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Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness.

Background: The incidence of catheter-related bloodstream infections (CRBSI) has fallen over the last decade, especially in intensive care units (ICUs). Aim: to assess the existence of concomitant trends in outcomes and to analyse the current risk factors for mortality. Methods: A multicentre retrospective cohort study was conducted at 24 Catalan hospitals participating in the Surveillance of healthcare associated infections in Catalonia (VINCat). All hospital-acquired CRBSI episodes diagnosed from January 2010 to December 2019 were included. A common protocol including epidemiological, clinical and microbiological data was prospectively completed. Mortality at days after bacteraemia onset was analysed using the Cox regression model. Findings: Over the study period, 4,795 episodes of CRBSI were diagnosed. Among them, 75% were acquired in conventional wards and central venous catheters were the most frequently involved (61%). The 30-day mortality rate was 13.8%, presenting a significant downward trend over the study period: from 17.9% in 2010 to 10.6% in 2019 (HR 0.95 [0.92-0.98]). The multivariate analysis identified age (HR 1.03 83 [1.02-1.04]), femoral catheter (HR 1.78 [1.33-2.38]), medical ward acquisition (HR 2.07 [1.62-2.65] and ICU acquisition (HR 3.45 [2.7-4.41]), S. aureus (HR 1.59 [1.27-1.99]) and Candida sp. (HR 2.19 [1.64-2.94]) as risk factors for mortality while the mortality rate associated with episodes originating in peripheral catheters was significantly lower (HR 0.69 [0.54-0.88]). Conclusions: Mortality associated with CRBSI has fallen in recent years but remains high. Intervention programs should focus especially on ICUs and medical wards, where incidence and mortality rates are highest.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): MPL received the Catalan Society of Cardiology Research Grant in 2019 and 2020 (Catalonia, Spain); the Josep Font Grant (2019-2022) from Hospital Clínic Barcelona (Catalonia, Spain). Background Left bundle branch pacing (LBBP) has emerged as an alternative to biventricular pacing. However, lack of a systematic stepwise application of the left bundle branch (LBB) capture criteria complicates implantation. Objective To define a stepwise application of LBBP capture criteria that will simplify implantation and ensure LBB capture. Methods A cohort of 24 patients from the LEVEL-AT trial who received LBBP and had electrocardiographic imaging (ECGI) at 45 days post-implant were included. The usefulness of ECG and electrogram based criteria to predict accurate LBB capture were analyzed. A two-step approach was developed to ensure LBB capture. The gold standard used to confirm LBB capture was the change in ventricular activation pattern and shortening in left ventricular activation time, assessed by ECGI. Results Twenty-two (91.6%) patients showed LBBP capture on ECGI. All patients fulfilled pre-screwing requisites: lead in septal position in left-oblique projection and W paced morphology in V1. In the first step, presence of either right bundle branch conduction delay pattern (qR or rSR in V1) or left bundle branch capture Plus (QRS ≤120ms) resulted in 95% sensitivity and 100% specificity to predict LBB capture, with an accuracy of 95.8%. In the second step, the presence of selective capture (100% specificity, only 41% sensitivity) or a spike-R Conclusions Stepwise application of ECG and electrogram criteria ensured an accurate assessment of left conduction system capture.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Catalan Society of Cardiology; Asociación del Ritmo Cardiaco (Spanish Society of Cardiology). Background Correction of dyssynchrony measured with echo strain, in conduction system pacing (CSP) vs biventricular pacing (BIVP) has not been reported. Objectives Our purpose was to compare echocardiographic dyssynchrony correction and strain improvement during follow-up between CSP and BIVP. Methods A treatment received analysis was performed in patients (n=29 CSP; BIVP 40). Patients were evaluated at baseline (ON and OFF programming) and at 6 and 12 months. All echocardiograms were completed by operators blinded to the type of device implanted. Intraventricular (septal flash), interventricular (difference between left and right ventricular outflow times), and auriculoventricular (diastolic filling time) dyssynchrony, as well as strain parameters (septal rebound, global longitudinal strain (GLS), and Risum pattern (typical left bundle branch block contraction pattern)) were analyzed. Results 32% (22/69) were women; baseline LVEF was 27.5% (7% SD) and left ventricular end-systolic volume (LVESV) 138ml (77ml SD) without differences between groups. At the 12-month follow-up, there were no differences in CSP vs. BIVP in LVEF (45.8% (10% SD) vs. 42.7% (12% SD), p=0.25) and LVESV (81.5 ml (41 ml SD) vs. 101.7 ml (56 ml SD), p=0.08). Longitudinal analyses showed that the improvement of all echocardiographic dyssynchrony parameters over time was similar between groups (p Conclusions CSP and BIVP provided a similar dyssynchrony and strain correction over time. Acute strain correction predicted ventricular remodeling at 12 months follow-up.

