Miracle-dz/UniFAR-FTUs huggingface dataset:
A semi-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) model of thrombocytopenia (TCP) characterizing the effect of trastuzumab-DM1 (T-DM1) on platelet counts in patients with HER2-positive MBC.

605 Background: T-DM1 is an antibody-drug conjugate in development for HER2-positive MBC. In clinical trials of single-agent T-DM1 for heavily pretreated patients (pts), TCP was the dose-limiting toxicity. TCP was generally transient, reversible and not associated with serious hemorrhage, with nadirs by day 8 post-treatment. In some pts, platelet (plt) time profiles drifted slowly down after multiple cycles of T-DM1, though development of grade ≥3 TCP was infrequent. METHODS A semi-physiologic population PK/PD model with transit compartments mimicking plt development and circulation was fit to the concentration-plt-time data from the phase I dose escalation study (TDM3569g; N=52) and a phase II study of single-agent T-DM1 (3.6 mg/kg q3w; TDM4258g; N=112). The rate and extent of plt drift was modeled as a time effect on the proliferation pool. NONMEM software was used for the modeling analyses, with a mixture model approach used to identify pt plt drifts. A separate phase II study (3.6 mg/kg; TDM4374g; N=110) was used for model validation. RESULTS The PK/PD model described the data well and predicted the 9% incidence of grade ≥3 TCP observed in the validation dataset (TDM4374g). The model also predicts that downward drifting plt profiles will eventually stabilize. In the model dataset, plt profiles from 25% of pts drifted downward much more rapidly than the rest of pts; these stabilized by 8 treatment cycles to typically 50% of the original baseline plt count. In 4374g, the overall plt response pattern was similar, with a subset of pts' plt profiles drifting then stabilizing by 8 treatment cycles. Pt baseline characteristics were not significantly correlated with plt kinetics. CONCLUSIONS The model accurately reflects clinical observations of plt counts during T-DM1 treatment and supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose, requiring minimal delays/reductions for TCP. In addition, the model supports partial depletion of the plt proliferation pool as a mechanism for the downward drift in plt count. Plt response to T-DM1 could not be predicted a priori from baseline characteristics.
ICI 182,780 (Faslodex™)

The nonsteroidal antiestrogen tamoxifen is well established as an effective treatment for patients with breast carcinoma, both for the treatment of metastatic disease and as an adjuvant to surgery for patients with primary breast carcinoma. In addition to exerting antagonistic effects on the estrogen receptor, tamoxifen and its derivatives act as partial agonists on certain tissues. These agonistic effects, for example, endometrial stimulation and stimulation of tumor growth after previous response to tamoxifen, may limit their clinical efficacy. ICI 182,780 (Faslodex™) from AstraZeneca (Cheshire, United Kingdom) is a novel, steroidal estrogen antagonist that was designed to be devoid of estrogen agonist activity in preclinical models.
Triple negative breast cancer: current understanding of biology and treatment options

Purpose of review We have made remarkable advances in treatment of breast cancer with combination chemotherapies, hormonal therapies, and modern targeted therapies. Triple negative breast cancers carry a poor prognosis, however, and they are insensitive to most available hormonal or targeted therapeutic agents thus far developed. A better understanding of pathophysiology, natural history, and currently available treatment options is necessary to improve outcomes of patients with triple negative breast cancer. Recent findings Gene expression profiling has allowed us to classify breast cancers into five subtypes based upon distinctive gene expression signatures. This subtyping is prognostic, and the recent literatures suggest that these ‘molecular portraits’ may be used to predict treatment outcomes in the future. Summary As we prepare for an era of targeted and individualized medicine, limited understanding of triple negative breast cancer biology presents a challenge in developing novel therapies. Identification of more molecular predictive signatures and their prospective validation will enable us to characterize triple negative breast cancers better and design optimal treatment modalities.
Mental health and resilience at older ages: bouncing back after adversity in the British Household Panel Survey

