Optimisation of vitamin D status in global populations.

Vitamin D is important for musculoskeletal health. Concentrations of 25-hydroxyvitamin D, the most commonly measured metabolite, vary markedly around the world and are influenced by many factors including sun exposure, skin pigmentation, covering, season and supplement use. Whilst overt vitamin D deficiency with biochemical consequences presents an increased risk of severe sequelae such as rickets, osteomalacia or cardiomyopathy and usually warrants prompt replacement treatment, the role of vitamin D supplementation in the population presents a different set of considerations. Here the issue is to keep, on average, the population at a level whereby the risk of adverse health outcomes in the population is minimised. This position paper, which complements recently published work from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, addresses key considerations regarding vitamin D assessment and intervention from the population perspective. This position paper, on behalf of the International Osteoporosis Foundation Vitamin D Working Group, summarises the burden and possible amelioration of vitamin D deficiency in global populations. It addresses key issues including screening, supplementation and food fortification.

Dose-response relationships in aluminium toxicity in humans.

INTRODUCTION: Aluminium exposure is associated with bone disease (an elevated bone content of aluminium and reduced bone formation on bone biopsy) and neurotoxicity (features of altered brain functions and/or typical spike and slow wave waveforms on electroencephalogram) in patients with elevated blood aluminium concentrations. OBJECTIVES: To critically analyse the literature to determine the dose-toxicity relationships between aluminium exposure and related bone disease and aluminium neurotoxicity. METHODS: A systematic review of the literature with collation and analysis of individual data of human cases of aluminium exposure was conducted between 1 January 1966 and 30 December 2020. Embase, MEDLINE (OVID MEDLINE), PubMed and TOXNET were searched with the following strategies: "Aluminium AND toxicity OR aluminium AND poisoning OR aluminium AND dialysis OR aluminium AND chronic renal failure OR aluminium AND intravenous" limited to "(human)". Inclusion criteria required individual data relating to aluminium exposure in humans. Papers in which features of aluminium toxicity and analytical confirmation of aluminium exposure could not be determined in individual patients were excluded. RESULTS: Thirty-seven papers were identified, which included data on 179 individuals exposed to aluminium. The sources of aluminium exposure (median duration of exposure) were: dialysis fluid (48 months) in 110 cases; oral aluminium hydroxide (20 months) in 20 cases; plasma exchange (2 months) in 16 cases; infant formula feed (minimal duration of 2 weeks) in 14 cases; intravesical exposures (2 days) in 13 oncology patients and potable water exposure in six cases. EXPOSURE TO DIALYSIS FLUID: Of the 110 patients exposed to dialysis fluid, 99 were adults and 11 children, who were analysed separated. Of the adults, 50 with aluminium neurotoxicity had a median aluminium concentration of 467 µg/L (IQR 230 - 752), 28 with aluminium bone disease had a median aluminium concentration of 142 µg/L (IQR 46-309) and 21 with asymptomatic aluminium overload had a median aluminium concentration of 35 µg/L (IQR 26-51). Median aluminium concentrations were significantly greater in patients with aluminium neurotoxicity compared to those with aluminium bone disease (p < 0.0001) or asymptomatic aluminium overload (p < 0.0001). ORAL ALUMINIUM HYDROXIDE: Of the 20 cases, 11 were adults and nine were children. Of the 11 adults, eight with aluminium neurotoxicity had a median aluminium concentration of 682 µg/L (IQR 438-770) and three with aluminium bone disease had a median aluminium concentration of 100 µg/L (IQR 62-138) (p = 0.007). Of the nine children, five had aluminium neurotoxicity with a median aluminium concentration of 335 µg/L (IQR 229-601), one had aluminium bone disease and an aluminium concentration of 1030 µg/L and three had asymptomatic aluminium overload with a median aluminium concentration 98 µg/L (IQR 65-365). PLASMA EXCHANGE: Three patients with stage 5 chronic kidney disease developed aluminium bone disease during plasma exchange; their median blood or serum aluminium concentration was 73 µg/L (IQR 59-81). Asymptomatic aluminium overload was reported in six patients receiving outpatient plasma exchange who had a median creatinine clearance of 71 mL/min (IQR 40-106) and a median aluminium concentration of 49 µg/L (IQR 34-116), and in seven intensive care patients with acute kidney injury whose median aluminium concentration was 30 µg/L (IQR 17-35); (p = 0.02). INTRAVESICAL EXPOSURES: All 13 intravesical exposures developed aluminium neurotoxicity and had a median aluminium concentration of 157 µg/L (IQR 45-276). POTABLE WATER: All six patients developed aluminium bone disease and their median blood aluminium concentration was 17 µg/L (IQR 13-100). CONCLUSIONS: Toxic aluminium exposure can result in neurotoxicity and bone disease, especially in patients with chronic kidney disease. Adults with stage 5 chronic kidney disease chronically exposed to aluminium developed aluminium neurotoxicity at higher concentrations than those with aluminium bone disease or with asymptomatic aluminium overload. Aluminium neurotoxicity was reported at lower concentrations following acute exposure to intravesical aluminium. Extrapolating the relevance of these concentrations to the general population is problematic in that the data were derived from oncology patients, however, the possibility that aluminium neurotoxicity may occur at concentrations lower that those reported historically in patients with stage 5 chronic kidney disease cannot be excluded.

Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial.

BACKGROUND: Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). PATIENTS AND METHODS: KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab. RESULTS: Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients. CONCLUSIONS: The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.

Plastic physicians: The surgical salamanders of the COVID-19 pandemic.

At the time of writing, coronavirus disease-2019 (COVID-19) has affected 6.42 million people globally and over 380,000 deaths, with the United Kingdom now having the highest death rate in Europe. The plastic surgery department at Leeds Teaching Hospitals put necessary steps in place to maintain an excellent urgent elective and acute service whilst also managing COVID-positive medical patients in the ward. We describe the structures and pathways implemented together with complex decision-making, which has allowed us to respond early and effectively. We hope these lessons will prove a useful tool as we look to open conversations around the recovery of normal activity.

Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Consensus statement from 2nd International Conference on Controversies in Vitamin D.

The 2nd International Conference on Controversies in Vitamin D was held in Monteriggioni (Siena), Italy, September 11-14, 2018. The aim of this meeting was to address ongoing controversies and timely topics in vitamin D research, to review available data related to these topics and controversies, to promote discussion to help resolve lingering issues and ultimately to suggest a research agenda to clarify areas of uncertainty. Several issues from the first conference, held in 2017, were revisited, such as assays used to determine serum 25-hydroxyvitamin D [25(OH)D] concentration, which remains a critical and controversial issue for defining vitamin D status. Definitions of vitamin D nutritional status (i.e. sufficiency, insufficiency and deficiency) were also revisited. New areas were reviewed, including vitamin D threshold values and how they should be defined in the context of specific diseases, sources of vitamin D and risk factors associated with vitamin D deficiency. Non-skeletal aspects related to vitamin D were also discussed, including the reproductive system, neurology, chronic kidney disease and falls. The therapeutic role of vitamin D and findings from recent clinical trials were also addressed. The topics were considered by 3 focus groups and divided into three main areas: 1) "Laboratory": assays and threshold values to define vitamin D status; 2) "Clinical": sources of vitamin D and risk factors and role of vitamin D in non-skeletal disease and 3) "Therapeutics": controversial issues on observational studies and recent randomized controlled trials. In this report, we present a summary of our findings.

Understanding primary parotid squamous cell carcinoma - A systematic review.

INTRODUCTION: The true incidence of primary parotid squamous cell carcinoma (SCC) is unknown and likely overestimated in the literature. The aim of this systematic review is to examine the diagnosis, aetiology and incidence of parotid SCC by analysing studies evaluating primary parotid SCC. METHODS: A systematic search of Medline, EMBASE and Cochrane library was performed. A narrative synthesis was done. RESULTS: A total of 14 observational retrospective studies on primary parotid SCC were included. There are currently no standard criteria for ascertainment of primary parotid SCC. Primary parotid SCC is thought to be due to squamous metaplasia within the ductal epithelium and subsequent invasive squamous carcinoma. Histological features that favour primary disease includes SCC confined to parotid parenchyma with no direct communication to the skin and the absence of mucin. Incidence of primary parotid SCC varied from 1.54 to 2.8 cases per million person-years. Around 30%-86% of patients recorded to have primary parotid SCC on clinical records, when scrutinised, were in fact secondary to parotid lymph node involvement following regional advancement from skin or upper aerodigestive tract SCC. CONCLUSION: Primary parotid SCC is rare and it is currently a diagnosis of exclusion. Thorough clinical assessment including endoscopy, preoperative imaging and the scrutiny of histopathological findings allow for differentiation between primary and secondary SCC within the parotid. This thus affects both initial treatment and subsequent follow-up.

Effects of a simple home exercise program and vitamin D supplementation on health-related quality of life after a hip fracture: a randomized controlled trial.

