Confirmatory validation analysis of the PROFFIT questionnaire to assess financial toxicity in cancer patients.

BACKGROUND: The Patient Reported Outcome for Fighting FInancial Toxicity (PROFFIT) questionnaire was developed to measure financial toxicity (FT) and identify its determinants. The aim of the present study was to confirm its validity in a prospective cohort of patients receiving anticancer treatment. PATIENTS AND METHODS: From March 2021 to July 2022, 221 patients were enrolled at 10 Italian centres. Selected items of the EORTC-QLQ-C30 questionnaire represented the anchors, specifically, question 28 (Q-28) on financial difficulties, and questions 29-30 measuring global health status/quality of life (HR-QOL). The study had 80% power to detect a 0.20 correlation coefficient (r) between anchors and PROFFIT-score (items 1-7, range 0-100, 100 indicating maximum FT) with bilateral alpha 0.05 and 80% power. Confirmatory factor analysis was conducted. FT determinants (items 8-16) were described. RESULTS: Median age of patients was 65 years, 116 (52.5%) were females, 96 (43.4%) had low education level. Confirmatory factor analysis confirmed goodness of fit of the PROFFIT-score. Significant partial correlation of PROFFIT-score was found with Q-28 (r = 0.51) and HR-QOL (r = -0.23). Mean (SD) PROFFIT-score at baseline was 36.5 (24.9); it was statistically significantly higher for patients living in South Italy, those with lower education level, those who were freelancer/unemployed at diagnosis and those who reported significant economic impact from the COVID-19 pandemic. Mean (SD) scores of determinants ranged from 17.6 (27.1) for item 14 (support from medical staff) to 49.0 (36.3) for item 10 (expenses for medicines or supplements). PROFFIT-score significantly increased with worsening response to determinants. CONCLUSIONS: External validation of PROFFIT-score in an independent sample of patients was successful. The instrument is now being used in clinical studies.

SMaSH: a scalable, general marker gene identification framework for single-cell RNA-sequencing.

BACKGROUND: Single-cell RNA-sequencing is revolutionising the study of cellular and tissue-wide heterogeneity in a large number of biological scenarios, from highly tissue-specific studies of disease to human-wide cell atlases. A central task in single-cell RNA-sequencing analysis design is the calculation of cell type-specific genes in order to study the differential impact of different replicates (e.g. tumour vs. non-tumour environment) on the regulation of those genes and their associated networks. The crucial task is the efficient and reliable calculation of such cell type-specific 'marker' genes. These optimise the ability of the experiment to isolate highly-specific cell phenotypes of interest to the analyser. However, while methods exist that can calculate marker genes from single-cell RNA-sequencing, no such method places emphasise on specific cell phenotypes for downstream study in e.g. differential gene expression or other experimental protocols (spatial transcriptomics protocols for example). Here we present SMaSH, a general computational framework for extracting key marker genes from single-cell RNA-sequencing data which reliably characterise highly-specific and niche populations of cells in numerous different biological data-sets. RESULTS: SMaSH extracts robust and biologically well-motivated marker genes, which characterise a given single-cell RNA-sequencing data-set better than existing computational approaches for general marker gene calculation. We demonstrate the utility of SMaSH through its substantial performance improvement over several existing methods in the field. Furthermore, we evaluate the SMaSH markers on spatial transcriptomics data, demonstrating they identify highly localised compartments of the mouse cortex. CONCLUSION: SMaSH is a new methodology for calculating robust markers genes from large single-cell RNA-sequencing data-sets, and has implications for e.g. effective gene identification for probe design in downstream analyses spatial transcriptomics experiments. SMaSH has been fully-integrated with the ScanPy framework and provides a valuable bioinformatics tool for cell type characterisation and validation in every-growing data-sets spanning over 50 different cell types across hundreds of thousands of cells.

Low-temperature ordering of the dimer phase of a two-dimensional model of core-softened particles.