Background: Resilience is having good outcomes despite adversity and risk and could be described in terms of preserving the same level of the outcome or rebounding back to that level after an initial set back. Using the latter definition, resilience as “bouncing back”, this paper aims (1) to identify those members of a panel survey who demonstrated resilience, and (2) to identify the characteristics of the resilient individuals and the predictors of their resilience. Methods: The study subjects were the 3581 participants in the British Household Panel Survey, selected from waves 1–14, who satisfied three requirements: exposure to an adversity; availability of consecutive General Health Questionnaire (GHQ)-12 scores; aged 50 or more years. The primary outcome variable was resilience, operationalised as a GHQ-12 score that increased after exposure to adversity and returned to its pre-exposure level in the next (after 1 year) wave of the survey. The adversities were: functional limitation; bereavement or marital separation; poverty. Results: The prevalence of resilience, as defined, was 14.5%. After adjusting for regression to the mean, the GHQ-12 score of the resilient dropped by a mean of 3.6 points in the post-adversity period. Women predominated among the resilient, with this gender difference stronger among older women than younger women. The resilient were more likely to have high social support than the non-resilient, but otherwise were not different socioeconomically. High social support pre-adversity and during adversity increased the likelihood of resilience by 40–60% compared with those with low social support. Conclusions: Resilience is relatively rare and favours older women. It is fostered by high levels of social support existing before exposure to adversity.
Patch Antennas With Loading of a Pair of Shorting Pins Toward Flexible Impedance Matching and Low Cross Polarization

Patch antennas with loading of a pair of shorting pins are proposed in this paper toward flexible impedance matching and low cross polarization. The shorting pins are introduced in the centerline of a square patch to strengthen the surface current density near the feeding point at edge. As these paired pins simultaneously move away from the center toward the two radiating edges of patch, the resonant input impedance of the microstrip-edge-fed patch antenna is increasingly reduced due to enlarged current density at the feeding point. Because of symmetric arrangement of these two shorting pins, surface current density on the patch is maintained as the odd-symmetric property with respect to the H-plane, thus tremendously degrading the cross-polarization level. Simulated and measured results are found in good agreement with each other in terms of input impedance and radiation pattern. They further demonstrate that co-polarization to cross-polarization ratio (CTCR) of the paired-pins-loaded patch antenna in H-plane is maintained at least 10 dB higher than that of its single-pin-loaded patch counterpart.
Low blood pressure and the risk of dementia in very old individuals

Background: The role of blood pressure (BP) as a risk factor for dementia is complex and may be age dependent. In very old individuals, low BP might increase risk for dementia, perhaps by reducing cerebral perfusion pressure. Methods: The association between BP and dementia was examined in the Bronx Aging Study, a prospective study of 488 community-dwelling elderly individuals over age 75, dementia-free at baseline (1980 to 1983) and followed at 12- to 18-month intervals. Subjects with baseline BP and with at least one follow-up visit were included (n = 406). Incident dementia was diagnosed using the criteria of the Diagnostic and Statistical Manual of Mental Disorders (3rd rev. ed.). Results: Over 21 years (median 6.7 years), 122 subjects developed dementia (65 Alzheimer’s disease [AD], 28 vascular dementia, 29 other dementias). Relative risk of dementia increased for each 10-mm Hg decrement in diastolic (hazard ratio [HR] 1.20, 95% CI 1.03 to 1.40) and mean arterial (HR 1.16, 95% CI 1.02 to 1.32) pressure, adjusted for age, sex, and education. Low diastolic BP significantly influenced risk of developing AD but not vascular dementia. Upon examination of groups defined by BP, mildly to moderately raised systolic BP (140 to 179 mm Hg) was associated with reduced risk for AD (HR vs normal systolic BP group 0.55, 95% CI 0.32 to 0.96), whereas low diastolic BP (≤70 mm Hg) was associated with increased risk of AD (HR vs normal diastolic BP group 1.91, 95% CI 1.05 to 3.48). Subjects with persistent low BP over 2 years had higher risk of developing dementia (HR 2.19, 95% CI 1.27 to 3.77). Conclusions: Low diastolic pressure is associated with higher risk of dementia in elderly individuals over age 75. Dementia risk was higher in subjects with persistently low BP.
No gender differences in prognosis and preventive treatment in patients with AMI without significant stenoses

