Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial.

BACKGROUND: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. PATIENTS AND METHODS: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. RESULTS: In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR). CONCLUSIONS: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer.

BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy. PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast). RESULTS: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031). CONCLUSIONS: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.

Evaluation of the reliability and validity of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) in paediatric cutaneous lupus among paediatric dermatologists and rheumatologists.

BACKGROUND: The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a reliable outcome measure for cutaneous lupus erythematosus (CLE) in adults used in clinical trials. However, it has not been validated in children, limiting clinical trials for paediatric CLE. OBJECTIVES: This study aimed to validate the CLASI in paediatrics. METHODS: Eleven paediatric patients with CLE, six dermatologists and six rheumatologists participated. The physicians were trained to use the CLASI and Physician's Global Assessment (PGA), and individually rated all patients using both tools. Each physician reassessed two randomly selected patients. Within each physician group, the intraclass correlation coefficient (ICC) was calculated to assess the reliability of each measure. RESULTS: CLASI activity scores demonstrated excellent inter- and intrarater reliability (ICC > 0·90), while the PGA activity scores had good inter-rater reliability (ICC 0·73-0·77) among both specialties. PGA activity scores showed excellent (ICC 0·89) and good intrarater reliability (ICC 0·76) for dermatologists and rheumatologists, respectively. Limitations of this study include the small sample size of patients and potential recall bias during the physician rerating session. CONCLUSIONS: CLASI activity measurement showed excellent inter- and intrarater reliability in paediatric CLE and superiority over the PGA. These results demonstrate that the CLASI is a reliable and valid outcome instrument for paediatric CLE.

The 2018 rift eruption and summit collapse of Kilauea Volcano.

In 2018, Kilauea Volcano experienced its largest lower East Rift Zone (LERZ) eruption and caldera collapse in at least 200 years. After collapse of the Pu'u 'O'o vent on 30 April, magma propagated downrift. Eruptive fissures opened in the LERZ on 3 May, eventually extending ~6.8 kilometers. A 4 May earthquake [moment magnitude (M w) 6.9] produced ~5 meters of fault slip. Lava erupted at rates exceeding 100 cubic meters per second, eventually covering 35.5 square kilometers. The summit magma system partially drained, producing minor explosions and near-daily collapses releasing energy equivalent to M w 4.7 to 5.4 earthquakes. Activity declined rapidly on 4 August. Summit collapse and lava flow volume estimates are roughly equivalent-about 0.8 cubic kilometers. Careful historical observation and monitoring of Kilauea enabled successful forecasting of hazardous events.

Child-onset systemic lupus erythematosus is associated with a higher incidence of myopericardial manifestations compared to adult-onset disease.

OBJECTIVES: There are no population-based estimates of the incidence or risk factors for acute cardiac manifestations in children with systemic lupus erythematosus (SLE) to guide screening and diagnostic imaging practices. We estimated the incidence and prevalence of acute cardiac manifestations of child-onset SLE compared to adult-onset SLE and identified factors associated with cardiac diagnoses. METHODS: We identified children (5-17 years) and adults (18-64 years) with incident SLE (≥3 International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 CM) code 710.0, > 30 days apart) using Clinformatics® DataMart (OptumInsight, Eden Prairie, MN) deidentified United States administrative claims (2000-2013). We calculated incidence and prevalence of three outcomes: ≥ 1 diagnosis code for (1) pericarditis and/or myocarditis, (2) endocarditis, or (3) valvular insufficiency. Negative binomial regression was used to identify characteristics associated with cardiac diagnoses in children and determine whether SLE onset in childhood vs adulthood was independently associated with cardiac involvement. RESULTS: There were 297 children and 6927 adults with new-onset SLE. A total of 17.8% of children had ICD-9 CM codes for acute cardiac diagnoses, the incidence of which were highest in the first year after SLE diagnosis (12.2 per 100 person-years). African American race (incidence rate ratio (IRR) 6.6, 95% confidence interval (CI) (2.9, 15.0), p < 0.01) and nephritis (IRR 7.0, 95% CI (2.6, 18.6), p < 0.01) were associated with acute cardiac diagnoses in children. Child-onset disease was independently associated with a 4.4-fold higher rate of pericarditis or myocarditis compared to adult-onset SLE after adjustment for other disease and demographic characteristics (95% CI (2.4, 8.0), p < 0.01). CONCLUSION: This study establishes baseline estimates of the incidence and prevalence of pericarditis and myocarditis in child-onset SLE, which is substantially higher than that of adult-onset SLE. Prospective echocardiographic evaluations are needed to validate incidence measures and characterize the natural history of acute cardiac manifestations in child-onset SLE, as well as identify risk factors for poor cardiac outcomes to inform screening and management.