Purely pairwise interactions of the core-softened type, i.e., featuring a soft repulsion followed by a hard-core interaction at shorter distance, give rise to nontrivial equilibrium structures entirely different from the standard close packing of spheres. In particular, in a suitable low-temperature region of their phase diagram, such interactions are well known to favor a transition from a fluid to a cluster crystal. The residual mutual interaction between individual clusters can lead to the formation of patterns of their reciprocal orientations. In this work, we investigate two examples of such models in two dimensions, at the density most appropriate to the dimer phase, whereby clusters consist of just two particles, studying them with optimization techniques and Monte Carlo simulations. We focus on the dimer crystal, and unveil a second phase transition at extremely low temperature. This transition leads from a triangular dimer lattice with randomly disordered dimer orientations at high temperature to a reduced-symmetry ground state with nematic orientational order and a slightly distorted structure characterized by a centered-rectangular lattice at low temperature.

Tissue distribution of sprifermin (recombinant human fibroblast growth factor 18) in the rat following intravenous and intra-articular injection.

Objective: Fibroblast growth factor 18 (FGF18) is involved in chondrogenesis and articular cartilage repair. We investigated tissue distribution and pharmacokinetics of radioactive [3H]sprifermin, a recombinant human FGF18, in rats after a single intravenous (i.v.) or intra-articular (i.a.) injection. Design: In two studies (48-96-h [n = 23] and 28-day [n = 12]), 35 male albino (Sprague Dawley) rats received single i.v. or i.a. dose [3H]sprifermin (0.24 mg/kg). Radioactivity was measured in blood, serum, and (in animals receiving i.a. administration) in the knee joint by liquid scintillation counting. Radioactivity in organs, tissues, and distribution in the whole body were measured with whole-body autoradiography. Results: After i.v. injection, radioactivity peaked in serum and whole blood after 4 and 24 h, respectively, with greater total radioactivity in serum. After i.a. injection, radioactivity peaked in serum and whole blood after 24 and 48 h, respectively; intact [3H]sprifermin was not detected in vena caval serum and systemic exposure was low, approximately 20% of that with i.v. injection. Following i.v. injection, radioactivity was mainly found in the liver, adrenal glands, kidney, and spleen; following i.a. injection, radioactivity was preferentially concentrated in articular cartilage after initial distribution in the joint capsule, and still evident in the joint after 28 days. Conclusions: After i.a. injection of [3H]sprifermin in rats, radioactivity was concentrated in the knee joint, particularly articular cartilage, with low levels in other investigated tissues. Systemic exposure to sprifermin was greater with i.v. than i.a. injection. Subsequent clinical investigation in patients with osteoarthritis has reported consistent results.

Ageing successfully with haemophilia: A multidisciplinary programme.

INTRODUCTION: Persons with haemophilia (PWH) born before the middle 1970s have spent a substantial part of their lives without the benefits of replacement therapy, that became available on a relative large scale only during the 1970s. As a consequence, this group of PWH, although still relatively young, suffers from musculoskeletal and functional problems that are typical of old people. METHODS: We report herewith the short-term results of a project based upon a multidisciplinary training programme led by a physiotherapist and an occupational therapist, that was implemented over a period of 12 months in 40 patients with severe or moderate hemophilia A or B born before the middle 1970s and regularly followed-up at a comprehensive haemophilia treatment centre in Italy. The project was aimed to provide information and skills in order to empower the older PWH carrying physical handicaps and functional limitations that had resulted from the inadequate management in their early ages, and to enable them to cope more efficiently with their crippling disease and prevent further disabilities. RESULTS AND CONCLUSIONS: The comparison of the data obtained before and after the 12-month programme found marginal improvements, but the purpose of this programme was indeed to offer a blueprint for the future. In this respect, the level of satisfaction for the programme was very high and we expect that it will be implemented long-term by our older PWH.

