Evidence-based guideline: unexplained infertility†.

STUDY QUESTION: What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature? SUMMARY ANSWER: The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI. WHAT IS KNOWN ALREADY: UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations-of which 29 were formulated as strong recommendations and 11 as weak-10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided. LIMITATIONS, REASONS FOR CAUTION: Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).

Research Note: Preliminary assessment of the impact of dietary yeast products on egg production and cecal microbial profiles of laying hens.

The objective of the current study was to conduct an initial comparison of commercial yeast products in layer hen diets on egg production parameters and the corresponding impact on the cecal microbiota. A short-term feeding study was conducted with 35 laying hens receiving either a control, or 1 of 4 different yeast fermentation products, Immunowall, Hilyses (both from ICC, São Paulo, Brazil), Citristim (ADM, Decatur, IL), and Maxi-Gen Plus (CBS Bio Platforms, Calgary, Canada) with 7 hens per treatment from 40 to 46 wk of age. At the end of the trial, hens were euthanized, the ceca removed and prepared for denatured gradient gel electrophoresis (DGGE) microbial compositional analyses. Although initial shell weight and shell thickness were similar among the treatment groups, hens fed Hilyses had lower shell weight and thickness at the end of the experiment. The most predominant DGGE bands with the strongest intensity were identified as Lactobacillus species and excised double bands were identified as Bacillus, Clostridium, or Lachnospiraceae. In this short-term feeding trial, the commercial yeast products tested had little effect on egg production and shell quality, and only moderately impacted the composition of mature layer hen cecal microbiota.

Autophagy Requirements for Eye Lens Differentiation and Transparency.

Recent evidence points to autophagy as an essential cellular requirement for achieving the mature structure, homeostasis, and transparency of the lens. Collective evidence from multiple laboratories using chick, mouse, primate, and human model systems provides evidence that classic autophagy structures, ranging from double-membrane autophagosomes to single-membrane autolysosomes, are found throughout the lens in both undifferentiated lens epithelial cells and maturing lens fiber cells. Recently, key autophagy signaling pathways have been identified to initiate critical steps in the lens differentiation program, including the elimination of organelles to form the core lens organelle-free zone. Other recent studies using ex vivo lens culture demonstrate that the low oxygen environment of the lens drives HIF1a-induced autophagy via upregulation of essential mitophagy components to direct the specific elimination of the mitochondria, endoplasmic reticulum, and Golgi apparatus during lens fiber cell differentiation. Pioneering studies on the structural requirements for the elimination of nuclei during lens differentiation reveal the presence of an entirely novel structure associated with degrading lens nuclei termed the nuclear excisosome. Considerable evidence also indicates that autophagy is a requirement for lens homeostasis, differentiation, and transparency, since the mutation of key autophagy proteins results in human cataract formation.

Age-related increases in reaction time result from slower preparation, not delayed initiation.

Recent work indicates that healthy younger adults can prepare accurate responses faster than their voluntary reaction times would suggest, leaving a seemingly unnecessary delay of 80-100 ms before responding. Here, we examined how the preparation of movements, initiation of movements, and the delay between them are affected by aging. Participants made planar reaching movements in two conditions. The "free reaction time" condition assessed the voluntary reaction times with which participants responded to the appearance of a stimulus. The "forced reaction time" condition assessed the minimum time actually needed to prepare accurate movements by controlling the time allowed for movement preparation. The time taken to both initiate movements in the free reaction time and to prepare movements in the forced response condition increased with age. Notably, the time required to prepare accurate movements was significantly shorter than participants' self-selected initiation times; however, the delay between movement preparation and initiation remained consistent across the lifespan (∼90 ms). These results indicate that the slower reaction times of healthy older adults are not due to an increased hesitancy to respond, but can instead be attributed to changes in their ability to process stimuli and prepare movements accordingly, consistent with age-related changes in brain structure and function.NEW & NOTEWORTHY Previous research argues that older adults have slower response times because they hesitate to react, favoring accuracy over speed. The present results challenge this proposal. We found the delay between the minimum time required to prepare movements and the self-selected time at which they initiated remained consistent at ∼90 ms from ages 21 to 80. We therefore suggest older adults' slower response times can be attributed to changes in their ability to process stimuli and prepare movements.

The role of FYCO1-dependent autophagy in lens fiber cell differentiation.

