KBG syndrome mimicking genetic generalized epilepsy.

•Several conditions may mimic Genetic Generalized Epilepsy GGE.•GGE is less frequently misdiagnosed compared to other subtypes of epilepsy.•KBG syndrome is a rare autosomal dominant condition.•KBG syndrome may mimic GGE.

A mixed methods pilot and feasibility open trial of internet-delivered cognitive behaviour therapy (iCanADAPT Advanced) for people with advanced cancer with depression and/or anxiety.

PURPOSE: Evaluate the feasibility, acceptability and potential efficacy of a form of online therapy for clinical depression and/or anxiety in people living with advanced cancer. METHODS: A single-arm open trial of a six-lesson clinician-supervised, internet-delivered cognitive behavioural therapy (iCBT) transdiagnostic intervention (iCanADAPT Advanced) was undertaken. Qualitative (semi-structured telephone interview conducted at 3-months) and quantitative data (questionnaires collected at pre-, post-, and 3-month follow-up) were analysed. RESULTS: 27 participants partook (26 women, 56% breast cancer, mean age 56yo; average number of mental health diagnoses 1.8, with majority (81%) meeting criteria for generalised anxiety disorder). Feasibility - Unanticipated numbers (48%) of participants had physical health deterioration (cancer progression or death). iCBT had high adherence overall (completion rates: 37% did 6 lessons; 70% did 4 lessons) but adherence was higher for those whose cancer remained stable (completion rates: 43% did 6 lessons; 85% did 4 lessons). Acceptability - the intervention was acceptable to the majority of participants, with high treatment satisfaction. Advisory data was achieved regarding future versions. Potential efficacy - regardless of physical health status, participants who completed the iCBT showed a significant decrease over time in anxiety and depression symptoms. CONCLUSIONS: Online therapies may be useful in assisting those living with advanced cancer dealing with clinical depression and anxiety disorders. The specific modality of clinician supervised iCBT has significant potential to be a suitable modality of online therapy.

Randomised controlled trial of internet-delivered cognitive behaviour therapy for clinical depression and/or anxiety in cancer survivors (iCanADAPT Early).

PURPOSE: To evaluate internet-delivered cognitive behavioural therapy (iCBT) on clinical depression and/or anxiety, distress, fear of cancer recurrence, and quality of life in cancer survivors. METHODS: Random assignation of 114 participants to iCBT or treatment-as-usual (TAU). The clinician-supervised iCBT program (iCanADAPT Early) consisted of eight lessons over 16 weeks. Self-report questionnaires occurred at baseline, midpoint, and posttreatment for both groups with 3-month follow-up for iCBT participants. A mixed modelling approach to compare groups occurred. RESULTS: iCBT was superior to TAU on all outcome measures at posttreatment. Compared with TAU, the iCBT group showed a significant decrease over time in anxiety and depression symptoms (primary outcome, Hospital Anxiety and Depression Scale, Hedges g = 1.51). Additionally the iCBT group had significantly lower general distress (Kessler-10, g = 1.56), fear of cancer recurrence (Fear of Cancer Recurrence Inventory, g = 0.39), and significantly higher quality of life (Functional Assessment of Cancer Therapy-General, g = 0.74) at posttreatment compared with the TAU group. High adherence and satisfaction were found for iCBT with low clinician time. CONCLUSION: Clinician-supervised iCBT has significant benefits for cancer survivors with clinical depression and anxiety disorders.

A phantom study of the performance of model-based iterative reconstruction in low-dose chest and abdominal CT: When are benefits maximized?