Medical decision making and risky choices: psychological and medicolegal consequences of HIV and HCV contamination of blood products.

AIMS: The overall goal of this article is to make a scientific comment about the psycho-social consequences of hemophilia patients affected by human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) and to point out the related medicolegal issues. METHODS: This commentary takes into account some published evidences about the current scenario of hemophilia patients infected by HIV and/or HCV who received contaminated blood products in the late 1970s through 1985. RESULTS: Several psychological and medicolegal consequences are related with HIV and HCV contamination of blood products. A multidisciplinary approach is needed to treat all the difficulties experienced by these patients and to ensure good clinical decisions in medical practice. CONCLUSION: The literature on the psychosocial functioning of hemophilia patients with human HIV and HCV infection offers a number of implications, including medicolegal issues, that can be discussed for guaranteeing a good level of care and safeguard of this group of patients.

Deoxycholic acid transformations catalyzed by selected filamentous fungi.

More than 100 filamentous fungi strains, mostly ascomycetes and zygomycetes from different phyla, were screened for the ability to convert deoxycholic acid (DCA) to valuable bile acid derivatives. Along with 11 molds which fully degraded DCA, several strains were revealed capable of producing cholic acid, ursocholic acid, 12-keto-lithocholic acid (12-keto-LCA), 3-keto-DCA, 15ß-hydroxy-DCA and 15ß-hydroxy-12-oxo-LCA as major products from DCA. The last metabolite was found to be a new compound. The ability to catalyze the introduction of a hydroxyl group at the 7(α/ß)-positions of the DCA molecule was shown for 32 strains with the highest 7ß-hydroxylase activity level for Fusarium merismoides VKM F-2310. Curvularia lunata VKM F-644 exhibited 12α-hydroxysteroid dehydrogenase activity and formed 12-keto-LCA from DCA. Acremonium rutilum VKM F-2853 and Neurospora crassa VKM F-875 produced 15ß-hydroxy-DCA and 15ß-hydroxy-12-oxo-LCA, respectively, as major products from DCA, as confirmed by MS and NMR analyses. For most of the positive strains, the described DCA-transforming activity was unreported to date. The presented results expand the knowledge on bile acid metabolism by filamentous fungi, and might be suitable for preparative-scale exploitation aimed at the production of marketed bile acids.

Reproductive long-term effects, endocrine response and fatty acid profile of rabbit does fed diets supplemented with n-3 fatty acids.

The effect of a diet enriched with polyunsaturated n-3 fatty acids (PUFA) on endocrine, reproductive, and productive responses of rabbit females and the litters has been studied. Nulliparous does (n=125) were fed ad libitum from rearing to second weaning two diets supplemented with different fat sources: 7.5g/kg lard for the control diet (group C; n=63) or 15g/kg of a commercial supplement containing a 50% ether extract and 35% of total fatty acids (FAs) as PUFA n-3 (Group P; n=62). Dietary treatments did not affect apparent digestibility coefficients of nutrients, or reproductive variables of does including milk production, mortality and average daily gain of kits over two lactations. However, on Day 5 and 7 post-induction of ovulation, progesterone of Group P tended to increase to a greater extent than in does of Group C. Total PUFAs, n-6 and n-3 and eicosapentanoic (EPA) contents were greater in adipose tissues of does in Group P than in Group C. Docosapentaenoic acid (DPA), EPA, and docosahexaenoic acid (DHA) concentrations were greater in peri-ovarian than in scapular fat with abdominal fat being intermediate in concentration. In PUFA supplemented does, kit mortality at the second parturition tended to be less than in control does. Also, kits born to does of the PUFA-supplemented group weighed more and were of greater length than from does of control group. In conclusion, effectiveness of dietary intervention on reproductive and performance response is greater in the second parity, which suggests an accumulative long-term beneficial effect of n-3 FA supplementation in reproductive rabbit does.

Reticular erythematous mucinosis: a review of patients' characteristics, associated conditions, therapy and outcome in 25 cases.