FYCO1 (FYVE and coiled-coil domain containing 1) is an adaptor protein, expressed ubiquitously and required for microtubule-dependent, plus-end-directed transport of macroautophagic/autophagic vesicles. We have previously shown that loss-of-function mutations in FYCO1 cause cataracts with no other ocular and/or extra-ocular phenotype. Here, we show fyco1 homozygous knockout (fyco1-/-) mice recapitulate the cataract phenotype consistent with a critical role of FYCO1 and autophagy in lens morphogenesis. Transcriptome coupled with proteome and metabolome profiling identified many autophagy-associated genes, proteins, and lipids respectively perturbed in fyco1-/- mice lenses. Flow cytometry of FYCO1 (c.2206C>T) knock-in (KI) human lens epithelial cells revealed a decrease in autophagic flux and autophagic vesicles resulting from the loss of FYCO1. Transmission electron microscopy showed cellular organelles accumulated in FYCO1 (c.2206C>T) KI lens-like organoid structures and in fyco1-/- mice lenses. In summary, our data confirm the loss of FYCO1 function results in a diminished autophagic flux, impaired organelle removal, and cataractogenesis.Abbreviations: CC: congenital cataracts; DE: differentially expressed; ER: endoplasmic reticulum; FYCO1: FYVE and coiled-coil domain containing 1; hESC: human embryonic stem cell; KI: knock-in; OFZ: organelle-free zone; qRT-PCR: quantitative real-time PCR; PE: phosphatidylethanolamine; RNA-Seq: RNA sequencing; SD: standard deviation; sgRNA: single guide RNA; shRNA: shorthairpin RNA; TEM: transmission electron microscopy; WT: wild type.

Adherens junction engagement regulates functional patterning of the cardiac pacemaker cell lineage.

Cardiac pacemaker cells (CPCs) rhythmically initiate the electrical impulses that drive heart contraction. CPCs display the highest rate of spontaneous depolarization in the heart despite being subjected to inhibitory electrochemical conditions that should theoretically suppress their activity. While several models have been proposed to explain this apparent paradox, the actual molecular mechanisms that allow CPCs to overcome electrogenic barriers to their function remain poorly understood. Here, we have traced CPC development at single-cell resolution and uncovered a series of cytoarchitectural patterning events that are critical for proper pacemaking. Specifically, our data reveal that CPCs dynamically modulate adherens junction (AJ) engagement to control characteristics including surface area, volume, and gap junctional coupling. This allows CPCs to adopt a structural configuration that supports their overall excitability. Thus, our data have identified a direct role for local cellular mechanics in patterning critical morphological features that are necessary for CPC electrical activity.

Optimizing screening for depression, anxiety disorders, and post-traumatic stress disorder in inpatient addiction treatment: A preliminary investigation.

OBJECTIVE: Substance use disorders (SUD) are frequently comorbid with other psychiatric conditions, but a comprehensive diagnostic assessment is often not feasible clinically. Efficient psychometrically-validated screening tools exist for commonly comorbid conditions, but cutoff accuracies have typically not been evaluated in addiction treatment settings. This study examined the performance of several widely-used screening measures in relation to diagnostic status from a clinical interview to identify and validate cutoff scores in an inpatient SUD treatment setting. METHOD: Participants were 99 patients in a large residential SUD treatment program in Ontario, Canada. Participants completed a screening battery, including the Patient Health Questionnaire - 9 (PHQ-9), Generalized Anxiety Disorder - 7 (GAD-7), and Post-Traumatic Stress Disorder Checklist-5 (PCL-5), and underwent a semi-structured diagnostic clinical interview. Receiver operating characteristic curves were used to determine optimal cutoff scores on the screening tool against the interview-based diagnosis. RESULTS: Area under the curve (AUC) was statistically significant for all screens and were as follows: PHQ-9 = 0.70 (95% CI = 0.59-0.80), GAD-7 = 0.74 (95% CI = 0.63-0.84), and PCL-5 = 0.79 (95% CI = 0.66-0.91). The optimal accuracy cutoff scores based on sensitivity and specificity were: PHQ-9 ≥ 16, GAD-7 ≥ 9, the PCL-5 ≥ 42. CONCLUSIONS: In general, the candidate screeners performed acceptably in this population. However, the optimal cutoff scores were notably higher than existing guidelines for depression and PTSD, potentially due to the general elevations in negative affectivity among individuals initiating SUD treatment. Further validation of these cutoff values is warranted. PUBLIC HEALTH SIGNIFICANCE: This study provides modified screening cutoff scores for major depression, anxiety disorders, and post-traumatic stress disorder in addiction treatment settings.

Novel mitochondrial derived Nuclear Excisosome degrades nuclei during differentiation of prosimian Galago (bush baby) monkey lenses.