PURPOSE: To test the effects of vitamin D intervention and a simple home exercise program (HE) on health-related quality of life (HRQL) in the first 12 months after hip fracture. METHODS: HRQL was reported in 173 acute hip fracture patients (mean age 84 years, 79% females, 77% community dwelling) who were enrolled in the 12-month 2 × 2 factorial Zurich Hip Fracture Trial. Pre-fracture HRQL was assessed at baseline (4.2 ± 2.2 days post-surgery) and then again at 6 and 12 months after hip fracture surgery by the EuroQol EQ-5D-3L index value (EQ-5D-3L questionnaire). The effects of vitamin D intervention (2000 vs. 800 IU vitamin D3) and exercise (HE vs. no HE) or of the combined interventions on HRQL were assessed using multivariable-adjusted repeated-measures linear mixed-effects regression models. RESULTS: The EQ-5D-3L index value significantly worsened from 0.71 pre-fracture to 0.57 over 12 months, but the degree of worsening did not differ between individual or combined interventions. However, regarding only the late recovery between 6 and 12 months, the group receiving neither intervention (800 IU/day and no HE) experienced a significant further decline in the EQ-5D-3L index value (adjusted mean change = 0.08 [95% CI 0.009, 0.15], p = 0.03) while all other groups remained stable. CONCLUSION: Hip fractures have a long-lasting negative effect on HRQL up to 12 months after hip fracture. However, HE and/or 2000 IU vitamin D per day may help prevent a further decline in HRQL after the first 6 months following the acute hip fracture event.

Impact of smoking on imiquimod response in patients with vulval intraepithelial neoplasia.

BACKGROUND: Vulval intraepithelial neoplasia (VIN) is a precancerous condition that may progress to invasive malignancy. VIN is associated with human papillomavirus (HPV) infection in most cases, and with inflammatory skin disorders in a smaller proportion of patients. Treatment of VIN has traditionally been surgical excision; however, topical treatments, including imiquimod cream, are becoming increasingly used. Patient factors influencing response to imiquimod therapy, in particular smoking, have not yet been published. AIM: To assess the impact of smoking and other patient characteristics that may influence the treatment response to topical imiquimod for VIN. METHODS: This was a retrospective cohort study of 46 women treated with topical imiquimod for VIN in a single centre dermatology unit from January 2011 to July 2017. RESULTS: Complete clinical resolution of VIN was observed in 28 of 46 patients (61%), but was significantly reduced in the smoking cohort. CONCLUSIONS: Smoking may impair response to imiquimod for VIN, and should be considered when discussing VIN treatment options with patients.

Gender-specific association between dietary acid load and total lean body mass and its dependency on protein intake in seniors.

Diet-related mild metabolic acidosis may play a role in the development of sarcopenia. We investigated the relationship between dietary acid load and total lean body mass in male and female seniors age ≥ 60 years. We found that a more alkaline diet was associated with a higher %TLM only among senior women. INTRODUCTION: The aim of this study was to determine if dietary acid load is associated with total lean body mass in male and female seniors age ≥ 60 years. METHODS: We investigated 243 seniors (mean age 70.3 ± 6.3; 53% women) age ≥ 60 years who participated in the baseline assessment of a clinical trial on vitamin D treatment and rehabilitation after unilateral knee replacement due to severe knee osteoarthritis. The potential renal acid load (PRAL) was assessed based on individual nutrient intakes derived from a food frequency questionnaire. Body composition including percentage of total lean body mass (%TLM) was determined using dual-energy X-ray absorptiometry. Cross-sectional analyses were performed for men and women separately using multivariable regression models controlling for age, physical activity, smoking status, protein intake (g/kg BW per day), energy intake (kcal), and serum 25-hydroxyvitamin D concentration. We included a pre-defined subgroup analysis by protein intake (< 1 g/kg BW day, > 1 g/kg BW day) and by age group (< 70 years, ≥ 70 years). RESULTS: Adjusted %TLM decreased significantly across PRAL quartiles only among women (P trend = 0.004). Moreover, in subgroup analysis, the negative association between the PRAL and %TLM was most pronounced among women with low protein intake (< 1 g/kg BW per day) and age below 70 years (P = 0.002). Among men, there was no association between the PRAL and %TLM. CONCLUSION: The association between dietary acid load and %TLM seems to be gender-specific, with a negative impact on total lean mass only among senior women. Therefore, an alkaline diet may be beneficial for preserving total lean mass in senior women, especially in those with low protein intake.

Inhibition of indoleamine 2,3-dioxygenase activity by fatty acids and prostaglandins: A structure function analysis.