BACKGROUND: Reticular erythematous mucinosis (REM) is an uncommon disease, the nosology and specific characteristics of which are controversial because most reports deal with single cases or small series. OBJECTIVES: To describe the characteristics of patients with REM regarding demographics, clinical and pathological features, comorbidities, treatment and course. METHODS: A retrospective and prospective study was conducted on 25 patients diagnosed with REM in the setting of university-affiliated dermatology departments and dermatopathology centres. RESULTS: Of the 25 patients with REM, 16 were women (sex ratio 2 : 1) and the mean age was 46 years. The roles of sun exposure and oral contraceptives were ambiguous. Associated diseases included hypertension (n = 4), malignancies (n = 3), autoimmune diseases (n = 3) and Borrelia infection (n = 1). Immunological studies (including serology and direct immunofluorescence) were noncontributory. The response to antimalarial treatment was good in > 80% of cases. Worsening or recurrence of the lesion after treatment discontinuation, or in the course of the disease, occurred in 31% of patients. CONCLUSIONS: We present the largest REM case series to date. The reticular pattern with involvement of the midline of the chest and back, the predilection for middle-aged women, the controversial relationship with photosensitivity and the possible association with other conditions such as malignancies and thyroid dysfunctions are the main characteristics that makes REM a recognizable disease.

Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study.

Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health-related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short-Form (SF)-36 Health Survey and the EQ-5D questionnaire in subjects ≥ 14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on-demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on-demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF-36 dimensions except for vitality/energy and physical functioning. After prophylaxis, 'good responders,' defined as patients experiencing ≥ 50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role - physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ-5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on-demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ-5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on-demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on-demand treatment.

Efficacy of combined antiviral therapy with lamivudine and tenofovir in a liver transplanted girl with de novo hepatitis B virus infection.

The management of de novo hepatitis B (HBV) infection in children after liver transplantation is not well defined. Because this infection may induce severe liver disease in the graft liver, an efficient antiviral therapy is desirable. Here, we describe the favorable viral outcome observed in a liver transplanted girl with de novo HBV infection following combination therapy with lamivudine and tenofovir.

Hydroxylation of lithocholic acid by selected actinobacteria and filamentous fungi.

Selected actinobacteria and filamentous fungi of different taxonomy were screened for the ability to carry out regio- and stereospecific hydroxylation of lithocholic acid (LCA) at position 7ß. The production of ursodeoxycholic acid (UDCA) was for the first time shown for the fungal strains of Bipolaris, Gibberella, Cunninghamella and Curvularia, as well as for isolated actinobacterial strains of Pseudonocardia, Saccharothrix, Amycolatopsis, Lentzea, Saccharopolyspora and Nocardia genera. Along with UDCA, chenodeoxycholic (CDCA), deoxycholic (DCA), cholic (CA), 7-ketodeoxycholic and 3-ketodeoxycholic acids were detected amongst the metabolites by some strains. A strain of Gibberella zeae VKM F-2600 expressed high level of 7ß-hydroxylating activity towards LCA. Under optimized conditions, the yield of UDCA reached 90% at 1g/L of LCA and up to 60% at a 8-fold increased substrate loading. The accumulation of the major by-product, 3-keto UDCA, was limited by using selected biotransformation media.

Gene expression profiling in dermatitis herpetiformis skin lesions.