Objective: To investigate possible gender differences in patients with acute myocardial infarction (AMI) and without significant stenoses on coronary angiography (CAG) regarding prognosis and use of secondary preventive medication. Design: Nationwide register-based cohort study. Patients: By compiling data from Danish registries, we identified 20,800 patients hospitalized with AMI during 2005–2007. We included the 834 women and 761 men without significant stenoses on CAG who were discharged and alive after 60 days. Main outcome measures: All-cause mortality, recurrent AMI, and redeeming a prescription for a lipid-lowering drug, beta-blocker, clopidogrel, or aspirin within 60 days of discharge. Results: During follow-up, 97 women and 60 men died, resulting in a crude female/male hazard ratio (HR) of 1.51 (95% CI 1.09–2.08). After adjustment for age, time-period, and comorbidity, the gender difference was attenuated (HR 1.22, 95% CI 0.86–1.72). AMI recurrence was experienced by 28 women and 29 men with a female/male HR 0.88 (95% CI 0.52–1.48). After multivariable adjustment results were similar (HR 0.84, 95% CI 0.50–1.43). More women than men redeemed a prescription for lipid-lowering drugs with no differences in other medication. In the adjusted models lipid-lowering drugs, beta-blockers, clopidogrel, and aspirin were all redeemed equally with odds ratio (OR) 1.25 (95% CI 0.99–1.59), OR 1.10 (95% CI 0.88–1.37), OR 1.09 (95% CI 0.88–1.34), and OR 1.13 (95% CI 0.90–1.42), respectively. Conclusion: Our study shows that in a population of patients with a first admission for AMI and no significant stenoses on CAG, women share the same prospects as men regarding long-term prognosis and the extent of secondary preventive medical treatment.
New era for personalized medicine: the diagnosis and management of age‐related macular degeneration

It can be argued that age‐related macular degeneration is one of the best characterized complex trait diseases. Extensive information related to genetic and environmental risk factors exists, and a number of different biological pathways are strongly implicated in its aetiology. Along with recent improvements in high throughput and relatively inexpensive genetic technologies, we are now in a position to consider developing a presymptomatic, personalized approach towards the assessment, management and treatment of this disease. We explore the applicability and challenges of this approach if it is to become commonplace for guiding treatment decisions for individuals with pre‐existing disease or for those at high risk of developing it.
Low levels of sarin affect the eeg in marmoset monkeys: a pilot study

The main purpose of this pilot study was to estimate the lowest observable adverse effect level (LOAEL) for the electroencephalogram (EEG) upon long‐term, low‐level exposure of vehicle‐pretreated and pyridostigmine‐pretreated marmoset monkeys to sarin vapour. This is the C·t value (t = 5 h) of exposure at which the EEG becomes signiﬁcantly different from that resulting from air exposure of the same animals. The LOAELs for effects on the EEG in vehicle‐ and pyridostigmine‐pretreated marmosets appeared to be 0.2 and 0.1 mg min m−3, respectively. Comparatively, the latter LOAEL values are at least an order of magnitude lower than the previously established LOAEL for miosis and only 2–5 times higher than the lowest observable effect level (LOEL) of bound sarin in blood.
The Brief Child and Family Phone Interview (BCFPI): 2. Usefulness in screening for child and adolescent psychopatholog.

BACKGROUND This study examines the use of the Brief Child and Family Phone Interview (BCFPI) to screen for childhood psychiatric disorder based on Diagnostic Interview Schedule for Children Version IV (DISC-IV) classifications of attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD), separation anxiety (SAD), generalized anxiety (GAD) and major depression (MDD). METHODS Data for analysis come from a sample of 399 children and adolescents aged 5-17 years old referred to child mental health outpatient services in three Ontario cities. Mothers were administered the BCFPI on three occasions: baseline, 2 and 13 months; and the DISC-IV on two occasions: 1 and 12 months. RESULTS Based on kappa, test-retest reliability for disorders classified by the BCFPI exceeded . 50 for all conditions except MDD (.45). In receiver operating characteristic (ROC) analysis, area-under-the-curve (AUC) estimates for BCFPI scale score associations with DISC-IV classifications of disorder exceeded . 80 for CD, ODD, ADHD and SAD; and were lower for GAD (.76) and MDD (.75). In stratified analyses, there were no statistically significant differences in AUC estimates for boys versus girls and 5 to 11 versus 12 to 17-year-olds. CONCLUSIONS Classifications of childhood disorder derived from the BCFPI provided a reasonable approximation to disorders classified by the DISC-IV administered by lay interviewers.
Prescribing and Regulating Exercise with RPE after Heart Transplant: A Pilot Study.