Indoleamine 2,3-dioxygenase-1 (IDO-1) catalyses the first and rate-limiting step in the metabolism of L-tryptophan. Degradation of L-Trp leads to the production of several immunosuppressive metabolites, including N-formyl kynurenine and kynurenine (Kyn). Apart from a normal physiological role, IDO-1 has also been identified to play a crucial role in immune suppression and tumour induced tolerance. Indeed, many primary tumours express high levels of IDO-1 compared to normal cells of the same stroma. IDO-1 is accepted as being an inducible negative regulator of T cell viability, proliferation and activation. As such, IDO-1 has become a target of intense interest for pharmacological inhibition, for the treatment of cancer. We have previously demonstrated that AA and the prostaglandin metabolite, PGD2, repressed the IFNγ mediated activity of IDO-1 in THP-1 cells and human monocytes. In this study, we characterise the structure-function relationship of fatty acids and eicosanoids towards inhibition of IDO-1 activity in THP-1 cells and human monocytes. Using a commercial library of fatty acids, 55% of fatty acids inhibited IDO-1 activity. The activity of individual FAs was affected by chain length, number of double bonds and bond configuration. Interrogation of an AA derived eicosanoid library identified 13 PGs with significant inhibitory activity. A structure-function analysis revealed that the γ position of the cyclopentenone ring, double bond in the α-ß position of the cyclopentenone ring, the presence of multiple OH groups in the side arm and the addition of an ethanolamide group, significantly increased the inhibitory activity of the PGs. Based on this data we have identified the structure of two possible compounds that may be even more potent pharmacological repressors of IDO-1.

Cross-Comparison of Human Wastewater-Associated Molecular Markers in Relation to Fecal Indicator Bacteria and Enteric Viruses in Recreational Beach Waters.

Detection of human wastewater contamination in recreational waters is of critical importance to regulators due to the risks posed to public health. To identify such risks, human wastewater-associated microbial source tracking (MST) markers have been developed. At present, however, a greater understanding of the suitability of these markers for the detection of diluted human wastewater in environmental waters is necessary to predict risk. Here, we compared the process limit of detection (PLOD) and process limit of quantification (PLOQ) of six human wastewater-associated MST markers (Bacteroides HF183 [HF183], Escherichia coli H8 [EC H8], Methanobrevibacter smithiinifH, human adenovirus [HAdV], human polyomavirus [HPyV], and pepper mild mottle virus [PMMoV]) in relation to a fecal indicator bacterium (FIB), Enterococcus sp. 23S rRNA (ENT 23S), and three enteric viruses (human adenovirus serotypes 40/41 [HAdV 40/41], human norovirus [HNoV], and human enterovirus [EV]) in beach water samples seeded with raw and secondary-treated wastewater. Among the six MST markers tested, HF183 was the most sensitive measure of human fecal pollution and was quantifiable up to dilutions of 10-6 and 10-4 for beach water samples seeded with raw and secondary-treated wastewater, respectively. Other markers and enteric viruses were detected at various dilutions (10-1 to 10-5). These MST markers, FIB, and enteric viruses were then quantified in beach water (n = 12) and sand samples (n = 12) from South East Queensland (SEQ), Australia, to estimate the levels of human fecal pollution. Of the 12 sites examined, beach water and sand samples from several sites had quantifiable concentrations of HF183 and PMMoV markers. Overall, our results indicate that while HF183 is the most sensitive measure of human fecal pollution, it should be used in conjunction with a conferring viral marker to avoid overestimating the risk of gastrointestinal illness.IMPORTANCE MST is an effective tool to help utilities and regulators improve recreational water quality around the globe. Human fecal pollution poses significant public health risks compared to animal fecal pollution. Several human wastewater-associated markers have been developed and used for MST field studies. However, a head-to-head comparison in terms of their performance to detect diluted human fecal pollution in recreational water is lacking. In this study, we cross-compared the performance of six human wastewater-associated markers in relation to FIB and enteric viruses in beach water samples seeded with raw and secondary-treated wastewater. The results of this study will provide guidance to regulators and utilities on the appropriate application of MST markers for tracking the sources of human fecal pollution in environmental waters and confer human health risks.

An analysis of incidental and symptomatic pulmonary embolism (PE) in medical oncology patients.

AIM: To determine the incidence of symptomatic versus incidental pulmonary embolism (PE) in oncology patients, characterize the nature and extent of incidental PE and the factors contributing to diagnosis. METHODS: Specialized web search engine was used to identify oncology patients with positive imaging studies for PE. PE identified at staging CT scans were classified as incidental PEs, whereas PE diagnosed by CTPA/VQ scan were classified as symptomatic PEs. RESULTS: A total of 111 patients with PE were identified over the period of three years. Of these, 67 (60%) patients had symptomatic whereas 44 (40%) patients had incidental PE. Most PEs were segmental and non-occlusive irrespective of the type of PE or stage of the disease. Incidence of PE was equal with/without chemotherapy. Platinum-based chemotherapy was more commonly associated with PE. Most patients received anticoagulation irrespective of type of PE. CONCLUSION: Forty percent of the diagnosed PEs were incidental, more common in the metastatic group. This may be due to the increased frequency of staging scans performed in patients with metastatic disease, as well as the inherent disease biology of metastatic compared with localized disease. Further prospective analysis of survival by PE subtype and optimal length of anticoagulation in incidental PE is warranted.