INTRODUCTION: The aim of this study was to assess and compare the effects of CT image reconstruction techniques on low-dose CT image quality using phantoms. METHODS: Anthropomorphic torso and spatial/contrast-resolution phantoms were scanned at decreasing tube currents between 400 and 10 mA. CT thorax and abdomen/pelvis series were reconstructed with filtered back projection (FBP) alone, combined 40% adaptive statistical iterative reconstruction & FBP (ASIR40), and model-based iterative reconstruction (MBIR) [(resolution-preference 05 (RP05) and RP20 in the thorax and RP05 and noise-reduction 05 (NR05) in the abdomen)]. Two readers rated image quality quantitatively and qualitatively. RESULTS: In thoracic CT, objective image noise on MBIR RP05 data sets outperformed FBP at 200, 100, 50 and 10 mA and outperformed ASIR40 at 50 and 10 mA (p < 0.001). MBIR RP20 outperformed FBP at 50 and 10 mA and outperformed ASIR40 at 10 mA (p < 0.001). Compared with both FBP and ASIR40, MBIR RP05 demonstrated significantly better signal-to-noise ratio (SNR) at 10 mA. In abdomino-pelvic CT, MBIR RP05 and NR05 outperformed FBP and ASIR at all tube current levels for objective image noise. NR05 demonstrated greater SNR at 200, 100, 50 and 10 mA and RP05 demonstrated greater SNR at 50 and 10 mA compared with both FBP and ASIR. MBIR images demonstrated better subjective image quality scores. Spatial resolution, low-contrast detectability and contrast-to-noise ratio (CNR) were comparable between image reconstruction techniques. CONCLUSION: CTs reconstructed with MBIR have lower image noise and improved image quality compared with FBP and ASIR. These effects increase with reduced radiation exposure confirming optimal use for low-dose CT imaging.

Warty (follicular) dyskeratoma on the mons pubis.

Warty (follicular) dyskeratoma (WD) is a discrete nodular lesion that demonstrates the characteristic histopathologic findings of acantholysis and dyskeratosis. WDs most commonly occur on the head and neck of adults. We present a case of WD that occurred on the mons pubis of a 53-year-old woman. Only a few other cases of WDs occurring on the vulva have been reported. WD most likely represents a tumor of the follicular infundibulum. Despite its name, there is no evidence that WD is caused by a human papillomavirus (HPV) infection. Although occurrences on the vulva are rare, they must be distinguished from HPV-induced squamous tumors when found in this area.

iCanADAPT Early protocol: randomised controlled trial (RCT) of clinician supervised transdiagnostic internet-delivered cognitive behaviour therapy (iCBT) for depression and/or anxiety in early stage cancer survivors -vs- treatment as usual.

BACKGROUND: This RCT with two parallel arms will evaluate the efficacy of an internet-delivered transdiagnostic cognitive behavioural therapy (iCBT) intervention for the treatment of clinical depression and/or anxiety in early stage cancer survivors. METHODS/DESIGN: Early stage cancer survivors will be recruited via the research arm of a not-for-profit clinical research unit and randomised to an intervention (iCBT) group or a 'treatment as usual' (TAU) control group. The minimum sample size for each group is 45 people (assuming effect size > 0.6, power of 80%, and alpha at .05), but 10% more will be recruited to account for attrition. A solitary or cumulative diagnosis(es) of Major Depressive Episode (current), Generalised Anxiety Disorder, Illness Anxiety Disorder, Panic Disorder, Agoraphobia, and/or Adjustment disorder will be determined using modules from the Anxiety Disorders Interview Schedule for DSM-5. Depression and anxiety levels with be measured via the total score of the Hospital Anxiety and Depression scale (HADS-T), the primary outcome measure. Secondary measures will include the Kessler 10 to measure general distress, the Fear of Cancer Recurrence Inventory (FCRI) to measure the specific fear of cancer recurrence and the Functional Assessment of Cancer Therapy, General Version 4 (FACT-G) for self-report of physical, social, emotional and functional well-being. iCBT participants will complete the measures before lessons 1 and 5, at post-treatment and at 3-month follow-up. The TAU group will complete similar measures at weeks 1, 8 and 16 of the waiting period. Program efficacy will be determined using intent-to-treat mixed models. Maintenance of gains will be assessed at 3-month follow-up. Mediation analyses using PROCESS will be used to examine the association between change in depressive and anxious symptoms over time and changes in FCRI and FACT-G QOL in separate analysis. DISCUSSION: This is the first RCT looking at iCBT specifically for clinical depression and/or anxiety in a cancer population. Findings will help to direct the role of iCBT in streamlined psycho-social care pathways. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12616000231448, registered 19th February 2016 ( www.anzctr.org.au ). This trial protocol is in compliance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.

