A total of 308,036 women were selected from the European Prospective Investigation into Cancer and Nutrition (EPIC) study to evaluate the association between tobacco smoking and the risk of cervical ...intraepithelial neoplasia of grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). At baseline, participants completed a questionnaire and provided blood samples. During a mean follow‐up time of 9 years, 261 ICC cases and 804 CIN3/CIS cases were reported. In a nested case–control study, the baseline sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11, 16, 18, 31, 33, 35, 45, 52, 58, and antibodies against Chlamydia trachomatis (CT), and Human Herpes Virus 2 (HHV‐2). Cervical samples were not available for HPV‐DNA analysis in this study. Multivariate analyses were used to estimate associations between smoking and risk of CIN3/CIS and ICC in the cohort and the case–control studies. In the cohort analyses smoking status, duration and intensity showed a two‐fold increased risk of CIN3/CIS and ICC, while time since quitting was associated with a two‐fold reduced risk. In the nested case–control study, consistent associations were observed after adjustment for HPV, CT and HHV‐2 serostatus, in both HPV seronegative and seropositive women. Results from this large prospective study confirm the role of tobacco smoking as an important risk factor for both CIN3/CIS and ICC, even after taking into account HPV exposure as determined by HPV serology. The strong beneficial effect of quitting smoking is an important finding that will further support public health policies for smoking cessation.
What's new?
Tobacco smoking is a cited cause of cervical cancer, but whether it causes cervical malignancy independent of human papillomavirus (HPV) infection is unclear. Here, strong associations were found between most measures of tobacco smoking and the risk of cervical intraepithelial neoplasia of grade 3/carcinoma in situ and invasive cervical cancer, after taking into account past exposure to HPV infection. Quitting smoking was associated with a 2‐fold risk reduction. The findings confirm the role of tobacco smoking in cervical carcinogenesis and show that quitting the habit has important benefits for cancer protection.
Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best ...predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3- 4 and ≥5 abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (κ=0.507; P<0.001). Discordant classification was obtained in 100 patients (29.4%), including 3% classified in opposite risk groups. Most discrepancies were technique-dependent and no greater correlation in the number of abnormalities was achieved when different filtering strategies were applied for GM. Nonetheless, both methods showed a similar concordance index for prediction of time to first treatment (TTFT) (CBA: 0.67 vs. GM: 0.65) and overall survival (CBA: 0.55 vs. GM: 0.57). High complexity maintained its significance in the multivariate analysis for TTFT including TP53 and IGHV status when defined by CBA (hazard ratio HR 3.23; P<0.001) and GM (HR 2.74; P<0.001). Our findings suggest that both methods are useful but not equivalent for risk stratification of CLL patients. Validation studies are needed to establish the prognostic value of genome complexity based on GM data in future prospective studies.
The optimal diuretic treatment strategy for patients with acute heart failure and renal dysfunction remains unclear. Plasma carbohydrate antigen 125 (CA125) is a surrogate of fluid overload and a ...potentially valuable tool for guiding decongestion therapy. The aim of this study was to determine if a CA125-guided diuretic strategy is superior to usual care in terms of short-term renal function in patients with acute heart failure and renal dysfunction at presentation.
This multicenter, open-label study randomized 160 patients with acute heart failure and renal dysfunction into 2 groups (1:1). Loop diuretics doses were established according to CA125 levels in the CA125-guided group (n = 79) and in clinical evaluation in the usual-care group (n = 81). Changes in estimated glomerular filtration rate (eGFR) at 72 and 24 hours were the co-primary endpoints, respectively.
The mean age was 78 ± 8 years, the median amino-terminal pro-brain natriuretic peptide was 7765 pg/mL, and the mean eGFR was 33.7 ± 11.3 mL/min/1.73m2. Over 72 hours, the CA125-guided group received higher furosemide equivalent dose compared to usual care (P = 0.011), which translated into higher urine volume (P = 0.042). Moreover, patients in the active arm with CA125 >35 U/mL received the highest furosemide equivalent dose (P <0.001) and had higher diuresis (P = 0.013). At 72 hours, eGFR (mL/min/1.73m2) significantly improved in the CA125-guided group (37.5 vs 34.8, P = 0.036), with no significant changes at 24 hours (35.8 vs 39.5, P = 0.391).
