The association of smoking with ultrasound-measured kidney dimensions
.

PURPOSE: Ultrasound is considered a preferred first-line imaging technique for the assessment of kidney function. The potential relationship between tobacco smoke exposure and ultrasound-measured renal characteristics has yet to be explored. We hypothesized that exposure to tobacco smoke would be associated with reduced kidney dimensions. MATERIALS AND METHODS: This was a cross-sectional study that included all individuals over age 18 at a single site in Mojokerto, Indonesia. A questionnaire was used to assess prior history and environmental exposure, and blinded evaluators performed ultrasound assessments. Six kidney parameters (length, width, and parenchymal thickness of each kidney) were considered as dependent variables, and statistical relationships were assessed using multivariate analysis. Echogenicity was evaluated using a 5-point grading scale described previously. RESULTS: Of the 445 participants assessed, a total of 138 male and 269 female subjects were included in the final analysis. There was a statistically significant association between kidney measures and the following independent variables: pack years smoking (p < 0.001), height (p < 0.001), weight (p < 0.001), and beginning to smoke at the age of 25 or younger (p < 0.001). There was not a statistically significant association between kidney measures and hypertension (p > 0.05) or diabetes (p > 0.05). Echogenicity was similar among all smoking groups. CONCLUSION: Kidney dimensions were decreased in individuals with increased smoking history. This association is notable, particularly given that statistically significant associations were not observed between renal dimensions and hypertension or diabetes. The null findings using echogenicity are consistent with previous studies.

Evaluation of a point-of-care ultrasound curriculum taught by medical students for physicians, nurses, and midwives in rural Indonesia.

PURPOSE: In the Indonesian health-care system, nurses and midwives often serve as the primary health-care providers due to physician shortages. Seeking to address the need for medical care in resource-limited environments, some have advocated for portable equipment in the hands of health-care providers. We hypothesized that medical students are able to effectively teach point-of-care ultrasound (POCUS) to physicians, nurses, and midwives in rural Indonesia. METHODS: We conducted a prospective, observational study using health-care practitioners from a clinic and accredited school for nursing and midwifery in Mojokerto, East Java, Indonesia. Enrolled practitioners took part in a 4-week POCUS course followed by postinstructional testing. RESULTS: A total of 55 health-care practitioners completed the course. This included 19 physicians, 13 nurses, and 19 midwives. Of the 55 clinicians, 43 (72%) passed the course and 12 (28%) failed. CONCLUSIONS: Physicians, nurses, and midwives in rural Indonesia showed significant acquisition of ultrasound (US) knowledge and skills following a 4-week US course. Following training, all three groups displayed skills in practical US use during a postcourse practical examination. This is one of the first studies to assess the efficacy of medical students teaching POCUS to midwives and nurses.

Sex differences in the association of cutaneous melanoma incidence rates and geographic ultraviolet light exposure.

BACKGROUND: Cutaneous melanoma (CM) incidence rates continue to increase, and the reasons are unknown. Previously, we reported a unique age-specific sex difference in melanoma that suggested additional causes other than solar ultraviolet (UV) radiation. OBJECTIVE: This study attempted to understand whether and how UV radiation differentially impacts the CM incidence in men and women. METHODS: CM data and daily UV index (UVI) from 31 cancer registries were collected for association analysis. A second dataset from 42 US states was used for validation. RESULTS: There was no association between log-transformed female CM rates and levels of UVI, but there was a significant association between male rates and UVI and a significant association between overall rates and UVI. The 5-year age-specific rate-UVI association levels (represented by Pearson's coefficient ρ) increased with age in men, but age-specific ρ levels remained low and unchanged in women. The significant rate-UVI association in men and nonassociation in women was validated in a population of white residents of the United States. LIMITATIONS: Confounders, including temperature and latitude, are difficult to separate from UVI. CONCLUSIONS: Ambient UVI appears to be associated with melanoma incidence in males but not in females.

Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes.