PURPOSE The objective of this study is to analyze the use of the 6-20 RPE scale for prescribing and self-regulating heated water-based exercise (HEx) and land-based exercise (LEx) in heart transplant recipients. METHODS Fifteen (five females) clinically stable heart transplant recipients (time since surgery = 4.0 ± 2.5 yr) age 46.7 ± 11.8 yr underwent a symptom-limited maximal graded exercise test on a treadmill to determine their HR at anaerobic threshold (HRAT), respiratory compensation point (HRRCP), and maximal effort (HRmax). After a week, patients were randomized to perform 30 min of both HEx (walking inside the pool) and LEx (treadmill walking) sessions at a pace between 11 and 13 on the 6-20 RPE scale and had their HR measured every 4 min. The interval between sessions was 48-72 h. RESULTS No significant differences between sessions were found in the average HR during HEx and LEx. Patients showed a delay in HR increase during both interventions, with the stabilization beginning after 8 min of exercise. Exercise HR was maintained between the HRAT and HRRCP (in the aerobic exercise training zone) for the most part of both HEx (72% of HR measurements) and LEx (66% of HR measurements). Only a few HR measurements stayed below HRAT (HEx = 9%, LEx = 13%) or above HRRCP (HEx = 19%, LEx = 21%) during both exercise sessions. CONCLUSION Exercise HR was maintained in the aerobic exercise training zone (between HRAT and HRRCP) for the most part of both sessions, suggesting that the 6-20 RPE scale may be an efficient tool for prescribing and self-regulating HEx and LEx in heart transplant recipients.
The Comparison and Estimation of the Prognostic Value of Lipid Profiles in Patients With Prostate Cancer Depends on Cancer Stage Advancement

Lipid profiles and prostate cancer have a controversial relationship, and the predictive ability of lipids in determining cancer risk estimation is still questionable. This study demonstrates a significance assessment of the plasma lipid profiles of subjects with prostate cancer. Locoregional subjects irradiated with external beam therapy were compared to prostate cancer subjects with bone metastases. The histopathologic diagnosis of 103 subjects (71 locoregional [Group 1] and 32 palliative [Group 2]) were analyzed and compared using their blood samples, total cholesterol (CHL), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. The HDL/CHL, LDL/CHL, and TG/HDL ratios were used for better fit and comparison. Subjects were grouped according to their cancer stages and assessed using statins in both groups. In this study, serum HDL/CHL was significantly increased in Group 1 compared to Group 2 (p = .02), and time–statin factor in relation was statistically significant (p = .02). For Group 2, this index decreased with each day after radiotherapy (p = .07), which means the CHL was increased. Negative effects were noticed at the time of observation of the LDL/HDL ratio with an approximate increase of 0.0025 each day in palliative subjects. This ratio showed a statically significant elevation (p = .04). There was not a statistically significant difference in the value of the TG/HDL ratio between both groups. As the survival of cancer subjects increases, frequent control of the lipid profile gains importance.
Effects of mutations in stem and loop regions on the structure and function of adenovirus VA RNAI.

Adenovirus virus‐associated (VA) RNAI is required for efficient protein synthesis at late times of adenoviral infection, and in some other situations where double‐stranded RNA (dsRNA) is present. It prevents inhibition of protein synthesis by a dsRNA‐activated protein kinase and the secondary structure of VA RNAI is though to be important for its activity. To test this idea and to define structures and sequences responsible for VA RNAI activity, we constructed several mutant VA RNA genes and tested them in a transient expression assay. Activity is unaffected by deletions within a small region near the center of the gene, nt 72‐85, but it is greatly diminished by deletion or substitution of sequences on the 3′ side of this region. The structures of wild‐type and mutant RNAs were examined by nuclease‐sensitivity analysis. We propose a model for wild‐type VA RNAI which differs from that predicted to be the most stable structure. Surprisingly disruption of the longest duplex region in the molecule is tolerated, provided that adjacent structural elements are not rearranged. However, perturbations of elements located in the center of the structure correlate well with loss of function.
Exploring the ideas and expectations of German medical students towards career choices and the speciality of psychiatry