The unique cellular organization and transparent function of the ocular lens depend on the continuous differentiation of immature epithelial cells on the lens anterior surface into mature elongated fiber cells within the lens core. A ubiquitous event during lens differentiation is the complete elimination of organelles required for mature lens fiber cell structure and transparency. Distinct pathways have been identified to mediate the elimination of non-nuclear organelles and nuclei. Recently, we reported the discovery of a unique structure in developing fiber cells of the chick embryo lens, called the Nuclear Excisosome, that is intractably associated with degrading nuclei during lens fiber cell differentiation. In the chick lens, the Nuclear Excisosome is derived from projections of adjacent cells contacting the nuclear envelope during nuclear elimination. Here, we demonstrate that, in contrast to the avian model, Nuclear Excisosomes in a primate model, Galago (bush baby) monkeys, are derived through the recruitment of mitochondria to form unique linear assemblies that define a novel primate Nuclear Excisosome. Four lenses from three monkeys aged 2-5 years were fixed in formalin, followed by paraformaldehyde, then processed for Airyscan confocal microscopy or transmission electron microscopy. For confocal imaging, fluorescent dyes labelled membranes, carbohydrate in the extracellular space, filamentous actin and nuclei. Fiber cells from Galago lenses typically displayed prominent linear structures within the cytoplasm with a distinctive cross-section of four membranes and lengths up to 30 µm. The outer membranes of these linear structures were observed to attach to the outer nuclear envelope membrane to initiate degradation near the organelle-free zone. The origin of these unique structures was mitochondria in the equatorial epithelium (not from plasma membranes of adjacent cells as in the chick embryo model). Early changes in mitochondria appeared to be the collapse of the cristae and modification of one side of the mitochondrial outer membrane to promote accumulation of protein in a dense cluster. As a mitochondrion surrounded the dense protein cluster, an outer mitochondrial membrane enclosed the protein to form a core and another outer mitochondrial membrane formed the outermost layer. The paired membranes of irregular texture between the inner core membrane and the outer limiting membrane appeared to be derived from modified mitochondrial cristae. Several mitochondria were involved in the formation and maturation of these unique complexes that apparently migrated around the fulcrum into the cytoplasm of nascent fiber cells where they were stabilized until the nuclear degradation was initiated. Thus, unlike in the chick embryo, the Galago lenses degraded nuclear envelopes with a Nuclear Excisosome derived from multiple mitochondria in the epithelium that formed novel linear assemblies in developing fiber cells. These findings suggest that recruitment of distinct structures is required for Nuclear Excisosome formation in different species.

Mass and the Dangers of Syncope.

Introduction Syncope is defined as a transient, self-limited loss of consciousness with an inability to maintain postural tone that is followed by spontaneous recovery. We revisit situational syncope focusing on one situation, Mass. Methods We interrogated our electronic syncope database for key terms associated with situational syncope. From the most commonly encountered situation, Mass, we interrogated the results of tilt testing performed to identify evidence of orthostatic hypotension. Results There were 110 cases of situational syncope identified with 56.3% (n=62) taking place at mass. All had tilt table testing performed and 15.4% (n=17) had evidence of orthostatic hypotension. Conclusion The multiple sudden changes in position during mass from sitting to kneeling to standing can precipitate an episode of orthostatic hypotension. Consideration should be given as to whether it is safe for older mass goers to be subjected to such significant orthostatic stress.

Effect of non-vitamin-K oral anticoagulants on stroke severity compared to warfarin: a meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: In addition to lowering stroke risk, warfarin use is also associated with reduced stroke severity in patients with atrial fibrillation and acute ischaemic stroke. It was sought to determine whether the effect of non-vitamin-K oral anticoagulants (NOACs), compared to warfarin, differed by stroke severity. METHODS: Phase III randomized controlled trials with participants who were randomized to receive NOACs or warfarin for stroke prevention in the setting of non-valvular atrial fibrillation were identified. Stroke was classified into two categories, fatal or disabling stroke and non-disabling stroke, and meta-analyses were completed for both outcomes and for comparative case fatality of stroke amongst trials. RESULTS: Five randomized controlled trials met our inclusion criteria. In clinical trials evaluating the NOACs usually prescribed in clinical practice (four trials), acute stroke was reported in 1403 (1.86%) participants, 787 (1.04%) in the NOAC group [386 (0.51%) fatal or disabling, 401 (0.53%) non-disabling] and 616 (0.82%) in the warfarin group [367 (0.49%) fatal or disabling, 249 (0.33%) non-disabling]. On meta-analysis NOACs were significantly superior to warfarin for fatal or disabling stroke (odds ratio [OR] 0.77; 95% confidence interval [CI] 0.66-0.89, I2  = 21%) and non-disabling stroke (OR 0.85; 95% CI 0.73-0.98, I2  = 2%). The case fatality of stroke was no different between groups (OR 0.90, 95% CI 0.75-1.13, I2  = 0%), but the point estimate favoured NOACs. CONCLUSION: In phase III trials of NOACs, for prevention of stroke in atrial fibrillation, NOACs are associated with a lower risk of both fatal/disabling and non-disabling stroke compared to warfarin.

