Genome-wide association study and functional follow-up identify 14q12 as a candidate risk locus for cervical cancer.

Cervical cancer is among the leading causes of cancer-related death in females worldwide. Infection by human papillomavirus (HPV) is an established risk factor for cancer development. However, genetic factors contributing to disease risk remain largely unknown. We report on a genome-wide association study (GWAS) on 375 German cervical cancer patients and 866 healthy controls, followed by a replication study comprising 658 patients with invasive cervical cancer, 1361 with cervical dysplasia and 841 healthy controls. Functional validation was performed for the top GWAS variant on chromosome 14q12 (rs225902, close to PRKD1). After bioinformatic annotation and in silico predictions, we performed transcript analysis in a cervical tissue series of 317 samples and demonstrate rs225902 as an expression quantitative trait locus (eQTL) for FOXG1 and two tightly co-regulated long non-coding RNAs at this genomic region, CTD-2251F13 (lnc-PRKD1-1) and CTD-2503I6 (lnc-FOXG1-6). We also show allele-specific effects of the 14q12 variants via luciferase assays. We propose a combined effect of genotype, HPV status and gene expression at this locus on cervical cancer progression. Taken together, this work uncovers a potential candidate locus with regulatory functions and contributes to the understanding of genetic susceptibility to cervical cancer.

Rethinking parameters of "success" in breaking bad news conversations from patient's perspective: the successful delivery process model.

PURPOSE: Studies that focus on improving the difficult process of breaking bad news in oncology should include the patient perspective and be guided by appropriate outcome measures. Endpoints such as "patient satisfaction" fall short to capture the complex nature of breaking bad news (BBN) conversations. However, this is true of many studies. The present study attempts to develop a framework model from a new, patient-centered perspective, which can be applied equally in clinical practice and in education. METHODS: Semi-structured in-depth interviews with twelve cancer patients were conducted. Transcripts were analyzed by "qualitative content analysis" following Mayring. Outcomes were further extrapolated in interpretational steps, and a model of "success" from patients view in BBN was developed. RESULTS: Two central needs of the patients could be identified: understanding and feelings. Their fulfillment depends on two groups of variables: first, structural characteristics, such as the inevitable shock, individuality, and processability; second, strongly influenceable variables, such as relationship, transfer of knowledge, and atmosphere. From these results, a framework model for successful breaking of bad news from the patient's perspective was developed: The successful delivery process model (SDP model). CONCLUSION: As a basic model for the framework for breaking bad news from the patient's perspective, the SDP model can be applied to many different situations in oncology and help to frame the difficult conversations by tailoring the BBN conversations on determinants that favorably influence the process in a patient centered manner. In this sense, the model can be useful in clinical practice as well as in education.

Extra-axonal contribution to double diffusion encoding-based pore size estimates in the corticospinal tract.

OBJECTIVE: To study the origin of compartment size overestimation in double diffusion encoding MRI (DDE) in vivo experiments in the human corticospinal tract. Here, the extracellular space is hypothesized to be the origin of the DDE signal. By exploiting the DDE sensitivity to pore shape, it could be possible to identify the origin of the measured signal. The signal difference between parallel and perpendicular diffusion gradient orientation can indicate if a compartment is regular or eccentric in shape. As extracellular space can be considered an eccentric compartment, a positive difference would mean a high contribution to the compartment size estimates. MATERIALS AND METHODS: Computer simulations using MISST and in vivo experiments in eight healthy volunteers were performed. DDE experiments using a double spin-echo preparation with eight perpendicular directions were measured in vivo. The difference between parallel and perpendicular gradient orientations was analyzed using a Wilcoxon signed-rank test and a Mann-Whitney U test. RESULTS: Simulations and MR experiments showed a statistically significant difference between parallel and perpendicular diffusion gradient orientation signals ([Formula: see text]). CONCLUSION: The results suggest that the DDE-based size estimate may be considerably influenced by the extra-axonal compartment. However, the experimental results are also consistent with purely intra-axonal contributions in combination with a large fiber orientation dispersion.

Cervical intraepithelial neoplasia grade 3: development during pregnancy and postpartum.