Current therapeutic approaches for Sézary syndrome (SS) do not achieve a significant improvement in long-term survival of patients, and they are mainly focused on reducing blood tumor burden to improve quality of life. Eradication of SS is hindered by its genetic and molecular heterogeneity. Determining effective and personalized treatments for SS is urgently needed. The present work compiles the current methods for SS patient–derived xenograft (PDX) generation and management to provide new perspectives on treatment for patients with SS. Mononuclear cells were recovered by Ficoll gradient separation from fresh peripheral blood of patients with SS (N = 11). A selected panel of 26 compounds that are inhibitors of the main signaling pathways driving SS pathogenesis, including NF-kB, MAPK, histone deacetylase, mammalian target of rapamycin, or JAK/STAT, was used for in vitro drug sensitivity testing. SS cell viability was evaluated by using the CellTiter-Glo_3D Cell Viability Assay and flow cytometry analysis. We validated one positive hit using SS patient–derived Sézary cells xenotransplanted (PDX) into NOD-SCID-γ mice. In vitro data indicated that primary malignant SS cells all display different sensitivities against specific pathway inhibitors. In vivo validation using SS PDX mostly reproduced the responses to the histone deacetylase inhibitor panobinostat that were observed in vitro. Our investigations revealed the possibility of using high-throughput in vitro testing followed by PDX in vivo validation for selective targeting of SS tumor cells in a patient-specific manner.

Molecular and cytogenetic studies are essential for diagnosis and prognosis in patients with myelodysplastic syndromes (MDSs). Cell-free DNA (cfDNA) analysis has been reported to be a reliable noninvasive approach for detecting molecular abnormalities in MDS; however, there is limited information about cytogenetic alterations and monitoring in cfDNA. We assessed the molecular and cytogenetic profile of a cohort of 70 patients with MDS by next-generation sequencing (NGS) of cfDNA and compared the results to sequencing of paired bone marrow (BM) DNA. Sequencing of BM DNA and cfDNA showed a comparable mutational profile (92.1% concordance), and variant allele frequencies (VAFs) strongly correlated between both sample types. Of note, SF3B1 mutations were detected with significantly higher VAFs in cfDNA than in BM DNA. NGS and microarrays were highly concordant in detecting chromosomal alterations although with lower sensitivity than karyotype and fluorescence in situ hybridization. Nevertheless, all cytogenetic aberrations detected by NGS in BM DNA were also detected in cfDNA. In addition, we monitored molecular and cytogenetic alterations and observed an excellent correlation between the VAFs of mutations in BM DNA and cfDNA across multiple matched time points. A decrease in the cfDNA VAFs was detected in patients responding to therapy, but not in nonresponding patients. Of note, cfDNA analysis also showed cytogenetic evolution in 2 nonresponsive cases. In summary, although further studies with larger cohorts are needed, our results support the analysis of cfDNA as a promising strategy for performing molecular characterization, detection of chromosomal aberrations and monitoring of patients with MDS.

