Novel Prognostic Markers in Triple-Negative Breast Cancer Discovered by MALDI-Mass Spectrometry Imaging

There are no widely-accepted prognostic markers currently available to predict outcomes in patients with triple-negative breast cancer (TNBC), and no targeted therapies with confirmed benefit. We have used MALDI mass spectrometry imaging (MSI) of tryptic peptides to compare regions of cancer and benign tissue in 10 formalin-fixed, paraffin-embedded sections of TNBC tumors. Proteins were identified by reference to a peptide library constructed by LC-MALDI-MS/MS analyses of the same tissues. The prognostic significance of proteins that distinguished between cancer and benign regions was estimated by Kaplan-Meier analysis of their gene expression from public databases. Among peptides that distinguished between cancer and benign tissue in at least 3 tissues with a ROC area under the curve >0.7, 14 represented proteins identified from the reference library, including proteins not previously associated with breast cancer. Initial network analysis using the STRING database showed no obvious functional relationships except among collagen subunits COL1A1, COL1A2, and COL63A, but manual curation, including the addition of EGFR to the analysis, revealed a unique network connecting 10 of the 14 proteins. Kaplan-Meier survival analysis to examine the relationship between tumor expression of genes encoding the 14 proteins, and recurrence-free survival (RFS) in patients with basal-like TNBC showed that, compared to low expression, high expression of nine of the genes was associated with significantly worse RFS, most with hazard ratios >2. In contrast, in estrogen receptor-positive tumors, high expression of these genes showed only low, or no, association with worse RFS. These proteins are proposed as putative markers of RFS in TNBC, and some may also be considered as possible targets for future therapies

Accuracy of prospective two-dimensional/Doppler echocardiography in the assessment of reparative surgery

Between January 1987 and January 1989, all 129 patients (aged 11 days to 25 years, median 39 months) undergoing both an echocardiographic examination and cardiac catheterization after reparative surgery were prospectively included in a study to assess the accuracy of combined two-dimensional and Doppler color flow imaging. The patient diagnoses were transposition of the great arteries (n = 20), tetralogy of Fallot (n = 38), coarctation of the aorta (n = 24), complete atrioventricular (AV) canal (n = 15), atrial septal defect (n = 8), ventricular septal defects (n = 3), pulmonary stenosis (n = 4), aortic stenosis (n = 8) and subaortic stenosis (n = 9).In arterial tract stenosis, there was high correlation between Doppler estimates and catheterization-derived measurements of residual right ventricular outflow tract obstruction in patients after the arterial switch operation for transposition of the great arteries (r = 0.95) as well as in patients after corrective repair of tetralogy of Fallot (r = 0.84).In semilunar/AV valve regurgitation, graded as none, mild, moderate or severe, echocardiographic estimates correlated exactly with angiographic grading in 84% and differed by one angiographic grade in the other 16%.In residual left to right shunting, no hemodynamically significant shunt was missed by echocardiography. For residual shunts at the ventricular level (n = 32), addition of Doppler color flow imaging improved the sensitivity (from 63% to 94%) and the negative predictive value (from 88% to 98%).In elevated right ventricular pressure, Doppler-derived right ventricular-right atrial pressure estimates in 24 patients correlated well with catheterization measurements (r = 0.93).Combined two-dimensional and Doppler color flow echocardiography was highly accurate in the prospective evaluation of these four types of postoperative residua

Does pyrite act as an important host for molybdenum in modern and ancient euxinic sediments?