PURPOSE: Cardiovascular (CV) diseases in type 2 diabetes (T2DM) represent an enormous burden with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a new antidiabetic class that improves glucose control, as well as body weight and blood pressure with no increased risk of hypoglycemia. The first CV outcome study terminated with empagliflozin, a specific SGLT2 inhibitor, has shown a reduction in CV mortality and in heart failure hospitalization, suggesting a beneficial impact on cardiac function which remains to be demonstrated. This study was designed to examine the chronic effect of empagliflozin on left ventricular (LV) systolic and diastolic functions in a genetic model of T2DM, ob/ob mice. METHODS AND RESULTS: Cardiac phenotype was characterized by echocardiography, in vivo hemodynamics, histology, and molecular profiling. Our results demonstrate that empagliflozin significantly lowered HbA1c and slightly reduced body weight compared to vehicle treatment with no obvious changes in insulin levels. Empagliflozin also improved LV maximum pressure and in vivo indices of diastolic function. While systolic function was grossly not affected in both groups at steady state, response to dobutamine stimulation was significantly improved in the empagliflozin-treated group, suggesting amelioration of contractile reserve. This was paralleled by an increase in phospholamban (PLN) phosphorylation and increased SERCA2a/PLN ratio, indicative of enhanced SERCA2a function, further supporting improved cardiac relaxation and diastolic function. In addition, empagliflozin reconciled diabetes-associated increase in MAPKs and dysregulated phosphorylation of IRS1 and Akt, leading to improvement in myocardial insulin sensitivity and glucose utilization. CONCLUSION: The data show that chronic treatment with empagliflozin improves diastolic function, preserves calcium handling and growth signaling pathways and attenuates myocardial insulin resistance in ob/ob mice, findings suggestive of a potential clinical utility for empagliflozin in the treatment of diastolic dysfunction.

Injury and Mortality Profiles in Level II and III Trauma Centers.

BACKGROUND: While the benefit of admission to trauma centers compared to non-trauma centers is well-documented and differences in outcomes between Level-I and Level-II trauma centers are well-studied, data on the differences in outcomes between Level-II trauma centers (L2TCs) and Level-III trauma centers (L3TCs) are scarce. OBJECTIVES: We sought to compare mortality risk between patients admitted to L2TCs and L3TCs, hypothesizing no difference in mortality risk for patients treated at L3TCs compared to L2TCs. METHODS: A retrospective analysis of the 2016 Trauma Quality Improvement Program (TQIP) database was performed. Patients aged 18+ years were divided into 2 groups, those treated at American College of Surgeons (ACS) verified L2TCs and L3TCs. RESULTS: From 74,486 patients included in this study, 74,187 (99.6%) were treated at L2TCs and 299 (.4%) at L3TCs. Both groups had similar median injury severity scores (ISSs) (10 vs 10, P < .001); however, L2TCs had a higher mean ISS (14.6 vs 11.9). There was a higher mortality rate for L2TC patients (6.0% vs 1.7%, P = .002) but no difference in associated risk of mortality between the 2 groups (OR .46, CI .14-1.50, P = .199) after adjusting predictors of mortality. L2TC patients had a longer median length of stay (5.0 vs 3.5 days, P < .001). There was no difference in other outcomes including myocardial infarction (MI) and cerebrovascular accident (CVA) (P > .05). DISCUSSION: Patients treated at L2TCs had a longer LOS compared to L3TCs. However, after controlling for covariates, there was no difference in associated mortality risk between L2TC and L3TC patients.

Luteolin inhibits melanoma growth in vitro and in vivo via regulating ECM and oncogenic pathways but not ROS.

Luteolin inhibited growth of several cancer cells in vitro in previous studies, with limited in vivo studies, and no comprehensive understanding of molecular mechanisms at genomics level. This study identified luteolin as an effective agent to inhibit melanoma cell growth in vitro and in vivo. Molecular studies and genomic profiling were used to identify the mechanism of action of luteolin in melanoma cells. As a ROS (reactive oxygen species) scavenger, luteolin unexpectedly induced ROS; but co-treatment with antioxidants NAC or mito-TEMPO did not rescue cell growth inhibition, although the levels of ROS levels were reduced. Next, we profiled luteolin-induced differentially expressed genes (DEGs) in 4 melanoma cell lines using RNA-Seq, and performed pathway analysis using a combination of bioinformatics software including PharmetRx which was especially effective in discovering pharmacological pathways for potential drugs. Our results show that luteolin induces changes in three main aspects: the cell-cell interacting pathway (extracellular matrix, ECM), the oncogenic pathway and the immune response signaling pathway. Based on these results, we further validated that luteolin was especially effective in inhibiting cell proliferation when cells were seeded at low density, concomitantly with down-regulation of fibronectin accumulation. In conclusion, through extensive DEG profiling in a total of 4 melanoma cell lines, we found that luteolin-mediated growth inhibition in melanoma cells was perhaps not through ROS induction, but likely through simultaneously acting on multiple pathways including the ECM (extracellular matrix) pathway, the oncogenic signaling and the immune response pathways. Further investigations on the mechanisms of this promising compound are warranted and likely result in application to cancer patients as its safety pharmacology has been validated in autism patients.