A CA125-guided diuretic strategy significantly improved eGFR and other renal function parameters at 72 hours in patients with acute heart failure and renal dysfunction.
NEXT collaboration detectors are based on energy measured by an array of photomultipliers (PMT) and topological event filtering based on an array of silicon photomultipliers (SiPMs). The readout of ...the PMT sensors for low-frequency noise effects and detector safety issues requires a grounded cathode connection that makes the readout AC-couple with variations in the signal baseline. Strict detector requirements of energy resolution better than 1% FWHM require a precise baseline reconstruction that is performed offline for data analysis and detector performance characterization. Baseline variations make it inefficient to apply traditional lossy data compression techniques, such as zero-suppression, that help to minimize data throughput and, therefore, the dead time of the system. However, for the readout of the SiPM sensors with less demanding requirements in terms of accuracy, a traditional zero-suppression is currently applied with a configuration that allows for a compression ratio of around 71%. The third stage in the NEXT detectors program, the NEXT-100 detector, is a 100 kg detector that instruments approximately five times more PMT sensors and twice the number of SiPM sensors than its predecessor, the NEXT-White detector, putting more pressure in the DAQ throughput, expected to be over 900 MB/s with the current configuration, which will worsen the dead time of the acquisition data system. This paper describes the data compression techniques applied to the sensor data in the NEXT-100 detector, which reduces data throughput and minimizes dead time while maintaining the event rate to the level of its predecessor, around 50 Hz.
Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic ...hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (
), or
mutations detected in around 85% of ...cases. GISTs without
or platelet-derived growth factor receptor alpha (
) mutations are considered wild-type (WT), and their diverse molecular alterations and biological behaviors remain uncertain. They are usually not sensitive to tyrosine kinase inhibitors (TKIs). Recently, some molecular alterations, including neurotrophic tyrosine receptor kinase (
) fusions, have been reported in very few cases of WT GISTs. This novel finding opens the window for the use of tropomyosin receptor kinase (TRK) inhibitor therapy in these subtypes of GIST. Herein, we report a new case of
-fused WT high-risk GIST in a female patient with a large pelvic mass (large dimension of 20 cm). The tumor was removed, and the histopathology displayed spindle-predominant morphology with focal epithelioid areas, myxoid stromal tissue, and notable lymphoid infiltration with tertiary lymphoid structures. Ten mitoses were quantified in 50 high-power fields without nuclear pleomorphism. DOG1 showed strong and diffuse positivity, and CD117 showed moderate positivity. Succinate dehydrogenase subunit B (SDHB) was retained, Pan-TRK was focal positive (nuclear pattern), and the proliferation index Ki-67 was 7%. Next-generation sequencing (NGS) detected an
fusion, and this finding was confirmed by fluorescence in situ hybridization (FISH), which showed
rearrangement. In addition, an
mutation was found by NGS. The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered. After 3 months of follow-up, a new CT scan showed a complete response. Based on our results and the cases from the literature, GISTs with
fusions are very uncommon so far; hence, further screening studies, including more WT GIST cases, may increase the possibility of finding additional cases. The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with
fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.
Growing concerns of maintaining the best talent have contributed to the rising number of idiosyncratic deals (i-deals) at the workplace. I-deals refer to the personalised work arrangements between ...employees and their employers where the terms benefit both parties. Despite the acknowledgment that supervisors are key in creating i-deals, research to date has overlooked their role. Drawing on prosocial motives and social learning theory, we explore an overall model of what triggers employee flexibility i-deals and the consequences of such i-deals on employee outcomes. In so doing, we explore one of the key yet untested assumptions of i-deals theory: that they are intended to be mutually beneficial. We investigate our model with matched supervisor - employee data (n = 186) collected in El Salvador and Chile. Findings reveal that there is a positive association between supervisors' prosocial motives and employees' flexibility i-deals. Moreover, prosocial motives of supervisors trickle-down and shape employees' functioning at work (i.e. work performance and deviant behaviours) and lead them to be more prosocially motivated through employees' flexibility i-deals.