PURPOSE: The aims of the present study were to evaluate the development of untreated cervical intraepithelial neoplasia (CIN) 3 during pregnancy and to assess persistence, progression, and regression rates postpartum to identify factors associated with regression. METHODS: In a tertiary gynecology and obstetrics department, a total of 154 pregnant women with CIN 3 were treated in the dysplasia unit. The follow-up findings were analyzed retrospectively on the basis of histological, cytological, and human papillomavirus (HPV) testing of 154 pregnant women confirmed as having CIN 3 in colposcopically guided biopsies. RESULTS: The rates of persistence, regression, and progression of CIN 3 in these women were 76.1%, 20% and 3.2%, respectively. Data for the delivery mode was available for 126 women. The rate of regression was almost twice as high with vaginal delivery as with cesarean section, at 27.4 vs. 15.2%, whereas the rate of progression was lower with vaginal delivery, at 2.7 vs. 6.5%. CONCLUSION: The rate of persistence of CIN observed in this study is comparable to that reported in other studies. The study provides strong evidence for greater regression among women who have vaginal deliveries. Careful work-up is recommended postpartum for this group of women in order to rule out persistent CIN 3 or invasive disease.

Mobile-BAT-A Novel Ultra-Low Power Wildlife Tracking System.

We introduce a novel ultra-low power system for tracking animal movements over long periods with an unprecedented high-temporal-resolution. The localization principle is based on the detection of cellular base stations using a miniaturized software-defined radio, weighing 2.0 g, including the battery, and having a size equivalent to two stacked 1-euro cent coins. Therefore, the system is small and lightweight enough to be deployed on small, wide-ranging, or migrating animals, such as European bats, for movement analysis with an unprecedented spatiotemporal resolution. The position estimation relies on a post-processing probabilistic RF pattern-matching method based on the acquired base stations and power levels. In several field tests, the system has been successfully verified, and a run-time of close to one year has been demonstrated.

Terahertz referenceless wavefront sensing by means of computational shear-interferometry.

In this contribution, we demonstrate the first referenceless measurement of a THz wavefront by means of shear-interferometry. The technique makes use of a transmissive Ronchi phase grating to generate the shear. We fabricated the grating by mechanical machining of high-density polyethylene. At the camera plane, the +1 and -1 diffraction orders are coherently superimposed, generating an interferogram. We can adjust the shear by selecting the period of the grating and the focal length of the imaging system. We can also alter the direction of the shear by rotating the grating. A gradient-based iterative algorithm is used to reconstruct the wavefront from a set of shear interferograms. The results presented in this study demonstrate the first step towards wavefield sensing in the terahertz band without using a reference wave.

Chocolate inspection by means of phase-contrast imaging using multiple-plane terahertz phase retrieval.

Terahertz (THz) radiation has shown enormous potential for non-destructive inspection in many contexts. Here, we present a method for imaging defects in chocolate bars that can be extended to many other materials. Our method requires only a continuous wave (CW) monochromatic source and detector at relatively low frequencies (280 GHz) corresponding to a relatively long wavelength of 1.1 mm. These components are used to construct a common-path configuration enabling the capturing of several images of THz radiation diffracted by the test object at different axial depths. The captured diffraction-rich images are used to constrain the associated phase retrieval problem enabling full access to the wave field, i.e., real amplitude and phase distributions. This allows full-field diffraction-limited phase-contrast imaging. Thus, we experimentally demonstrate the possibility of identifying contaminant particles with dimensions comparable to the wavelength.

The global pandemic and changes in women's reproductive health: an observational study.

OBJECTIVE: The COVID-19 global pandemic has led to the death of millions around the world and impacted the overall health of many people. In this article we aim to compare reproductive health indicators in the first 6 months of 2020 to the prior year, as well as explore stress and quality of life during this time. METHODS: This retrospective observational study examined the menstrual cycles of 1159 women who were using a fertility tracking device to record their menstrual cycle and BBT data. We utilised a supplemental mobile application to administer a supplemental survey to collect data on stress and quality of life. Descriptive analyses were conducted with t-tests for two-group comparisons. RESULTS: Study participants from 15 countries contributed to a total of 13,194 cycles. 23.1% (268/1159) responded to the survey focussed on assessing psychosocial distress. 44.4% (119/268) of the study participants reported that they had noticed a change in their menstrual cycle, temperature curve, or menstruation in the past 12 months. Cycle analysis found the average cycle length and pre-ovulation phase length was longer in the first 6 months of 2019, while the average days of menstruation was slightly longer in 2020. DISCUSSION: Our findings indicate that menstrual cycle indicators changed only slightly in the first 6 months of 2020 but were still statistically significant. We were also able to understand that these study participants had some level of awareness of changes to their menstrual health.