Use of echocardiography at diagnosis and detection of acute cardiac disease in youth with systemic lupus erythematosus.

Objectives There are no guidelines on the use of echocardiography to detect cardiac manifestations of childhood-onset systemic lupus erythematosus (SLE). We quantify the prevalence of acute cardiac disease in youth with SLE, describe echocardiogram utilization at SLE diagnosis, and compare regional echocardiogram use with incident cardiac diagnoses. Methods Using the Clinformatics® DataMart (OptumInsight, Eden Prairie, MN) de-identified United States administrative database from 2000 to 2013, we identified youth ages 5-24 years with new-onset SLE (≥3 ICD-9 SLE codes 710.0, > 30 days apart) and determined the prevalence of diagnostic codes for pericardial disease, myocarditis, endocarditis, and valvular insufficiency. Multiple logistic regression was used to identify factors associated with echocardiography during the baseline period, up to one year before or six months after SLE diagnosis. We calculated a regional echocardiogram utilization index, which is the ratio of observed use over the mean predicted probability based on all available baseline characteristics. Spearman's rank correlation coefficient was used to evaluate the association between regional echocardiogram utilization indices and percentage of imaged youth diagnosed with their first cardiac manifestation following echocardiography. Results Among 699 youth with new-onset SLE, 18% had ≥ 1 diagnosis code for acute cardiac disease, of which valvular insufficiency and pericarditis were most common. Twenty-five percent of all youth underwent echocardiogram during the baseline period. Regional echocardiogram use was positively correlated with the percentage of imaged youth found to have cardiac disease (ρ = 0.71, p = 0.05). There was up to a five-fold difference in adjusted odds of baseline echocardiography between low- and high-utilizing regions (OR = 0.19, p = 0.007). Conclusion Nearly one-fifth of youth with new-onset SLE have acute cardiac manifestations; however, use of echocardiograms at SLE diagnosis is highly variable. There may be incremental diagnostic value to early use of echocardiography, but prospective studies are needed to determine whether greater use of echocardiograms modifies outcomes.

Training reproductive health providers to talk about intimate partner violence and reproductive coercion: an exploratory study.

To explore the effect of provider communication-skills training on frequency of intimate partner violence (IPV) and reproductive coercion (RC) assessment, four family planning clinics were randomized to IPV/RC communication-skills building workshop or standard knowledge-based IPV/RC training and compared to historical controls from the same clinics (before any training). Female patients aged 16-29 completed after-visit surveys. Primary outcomes included provider discussion about IPV/RC, receipt of safety card with IPV/RC resources and patient disclosure of IPV/RC. Chi-square tests were used to compare groups that received training and historical controls. Participants (training: n = 103; historical control: n = 576) were predominantly white with mean age of 22. More patients reported discussion about healthy relationships in both training groups (78-90%) compared to historical controls (49-52%, P < 0.001 for both). Discussion on birth control sabotage and pregnancy coercion was infrequent with patient-participants in both groups (6-17 and 4-13%, respectively). More patients in the clinics that received training reported receiving a safety card (72-84%) as compared to historical controls (9%, P < 0.001 for both). Overall, in this exploratory study, both communication-skills and standard training improved frequency of IPV communication when compared to historical controls but with few differences when compared to each other.