Acceptability of an internet cognitive behavioural therapy program for people with early-stage cancer and cancer survivors with depression and/or anxiety: thematic findings from focus groups.

PURPOSE: We developed an eight-lesson internet-delivered CBT (iCBT) program targeting anxiety and depression in early-stage cancer and cancer survivors. To explore the acceptability of the program, we showed volunteers the first two lessons and asked for their views. METHODS: Focus groups (n = 3) and individual interviews (n = 5) were undertaken with 15 participants (11 survivors) with mainly breast (11 of the 15) cancer, who had reviewed intervention materials. Participants were asked to consider the acceptability of the iCBT program content and implementation design (timing, duration). Semi-structured questions guided discussion. Thematic analysis was conducted of participant reactions to the acceptability and/or suitability of materials created for use in a psychological intervention. We took a data-driven (inductive) approach to semantic theme development across the data set. RESULTS: Participants reported high acceptability of the internet delivery format, good engagement and user-friendly material. Participants were broadly supportive of combining depression and anxiety iCBT resources for early-stage cancer patients and survivors. Participants further indicated that a separate course would be needed to address the needs of patients with advanced stage disease. CONCLUSIONS: Participants welcomed the general development of an internet-delivered CBT intervention program to treat patients with clinical depression and/or anxiety. Furthermore, the sessions reviewed were highly acceptable to all participants. Study findings informed researchers on the development of iCBT resources for the cancer community.

"Threshold-crossing": A Useful Way to Establish the Counterfactual in Clinical Trials?

A central question in the assessment of benefit/harm of new treatments is: how does the average outcome on the new treatment (the factual) compare to the average outcome had patients received no treatment or a different treatment known to be effective (the counterfactual)? Randomized controlled trials (RCTs) are the standard for comparing the factual with the counterfactual. Recent developments necessitate and enable a new way of determining the counterfactual for some new medicines. For select situations, we propose a new framework for evidence generation, which we call "threshold-crossing." This framework leverages the wealth of information that is becoming available from completed RCTs and from real world data sources. Relying on formalized procedures, information gleaned from these data is used to estimate the counterfactual, enabling efficacy assessment of new drugs. We propose future (research) activities to enable "threshold-crossing" for carefully selected products and indications in which RCTs are not feasible.

A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques.