Association of genomic variants at PAX8 and PBX2 with cervical cancer risk.

Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta-analysis, 2q14.1 (PAX8) and 6p21.32 (PBX2) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case-control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at PAX8 and rs2856437 at PBX2, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.91, P = 2.4 × 10-4 ; rs2856437: OR 1.52, 95% CI 1.14-2.02, P = .004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462: OR 0.80, 95% CI 0.68-0.94, P = .006; rs2856437: OR 1.56, 95% CI 1.03-2.36, P = .036) and with high-grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70-0.90, P = 1.9 × 10-4 ; rs2856437: OR 1.58, 95% CI 1.15-2.17, P = .005). A combined analysis of high-grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73-0.91, P = 2.4 × 10-4 ; rs2856437: OR 1.57, 95% CI 1.18-2.10, P = .002). No association was detected for rs2856437 with low-grade dysplasia, while rs10175462 showed weak evidence of association (P = .05). RNA analyses in cervical samples revealed that PAX8 transcripts were upregulated in HPV-positive lesions (P = .008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA PAX8-AS1 (P < .001). Taken together, our results extend the evidence for a link between genomic risk variants at the HLA region (PBX2) with cervical disease and support PAX8 as the first consistent non-HLA cervical cancer susceptibility locus.

Microcavity-enhanced Kerr nonlinearity in a vertical-external-cavity surface-emitting laser: erratum.

We correct a mistake in [Opt. Express27, 11914 (2019)10.1364/OE.27.011914] when calculating the focal length of the Kerr lens with the measured values of the nonlinear refractive index n2 and parameters of a prototypical self-mode-locking VECSEL cavity. We therefore update Fig. 1 of the original publication. The new calculation yields a significantly larger value of the Kerr lens focal length leading to a smaller perturbation of the cavity beam profile.

'It was like taking an inner bath': A qualitative evaluation of a collaborative advance care planning-approach.

BACKGROUND: Impaired readiness may hinder purposeful advance care planning in cancer patients. To reduce barriers to participation in end-of-life decision-making, a collaborative intervention was developed combining a psycho-oncological approach of dignity-based and cognitive-behavioural interventions, followed by a standardised advance care planning-process. AIM: To evaluate the novel collaborative advance care planning-approach by synthetising cancer patient and carer perspectives on communicational and relational effects. DESIGN: As a sub-project of a mixed-methods evaluation study, we conducted an inductive content analysis of qualitative interviews with advanced cancer patients and caregivers to deeply explore the focused impact of a collaborative advance care planning-approach on communication and relationship dynamics. SETTING/PARTICIPANTS: Twelve patients with advanced cancer and 13 carers who participated in a collaborative advance care planning-intervention. RESULTS: The collaborative advance care planning-approach was consistently evaluated positively by participants. Transcriptions of the semi-structured interviews were coded, analysed and merged under three main themes concerning communicational and relationship dynamics: action readiness, content readiness and impact on future communication and relationship. CONCLUSIONS: The novel intervention served to foster individual readiness - including action and content readiness - for advance care planning-discussions by addressing highly individualised barriers to participation, as well as specific end-of-life issues. In addition, societal readiness could be promoted. Although the brief psycho-oncological intervention could not fully meet the needs of all participants, it can be used to develop individual psychotherapeutic strategies to improve different facets of readiness. The collaborative advance care planning-approach might require more time and human resources, but could pioneer successful advance care planning.

Human papilloma virus genotype distribution in women with premalignant or malignant lesions of the uterine cervix.