Do stillbirth, miscarriage, and termination of pregnancy increase risks of attempted and completed suicide within a year? A population-based nested case-control study.

OBJECTIVE: To investigate the risks of attempted and completed suicide in women who experienced a stillbirth, miscarriage, or termination of pregnancy within 1 year postnatally and compare this risk with that in women who experienced a live birth. DESIGN: A nested case-control study. SETTING: Linking three nationwide population-based data sets in Taiwan: the National Health Insurance Research Database, the National Birth Registry and the National Death Registry. SAMPLE: In all, 485 and 350 cases of attempted and completed suicide, respectively, were identified during 2001-11; for each case, ten controls were randomly selected and matched to the cases according to the age and year of delivery. METHODS: Conditional logistic regression. MAIN OUTCOME MEASURES: Attempted and completed suicidal statuses were determined. RESULTS: The rates of attempted suicide increased in the women who experienced fetal loss. The risk of completed suicide was higher in women who experienced a stillbirth [adjusted odds ratio (aOR) 5.2; 95% CI 1.77-15.32], miscarriage (aOR 3.81; 95% CI 2.81-5.15), or termination of pregnancy (aOR 3.12; 95% CI 1.77-5.5) than in those who had a live birth. Furthermore, the risk of attempted suicide was significantly higher in women who experienced a miscarriage (aOR 2.1; 95% CI 1.66-2.65) or termination of pregnancy (aOR 2.5; 95% CI 1.63-3.82). In addition to marital and educational statuses, psychological illness increased the risk of suicidal behaviour. CONCLUSIONS: The risk of suicide might increase in women who experience fetal loss within 1 year postnatally. Healthcare professionals and family members should enhance their sensitivity to care for possible mental distress, particularly for women who have experienced a stillbirth. TWEETABLE ABSTRACT: Suicide risk increased in women who had a stillbirth, miscarriage, or termination of pregnancy within 1 year postnatally.

Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study.

BACKGROUND: Trastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1 + docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1 + docetaxel ± pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC). PATIENTS AND METHODS: Phase Ib (part 1) explored dose escalation, with T-DM1 + docetaxel administered for greater than or equal to six cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered less than or equal to six cycles of T-DM1 + docetaxel or T-DM1 + docetaxel + pertuzumab. Phase IIa explored the MTDs identified in phase Ib. RESULTS: Administered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m(2) in MBC. In LABC, the MTD was 100 mg/m(2) docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony-stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg) + pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m(2) with G-CSF support. Neutropenia was the most common grade 3-4 adverse event (AE; MBC, 72% and LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced AEs requiring dose modification. In MBC (median prior systemic agents = 5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3-93.2) and the median progression-free survival was 13.8 months (range, 1.6-33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1-71.5). Pharmacokinetic analyses indicated a low risk of drug-drug interaction between T-DM1 and docetaxel. CONCLUSIONS: T-DM1 combined with docetaxel ± pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced AEs requiring dose reductions with these T-DM1 combinations. CLINICALTRIALSGOV IDENTIFIER: NCT00934856.

Emergence of a sylvatic enzootic formosan ferret badger-associated rabies in Taiwan and the geographical separation of two phylogenetic groups of rabies viruses.

Taiwan had been declared rabies-free in humans and domestic animals for five decades until July 2013, when surprisingly, three Formosan ferret badgers (FB) were diagnosed with rabies. Since then, a variety of wild carnivores and other wildlife species have been found dead, neurologically ill, or exhibiting aggressive behaviors around the island. To determine the affected animal species, geographic areas, and environments, animal bodies were examined for rabies by direct fluorescent antibody test (FAT). The viral genomes from the brains of selected rabid animals were sequenced for the phylogeny of rabies viruses (RABV). Out of a total of 1016 wild carnivores, 276/831 (33.2%) Formosan FBs were FAT positive, with occasional biting incidents in 1 dog and suspected spillover in 1 house shrew. All other animals tested, including dogs, cats, bats, mice, house shrews, and squirrels, were rabies-negative. The rabies was badger-associated and confined to nine counties/cities in sylvatic environments. Phylogeny of nucleoprotein and glycoprotein genes from 59 Formosan FB-associated RABV revealed them to be clustered in two distinct groups, TWI and TWII, consistent with the geographic segregation into western and eastern Taiwan provided by the Central Mountain Range and into northern rabies-free and central-southern rabies-affected regions by a river bisecting western Taiwan. The unique features of geographic and genetic segregation, sylvatic enzooticity, and FB-association of RABV suggest a logical strategy for the control of rabies in this nation.

