Clinical applications of machine learning algorithms: beyond the black box

To maximise the clinical benefits of machine learning algorithms, we need to rethink our approach to explanation, argue David Watson and colleagues

The R-Process Alliance: Fourth Data Release from the Search for R-process-enhanced Stars in the Galactic Halo

This compilation is the fourth data release from the R-Process Alliance (RPA) search for r-process-enhanced stars and the second release based on "snapshot" high-resolution (R ~ 30,000) spectra collected with the du Pont 2.5 m Telescope. In this data release, we propose a new delineation between the r-I and r-II stellar classes at $[\mathrm{Eu}/\mathrm{Fe}]=+0.7$, instead of the empirically chosen $[\mathrm{Eu}/\mathrm{Fe}]=+1.0$ level previously in use, based on statistical tests of the complete set of RPA data released to date. We also statistically justify the minimum level of [Eu/Fe] for definition of the r-I stars, [Eu/Fe] > +0.3. Redefining the separation between r-I and r-II stars will aid in the analysis of the possible progenitors of these two classes of stars and determine whether these signatures arise from separate astrophysical sources at all. Applying this redefinition to previous RPA data, the number of identified r-II and r-I stars changes to 51 and 121, respectively, from the initial set of data releases published thus far. In this data release, we identify 21 new r-II, 111 new r-I (plus 3 re-identified), and 7 new (plus 1 re-identified) limited-r stars out of a total of 232 target stars, resulting in a total sample of 72 new r-II stars, 232 new r-I stars, and 42 new limited-r stars identified by the RPA to date

What parathyroid hormone levels should we aim for in children with stage 5 chronic kidney disease; what is the evidence?

The bone disease that occurs as a result of chronic kidney disease (CKD) is not only debilitating but also linked to poor growth and cardiovascular disease. It is suspected that abnormal bone turnover is the main culprit for these poor outcomes. Plasma parathyroid hormone (PTH) levels are used as a surrogate marker of bone turnover, and there is a small number of studies in children that have attempted to identify the range of PTH levels that correlates with normal bone histology. It is clear that high PTH levels are associated with high bone turnover, although the range is wide. However, the ability of PTH levels to distinguish between low and normal bone turnover is less clear. This is an important issue, because current guidelines for calcium and phosphate management are based upon there being an “optimum” range for PTH. This editorial takes a critical look at the evidence upon which these recommendations are based

Functional Characterization of Human Cancer-Derived TRKB Mutations

Cancer originates from cells that have acquired mutations in genes critical for controlling cell proliferation, survival and differentiation. Often, tumors continue to depend on these so-called driver mutations, providing the rationale for targeted anticancer therapies. To date, large-scale sequencing analyses have revealed hundreds of mutations in human tumors. However, without their functional validation it remains unclear which mutations correspond to driver, or rather bystander, mutations and, therefore, whether the mutated gene represents a target for therapeutic intervention. In human colorectal tumors, the neurotrophic receptor TRKB has been found mutated on two different sites in its kinase domain (TRKBT695I and TRKBD751N). Another site, in the extracellular part of TRKB, is mutated in a human lung adenocarcinoma cell line (TRKBL138F). Lastly, our own analysis has identified one additional TRKB point mutation proximal to the kinase domain (TRKBP507L) in a human melanoma cell line. The functional consequences of all these point mutations, however, have so far remained elusive. Previously, we have shown that TRKB is a potent suppressor of anoikis and that TRKB-expressing cells form highly invasive and metastatic tumors in nude mice. To assess the functional consequences of these four TRKB mutations, we determined their potential to suppress anoikis and to form tumors in nude mice. Unexpectedly, both colon cancer-derived mutants, TRKBT695I and TRKBD751N, displayed reduced activity compared to that of wild-type TRKB. Consistently, upon stimulation with the TRKB ligand BDNF, these mutants were impaired in activating TRKB and its downstream effectors AKT and ERK. The two mutants derived from human tumor cell lines (TRKBL138F and TRKBP507L) were functionally indistinguishable from wild-type TRKB in both in-vitro and in-vivo assays. In conclusion, we fail to detect any gain-of-function of four cancer-derived TRKB point mutations

Sec12 Binds to Sec16 at Transitional ER Sites

COPII vesicles bud from an ER domain known as the transitional ER (tER). Assembly of the COPII coat is initiated by the transmembrane guanine nucleotide exchange factor Sec12. In the budding yeast Pichia pastoris, Sec12 is concentrated at tER sites. Previously, we found that the tER localization of P. pastoris Sec12 requires a saturable binding partner. We now show that this binding partner is Sec16, a peripheral membrane protein that functions in ER export and tER organization. One line of evidence is that overexpression of Sec12 delocalizes Sec12 to the general ER, but simultaneous overexpression of Sec16 retains overexpressed Sec12 at tER sites. Additionally, when P. pastoris Sec12 is expressed in S. cerevisiae, the exogenous Sec12 localizes to the general ER, but when P. pastoris Sec16 is expressed in the same cells, the exogenous Sec12 is recruited to tER sites. In both of these experimental systems, the ability of Sec16 to recruit Sec12 to tER sites is abolished by deleting a C-terminal fragment of Sec16. Biochemical experiments confirm that this C-terminal fragment of Sec16 binds to the cytosolic domain of Sec12. Similarly, we demonstrate that human Sec12 is concentrated at tER sites, likely due to association with a C-terminal fragment of Sec16A. These results suggest that a Sec12–Sec16 interaction has a conserved role in ER export