OBJECTIVE: Cervical cancer is caused by persistent infection with high-risk human papillomavirus (hrHPV). Cytology-based national screening programs have reduced the incidence and mortality of cervical cancer. Different hrHPV subtypes have different carcinogenic potentials. This study evaluated the distribution of different types of hrHPV relative to age in cervical cancer and its precursor lesions. METHODS: HPV testing was performed between November 2018 and February 2020 using the Abbott RealTime high-risk HPV assay on an Abbott m2000sp instrument. This assay separately detects HPV-16, HPV-18, and a pool of 12 additional hrHPV types (HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, and -68). RESULTS: The study included 652 women with HPV samples and biopsies of the cervix or histology samples obtained during surgery. In all, 30.8% (95% CI, 27.3-34.6%) were HPV-negative. Among HPV-positive women, HPV-16, HPV-18, and "HPV other" types were found in 33.5, 4.4, and 49.4%, respectively. Cervical intraepithelial neoplasia (CIN) 3/high-grade squamous intraepithelial lesions (HSILs) in women ≤ 34 years were positive for HPV-16 in 54.5% of cases and in those ≥ 35 years in 45.4% of cases. Among women with cervical cancer, 75.8% were infected with HPV-16 or had coinfection with HPV-16 and "HPV other". CONCLUSIONS: HPV-16 is the most common type of hrHPV in HSIL + lesions. It is more common in women diagnosed with CIN 3/HSIL who are aged ≤ 35 and is decreasing with age. Therefore, women age ≥ 35 with persistent infection with this type of hrHPV need careful surveillance, as they are at high risk of progression to cervical cancer.

The performance of a fertility tracking device.

OBJECTIVE: Fertility tracking devices offer women direct-to-user information about their fertility. The objective of this study is to understand how a fertility tracking device algorithm adjusts to changes of the individual menstrual cycle and under different conditions. METHODS: A retrospective analysis was conducted on a cohort of women who were using the device between January 2004 and November 2014. Available temperature and menstruation inputs were processed through the Daysy 1.0.7 firmware to determine fertility outputs. Sensitivity analyses on temperature noise, skipped measurements, and various characteristics were conducted. RESULTS: A cohort of 5328 women from Germany and Switzerland contributed 107,020 cycles. Mean age of the sample was 30.77 [SD 5.1] years, with a BMI of 22.07 kg/m^2 [SD 2.4]. The mean cycle length reported was 29.54 [SD 3.0] days. The majority of women were using the device 80-100% of the time during the cycle (53.1%). For this subset of women, the fertility device identified on average 41.4% [SD 6.4] possibly fertile (red) days, 42.4% [SD 8.7] infertile (green) days and 15.9% [SD 7.3] yellow days. The number of infertile (green) days decreases proportionally to the number of measured days, whereas the number of undefined (yellow) days increases. CONCLUSION: Overall, these results showed that the fertility tracker algorithm was able to distinguish biphasic cycles and provide personalised fertility statuses for users based on daily basal body temperature readings and menstruation data. We identified a direct linear relationship between the number of measurements and output of the fertility tracker.

Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels.

The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single-nucleotide polymorphisms in a large case-control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at HLA-DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79-0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04-1.31, P = .008) and with high-grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70-0.87, P = 7.1 × 10-6 ; rs2844511: OR 1.13, 95% CI 1.01-1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75-0.91, P = 6.9 × 10-5 ; rs2844511: OR 1.14, 95% CI 1.04-1.26, P = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low-grade dysplasia (OR 1.26, 95% CI 1.04-1.54, P = .019). In case-only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA-DQA1, suggesting extensive co-regulation. All three genes were upregulated in HPV16-positive samples. In stratified analyses, rs9272117 was associated with HLA-DQA1 levels, specifically in HPV-positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA-DQA1. Altogether, our results support 6p21.32-33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of HLA-DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.

Terahertz beam steering using active diffraction grating fabricated by 3D printing.

In this article, we propose variable-period diffraction gratings for terahertz frequencies. The design, fabrication and characterization of such devices are presented. Our measurements show the possibility to actively shift of the deflection angle for each frequency using this device. We also demonstrated that, when driven by a speaker, these variable gratings can be used for active beam steering with potential application in terahertz communications.

Analysis of ancient ceramics using terahertz imaging and photogrammetry.