Alteration by p11 of mGluR5 localization regulates depression-like behaviors.

Mood disorders and antidepressant therapy involve alterations of monoaminergic and glutamatergic transmission. The protein S100A10 (p11) was identified as a regulator of serotonin receptors, and it has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors. Here we report that p11 can also regulate depression-like behaviors via regulation of a glutamatergic receptor in mice. p11 directly binds to the cytoplasmic tail of metabotropic glutamate receptor 5 (mGluR5). p11 and mGluR5 mutually facilitate their accumulation at the plasma membrane, and p11 increases cell surface availability of the receptor. Whereas p11 overexpression potentiates mGluR5 agonist-induced calcium responses, overexpression of mGluR5 mutant, which does not interact with p11, diminishes the calcium responses in cultured cells. Knockout of mGluR5 or p11 specifically in glutamatergic neurons in mice causes depression-like behaviors. Conversely, knockout of mGluR5 or p11 in GABAergic neurons causes antidepressant-like behaviors. Inhibition of mGluR5 with an antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), induces antidepressant-like behaviors in a p11-dependent manner. Notably, the antidepressant-like action of MPEP is mediated by parvalbumin-positive GABAergic interneurons, resulting in a decrease of inhibitory neuronal firing with a resultant increase of excitatory neuronal firing. These results identify a molecular and cellular basis by which mGluR5 antagonism achieves its antidepressant-like activity.

An analysis of attitude toward infant sleep safety and SIDS risk reduction behavior among caregivers of newborns and infants.

OBJECTIVE: To explore beliefs and attitude toward infant sleep safety and sudden infant death syndrome (SIDS) risk reduction behaviors among caregivers of newborns and infants. STUDY DESIGN: A convenience sample comprised of 121 caregivers of newborns at Staten Island University Hospital completed a questionnaire. RESULTS: Despite an overall favorable attitude toward safe sleep practices, a majority disagreed with use of pacifiers (53%) and believed that swaddling (62%) as well as the use of home monitors (59%) are acceptable practices. The caregivers who recalled being taught about safe sleep had higher perception of infant vulnerability (P<0.001), more confidence in their ability to implement safe sleep behaviors (P<0.0006) and stronger belief that safe sleep behaviors are effective (P<0.01). CONCLUSION: Active caregiver education may result in more effective demonstration of safe sleep and SIDS risk reduction behaviors. Further study is needed to assess if favorable attitudes toward safe sleep practices correlate with actual demonstrated behaviors.

Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer.

Signal transducer and activator of transcription (STAT) 3 regulates many cardinal features of cancer including cancer cell growth, apoptosis resistance, DNA damage response, metastasis, immune escape, tumor angiogenesis, the Warburg effect and oncogene addiction and has been validated as a drug target for cancer therapy. Several strategies have been used to identify agents that target Stat3 in breast cancer but none has yet entered into clinical use. We used a high-throughput fluorescence microscopy search strategy to identify compounds in a drug-repositioning library (Prestwick library) that block ligand-induced nuclear translocation of Stat3 and identified piperlongumine (PL), a natural product isolated from the fruit of the pepper Piper longum. PL inhibited Stat3 nuclear translocation, inhibited ligand-induced and constitutive Stat3 phosphorylation, and modulated expression of multiple Stat3-regulated genes. Surface plasmon resonance assay revealed that PL directly inhibited binding of Stat3 to its phosphotyrosyl peptide ligand. Phosphoprotein antibody array analysis revealed that PL does not modulate kinases known to activate Stat3 such as Janus kinases, Src kinase family members or receptor tyrosine kinases. PL inhibited anchorage-independent and anchorage-dependent growth of multiple breast cancer cell lines having increased pStat3 or total Stat3, and induced apoptosis. PL also inhibited mammosphere formation by tumor cells from patient-derived xenografts. PL's antitumorigenic function was causally linked to its Stat3-inhibitory effect. PL was non-toxic in mice up to a dose of 30 mg/kg/day for 14 days and caused regression of breast cancer cell line xenografts in nude mice. Thus, PL represents a promising new agent for rapid entry into the clinic for use in treating breast cancer, as well as other cancers in which Stat3 has a role.