Evidence summaries and recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome: assessment and treatment of infertility.

STUDY QUESTION: What is the recommended assessment and management of infertile women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertize and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 44 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of infertile women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines on PCOS lacked rigorous evidence-based processes, failed to engage consumer and multidisciplinary perspectives or were outdated. The assessment and management of infertile women with PCOS are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. PARTICIPANTS/MATERIALS SETTING METHODS: Governance included a six continent international advisory and a project board, a multidisciplinary international guideline development group (GDG), consumer and translation committees. Extensive health professional and consumer engagement informed the guideline scope and priorities. The engaged international society-nominated panel included endocrinology, gynaecology, reproductive endocrinology, obstetrics, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Extensive online communication and two face-to-face meetings over 15 months addressed 19 prioritized clinical questions involving nine evidence-based reviews and 10 narrative reviews. Evidence-based recommendations (EBRs) were formulated prior to consensus voting within the guideline panel. STUDY DESIGN SIZE DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. A (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, desirable and undesirable consequences, feasibility, acceptability, cost, implementation and ultimately recommendation strength. The guideline was peer-reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE II criteria and underwent methodological review. This guideline was approved by all members of the GDG and has been approved by the NHMRC. MAIN RESULTS AND THE ROLE OF CHANCE: The quality of evidence (QOE) for the EBRs in the assessment and management of infertility in PCOS included very low (n = 1), low (n = 9) and moderate (n = 4) quality with no EBRs based on high-quality evidence. The guideline provides 14 EBRs, 10 clinical consensus recommendations (CCRs) and 20 clinical practice points on the assessment and management of infertility in PCOS. Key changes in this guideline include emphasizing evidence-based fertility therapy, including cheaper and safer fertility management. LIMITATIONS REASONS FOR CAUTION: Overall evidence is generally of low to moderate quality, requiring significantly greater research in this neglected, yet common condition. Regional health systems vary and a process for adaptation of this guideline is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of infertility in PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTERESTS: The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine (ASRM). GDG members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Norman has declared a minor shareholder interest in the IVF unit Fertility SA, travel support from Merck and grants from Ferring. Prof. Norman also has scientific advisory board duties for Ferring. The remaining authors have no conflicts of interest to declare.This article was not externally peer-reviewed by Human Reproduction Open.

Quantitative vibratory sensation measurement is related to sensory cortical thickness in MS.

Objective: Vibratory sensation is a quantifiable measure of physical dysfunction and is often related to spinal cord pathology; however, its association with relevant brain areas has not been fully explored. Our objective was to establish a cortical structural substrate for vibration sensation. Methods: Eighty-four individuals with multiple sclerosis (MS) (n = 54 relapsing, n = 30 progressive) and 28 controls participated in vibratory sensation threshold quantification at the great toe and a 3T MRI evaluating volume of the thalamus and cortical thickness primary and secondary sensory cortices. Results: After controlling for age, sex, and disability level, vibratory sensation thresholds were significantly related to cortical thickness of the anterior cingulate (P = 0.041), parietal operculum (P = 0.022), and inferior frontal gyrus pars operculum (P = 0.044), pars orbitalis (P = 0.007), and pars triangularis (P = 0.029). Within the progressive disease subtype, there were significant relationships between vibratory sensation and thalamic volume (P = 0.039) as well as reduced inferior frontal gyrus pars operculum (P = 0.014) and pars orbitalis (P = 0.005) cortical thickness. Conclusions: The data show significant independent relationships between quantitative vibratory sensation and measures of primary and secondary sensory cortices. Quantitative clinical measurement of vibratory sensation reflects pathological changes in spatially distinct brain areas and may supplement information captured by brain atrophy measures. Without overt relapses, monitoring decline in progressive forms of MS has proved challenging; quantitative clinical assessment may provide a tool to examine pathological decline in this cohort. These data suggest that quantitative clinical assessment may be a reliable way to examine pathological decline and have broader relevance to progressive forms of MS.

All-or-None Context Dependence Delineates Limits of FEF Visual Target Selection.