Molybdenum (Mo) is a popular paleoproxy for tracking the spatiotemporal pattern of euxinic (anoxic and sulfidic) conditions in the ancient ocean, yet surprisingly little is known about the processes leading to its fixation under sulfidic conditions. Pyrite has been proposed to be the main host phase for Mo sequestration. To clarify the role played by pyrite, and thus to refine the utility of this paleoproxy, modern and ancient samples from six different study sites were analyzed, all representing euxinic conditions, using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Although pyrite often shows substantial enrichments relative to average crust and even matrix samples of similar size, our results show that most of the Mo in euxinic muds and shales is found in the non-pyrite matrix (80–100%) and not in the pyrite grains (0–20%)—simply because the volume of matrix dominates the bulk sediments/rocks. A relationship between the percent of Mo hosted by pyrite and the sulfur isotope composition of that pyrite is observed and can be linked to post-depositional alteration. Specifically, the oldest, typically most altered samples, show the highest δ^(34)S values because of limited sulfate availability at the time of their formation in the early ocean. In these old samples, the relatively small amount of Mo sequestered initially within pyrite is more likely to have been released to the matrix during the strong recrystallization overprints that these rocks have disproportionately suffered. Despite the universal importance of appreciable H_2S availability during Mo uptake, we conclude that pyrite should be viewed as a nontrivial sink for Mo but clearly not the primary host in most euxinic shales and rather suggest that other burial pathways should be emphasized in future studies of the mechanisms of Mo sequestration in such settings

Medical causes of admissions to hospital among adults in Africa: a systematic review.

BACKGROUND: Despite the publication of several studies on the subject, there is significant uncertainty regarding the burden of disease among adults in sub-Saharan Africa (sSA). OBJECTIVES: To describe the breadth of available data regarding causes of admission to hospital, to systematically analyze the methodological quality of these studies, and to provide recommendations for future research. DESIGN: We performed a systematic online and hand-based search for articles describing patterns of medical illnesses in patients admitted to hospitals in sSA between 1950 and 2010. Diseases were grouped into bodily systems using International Classification of Disease (ICD) guidelines. We compared the proportions of admissions and deaths by diagnostic category using χ2. RESULTS: Thirty articles, describing 86,307 admissions and 9,695 deaths, met the inclusion criteria. The leading causes of admission were infectious and parasitic diseases (19.8%, 95% confidence interval [CI] 19.6-20.1), respiratory (16.2%, 95% CI 16.0-16.5) and circulatory (11.3%, 95% CI 11.1-11.5) illnesses. The leading causes of death were infectious and parasitic (17.1%, 95% CI 16.4-17.9), circulatory (16%, 95% CI 15.3-16.8) and digestive (16.2%, 95% CI 15.4-16.9). Circulatory diseases increased from 3.9% of all admissions in 1950-59 to 19.9% in 2000-2010 (RR 5.1, 95% CI 4.5-5.8, test for trend p<0.00005). The most prevalent methodological deficiencies, present in two-thirds of studies, were failures to use standardized case definitions and ICD guidelines for classifying illnesses. CONCLUSIONS: Cardiovascular and infectious diseases are currently the leading causes of admissions and in-hospital deaths in sSA. Methodological deficiencies have limited the usefulness of previous studies in defining national patterns of disease in adults. As African countries pass through demographic and health transition, they need to significantly invest in clinical research capacity to provide an accurate description of the disease burden among adults for public health policy

Essential prescribing tips for GP Associates-in-Training

Prescribing is an essential role in general practice but it is also, at times, a high risk activity. GP Associates-in-Training (GP AiTs) have been highlighted as needing further support to reduce the risk of prescribing errors. This article highlights some common prescribing errors to help GP AiTs to review their prescribing and develop prescribing habits to avoid errors. The general practice workforce is changing and there are more pharmacists working in general practice. This article describes the role of clinical pharmacists in prescribing safety and in supporting GP AiTs

Multimodality Treatment Improves Locoregional Control, Progression-Free and Overall Survival in Patients with Anaplastic Thyroid Cancer:A Retrospective Cohort Study Comparing Oncological Outcomes and Morbidity between Multimodality Treatment and Limited Treatment (May, 10.1245/s10434-021-10146-3, 2021)