STUDY QUESTION: Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health? SUMMARY ANSWER: This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates. WHAT IS KNOWN ALREADY: The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus-oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation. STUDY DESIGN, SIZE, DURATION: First, controlled ovulation protocols were performed in adult, female rhesus monkeys to analyze the mRNA levels for genes encoding PGE2 synthesis and signaling components in the naturally selected pre-ovulatory follicle at different times after the ovulatory hCG stimulus (0, 12, 24, 36 h pre-ovulation; 36 h post-ovulation, n = 3-4/time point). Second, controlled ovarian stimulation cycles were utilized to obtain multiple cumulus-oocyte complexes (COCs) from rhesus monkeys to evaluate the role of PGE2 in C-OE in vitro (n = 3-4 animals/treatment; ≥3 COCs/animal/treatment). Third, adult cycling female cynomolgus macaques were randomly assigned (n = 10/group) to vehicle (control) or PTGER2 antagonist (BAY06) groups to perform a contraceptive trial. After the first treatment cycle, a male of proven fertility was introduced into each group and they remained housed together for the duration of the 5-month contraceptive trial that was followed by a post-treatment reversibility trial. PARTICIPANTS/MATERIALS, SETTING, METHODS: Quantitative real-time PCR, COC culture and expansion, immunofluorescence/confocal microscopy, enzyme immunoassay, contraceptive trial, ultrasonography, complete blood counts, serum biochemistry tests and blood lipid profiles. MAIN RESULTS AND THE ROLE OF CHANCE: Several mRNAs encoding proteins involved in PGE2 synthesis, metabolism and signaling increase (P < 0.05) in the periovulatory follicle after administration of an ovulatory hCG bolus. PGE2 signaling through PTGER2 induces cumulus cell expansion and production of hyaluronic acid, which are critical events for fertilization. Moreover, chronic administration of a selective PTGER2 antagonist resulted in a significant (P < 0.05 versus vehicle-treated controls) contraceptive effect without altering steroid hormone patterns or menstrual cyclicity during a 5-months contraceptive trial. Fertility recovered as early as 1 month after ending treatment. LIMITATIONS, REASONS FOR CAUTION: This is a proof-of-concept study in a non-human primate model. Further investigations are warranted to elucidate the mechanism(s) of PTGER2 antagonist action in the primate ovary. Although PTGER2 antagonist treatment did not produce any obvious undesirable effects, improvements in the mode of administration, as well as the efficacy of these compounds, are necessary to consider such a contraceptive for women. WIDER IMPLICATIONS OF THE FINDINGS: Monitoring as well as improving the efficacy and safety of female contraceptives is an important public health activity. Even though hormonal contraceptives are effective for women, concerns remain regarding their side-effects and long-term use because of the widespread actions of such steroidal products in many tissues. Moreover, some women cannot take hormones for medical reasons. Thus, development of non-hormonal contraceptives for women is warranted. STUDY FUNDING/COMPETING INTEREST(S): Supported by Bayer HealthCare Pharmaceuticals, The Eunice Kennedy Shriver NICHD Contraceptive Development and Research Center (U54 HD055744), NIH Office of the Director (Oregon National Primate Research Center P51 OD011092), and a Lalor Foundation Postdoctoral Basic Research Fellowship (MCP). The use of the Leica confocal was supported by grant number S10RR024585. Some of the authors (N.B., A.R., K.-H.F., U.F., B.B. and B.L.) are employees of Bayer Healthcare Pharma.

Nodular localized primary cutaneous amyloidosis: a bullous variant.

Primary cutaneous amyloidosis describes a group of disorders in which amyloid is deposited in the skin without evidence of systemic involvement. Nodular localized primary cutaneous amyloidosis (NLPCA) is a rare form of these skin-restricted amyloidoses. We present an unusual case of NLPCA in a 51-year-old man, who had clinical and histopathological evidence of subepidermal bullous formation, a unique feature in NLPCA. The possible pathogenesis of this change is discussed.

Thermal relaxation times: an outdated concept in photothermal treatments.

Thermal relaxation times were introduced into modern skin-laser science with the inception of selective photothermolysis. As a result, laser pulsewidths were determined according to the thermal relaxation times of the tissue targets. The Arrhenius Damage Integral shows that this approach is incorrect. The important parameter is the time required to induce irreversible protein denaturation within the target. This time is determined by the tissue's intrinsic structure, not its physical dimensions. This report explains why thermal relaxation times should not be considered when treating many skin conditions with lasers or IPL systems.

The effect of temperature elevation on cryopreserved mesenchymal stem cells.

