Familial multiple myeloma. Two more families

The authors report on two multiple myeloma sibling pairs. In the absence of a known disease-specific marker one can only speculate on an explanation: is it because of inherited errors or is it related to the same environmental exposure, or both? In this study HLA typing and metabolizing enzyme polymorphism studies have been carried out with the aim of finding inherited similarities in the siblings or characteristics that might differ from the average population. Sibling pair 1 shared an HLA haplotype. Sibling pair 2 shared only HLA-B51, DR4, DRw53, DQ3. Sibling 1/1 was GSTT1/GSTM1 null and GSTP1 Ile105Val; sibling 1/2 was a GSTT1/GSTM1 heterozygote and GSTP1 Ile105Val; sibling 2/1 and 2/2 were GSTT1 heterozygotes and shared GSTM1 null/GSTP1 Ile105Ile. The siblings had identical light chain or heavy chain secretion, or both. The similarities found in the inherited factors together with the same environmental exposure in the siblings' first 20 years of life imply that the development of the same disease cannot be a coincidence

Paroxysmalis nocturnalis haemoglobinuriával szövődött várandósság ritka esete

Paroxysmal nocturnal hemoglobinuria is a rare hematological disease. It is associated with increased maternal and fetal complications to such an extent that pregnancy has been considered relatively contraindicated in woman with paroxysmal nocturnal haemoglobinuria. Recently, eculizumab, a monoclonal antibody, has been shown to decrease complications during pregnancies. The highest risk is thromboembolic complication and, therefore, anticoagulant is a standard therapy during pregnancy. In the presented case, a 29-year-old woman with a 5-year history of paroxysmal nocturnal haemoglobinuria had a pregnancy. It was her first pregnancy and was complicated by a sinus thrombosis at the 11th gestational week. After the introduction of eculizumab treatment, the remaining period of pregnancy and delivery were uncomplicated. There are only a few cases in the literature about pregnancy in woman with paroxysmal nocturnal hemoglobinuria who are treated with eculizumab. This monoclonal antibody seems to be safe and it likely prevents many of the complications otherwise observed. Orv. Hetil., 2016, 157(23), 916-918

Addendum to: Capillary floating and the billiard ball problem

We compare the results of our earlier paper on the floating in neutral equilibrium at arbitrary orientation in the sense of Finn-Young with the literature on its counterpart in the sense of Archimedes. We add a few remarks of personal and social-historical character.Comment: This is an addendum to my article Capillary floating and the billiard ball problem, Journal of Mathematical Fluid Mechanics 14 (2012), 363 -- 38

On recurrence and ergodicity for geodesic flows on noncompact periodic polygonal surfaces

We study the recurrence and ergodicity for the billiard on noncompact polygonal surfaces with a free, cocompact action of $\Z$ or $\Z^2$. In the $\Z$-periodic case, we establish criteria for recurrence. In the more difficult $\Z^2$-periodic case, we establish some general results. For a particular family of $\Z^2$-periodic polygonal surfaces, known in the physics literature as the wind-tree model, assuming certain restrictions of geometric nature, we obtain the ergodic decomposition of directional billiard dynamics for a dense, countable set of directions. This is a consequence of our results on the ergodicity of \ZZ-valued cocycles over irrational rotations.Comment: 48 pages, 12 figure

On the equilibria of finely discretized curves and surfaces

Our goal is to identify the type and number of static equilibrium points of solids arising from fine, equidistant $n$-discretrizations of smooth, convex surfaces. We assume uniform gravity and a frictionless, horizontal, planar support. We show that as $n$ approaches infinity these numbers fluctuate around specific values which we call the imaginary equilibrium indices associated with the approximated smooth surface. We derive simple formulae for these numbers in terms of the principal curvatures and the radial distances of the equilibrium points of the solid from its center of gravity. Our results are illustrated on a discretized ellipsoid and match well the observations on natural pebble surfaces.Comment: 21 pages, 2 figure

Frail2Fit study protocol: a feasibility and acceptability study of a virtual multimodal intervention delivered by volunteers to improve functional outcomes in older adults with frailty after discharge from hospital.

INTRODUCTION: Physical activity (PA) and replete nutritional status are key to maintaining independence and improving frailty status among frail older adults. In response to the COVID-19 pandemic, healthcare has increasingly turned to virtual modes of delivery and there is interest in the use of trained volunteers to deliver PA and nutrition interventions. We aim to evaluate the feasibility and acceptability of training hospital volunteers to deliver an online intervention, comprising exercise, behaviour change and nutrition support, to older people with frailty after discharge from hospital. METHODS: We will use a quasi-experimental mixed methods approach. Hospital volunteers (n=6) will be trained to deliver an online, 3-month, multimodal intervention to frail (Clinical Frailty Scale ≥5) adults ≥65 years (n=30) after discharge from hospital. Feasibility will be assessed by determining the number of volunteers recruited, trained and retained at the end of the study; the proportion of intervention sessions delivered; participant recruitment, retention and adherence to the intervention. To determine the acceptability of the intervention, interviews will be conducted among a purposive sample of older adults, and volunteers. Secondary outcomes will include physical function, appetite, well-being, quality of life, anxiety and depression, self-efficacy for managing chronic disease and PA. Outcomes will be measured at baseline, 3 months and 6 months. ANALYSIS: Descriptive statistics will be used to describe feasibility and adherence to the intervention. Secondary outcomes at baseline will be compared at 3 and 6 months. Interviews will be transcribed verbatim and analysed using thematic analysis. ETHICS AND DISSEMINATION: Health Research Authority ethical approval was obtained on 30 May 2022 (reference: 22/WA/0155). Results will be disseminated through peer-reviewed journal articles, volunteer organisations, National Health Service communication systems and social media platforms. A toolkit will be developed to facilitate roll out of volunteer training. TRIAL REGISTRATION NUMBER: NCT05384730