Background: Patients with anaplastic thyroid cancer (ATC) have poor overall survival, and the optimal management approach remains unclear. The aim of this study is to evaluate our experience with multimodality (MMT) versus limited treatment (LT) for ATC. Patients and Methods: A cohort study of patients with ATC managed in a tertiary referral center was undertaken. The outcomes of MMT were compared with those of LT. The primary outcome measures were locoregional control and progression-free and overall survival. Secondary outcome measures were treatment-related complications and factors associated with improved survival. Results: In total, 59 patients (35 females) with a median age of 73 years (range 39-99 years) and ATC stage IVA (n = 2), IVB (n = 28), or IVC (n = 29) were included. LT was utilized in 25 patients (42%), and 34 cases had MMT. MMT patients had a longer time of locoregional control (18.5 versus 1.9 months; p < 0.001), progression-free survival (3.5 versus 1.2 months; p < 0.001), and overall survival (6.9 versus 2.0 months; p < 0.001) when compared with LT. For patients with stage IVC ATC, locoregional control (p = 0.03), progression-free survival (p < 0.001), and overall survival (p < 0.001) were superior in the MMT cohort compared with LT. MMT had more treatment-related complications than LT (p < 0.001). An Eastern Cooperative Oncology Group performance status < 2 (HR 0.30; p = 0.001) and MMT (HR 0.35; p = 0.008) were associated with improved overall survival. Conclusion: MMT is likely to improve locoregional control, progression-free survival, and overall survival in selected ATC patients including stage IVC tumors but comes with a greater complication risk

Multimodality Treatment Improves Locoregional Control, Progression-Free and Overall Survival in Patients with Anaplastic Thyroid Cancer:A Retrospective Cohort Study Comparing Oncological Outcomes and Morbidity between Multimodality Treatment and Limited Treatment

Background: Patients with anaplastic thyroid cancer (ATC) have poor overall survival, and the optimal management approach remains unclear. The aim of this study is to evaluate our experience with multimodality (MMT) versus limited treatment (LT) for ATC. Patients and Methods: A cohort study of patients with ATC managed in a tertiary referral center was undertaken. The outcomes of MMT were compared with those of LT. The primary outcome measures were locoregional control and progression-free and overall survival. Secondary outcome measures were treatment-related complications and factors associated with improved survival. Results: In total, 59 patients (35 females) with a median age of 73 years (range 39-99 years) and ATC stage IVA (n = 2), IVB (n = 28), or IVC (n = 29) were included. LT was utilized in 25 patients (42%), and 34 cases had MMT. MMT patients had a longer time of locoregional control (18.5 versus 1.9 months; p < 0.001), progression-free survival (3.5 versus 1.2 months; p < 0.001), and overall survival (6.9 versus 2.0 months; p < 0.001) when compared with LT. For patients with stage IVC ATC, locoregional control (p = 0.03), progression-free survival (p < 0.001), and overall survival (p < 0.001) were superior in the MMT cohort compared with LT. MMT had more treatment-related complications than LT (p < 0.001). An Eastern Cooperative Oncology Group performance status < 2 (HR 0.30; p = 0.001) and MMT (HR 0.35; p = 0.008) were associated with improved overall survival. Conclusion: MMT is likely to improve locoregional control, progression-free survival, and overall survival in selected ATC patients including stage IVC tumors but comes with a greater complication risk

Mystery Solved: The Identification of the Two Missing Romanov Children Using DNA Analysis