BACKGROUND: Cryopreservation is of particular importance in stem cell research and regenerative medicine as it permits long term stabilisation of biological cells. Cells retain their regenerative capacity after years of storage at cryogenic temperatures. However, elevation of temperature may occur due to variety of reasons, for example in the event of equipment malfunction or during delays in transportation. To date, a limited amount research has been carried out to examine the effects of temperature elevation on stem cell survival during cryopreservation. METHODS: Mesenchymal Stem Cells (MSCs) obtained from 8-12 week Sprague Dawley male rats were cryopreserved according to the standard procedures. Under experimental conditions, cryopreserved specimens were exposed to elevated temperatures ranging from -20 C to 37 C and cellular membrane integrity assessed via trypan-blue exclusion at various time points. RESULTS: An approximating model of multiple regression was fitted to the experimental data and optimisation of model parameters was carried out. This model provides an approximation of cell viability in response to elevated temperature conditions. DISCUSSION: The results demonstrate that elevation of temperature has a dramatic effect, even over short periods of time, on the viability of cryopreserved specimens. The model presented here could be used to predict the damage suffered by a specimen due to exposure to elevated temperature over a defined period of time.

Effectiveness of statins in chronic kidney disease.

BACKGROUND: Previous studies show that statins reduce total cholesterol (TC) concentration by both 21% in primary prevention (PP) and secondary prevention (SP) in clinical trials and by ∼24% in the general population. There are few data about the efficacy of statins on TC concentration and cardiovascular (CV) outcome in patients with chronic kidney disease (CKD). We evaluated the reduction of TC concentration and subsequent risk of CV morbidity and mortality with statins in CKD patients. METHODS: A population-based cohort study using a record-linkage database in Tayside, Scotland. A total of 2369 patients who had a primary diagnosis of CKD from Scottish Morbidity Record data or biochemistry database (serum creatinine of 220 µmol/l or higher) and who had at least two separate TC measurements between 1993 and 2007 were studied. Patients were categorized into statin-exposed and statin-unexposed groups according to statin use status during the follow-up. They were also classified into PP (n = 1325) and SP (n = 1044) cohorts at the entry date. The main outcomes were TC concentration change from baseline, CV events [Antiplatelet Trialist's Collaboration (APTC)] and all-cause mortality during the follow-up. Cox regression models, in which statin use was a time-dependent variable, were employed to assess the risk of outcome and adjusted for other known confounders. RESULTS: Statin-associated TC concentrations decreased by 0.59 mmol/l (12%) in PP cohort and 0.56 mmol/l (13%) in SP cohort from 4.77 and 4.48 mmol/l at baselines, respectively. Statin use was associated with a reduced risk of APTC events, CV mortality or all-cause mortality in PP {adjusted hazard ratio (HR), 0.65 [95% confidence interval (CI) 0.48-0.88]; 0.73 (95% CI 0.52-0.98); 0.59 (95% CI 0.48-0.73)} and SP [adjusted HR, 0.66 (95% CI 0.52-0.84); 0.60 (95% CI 0.47-0.77); 0.56 (95% CI 0.47-0.68)], respectively. CONCLUSION: Statin use reduced TC concentrations by ∼13% in patients with CKD. Statins were protective of APTC events, CV mortality and all-cause mortality in patients with or without established CV disease.

WE-E-213CD-05: A Non-Rigid Image Registration Algorithm That Accommodates Organ Segmentation Error.

PURPOSE: To introduce a new deformable image registration algorithm based on surface matching that accommodates organ delineation error in daily Cone-beam CT images based on a priori knowledge of inter-observer segmentation uncertainty. METHODS: The dataset includes four prostate cancer patients who underwent primary external beam radiotherapy and had tumors that were confined to the prostate. All imaging was performed without intravenous contrast. Organ surface segmentation errors in a multiple observer-contouring study on the pelvic organs in Fan-beam CT (FBCT) and Cone-beam CT (CBCT) were estimated from the training dataset. A novel deformable image registration algorithm is presented where the organ surface matching is penalized by this error. Portions of the organ surface that are delineated reliably are used to guide the registration whereas the portions that are highly uncertain are ignored. This approach reduces the impact of delineation errors in CBCT. An evaluation experiment compares three algorithms, namely intensity-only registration (INT), equally-weighted surface and image registration (EWSIR) and the proposed uncertainty- weighted surface and image registration. RESULTS: The surface dissimilarity was reduced from 0.172 to 0.134, 0.043 and 0.044 respectively after registration. The Jacobian of the transformation found by the proposed method was closer to one than that of EWSIR in the prostate. CONCLUSIONS: In prostate external-beam radiotherapy, slice-by-slice 2D manual contouring has variable spatial accuracy. For deformable image registration methods that match segmented surfaces, regions of high inaccuracy can misguide the registration. In contrast to the image registration methods where the FBCT and CBCT surfaces (or other features) are assumed to be exact, our method takes this uncertainty into account. Preliminary results show an improved registration performance suggesting a potential use in IGRT. This work was supported by National Cancer Institute Grant No. P01 CA 116602.