Management of unstable pertrochanteric fractures, evaluation of forgotten treatment options.

INTRODUCTION: Unstable trochanteric fractures are challenging with a high rate of implant failure and re-operation. Cephalomedullary nails proved to be a rational management choice for these injuries, yet other management options have not been well assessed. The aim of this study was to compare the use of DHS with trochanteric stabilizing plate (TSP) and proximal femoral locked plate (PFLP) in unstable pertrochanteric fractures. METHODS: This randomized controlled trial (RCT) included 40 patients (22 males, 18 females) with unstable pertrochanteric fractures (AO/OTA 31A2.2/A2.3). The patients were randomized into group 1 managed by DHS with TSP while group 2 was managed by PFLP. All patients were followed up for 1 year. Patients were assessed radiographically and clinically using Harris hip score (HHS) at 3, 6 and 12 months. Operative time, estimated blood loss and time to union were also compared. RESULTS: The difference of intra-operative variables, including operative time and intra-operative blood loss, between both groups was statistically insignificant. Time to bony union was faster in the first group with a statistically significant P value (p = 0.04). Functional outcome per HHS was significantly better in group 1 (p < 0.01) and implant failure in group 1 occurred statistically lesser (p < 0.01). DISCUSSION: DHS with TSP appears to be a good option of management for unstable pertrochanteric fractures. In contrast, the use of PFLP in unstable pertrochanteric fractures in the elderly does not appear to be a good alternative.

Obese trauma patients have increased need for dialysis.

PURPOSE: Obesity is a risk factor for the development of acute kidney injury but its effect on the need for dialysis in trauma has not been elucidated. Additionally, the contribution that obesity has towards risk of mortality in trauma is unclear. We hypothesized that patients with a higher body mass index (BMI) will have a higher risk for need of dialysis and mortality after trauma. METHODS: This is a retrospective analysis using the National Trauma Data Bank. All patients ≥ 8 years old were grouped based on BMI: normal (18.5-24.99 kg/m2), obese (30-34.99 kg/m2), severely obese (35-39.99 kg/m2) and morbidly obese (≥ 40 kg/m2). The primary outcome was hemodialysis initiation. The secondary outcome was mortality during the index hospitalization. RESULTS: From 988,988 trauma patients, 571,507 (57.8%) had a normal BMI, 233,340 (23.6%) were obese, 94,708 (9.6%) were severely obese, and 89,433 (9.0%) were morbidly obese. The overall rate of hemodialysis was 0.3%. After adjusting for covariates, we found that obese (OR 1.36, CI 1.22-1.52, p < 0.001), severely obese (OR 1.89, CI 1.66-2.15, p < 0.001) and morbidly obese (OR 2.04, CI 1.82-2.29, p < 0.001) patients had a stepwise increased need for hemodialysis after trauma. Obese patients had decreased (OR 0.92, CI 0.88-0.95, p < 0.001), severely obese had similar (OR 1.02, CI 0.97-1.08, p = 0.50) and morbidly obese patients had increased (OR 1.06, CI 1.01-1.12, p = 0.011) risk of mortality after trauma. CONCLUSIONS: Obesity was associated with an increased risk for dialysis after trauma. Mortality risk was reduced in obese, similar in severely obese, and increased in morbidly obese trauma patients suggesting an inflection threshold BMI for risk of mortality in trauma.

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma.

BACKGROUND: Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. METHODS: The cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non-genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. RESULTS: Downregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors. CONCLUSIONS: The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy-resistant cancer.