One of the greatest mysteries for most of the twentieth century was the fate of the Romanov family, the last Russian monarchy. Following the abdication of Tsar Nicholas II, he and his wife, Alexandra, and their five children were eventually exiled to the city of Yekaterinburg. The family, along with four loyal members of their staff, was held captive by members of the Ural Soviet. According to historical reports, in the early morning hours of July 17, 1918 the entire family along with four loyal members of their staff was executed by a firing squad. After a failed attempt to dispose of the remains in an abandoned mine shaft, the bodies were transported to an open field only a few kilometers from the mine shaft. Nine members of the group were buried in one mass grave while two of the children were buried in a separate grave. With the official discovery of the larger mass grave in 1991, and subsequent DNA testing to confirm the identities of the Tsar, the Tsarina, and three of their daughters – doubt persisted that these remains were in fact those of the Romanov family. In the summer of 2007, a group of amateur archeologists discovered a collection of remains from the second grave approximately 70 meters from the larger grave. We report forensic DNA testing on the remains discovered in 2007 using mitochondrial DNA (mtDNA), autosomal STR, and Y- STR testing. Combined with additional DNA testing of material from the 1991 grave, we have virtually irrefutable evidence that the two individuals recovered from the 2007 grave are the two missing children of the Romanov family: the Tsarevich Alexei and one of his sisters

A pilot randomised controlled trial of personalised care for depressed patients with symptomatic coronary heart disease in South London general practices: the UPBEAT-UK RCT protocol and recruitment.

ABSTRACT: Background: Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings. Methods: This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care. 81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire. Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems. Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation. Discussion: This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care. Trial registration: ISRCTN21615909

Effect on life expectancy of temporal sequence in a multimorbidity cluster of psychosis, diabetes, and congestive heart failure among 1·7 million individuals in Wales with 20-year follow-up: a retrospective cohort study using linked data

BACKGROUND: To inform targeted public health strategies, it is crucial to understand how coexisting diseases develop over time and their associated impacts on patient outcomes and health-care resources. This study aimed to examine how psychosis, diabetes, and congestive heart failure, in a cluster of physical-mental health multimorbidity, develop and coexist over time, and to assess the associated effects of different temporal sequences of these diseases on life expectancy in Wales. METHODS: In this retrospective cohort study, we used population-scale, individual-level, anonymised, linked, demographic, administrative, and electronic health record data from the Wales Multimorbidity e-Cohort. We included data on all individuals aged 25 years and older who were living in Wales on Jan 1, 2000 (the start of follow-up), with follow-up continuing until Dec 31, 2019, first break in Welsh residency, or death. Multistate models were applied to these data to model trajectories of disease in multimorbidity and their associated effect on all-cause mortality, accounting for competing risks. Life expectancy was calculated as the restricted mean survival time (bound by the maximum follow-up of 20 years) for each of the transitions from the health states to death. Cox regression models were used to estimate baseline hazards for transitions between health states, adjusted for sex, age, and area-level deprivation (Welsh Index of Multiple Deprivation [WIMD] quintile). FINDINGS: Our analyses included data for 1 675 585 individuals (811 393 [48·4%] men and 864 192 [51·6%] women) with a median age of 51·0 years (IQR 37·0-65·0) at cohort entry. The order of disease acquisition in cases of multimorbidity had an important and complex association with patient life expectancy. Individuals who developed diabetes, psychosis, and congestive heart failure, in that order (DPC), had reduced life expectancy compared with people who developed the same three conditions in a different order: for a 50-year-old man in the third quintile of the WIMD (on which we based our main analyses to allow comparability), DPC was associated with a loss in life expectancy of 13·23 years (SD 0·80) compared with the general otherwise healthy or otherwise diseased population. Congestive heart failure as a single condition was associated with mean a loss in life expectancy of 12·38 years (0·00), and with a loss of 12·95 years (0·06) when preceded by psychosis and 13·45 years (0·13) when followed by psychosis. Findings were robust in people of older ages, more deprived populations, and women, except that the trajectory of psychosis, congestive heart failure, and diabetes was associated with higher mortality in women than men. Within 5 years of an initial diagnosis of diabetes, the risk of developing psychosis or congestive heart failure, or both, was increased. INTERPRETATION: The order in which individuals develop psychosis, diabetes, and congestive heart failure as combinations of conditions can substantially affect life expectancy. Multistate models offer a flexible framework to assess temporal sequences of diseases and allow identification of periods of increased risk of developing subsequent conditions and death. FUNDING: Health Data Research UK