Quantitative assessment of the expanding complementarity between public and commercial databases of bioactive compounds

<p>Abstract</p> <p>Background</p> <p>Since 2004 public cheminformatic databases and their collective functionality for exploring relationships between compounds, protein sequences, literature and assay data have advanced dramatically. In parallel, commercial sources that extract and curate such relationships from journals and patents have also been expanding. This work updates a previous comparative study of databases chosen because of their bioactive content, availability of downloads and facility to select informative subsets.</p> <p>Results</p> <p>Where they could be calculated, extracted compounds-per-journal article were in the range of 12 to 19 but compound-per-protein counts increased with document numbers. Chemical structure filtration to facilitate standardised comparisons typically reduced source counts by between 5% and 30%. The pair-wise overlaps between 23 databases and subsets were determined, as well as changes between 2006 and 2008. While all compound sets have increased, PubChem has doubled to 14.2 million. The 2008 comparison matrix shows not only overlap but also unique content across all sources. Many of the detailed differences could be attributed to individual strategies for data selection and extraction. While there was a big increase in patent-derived structures entering PubChem since 2006, GVKBIO contains over 0.8 million unique structures from this source. Venn diagrams showed extensive overlap between compounds extracted by independent expert curation from journals by GVKBIO, WOMBAT (both commercial) and BindingDB (public) but each included unique content. In contrast, the approved drug collections from GVKBIO, MDDR (commercial) and DrugBank (public) showed surprisingly low overlap. Aggregating all commercial sources established that while 1 million compounds overlapped with PubChem 1.2 million did not.</p> <p>Conclusion</p> <p>On the basis of chemical structure content <it>per se </it>public sources have covered an increasing proportion of commercial databases over the last two years. However, commercial products included in this study provide links between compounds and information from patents and journals at a larger scale than current public efforts. They also continue to capture a significant proportion of unique content. Our results thus demonstrate not only an encouraging overall expansion of data-supported bioactive chemical space but also that both commercial and public sources are complementary for its exploration.</p

A polygenic risk score for multiple myeloma risk prediction

There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53–4.69, p = 3.55 × 10−15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34–4.33, p = 1.62 × 10−13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population

Risk factors for treatment failure and mortality among hospitalized patients with complicated urinary tract infection: A multicenter retrospective cohort study (RESCUING study group)

Background. Complicated urinary tract infections (cUTIs) are responsible for a major share of all antibiotic consumption in hospitals. We aim to describe risk factors for treatment failure and mortality among patients with cUTIs. Methods. A multinational, multicentre retrospective cohort study, conducted in 20 countries in Europe and the Middle East. Data were collected from patients' files on hospitalised patients with a diagnosis of cUTI during 2013-2014. Primary outcome was treatment failure, secondary outcomes included 30 days all-cause mortality,among other outcomes. Multivariable analysis using a logistic model and the hospital as a random variable was performed to identify independent predictors for these outcomes. Results. A total of 981 patients with cUTI were included. Treatment failure was observed in 26.6% (261/981), all cause 30-day mortality rate was 8.7% (85/976), most of these in patients with catheter related UTI (CaUTI). Risk factors for treatment failure in multivariable analysis were ICU admission (OR 5.07, 95% CI 3.18-8.07), septic shock (OR 1.92, 95% CI 0.93-3.98), corticosteroid treatment (OR 1.92, 95% CI 1.12-3.54), bedridden (OR 2.11, 95%CI 1.4-3.18), older age (OR 1.02, 95% CI 1.0071.03-), metastatic cancer (OR 2.89, 95% CI 1.46-5.73) and CaUTI (OR 1.48, 95% CI 1.04-2.11). Management variables, such as inappropriate empirical antibiotic treatment or days to starting antibiotics were not associated with treatment failure or 30-day mortality. More patients with pyelonephritis were given appropriate empirical antibiotic therapy than other CaUTI [110/171; 64.3% vs. 116/270; 43%, p &lt;0.005], nevertheless, this afforded no advantage in treatment failure rates nor mortality in these patients. Conclusions. In patients with cUTI we found no benefit of early appropriate empirical treatment on survival rates or other outcomes. Physicians might consider supportive treatment and watchful waiting in stable patients until the causative pathogen is defined