Helping employees juggle work and family responsibilities is crucial at a time when the boundaries between work and family life are increasingly blurred. Family-supportive supervisor behaviours ...(FSSBs) contribute to this and benefit both employees and organizations. Yet, employees and supervisors do not necessarily agree about the displayed FSSBs. We explore how employee–supervisor (dis) agreement concerning FSSB perceptions relates to employees' intrinsic motivation and turnover intentions. Moreover, we incorporate work–family culture and employees' desire for segmentation as boundary conditions. Using 569 employee–supervisor dyads from El Salvador, we found that intrinsic motivation is highest when employees and supervisors agree about strongly exhibited FSSBs, but only when employees desire work/home segmentation. When employees desire integration, such FSSB agreement is associated with relatively low intrinsic motivation. Moreover, turnover intentions are lowest when employees and supervisors agree that the supervisor exhibits a strong level of FSSBs, but only when work–family culture is strong. We contribute to FSSB research by demonstrating the importance of employees and supervisors seeing eye to eye (the level of) FSSBs, as well as the need for a good fit with the work–family culture of an organization and employees' desire for segmentation.
•Employee-supervisor agreement on FSSBs relates positively to employees' intrinsic motivation.•Only in a strong work-family culture and when employees and supervisors agree on high levels of FSSBs, retention is highest.•When employees wish to segment, intrinsic motivation is highest in case of strong employee-supervisor FSSB perceptions.•When employees wish to integrate, intrinsic motivation is highest in case of weak employee-supervisor FSSB perceptions.
Purpose
Some women undergoing stimulated cycles have elevated serum progesterone (P) on the day of ovulation trigger, but its effect on embryo quality is unclear. We analyze embryo quality among ...patients with high and low serum P undergoing preimplantation genetic testing for aneuploidy (PGT-A).
Methods
This retrospective study included 1597 patients divided into two groups by serum P values: < 1.5 ng/mL or ≥ 1.5 ng/mL. A gonadotrophin-releasing hormone (GnRH) antagonist protocol was established for each patient. Serum P levels were measured on the day of triggering. Propensity score matching and Poisson regression were done. Age, body mass index, and ovarian sensitivity index were also compared.
Results
Elevated serum P was not significantly associated with euploid embryo rate or other embryo-quality variables evaluated in our study. Age was the only variable associated with euploidy rate (per MII oocyte,
P
< 0.001; per biopsied embryo,
P
= 0.008), embryo biopsy rate (
P
< 0.001), absolute number of euploid embryos (
P
= 0.008), and top-quality embryo rate (
P
= 0.008). Categorical variables decreased in value for every year of increased age in patients with high serum P.
Conclusions
Elevated serum P did not affect the number of euploid and good-quality embryos for transfer in GnRH antagonist intracytoplasmic sperm injection (ICSI) cycles. Contrary to the clear influence of premature P elevation on endometrial receptivity based on literature, our results may help to tip the balance towards the absence of a negative effect of P elevation on embryo competence. More studies are needed to fully understand the effect of P elevation on reproductive outcomes.
COVID-19 has driven several global offline communities to go online. Restrictions to the free movement of people in response to the coronavirus pandemic triggered a profound rethinking of jobs, ...products and services, and among them, the activities of religious communities, which are well consolidated in the offline sphere. In Spain, since the lockdown established by the government in March 2020, the Catholic Church has reinvented its activity, as all the churches and other places of worship have been closed. This constituted a considerable challenge, considering the history and dynamics of the institution. This paper aims to analyze how Catholicism, as one of the most consolidated offline communities, reworked its communication, going online in a matter of days. With this objective, researchers surveyed each and every one of the 70 Spanish dioceses, taking them as representatives of the global Catholic community in the country. Their responses are complemented with an in-depth interview with the Director of Communications at the Spanish Conference of Bishops. The results highlight the huge and unprecedented step towards the digitalization of the community through consistent, creative and efficient action. New methods, platforms and languages have been implemented, even broadening community membership. Despite an offline essence that is still detected in some decisions, this pandemic has brought a new communicative paradigm to the Spanish Catholic community. Digitalization has been consolidated whilst preserving the best aspects of direct contact and action.
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