Dosing rate decisions for drugs and changes in dosing in a patient due to disease states, drug interactions and pharmacogenomics are all based on clearance, a measure of the body's ability to ...eliminate drug. The primary organs of elimination are the liver and the kidney. Clearance for each of these organs is a summative composition of biologic processes. In 1857, Gustav Kirchhoff first developed his laws to describe the “motion of electricity in conductors... and ...in wires”, recognizing that summative processes occur either in parallel or in series. Since then, Kirchhoff's Laws have also been applied to heat transfer, diffusion and drag force on falling objects, but not to pharmacology. Although not previously recognized, renal clearance always follow Kirchhoff's Laws, as does hepatic clearance for drugs where basolateral transporters are not clinically relevant. However, when basolateral transporters are clinically relevant, we demonstrate that the present accepted approach is inconsistent with recognized drug disposition processes. However, this clearance relationship can be easily corrected using Kirchhoff's Laws. The purpose of this review is to demonstrate that Kirchhoff's Laws, which define how to approach rate processes that occur in parallel versus processes that occur in series, can be applicable to pharmacology in addition to the over 160-year recognition of their use in physical sciences. We anticipate that the application to clearance will be only the first of many such pharmacological analyses.
There has been a dramatic rise in opioid abuse, and diversion of excess, unused prescriptions is a major contributor. We assess the impact of implementing a new standardized pain care bundle to ...reduce postoperative opioids in outpatient general surgical procedures.
This study was designed to demonstrate non-inferiority for the primary end point: patient-reported average pain in the first 7 postoperative days. We prospectively evaluated 224 patients who underwent laparoscopic cholecystectomy or open hernia repair (inguinal, umbilical) pre-intervention to 192 patients post-intervention. We implemented a multimodal intra- and postoperative analgesic bundle, including promoting co-analgesia, opioid-reduced prescriptions, and patient education designed to clarify patient expectations. Patients completed a brief pain inventory at their first postoperative visit. Groups were compared using chi-square test, Mann-Whitney U test, and independent samples t-test, where appropriate.
No difference was seen in average postoperative pain scores in the pre- vs post-intervention groups (2.3 vs 2.1 of 10; p = 0.12). The reported quality of pain control improved post-intervention (good/very good pain control in 69% vs 85%; p < 0.001). The median total morphine equivalents for prescriptions filled in the post-intervention group were significantly less (100; interquartile range 75 to 116 pre-intervention vs 50; interquartile range 50 to 50 post-intervention; p < 0.001). Only 78 of 172 (45%) patients filled their opioid prescription in the post-intervention group (p < 0.001), with no significant difference in prescription renewals (3.5% pre-intervention vs 2.6% post-intervention; p = 0.62).
For outpatient open hernia repair and cholecystectomy, a standardized pain care bundle decreased opioid prescribing significantly and frequently eliminated opioid use, while adequately treating postoperative pain and improving patient satisfaction.
Kadour et al examine surgical pathology and Cancer Care Ontario summary data from the London Health Sciences Centre and St. Joseph's Health Care in London, Ontario. In Apr 2020, the total number of ...specimens received decreased by 67.5%, and resection specimens decreased by 51.4%. Cancer Care Ontario report submissions, largely reflecting newly staged cancer cases, decreased by 30.5%. The relatively modest drop in resections and Cancer Care Ontario submissions relative to total specimens likely reflects efforts to prioritize cancer surgeries.
Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates ...in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.
Dystocia is a stressful and traumatic event for both the cow and calf. As the prevalence of dystocia has increased over time, attention has been focused on maintaining the health and longevity of the ...cow. Lack of vitality in the newborn calf may go unnoticed and result in short or long-term implications for calf health and performance.
A prolonged or assisted delivery may increase birth stress in calves causing a variety of effects including injury, inflammation, hypoxia, acidosis, pain and an inability to maintain homeostasis. Each of these effects can further contribute to a reduced state of vitality in the newborn calf. Newborn vitality is essential to the health, survival and welfare of the calf. If the calf is not vital at birth, it may be unwilling or unable to get up and suckle colostrum in a timely manner. Early colostrum intake improves passive transfer of immunoglobulins, energy uptake and thermoregulation. Intervention may be required to assist these calves such as respiratory and thermal support, manual feeding of colostrum or the administration of non-steroidal anti-inflammatory drugs to aid health and long-term survival. However, more research is needed to determine ways in which newborn calf vitality can be assessed and improved in order to reduce the increased risk of morbidity and mortality and long-term effects on performance.