Translocation analysis using fluorescence in situ hybridization (FISH) is the method of choice for dose assessment in case of chronic or past exposures to ionizing radiation. Although it is a widespread technique, unlike dicentrics, the number of FISH-based inter-laboratory comparisons is small. For this reason, although the current Running the European Network of Biological and Physical retrospective Dosimetry (RENEB) inter-laboratory comparison 2021 was designed as a fast response to a real emergency scenario, it was considered a good opportunity to perform an inter-laboratory comparison using the FISH technique to gain further experience. The Bundeswehr Institute of Radiobiology provided peripheral blood samples from one healthy human volunteer. Three test samples were irradiated with blinded doses of 0, 1.2, and 3.5 Gy, respectively. Samples were then sent to the seven participating laboratories. The FISH technique was applied according to the standard procedure of each laboratory. Both, the frequency of translocations and the estimated dose for each sample were sent to the coordinator using a special scoring sheet for FISH. All participants sent their results in due time. However, although it was initially requested to send the results based on the full analysis, evaluating 500 equivalent cells, most laboratories only sent the results based on triage, with a smaller number of analyzed cells. In the triage analysis, there was great heterogeneity in the number of equivalent cells scored. On the contrary, for the full analysis, this number was more homogeneous. For all three samples, one laboratory showed outlier yields compared to the other laboratories. Excluding these results, in the triage analysis, the frequency of translocations in sample no. 1 ranged from 0 to 0.013 translocations per cell, and for samples no. 2 and no. 3 the genomic mean frequency were 0.27 ± 0.03 and 1.47 ± 0.14, with a coefficient of variation of 0.29 and 0.23 respectively. Considering only results obtained in the triage analysis for sample no. 1, all laboratories, except one, classified this sample as the non-irradiated one. For sample no. 2, excluding the outlier value, the mean reported dose was 1.74 ± 0.16 Gy indicating a mean deviation of about 0.5 Gy to the delivered dose of 1.2 Gy. For sample no. 3 the mean dose estimated was 4.21 ± 0.21 Gy indicating a mean deviation of about 0.7 Gy to the delivered dose of 3.5 Gy. In the frame of RENEB, this is the second FISH-based inter-laboratory comparison. The whole exercise was planned as a response to an emergency, therefore, a triage analysis was requested for all the biomarkers except for FISH. Although a full analysis was initially requested for FISH, most of the laboratories reported only a triage-based result. The main reason is that it was not clearly stated what was required before starting the exercise. Results show that most of the laboratories successfully discriminated unexposed and irradiated samples from each other without any overlap. A good agreement in the observed frequencies of translocations was observed but there was a tendency to overestimate the delivered doses. Efforts to improve the harmonization of this technique and subsequent exercises to elucidate the reason for this trend should be promoted.

Clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in non-conditioned Fanconi anemia (FA) patients resulting from the proliferative advantage of corrected FA HSPCs, however it is yet unknown if gene therapy can revert affected molecular pathways in diseased HSPCs. Single-cell RNA sequencing was performed in chimeric populations of corrected and uncorrected HSPCs coexisting in the BM of gene therapy treated FA patients. Our study demonstrates that gene therapy reverts the transcriptional signature of FA HSPCs, which then resembles the transcriptional program of healthy donor HSPCs. This includes a downregulated expression of TGF-β and p21, typically upregulated in FA HSPCs, and upregulation of DNA damage response and telomere maintenance pathways. Our results show for the first time the potential of gene therapy to rescue defects in the HSPC transcriptional program from patients with inherited diseases, in this case in FA characterized by BMF and cancer predisposition.

Few cases of isolated (nonsyndromic, nonendocrinopathy) familial acanthosis nigricans (FAN) have been described, and most have not included genetic testing. We present a three-generation family with isolated FAN, whose genetic study revealed a heterozygous FGFR3 gene variant [NM_0001425: c.2302G>T; p.(Glu768Ter); E768X]. We propose genetic mechanisms that could explain the pro-mitogenic effect on the skin without bone involvement and the spectrum of clinical manifestations associated with germline FGFR3 mutations.

