001, 95% CI [0.009, 0.024]), and this effect was partly mediated by the level of depression (22.727% of the total effect of cumulative life course adversity on cognitive flexibility was mediated by depression (β = .005, p < .001, 95% CI [0.004, 0.007])). No association between cumulative life course adverse experiences and intra-individual variability in reaction time was found, nor was any indirect association between cumulative life course adversity and performance in cognitive flexibility via intra-individual variability in reaction time. The association between cumulative life course adversity, depression, and performance in cognitive flexibility has been highlighted. In contrast, no indirect effect between cumulative life course adversity and performance in cognitive flexibility via intra-individual variability in reaction time was found, suggesting that it is not a potential mechanism underlying the association between cumulative life course adversity and executive function.

Putative anoikis resistant subpopulations are enriched in lymph node metastases and indicate adverse prognosis in colorectal carcinoma

Anoikis refers to apoptosis induced by the loss of contact with the extracellular matrix. Anoikis resistance is essential for metastasis. We have recently shown that it is possible to quantitatively evaluate putative anoikis resistant (AR) subpopulations in colorectal carcinoma (CRC). Abundance of these multi-cell structures is an independent marker of adverse prognosis. Here, we have quantified putative AR subpopulations in lymph node (LN) metastases of CRC and evaluated their prognostic value and relationship with the characteristics of primary tumors. A case series included 137 unselected CRC patients, 54 with LN metastases. Areal densities (structures/mm2) of putative AR structures in primary tumors had been analyzed previously and now were determined from all nodal metastases (n = 183). Areal density of putative AR structures was higher in LN metastases than in primary tumors. Variation of the areal density within different LN metastases of a single patient was lower than between metastases of different patients. Abundance of putative AR structures in LN metastases was associated with shorter cancer specific survival (p = 0.013), and this association was independent of T and N stages. Abundance of putative AR structures in primary tumors and LN metastases had a cumulative adverse effect on prognosis. Enrichment of putative AR subpopulations in LN metastases suggest that in metastasis formation, there is a selection favoring cells capable of forming these structures. Higher intra-case constancy relative to inter-case variation suggests that such selection is stable in metastasis development. Our findings indirectly support the biological validity of our concept of putative AR structures.

Redundancy of Respiratory Humidification &amp; Dysfunction of Defence Mechanisms at Upper Airways of Large Number of People Due to Cumulative Adverse Effects of Climate Change -The Root Cause of the COVID-19 Outbreak

The COVID-19 has returned in the form of an outbreak of new variants. Viruses have evolved and accompanied mankind from times immemorial but seem to be increasingly threatening the survival of the human race especially in the last four decades. Various theories are available with respect to initial transmissions to humans yet none is endorsed in totality. At the same time climate change poses the greatest threat to human health and its effects are more pronounced in the last four decades than ever before. The purpose of this perspective is to establish scientifically a correlation between the outbreak of COVID-19 or its variants and climate change. This presentation is based on hitherto overlooked yet proven physics and engineering involved in the human respiratory humidification. Respiratory humidification is a uniquely evolved process of Natural Selection to withstand complex and dynamic environments. As COVID-19 is a respiratory viral disease, the gas exchange mechanism and human body’s normal temperature and alveolar air parameters are first explained to justify its uniqueness. A step by step review of physics and engineering involved in respiratory humidification is also done. It is then analyzed in context of Climate Change of a location and its impact on inspired air parameters. Based on Meteorological Data of Wuhan; the place of COVID-19 outbreak; it is established that the Climate Change resulted in redundancy of respiratory humidification and dysfunction of associated immune defence mechanisms of many inhabitants and facilitated viruses like SARS-CoV-2 an unchallenged access to the lungs. The outbreak of COVID-19 and subsequent pandemic was its outcome.

Effects of clonidine premedication on perioperative hemodynamic response, anesthetic requirements and postoperative analgesia for patients undergoing laparoscopic gynecological surgeries: A randomized study