Imaging using terahertz time-domain spectroscopy is a valuable diagnostic tool for material inspection. However, in the case of samples with inhomogeneous shape and composition, the reliable extraction of spatially varying dielectric properties can be very challenging. Here, we demonstrate a new approach which combines THz-TDS with photogrammetric reconstruction. We show that this technique can be used to estimate the local refractive index of samples with a complex geometry. We employ this method to study samples of ancient pottery, and demonstrate that THz techniques can provide a valuable new tool for this branch of archaeological science.

Recognition of coal from other minerals in powder form using terahertz spectroscopy.

Currently a significant fraction of the world energy is still produced from the combustion of mineral coal. The extraction of coal from mines is a relatively complex and dangerous activity that still requires the intervention of human miners, and therefore in order to minimize risks, automation of the coal mining process is desirable. An aspect that is still under investigation is potential techniques that can recognize on-line if the mineral being extracted from the mine is coal or if it is the surrounding rock. In this contribution we present the proof of concept of a method that has potential for recognition of the extraction debris from mining based on their terahertz transmission.

Repeatability of material parameter extraction of liquids from transmission terahertz time-domain measurements.

Recently, many research groups worldwide have reported on the THz properties of liquids. Often these parameters, i.e., refractive index and absorption coefficient, are determined using liquids in cuvettes and terahertz time-domain spectroscopy. Here, we discuss the measurement process and determine how repeatable such measurements and the data extraction are using rapeseed oil as a sample. We address system stability, cuvette positioning, cuvette cleaning and cuvette assembly as sources affecting the repeatability. The results show that system stability and cuvette assembly are the most prominent factors limiting the repeatability of the THz measurements. These findings suggest that a single cuvette with precise positioning and thorough cleaning of the cuvette delivers the best discrimination among different liquid samples. Furthermore, when using a single cuvette and measurement systems of similar stability, the repeatability calculated based on several consecutive measurements is a good estimate to tell whether samples can be discriminated.

Nonlinear refraction in CH3NH3PbBr3 single crystals.

We measure both nonlinear absorption and nonlinear refraction in a ${{\rm CH}_3}{{\rm NH}_3}{{\rm PbBr}_3}$CH3NH3PbBr3 single crystal using the Z-scan technique with femtosecond laser pulses. At 1000 nm, we obtain values of 5.2 cm/GW and ${+}{9.5} \cdot {{10}^{ - 14}}\;{{\rm cm}^2}/{\rm W}$+9.5⋅10-14cm2/W for nonlinear absorption and nonlinear refraction, respectively. The sign and magnitude of the observed refractive nonlinearity are reproduced well by the two-band model. Our results suggest that the large nonlinear refractive index measured in perovskite nanostructures cannot be explained by an intrinsically high bound-electronic nonlinear refractive index in this emerging material class but is possibly caused by free carriers or quantum confinement effects.

Concordance rate of vulvoscopic findings in detecting early vulvar neoplasia.

PURPOSE: Colposcopy-guided punch biopsy is a cornerstone method for diagnosing vulvar diseases. The aim of this study was to evaluate the concordance rate of clinical findings in vulvar diseases during examinations, in comparison with colposcopy-directed punch biopsy. We also developed a new classification to simplify the categorization of vulvoscopic findings. METHODS: The concordance rate of the clinical findings was compared with the final histology results from punch biopsies. The data were collected between January 2014 and May 2017 at the Erlangen University Hospital. RESULTS: A total of 482 colposcopy-directed punch biopsies of the vulva were obtained in 420 women. The overall concordance rate of the clinical findings in comparison with the histological vulvar punch-biopsy findings was 53.9% for all entities - benign lesions, lichen, low- and high-grade squamous intraepithelial lesions (LSIL/HSILs), and vulvar carcinoma. The concordance rate for detecting LSILs was 64.3% (45/70). The concordance rate for detecting HSILs was 62.3% and for Vulvar carcinoma 65.2%. CONCLUSIONS: Punch biopsy of suspicious lesions continues to be a cornerstone in diagnosing HSILs and carcinoma of the vulva. Careful work-up of the vulva is recommended when patients have symptoms such as pruritus or pain. The new classification is more specific for diagnosing lesions in the vulva.