The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in sheep and goats.

OBJECTIVE: Sheep and goats are commonly used large animal species for studying pathogenesis and treatment of osteoarthritis (OA). This review focuses on the macroscopic and microscopic criteria for assessing OA in sheep and goats and recommends particular assessment criteria to assist standardization in the conduct and reporting of preclinical trials of OA. METHODS: A review was conducted of all published OA studies using sheep and goats and the most common macroscopic, microscopic, or ultrastructural scoring systems were summarised. General recommendations regarding methods of OA assessment in the sheep and goat have been made and a preliminary study of their reliability and utility was undertaken. RESULTS: The modified Mankin scoring system is recommended for semiquantitative histological assessment of OA due to its already widespread adoption, ease of use, similarity to scoring systems used for OA in humans, and its achievable inter-rater reliability. Specific recommendations are also provided for histological scoring of synovitis and scoring of macroscopic lesions of OA. CONCLUSIONS: The proposed system for assessment of sheep and goat articular tissues appears to provide a useful versatile method to quantify OA change. It is hoped that by adopting more standardised quantitative outcome measures, better comparison between different studies and arthritis models will be possible. The suggested scoring systems can be modified in the future as our knowledge of disease pathophysiology advances.

Novel cleft susceptibility genes in chromosome 6q.

Cleft lip/palate is a defect of craniofacial development. In previous reports, chromosome 6q has been suggested as a candidate region for cleft lip/palate. A multipoint posterior probability of linkage analysis of multiplex families from the Philippines attributed an 88% probability of harboring a cleft-susceptibility gene to a narrower region on bands 6q14.2-14.3. We genotyped 2732 individuals from families and unrelated individuals with and without clefts to investigate the existence of possible cleft-susceptibility genes in this region. We found association of PRSS35 and SNAP91 genes with cleft lip/palate in the case-control cohort and in Caucasian families. Haplotype analyses support the individual associations with PRSS35. We found Prss35 expression in the head and palate of mouse embryos at critical stages for palatogenesis, whereas Snap91 was expressed in the adult brain. We provide further evidence of the involvement of chromosome 6q in cleft lip/palate and suggest PRSS35 as a novel candidate gene.

The advanced helical generator.

A high explosive pulsed power generator called the advanced helical generator (AHG) has been designed, built, and successfully tested. The AHG incorporates design principles of voltage and current management to obtain a high current and energy gain. Its design was facilitated by the use of modern modeling tools as well as high precision manufacture. The result was a first-shot success. The AHG delivered 16 MA of current and 11 MJ of energy to a quasistatic 80 nH inductive load. A current gain of 160 times was obtained with a peak exponential rise time of 20 micros. We will describe in detail the design and testing of the AHG.

Note: The full function test explosive generator.

We have conducted three tests of a new pulsed power device called the full function test. These tests represented the culmination of an effort to establish a high energy pulsed power capability based on high explosive pulsed power (HEPP) technology. This involved an extensive computational modeling, engineering, fabrication, and fielding effort. The experiments were highly successful and a new U.S. record for magnetic energy was obtained.