Abstract The aim of this study was to explore the ideas and expectations of medical students toward their career choices and the speciality of psychiatry. A total of 323 students of the Hannover Medical School filled in a questionnaire about their career choices, preferred medical specialization, factors of influence on career choices and attitude towards psychiatry. The three most important factors of influence appeared to be: (1) work–life balance, (2) flexible working hours, (3) career prospects. Although expectations towards the professional life of psychiatrists were quite positive among the students, there was only a small number of students (n = 53 of 318 respondents, 17%) interested in specializing in psychiatry. Important reasons for choosing psychiatry included personal experience with somatic or mental health issues and practical experience in psychiatry. Most of the students experienced clinical exposure to psychiatry but at a much later period in the curriculum. For a career choice of psychiatry as a speciality it seems to be important to start psychiatric education in medical school early. The positive aspects of the professional life in psychiatry, such as flexible working hours, career prospects and good work–life balance should be more emphasized.
Knee Arthrodesis With Simultaneous Lengthening Using the Ilizarov Method

Objective: To determine whether knee arthrodesis with simultaneous lengthening using the Ilizarov method for a nonreconstructable knee joint with bone loss and infection is a successful salvage procedure. Design: Retrospective review of patients. Setting: University hospital-based orthopaedic practice. Patients: From 1999 to 2001, 4 consecutive patients with a nonreconstructable knee joint, bone loss, and infection after trauma underwent knee arthrodesis with simultaneous lengthening. Intervention: Arthrodesis of the knee with simultaneous limb lengthening through an osteotomy of the tibia and/or femur and the use of an Ilizarov frame. External bone stimulation was used at the knee arthrodesis site and the lengthening sites. Application of this device began during the early distraction phase and continued until frame removal. Main Outcome Measures: Bony union at the arthrodesis and bone lengthening sites, alignment of the lower extremity, limb length discrepancy, infection, pain, and outcome scales (SF-36 scores and American Academy of Orthopaedic Surgeons lower limb modules). Results: Bony union of the knee arthrodesis and lengthening sites and good alignment were achieved in all 4 patients. Mean amount of lengthening was 5.4 cm (range 2.5-11.5 cm). Average time in frame was 11 months (range 6-17 months). Limb length discrepancy after treatment averaged 1.8 cm (range 0.6-3.7 cm). Mean duration of follow-up after frame removal was 35 months (range 28-48 months). At follow-up, infection had not recurred, pain was not present, and assistive devices were not needed for ambulation. Average SF-36 scores improved in all 8 categories, and the average American Academy of Orthopaedic Surgeons lower limb modules improved from a mean of 33 (range 11-37) to a mean of 68 (range 51-76). Conclusion: Knee arthrodesis with simultaneous lengthening can be performed successfully using the Ilizarov method. It enables surgeons to optimize limb length during knee arthrodesis. The use of external fixation and the avoidance of internal implants may be advantageous in the presence of or history of infection. The Ilizarov frame provides stability that allows weight bearing during treatment.
Composition of human breast milk in acute kidney injury

Background Breastfeeding is a widely encouraged practice due to its benefits for mother and the infant. Little is known about the impact of disease states, such as kidney dysfunction and childbirth complications, on the composition of breast milk. Methods We describe a case of a 35-year-old woman who suffered a postpartum hemorrhage, was administered a contrast dye prior to computer tomography, and developed an acute kidney injury. Using nuclear magnetic resonance spectrometry, we measured composition of milk in acute kidney injury. The amount of dye secreted into milk was determined using a spectroscopic assay. Results Here we show that acute kidney injury results in changes in milk composition, but it does not significantly affect major macronutrients. We also determine that iodinated computer tomography contrast dye does not accumulate in milk in appreciable amounts. Conclusion Acute kidney injury has impact on breast milk. Intravenous administration of computer tomography contrast dye does not result in significantly elevated levels in milk.