Population-based comparison of prognostic factors in invasive micropapillary and invasive ductal carcinoma of the breast.

BACKGROUND: Invasive micropapillary carcinoma (IMPC) is a variant of breast carcinoma with a higher propensity for lymph node metastases compared with invasive ductal carcinoma (IDC). METHODS: Retrospective analysis of 636 IMPC and 297 735 IDC cases in the Surveillance, Epidemiology and End RESULTS database comparing disease-specific survival (DSS) and overall survival (OS) between IMPC and IDC. RESULTS: A higher percentage of IMPC cases (52.0%) had nodal metastases compared with IDC cases (34.6%). The 5-year DSS and OS for IMPC was 91.8% and 82.9%, respectively compared with 88.6% and 80.5% for IDC, respectively. For both IMPC and IDC, oestrogen-receptor positivity was associated with better survival, while having four or more positive lymph nodes or larger tumour size correlated with worse survival. Radiotherapy provided a survival benefit for both histological types. CONCLUSIONS: Despite IMPC's higher propensity for lymph node metastasis, IMPC has DSS and OS that compare favourably with IDC.

Microdecompression in spinal stenosis: a review.

A goal of surgical treatment is to effectively treat pathology with minimizing injury of normal tissue. Microdecompression techniques are traditionally defined as procedures performed with a small incision using magnification and minimization of destruction to non-pathologic tissues. The good candidates are patients diagnosed of spinal stenosis who fail an appropriate course of non-operative management. These patients should have radiographic evidence of localized spinal stenosis without associated structural instability. Various techniques of microdecompression have been introduced until now. Although more technically challenging, microdecompression have produced long-lasting favorable outcomes via proper patient selection and surgeon training. In addition, the minimally invasive access techniques can greaten the results of microdecompression in the acute postoperative period. Through advanced minimally invasive techniques, the microdecompression will evolve in the future for sure.

Palliative care education in gynecologic oncology: a survey of the fellows.

INTRODUCTION: Gynecologic oncologists regularly care for patients at the end of life, yet little is known about their training or preparedness to deal with issues of palliative care. We sought to examine the training provided to gynecologic oncology fellows as well as their perceived preparedness to provide palliative care. METHODS: A self-administered survey was distributed to all fellows enrolled in all gynecologic oncology fellowships during the 2009 academic year. The instrument assessed attitudes, training, experience, and preparedness regarding caring for patients at the end of life. Descriptive, bivariate and multivariable analyses were performed. RESULTS: Sixty-one percent (103/168) of fellows completed the survey. Most (89%) feel that palliative care is integral to their training, but few (11%) have had any palliative care training, including either a rotation or fellowship. Using a scale of 1-10, fellows rated teaching quality on two common training opportunities, specifically managing postoperative complications (7.8) and endometrial cancer patients (8.7), as significantly higher than teaching on managing patients at the end of life (5.5; p<0.001). Fellows rated the quality of end of life teaching as significantly lower than overall teaching (55% vs. 92%; p=0.001). Their self-assessment regarding overall preparedness to deal with end of life issues was associated with higher end of life teaching quality and experience caring for more than 10 dying patients. CONCLUSIONS: The quantity and quality of training in palliative care are lower compared to other common procedural and oncological issues. Gynecologic oncology fellowship programs need to incorporate a palliative care training curriculum.