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease associated with gluten-sensitive enteropathy (CD). In order to investigate the pathogenesis of skin lesions at molecular level, we analysed the gene expression profiles in skin biopsies from 6 CD patients with DH and 6 healthy controls using Affymetrix HG-U133A 2.0 arrays. 486 genes were differentially expressed in DH skin compared to normal skin: 225 were upregulated and 261 were downregulated. Consistently with the autoimmune origin of DH, functional classification of the differentially expressed genes (DEGs) indicates a B- and T-cell immune response (LAG3, TRAF5, DPP4, and NT5E). In addition, gene modulation provides evidence for a local inflammatory response (IL8, PTGFR, FSTL1, IFI16, BDKRD2, and NAMPT) with concomitant leukocyte recruitment (CCL5, ENPP2), endothelial cell activation, and neutrophil extravasation (SELL, SELE). DEGs also indicate overproduction of matrix proteases (MMP9, ADAM9, and ADAM19) and proteolytic enzymes (CTSG, ELA2, CPA3, TPSB2, and CMA1) that may contribute to epidermal splitting and blister formation. Finally, we observed modulation of genes involved in cell growth inhibition (CGREF1, PA2G4, and PPP2R1B), increased apoptosis (FAS, TNFSF10, and BASP1), and reduced adhesion at the dermal epidermal junction (PLEC1, ITGB4, and LAMA5). In conclusion, our results identify genes that are involved in the pathogenesis of DH skin lesions.

Laparoscopic approach for an intra-abdominal kidney allograft nephrectomy after pediatric transplantation: a case report.

We report a case of minimally invasive nephrectomy of a kidney transplanted into the abdominal cavity in a child. A 15-year-old girl underwent transplantation with a cadaveric donor kidney due to congenital pyelonephritis, vesicoureteral reflux, and secondary bladder atrophy. The transplant was complicated by hyperacute rejection, cytomegalovirus infection, and anastomotic stenosis of the Bricker neobladder. After recurrent urinary tract infections, the patient was reintroduced to hemodialysis in 2010. After pneumo-peritoneum, we placed 2 10-mm trocars in the hypochondrium and left side and 2 5-mm in the left iliac fossa and right upper quadrant. The transplanted kidney was skeletonized, the artery and vein were cut to the end-to-side anastomoses to the juxta-renal aorta and cava using an automatic 35-mm, stapler, and the ureter was dissected and closed with clips. Via a Pfannestiel minilaparotomy we extracted the allograft. The patient was discharged on the third postoperative day. After 4 months of follow-up, she is alive an on dialysis. Laparoscopic nephrectomy of a kidney transplanted into the abdominal cavity is feasible and safe in centers with skilled minimally invasive techniques.

A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis.

The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99, P = 0.011). This finding was confirmed in a larger sample of 4,416 Sardinians cases/controls (OR = 1.18, 95% CI: 1.037-1.344, P = 0.011), but not in a population from Belgium. We provide one of the first instances of human/chimpanzee trans-specific coding variant located outside the major histocompatibility complex region. The selective pressure is likely to be virus driven; in modern populations, this variant associates with susceptibility to MS, possibly via the interaction with environmental factors.

Ultrasonography of haemophilic arthropathy.

Imaging is an essential tool for evaluation and monitoring of haemophilic arthropathy. Ultrasonography is increasingly used for joint assessment, due to its great sensitivity for soft tissue and relatively low cost. To assess the joint status and the role of ultrasonography in routine diagnosis and monitoring of joint disease in cohort haemophilic patients. Findings of patients with haemophilia, who routinely underwent ultrasonography were retrospectively evaluated to assess their joint status and the role of ultrasonography in routine diagnosis and monitoring of joint disease. Out of 325 joints examined (115 ankles, 210 knees), ultrasonography identified damages in 50% of ankles and 33% of knees in overall 111 patients, aged 7-80 years (median = 29 years). Synovial hypertrophy and cartilage abnormalities were the most frequent observations (88% and 76% in affected knees, respectively). Pristine joints were more frequently found in patients on primary prophylaxis, young age or no bleeding in the year prior to examination. Furthermore, no concordance was found between presence of joint changes at ultrasonography, and clinical joint status. Ultrasonography was shown to be able to detect joint damage involving soft tissues and bone surface. Its use might allow frequent monitoring of patients with haemophilia and early detection of arthropathy. For these reasons it might represent a valid tool in the routine management of haemophilia.