Vitamin D measurement standardization: The way out of the chaos.

Substantial variability is associated with laboratory measurement of serum total 25-hydroxyvitamin D [25(OH)D]. The resulting chaos impedes development of consensus 25(OH)D values to define stages of vitamin D status. As resolving this situation requires standardized measurement of 25(OH)D, the Vitamin D Standardization Program (VDSP) developed methodology to standardize 25(OH)D measurement to the gold standard reference measurement procedures of NIST, Ghent University and CDC. Importantly, VDSP developed protocols for standardizing 25(OH)D values from prior research based on availability of stored serum samples. The effect of such retrospective standardization on prevalence of "low" vitamin D status in national studies reported here for The Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) and the German Health Interview and Examination Survey for Children and Adolescents (KIGGS, 2003-2006) was such that in NHANES III 25(OH)D values were lower than original values while higher in KIGGS. In NHANES III the percentage with values below 30, 50 and 75 nmol/L increased from 4% to 6%, 22% to 31% and 55% to 71%, respectively. Whereas in KIGGS after standardization the percentage below 30, 50, and 70 nmol/L decreased from 28% to 13%, 64% to 47% and 87% to 85% respectively. Moreover, in a hypothetical example, depending on whether the 25(OH)D assay was positively or negatively biased by 12%, the 25(OH)D concentration which maximally suppressed PTH could vary from 20 to 35ng/mL. These examples underscore the challenges (perhaps impossibility) of developing vitamin D guidelines using unstandardized 25(OH)D data. Retrospective 25(OH)D standardization can be applied to old studies where stored serum samples exist. As a way forward, we suggest an international effort to identify key prior studies with stored samples for re-analysis and standardization initially to define the 25(OH)D level associated with vitamin D deficiency (rickets/osteomalacia). Subsequent work could focus on defining inadequacy. Finally, examples reported here highlight the importance of suspending publication of meta-analyses based on unstandardized 25(OH)D results.

Methyl isobutyl ketone-induced hepatocellular carcinogenesis in B6C3F1 mice: A constitutive androstane receptor (CAR)-mediated mode of action.

In a National Toxicology Program (NTP) chronic inhalation study with methyl isobutyl ketone (MIBK), increases in hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were observed in male and female B6C3F1 mice at 1800 ppm. A DNA reactive Mode-of-Action (MOA) for this liver tumor response is not supported by the evidence as MIBK and its major metabolites lack genotoxicity in both in vitro and in vivo studies. Constitutive androstane receptor (CAR) nuclear receptor-mediated activation has been hypothesized as the MOA for MIBK-induced mouse liver tumorigenesis. To further investigate the MOA for MIBK-induced murine liver tumors, male and female B6C3F1, C57BL/6, and CAR/PXR Knockout (KO) mice were exposed to either 0 or 1800 ppm MIBK for 6 h/day, 5 days/week for a total of 10 days. On day 1, mice were implanted with osmotic mini-pumps containing 5-Bromo-2-deoxyuridine (BrdU) 1 h following exposure and humanely euthanized 1-3 h following the final exposure. B6C3F1 and C57BL/6 mice had statistically significant increases in liver weights compared to controls that corresponded with hepatocellular hypertrophy and increased mitotic figures. Hepatocellular proliferation data indicated induction of S-phase DNA synthesis in B6C3F1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to control, and no increase was observed in MIBK exposed CAR/PXR KO mice. Liver gene expression changes indicated a maximally-induced Cyp2b10 (CAR-associated) transcript and a slight increase in Cyp3a11(PXR-associated) transcript in B6C3F1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to controls, but not in Cyp1a1 (AhR-associated) or Cyp4a10 (PPAR-α-associated) transcripts. CAR/PXR KO mice exposed to 1800 ppm MIBK showed no evidence of activation of AhR, CAR, PXR or PPAR-α nuclear receptors via their associated transcripts. MIBK induced hepatic effects are consistent with a phenobarbital-like MOA where the initiating events are activation of the CAR and PXR nuclear receptors and resultant hepatocellular proliferation leading to rodent liver tumors.