Heme Degrading Protein HemS Is Involved in Oxidative Stress Response of Bartonella henselae

Bartonellae are hemotropic bacteria, agents of emerging zoonoses. These bacteria are heme auxotroph Alphaproteobacteria which must import heme for supporting their growth, as they cannot synthesize it. Therefore, Bartonella genome encodes for a complete heme uptake system allowing the transportation of this compound across the outer membrane, the periplasm and the inner membranes. Heme has been proposed to be used as an iron source for Bartonella since these bacteria do not synthesize a complete system required for iron Fe3+uptake. Similarly to other bacteria which use heme as an iron source, Bartonellae must transport this compound into the cytoplasm and degrade it to allow the release of iron from the tetrapyrrole ring. For Bartonella, the gene cluster devoted to the synthesis of the complete heme uptake system also contains a gene encoding for a polypeptide that shares homologies with heme trafficking or degrading enzymes. Using complementation of an E. coli mutant strain impaired in heme degradation, we demonstrated that HemS from Bartonella henselae expressed in E. coli allows the release of iron from heme. Purified HemS from B. henselae binds heme and can degrade it in the presence of a suitable electron donor, ascorbate or NADPH-cytochrome P450 reductase. Knocking down the expression of HemS in B. henselae reduces its ability to face H2O2 induced oxidative stress

Presentations of patients of poisoning and predictors of poisoning-related fatality: Findings from a hospital-based prospective study

<p>Abstract</p> <p>Background</p> <p>Poisoning is a significant public health problem worldwide and is one of the most common reasons for visiting emergency departments (EDs), but factors that help to predict overall poisoning-related fatality have rarely been elucidated. Using 1512 subjects from a hospital-based study, we sought to describe the demographic and clinical characteristics of poisoning patients and to identify predictors for poisoning-related fatality.</p> <p>Methods</p> <p>Between January 2001 and December 2002 we prospectively recruited poisoning patients through the EDs of two medical centers in southwest Taiwan. Interviews were conducted with patients within 24 hours after admission to collect relevant information. We made comparisons between survival and fatality cases, and used logistic regressions to identify predictors of fatality.</p> <p>Results</p> <p>A total of 1512 poisoning cases were recorded at the EDs during the study period, corresponding to an average of 4.2 poisonings per 1000 ED visits. These cases involved 828 women and 684 men with a mean age of 38.8 years, although most patients were between 19 and 50 years old (66.8%), and 29.4% were 19 to 30 years. Drugs were the dominant poisoning agents involved (49.9%), followed by pesticides (14.5%). Of the 1512 patients, 63 fatalities (4.2%) occurred. Paraquat exposure was associated with an extremely high fatality rate (72.1%). The significant predictors for fatality included age over 61 years, insufficient respiration, shock status, abnormal heart rate, abnormal body temperature, suicidal intent and paraquat exposure.</p> <p>Conclusion</p> <p>In addition to well-recognized risk factors for fatality in clinical settings, such as old age and abnormal vital signs, we found that suicidal intent and ingestion of paraquat were significant predictors of poisoning-related fatality. Identification of these predictors may help risk stratification and the development of preventive interventions.</p

In utero exposure to low doses of environmental pollutants disrupts fetal ovarian development in sheep

Epidemiological studies of the impact of environmental chemicals on reproductive health demonstrate consequences of exposure but establishing causative links requires animal models using ‘real life’ in utero exposures. We aimed to determine whether prolonged, low-dose, exposure of pregnant sheep to a mixture of environmental chemicals affects fetal ovarian development. Exposure of treated ewes (n = 7) to pollutants was maximized by surface application of processed sewage sludge to pasture. Control ewes (n = 10) were reared on pasture treated with inorganic fertilizer. Ovaries and blood were collected from fetuses (n = 15 control and n = 8 treated) on Day 110 of gestation for investigation of fetal endocrinology, ovarian follicle/oocyte numbers and ovarian proteome. Treated fetuses were 14% lighter than controls but fetal ovary weights were unchanged. Prolactin (48% lower) was the only measured hormone significantly affected by treatment. Treatment reduced numbers of growth differentiation factor (GDF9) and induced myeloid leukaemia cell differentiation protein (MCL1) positive oocytes by 25–26% and increased pro-apoptotic BAX by 65% and 42% of protein spots in the treated ovarian proteome were differently expressed compared with controls. Nineteen spots were identified and included proteins involved in gene expression/transcription, protein synthesis, phosphorylation and receptor activity. Fetal exposure to environmental chemicals, via the mother, significantly perturbs fetal ovarian development. If such effects are replicated in humans, premature menopause could be an outcome