The creation of carbon dioxide (CO) pneumoperitoneum is frequent in laparoscopy, but has significant effect on the cardiopulmonary function of the patient. Clonidine by its central sympatholytic action reduces perioperative hemodynamic instability and has several advantages in the postoperative period, hence we consider it to be an effective premedication to contain the stress response to intubation and laparoscopy. With informed consent, 56 patients scheduled for elective laparoscopic gynecological surgeries under general anesthesia were randomly allocated into two groups to receive premedication with either oral Clonidine 100 µg (Group I, n = 28) or Vitamin C as placebo (Group II, n = 28) 90 minutes prior to induction. A balanced general anesthesia was used to manage these patients. Hemodynamic parameters, Sevoflurane concentration, pain and sedation scores, time to request analgesics, 24hr cumulative analgesic requirements and adverse effects between the two groups were collected as data and compared using Two sample t-test and Fisher’s exact test.When compared to the control group, oral Clonidine was found to be considerably superior significantly (p =0.00) in terms of maintaining stable hemodynamics (i.e. In group I, Mean HR ranged from 76.11±12.21 to 94.57±13.75, while in group II, it ranged from 79.04±7.11 to 112.00±12.75 and MAP ranged from 83.07±6.50 to 93.64±14.09 in group I, while in group II, it ranged from 88.04±9.03 to 116.14±13.23), having a Sevoflurane sparing effect and having a longer time (6.5 ± 1.6 hours) between the first request for analgesia postoperatively. In patients undergoing laparoscopic gynecological surgeries, administration of oral Clonidine 100µg as a premedication improves perioperative hemodynamic stability and reduces the intraoperative anesthetic and post-operative analgesic requirements.

Unpacking the Criminogenic Aspects of Stress Over the Life Course: The Joint Effects of Proximal Strain and Childhood Abuse on Violence and Substance Use in a High-Risk Sample of Women

Purpose: Drawing on concepts from strain, feminist, and life-course perspectives, we investigate the proximal effects of strain on violence and serious drug use along with the distal “carryover” effects of childhood abuse among women. Methods: Using 36 months of retrospective data collected from 778 incarcerated women, we estimate monthly within-person effects of four types of strain experienced in adulthood (i.e., negative life events and three forms of victimization) on respondent-initiated violence and serious drug use. Cross-level interactions assess the moderating “carryover” effects of childhood abuse and cumulative adversity. Results: Negative life events increased women's initiation of violence and serious drug use. Having a near violent experience was positively associated with violence, while violent conflict increased drug use. Experiencing both childhood physical and sexual abuse accentuated the effect of predatory victimization on violence, and physical victimization amplified the positive relationship between near violence and drug use. Unexpectedly, women who experienced childhood sexual abuse were less likely to use drugs after experiencing strain. The accumulation of adversity among abused women could not account for these moderating effects. Conclusion: Findings suggest women's recent life experiences can explain offending in the foreground, while childhood abuse can account for some within-sex heterogeneity in these relationships.

Cumulative and independent effects of experiences of social adversity on support for violent radicalization during the COVID-19 pandemic: the mediating role of depression.

PurposeSocial adversity experiences have increased during the pandemic and are potential risk factors for both depression and support for violent radicalization (VR). However, the cumulative and independent effects of various social adversity experiences on support for VR have yet to be explored. This paper examines the cumulative and independent effects of COVID- and non-COVID-related discrimination, exposure to violence, traditional and cyberbullying victimization on support for VR. In addition, we investigate whether depression mediates the relationship between these forms of social adversity and support for VR.MethodsA total of 6003 young adults (Mage = 27, SDage = 4.40, range 18–35) living in metropolitan areas in Canada responded to an online survey. We used multivariable regression models, controlling for socio-demographic characteristics, to infer covariate adjusted associations between social adversity measures and support for VR. Additionally, we conducted a formal mediation analysis to estimate the proportion mediated by depression.ResultsThere was a cumulative relationship between experiences of social adversity and support for VR (β = 1.52; 95% CI: 1.32, 1.72). COVID-related discrimination and cyberbullying victimization were independently associated with stronger support for VR. Depression partially mediated the effect of cumulative social adversity, COVID-related discrimination and cyberbullying on support for VR.ConclusionPrevention programs during the present pandemic should prioritize decreasing discrimination and providing psychosocial support to depressed young adults who experience social adversity. Practitioners should prioritize developing programs that foster digital literacy skills and critical thinking among young adults to address the concerning impact of cyberbullying on support for VR.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00127-022-02244-8.

Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients.

Study ObjectiveThis study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients.Design and SettingA cross‐sectional, open‐label, single center, 12‐h pharmacokinetic‐pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration‐time curve (AUC0–12), AUC0–4, 12‐h troughs (C 12 h), maximum concentrations (C max), oral clearance (Cl), with dose‐normalized AUC0–12, troughs, and C max with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate‐adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms.Patients65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post‐transplant were evaluated.Measurements and Main ResultsBlack recipients exhibited higher tacrolimus AUC0–12 (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC0–12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC0–12 was <100 ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%–19% of tacrolimus variability in dose (p = 0.002); AUC0–12 h* (p < 0.001), and Cl (p < 0.001).ConclusionsTacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC0–12 h.

47-Year-Old Woman With Bilateral Flank Pain

47-Year-Old Woman With Bilateral Flank Pain