Introduction The efficacy of perioperative bundled interventions implemented at a multicenter level has been poorly studied. Methods A colorectal 6-element prevention bundle (antibiotic prophylaxis, oral antibiotic prophylaxis (OAP), mechanical bowel preparation (MBP), laparoscopy, normothermia, and wound retractor), introduced in 61 hospitals, was analysed. Surgical site infection (SSI) rates were compared before (G1, 2011–2016), and after (G2, 2016–2020) the bundle implementation. Results 37849 procedures were included. 5462 overall SSI (14.43%), and 2838 (7.5%) organ-space SSI (O/S-SSI) were detected. SSI decreased from 18.38% to 10.62% with the application of the bundle (OR 0,503). Similarly, O/S-SSI diminished from 9.15% (G1) to 5.72% (G2), OR 0.602. Compared to the previous year, SSI decreased by 23% after the first year of bundle implementation. 29.26% of SSIs were diagnosed post-discharge. 54.5% required readmission. The reduction was similar between high, medium and low volume hospitals. Overall SSI was 16.71%, when no measure was applied, and 6.23% when all 6 were implemented. Lack of application of the bundle increased the probability of SSI (OR 3.020) and O/S-SSI (OR 1.556). In a univariate analysis, all measures except normothermia were associated with a decrease in overall SSI, while only laparoscopy and OAP were for O/S-SSI. Multivariate analysis confirmed that laparoscopy, OAP, and wound protectors decrease overall SSI, but only OAP and laparoscopy had an effect on O/S-SSI. Conclusions A preventive bundle decreased overall and O/S SSI rates in elective colon and rectal surgery. The OR for SSI was 1.5 to 3 times higher before than after the bundle implementation.

Primary cutaneous lymphomas (PCL) are uncommon. Observations based on the first year of data from the Spanish Registry of Primary Cutaneous Lymphomas (RELCP, in its Spanish abbreviation) of the Spanish Academy of Dermatology and Venereology (AEDV) were published in February 2018. This report covers RELCP data for the first 5 years.RELCP data were collected prospectively and included diagnosis, treatments, tests, and the current status of patients. We compiled descriptive statistics of the data registered during the first 5 years.Information on 2020 patients treated at 33 Spanish hospitals had been included in the RELCP by December 2021. Fifty-nine percent of the patients were men; the mean age was 62.2 years. The lymphomas were grouped into 4 large diagnostic categories: mycosis fungoides/Sézary syndrome, 1112 patients (55%); primary B-cell cutaneous lymphoma, 547 patients (27.1%); primary CD30+ lymphoproliferative disorders, 222 patients (11%), and other T-cell lymphomas, 116 patients (5.8%). Nearly 75% of the tumors were registered in stage I. After treatment, 43.5% achieved complete remission and 27% were stable at the time of writing. Treatments prescribed were topical corticosteroids (1369 [67.8%]), phototherapy (890 patients [44.1%]), surgery (412 patients [20.4%]), and radiotherapy (384 patients [19%]).The characteristics of cutaneous lymphomas in Spain are similar to those reported for other series. The large size of the RELCP registry at 5 years has allowed us to give more precise descriptive statistics than in the first year. This registry facilitates the clinical research of the AEDV's lymphoma interest group, which has already published articles based on the RELCP data.

We describe a patient with unilateral ulcerations on the forehead and scalp, occurring 3 months after herpes zoster infection. Further investigations were unremarkable. Histology showed epidermal and upper dermal ulceration associated with a mild nonspecific dermal inflammatory infiltrate composed of lymphoid cells and histiocytes.

Extensive subtypes of alopecia areata (AA) (totalis, universalis, or multifocal) still have no approved and effective treatments in Europe, although Janus kinase inhibitors, such as baricitinib, are promising treatments that have been recently approved by the FDA. Nowadays, the higher costs and the lower experience with Janus kinase inhibitors, provide more difficulties in its accessibility. On the other hand, different corticosteroids regimens have been evaluated with conflicting results from decades. In 2016, a new regimen of mini pulse corticosteroid therapy with oral dexamethasone (MPCT-OD) 0.1mg/kg/day twice per week for adult patients with alopecia areata totalis or universalis, was reported to be effective with a lower rate of adverse effects. We performed a retrospective and multicentric study to collect data from patients with extensive forms of alopecia areata who had received MPCTOD (0.1 mg/kg/day twice weekly of dexamethasone) for at least 24 weeks. We included adult patients (≥18 years) with extensive forms of AA (SALT index ≥ 10) that did not respond to previous treatments. Variables including epidemiological and clinical data were recorded. Therapeutic response was assessed through the % change in SALT score (from 0 to 100%) and the changes in eyebrow and eyelash alopecia index (EBA, ELA) from baseline to 24 weeks after the beginning of the treatment. Dexamethasone dosage, duration of the treatment, time until response, time to relapse, adverse effects, and discontinuation were also recorded.