The feeding ecology of broadbill swordfish (Xiphias gladius) in the California Current was described based on analysis of stomach contents collected by fishery observers aboard commercial drift ...gillnet boats from 2007 to 2014. Prey were identified to the lowest taxonomic level and diet composition was analyzed using univariate and multivariate methods. Of 299 swordfish sampled (74 to 245 cm eye-to-fork length), 292 non-empty stomachs contained remains from 60 prey taxa. Genetic analyses were used to identify prey that could not be identified visually. Diet consisted mainly of cephalopods but also included epipelagic and mesopelagic teleosts. Jumbo squid (Dosidicus gigas) and Gonatopsis borealis were the most important prey based on the geometric index of importance. Swordfish diet varied with body size, location and year. Jumbo squid, Gonatus spp. and Pacific hake (Merluccius productus) were more important for larger swordfish, reflecting the ability of larger specimens to catch large prey. Jumbo squid, Gonatus spp. and market squid (Doryteuthis opalescens) were more important in inshore waters, while G. borealis and Pacific hake predominated offshore. Jumbo squid was more important in 2007-2010 than in 2011-2014, with Pacific hake being the most important prey item in the latter period. Diet variation by area and year probably reflects differences in swordfish preference, prey availability, prey distribution, and prey abundance. The range expansion of jumbo squid that occurred during the first decade of this century may particularly explain their prominence in swordfish diet during 2007-2010. Some factors (swordfish size, area, time period, sea surface temperature) that may influence dietary variation in swordfish were identified. Standardizing methods could make future studies more comparable for conservation monitoring purposes.
The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; ...however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wild-type (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyperactivation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAFV600E, MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes’ response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.
•UVB exposure triggers PTEN interaction with wild-type, but not MC1R RHC variants•WT, but not MC1R RHC variants, protect PTEN from WWP2-mediated ubiquitination•MC1R deficiency leads to the onset of premature senescence in primary melanocytes•MC1R deficiency cooperates with BRAFV600E to drive melanomagenesis
No studies have estimated the population-level burden of morbidity in individuals diagnosed with cancer as children (ages 0-19 years). We updated prevalence estimates of childhood cancer survivors as ...of 2011 and burden of morbidity in this population reflected by chronic conditions, neurocognitive dysfunction, compromised health-related quality of life, and health status (general health, mental health, functional impairment, functional limitations, pain, and fear/anxiety).
Surveillance, Epidemiology, and End Results (SEER) Program data from 1975 to 2011 were used to update the prevalence of survivors of childhood cancers in the United States. Childhood Cancer Survivor Study data were used to obtain estimates of morbidity burden indicators, which were then extrapolated to SEER data to obtain population-level estimates.
There were an estimated 388,501 survivors of childhood cancer in the United States as of January 1, 2011, of whom 83.5% are ≥5 years after diagnosis. The prevalence of any chronic condition among ≥5-year survivors ranged from 66% (ages 5-19) to 88% (ages 40-49). Estimates for specific morbidities ranged from 12% (pain) to 35% (neurocognitive dysfunction). Generally, morbidities increased by age. However, mental health and anxiety remained fairly stable, and neurocognitive dysfunction exhibited initial decline and then remained stable by time since diagnosis.
The estimated prevalence of survivors of childhood cancer is increasing, as is the estimated prevalence of morbidity in those ≥5 years after diagnosis.
Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.
High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine ...whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome.
In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6–12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123.
Between June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 SD 17 years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1·10, 95% CI 0·75 to 1·61; p=0·620).
Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population.
The British Heart Foundation.
Entamoeba histolytica, a protozoan intestinal parasite, is the causative agent of human amebiasis. Amebiasis is the fourth leading cause of death and the third leading cause of morbidity due to ...protozoan infections worldwide(1), resulting in ~70,000 deaths annually. E. histolytica has been listed by the National Institutes of Health as a category B priority biodefense pathogen in the United States. Treatment relies on metronidazole(2), which has adverse effects(3), and potential resistance of E. histolytica to the drug is an increasing concern(4,5). To facilitate drug screening for this anaerobic protozoan, we developed and validated an automated, high-throughput screen (HTS). This screen identified auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for rheumatoid arthritis, as active against E. histolytica in culture. Auranofin was ten times more potent against E. histolytica than metronidazole. Transcriptional profiling and thioredoxin reductase assays suggested that auranofin targets the E. histolytica thioredoxin reductase, preventing the reduction of thioredoxin and enhancing sensitivity of trophozoites to reactive oxygen-mediated killing. In a mouse model of amebic colitis and a hamster model of amebic liver abscess, oral auranofin markedly decreased the number of parasites, the detrimental host inflammatory response and hepatic damage. This new use of auranofin represents a promising therapy for amebiasis, and the drug has been granted orphan-drug status from the FDA.
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