Rapid acceleration leads to rapid weakening in earthquake-like laboratory experiments.

After nucleation, a large earthquake propagates as an expanding rupture front along a fault. This front activates countless fault patches that slip by consuming energy stored in Earth's crust. We simulated the slip of a fault patch by rapidly loading an experimental fault with energy stored in a spinning flywheel. The spontaneous evolution of strength, acceleration, and velocity indicates that our experiments are proxies of fault-patch behavior during earthquakes of moment magnitude (M(w)) = 4 to 8. We show that seismically determined earthquake parameters (e.g., displacement, velocity, magnitude, or fracture energy) can be used to estimate the intensity of the energy release during an earthquake. Our experiments further indicate that high acceleration imposed by the earthquake's rupture front quickens dynamic weakening by intense wear of the fault zone.

In the face of chronic aspiration, prolonged ischemic time exacerbates obliterative bronchiolitis in rat pulmonary allografts.

Aspiration of gastric fluid into the lung mediates the development of obliterative bronchiolitis (OB) in orthotopic WKY-to-F344 rat pulmonary transplants that have been subjected to immunosuppression with cyclosporine. However, the contribution of ischemic time to this process remains unknown. In this study, the effect of long (n = 16) and short (n = 12) ischemic times (average of 6 h and of 73 min, respectively) on rat lung transplants receiving aspiration of gastric fluid was assessed. Long ischemic times (LIT) led to significantly (p < 0.05) greater development of OB (ratio of OB lesions/total airways = 0.45 ± 0.07, mean ± standard error) compared to short ischemic times (ratio = 0.19 ± 0.05). However, the development of OB was dependent on aspiration, as controls receiving aspiration with normal saline showed little development of OB, regardless of ischemic time (p < 0.05). These data suggest that LIT, while insufficient by itself to lead to OB, works synergistically with aspiration of gastric fluid to exacerbate the development of OB.

Prenatal and postnatal probiotics reduces maternal but not childhood allergic diseases: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The prevalence of atopic diseases has increased rapidly in recent decades globally. The administration of probiotics to reduce gastrointestinal inflammation has been popular, but its role in the prevention or treatment of allergic disease remains controversial. This study evaluated the effectiveness of prenatal and postnatal probiotics in the prevention of early childhood and maternal allergic diseases. METHODS: In a prospective, double-blind, placebo-controlled clinical trial, pregnant women with atopic diseases determined by history, total immunoglobulin (Ig)E > 100 kU/L, and/or positive specific IgE were assigned to receive either probiotics (Lactobacillus GG; ATCC 53103; 1 × 10(10) colony-forming units daily) or placebo from the second trimester of pregnancy. Both of clinical evaluation performed by questionnaires concerning any allergic symptoms and plasma total IgE, and allergen-specific IgE were obtained in high-risk parents and children at 0, 6, 18, and 36 months of age. The primary and secondary outcomes were the point and cumulative prevalence of sensitization and developing of allergic diseases, and improvement of maternal allergic symptom score and plasma immune parameters before and after intervention, respectively. RESULTS: In total, 191 pregnant women (LGG group, n = 95; control group, n = 96) were enrolled. No significant effects of prenatal and postnatal probiotics supplementation on sensitization, development of allergic diseases, and maternal IgE levels between placebo and LGG groups. Symptoms of maternal allergic scores improved significantly in the LGG group (P = 0.002). Maternal allergic diseases improvement was more prominent in pregnant women with IgE > 100 kU/L (P = 0.01) and significantly associated with higher interleukin-12p70 levels (P = 0.013). CONCLUSIONS: LGG administration beginning at the second trimester of pregnancy reduced the severity of maternal allergic disease through increment of Th1 response, but not the incidence of childhood allergic sensitization or allergic diseases (ClinicalTrials.govnumber, IDNCT00325273).