Choices of where to look are informed by perceptual judgments, which locate objects of current value or interest within the visual scene. This perceptual-motor transform is partly implemented in the frontal eye field (FEF), where visually responsive neurons appear to select behaviorally relevant visual targets and, subsequently, saccade-related neurons select the movements required to look at them. Here, we use urgent decision-making tasks to show (1) that FEF motor activity can direct accurate, visually informed choices in the complete absence of prior target-distracter discrimination by FEF visual responses and (2) that such discrimination by FEF visual cells shows an all-or-none reliance on the presence of stimulus attributes strongly associated with saliency-driven attentional allocation. The present findings suggest that FEF visual target selection is specific to visual judgments made on the basis of saliency and may not play a significant role in guiding saccadic choices informed solely by feature content.

A retrospective observational study to estimate the attrition of patients across lines of systemic treatment for metastatic colorectal cancer in Canada.

Background: Selection and sequencing of treatment regimens for individual patients with metastatic colorectal cancer (mcrc) is driven by maintaining reasonable quality of life and extending survival, as well as by access to and cost of therapies. The objectives of the present study were to describe, for patients with mcrc, attrition across lines of systemic therapy, patterns of therapy and their timing, and KRAS status. Methods: A retrospective chart review at 6 Canadian academic centres included sequential patients who were diagnosed with mcrc from 1 January 2009 onward and who initiated first-line systemic treatment for mcrc between 1 January and 31 December 2009. Death was included as a competing risk in the analysis. Results: The analysis included 200 patients who started first-line therapy. The proportions of patients who started second-, third-, and fourth-line systemic therapy were 70%, 30%, and 15% respectively. Chemotherapy plus bevacizumab was the most common first-line combination (66%). The most common first-line regimen was folfiri plus bevacizumab. KRAS testing was performed in 103 patients (52%), and 38 of 68 patients (56%, 19% overall) with confirmed KRAS wild-type tumours received an epidermal growth factor receptor inhibitor (egfri), which was more common in later lines. Most KRAS testing occurred after initiation of second-line therapy. Conclusions: In the modern treatment era, a high proportion of patients receive at least two lines of therapy for mcrc, but only 19% receive egfri therapy. Earlier KRAS testing and therapy with an egfri might allow a greater proportion of patients to access all 5 active treatment agents.

'Sit and tilt' preparation for subscapular system free flaps.

BACKGROUND: The ablation of advanced head and neck cancer often results in large three-dimensional defects that require free tissue transfer to optimally address functional and cosmetic issues. The subscapular system is a highly versatile donor site for flaps used for head and neck reconstruction. Traditional methods of harvesting subscapular flaps require repositioning and re-preparing, which significantly increases the operative time and prevents simultaneous harvesting of the flap. METHOD: This paper presents our experience of a single-stage 'sit and tilt' technique, which provides a convenient method for harvesting subscapular system free flaps without significant repositioning. RESULTS AND CONCLUSION: This technique was used for a variety of head and neck defects, and body habitus did not seem to affect free tissue harvesting. It is hoped that utilisation of this preparation and harvesting technique will make head and neck surgeons more willing to take advantage of the subscapular system.

Flexible and Stable Value Coding Areas in Caudate Head and Tail Receive Anatomically Distinct Cortical and Subcortical Inputs.

Anatomically distinct areas within the basal ganglia encode flexible- and stable-value memories for visual objects (Hikosaka et al., 2014), but an important question remains: do they receive inputs from the same or different brain areas or neurons? To answer this question, we first located flexible and stable value-coding areas in the caudate head (CDh) and caudate tail (CDt) of two rhesus macaque monkeys, and then injected different retrograde tracers into these areas of each monkey. We found that CDh and CDt received different inputs from several cortical and subcortical areas including temporal cortex, prefrontal cortex, cingulate cortex, amygdala, claustrum and thalamus. Superior temporal cortex and inferior temporal cortex projected to both CDh and CDt, with more CDt-projecting than CDh-projecting neurons. In superior temporal cortex and dorsal inferior temporal cortex, layers 3 and 5 projected to CDh while layers 3 and 6 projected to CDt. Prefrontal and cingulate cortex projected mostly to CDh bilaterally, less to CDt unilaterally. A cluster of neurons in the basolateral amygdala projected to CDt. Rostral-dorsal claustrum projected to CDh while caudal-ventral claustrum projected to CDt. Within the thalamus, different nuclei projected to either CDh or CDt. The medial centromedian nucleus and lateral parafascicular nucleus projected to CDt while the medial parafascicular nucleus projected to CDh. The inferior pulvinar and lateral dorsal nuclei projected to CDt. The ventral anterior and medial dorsal nuclei projected to CDh. We found little evidence of neurons projecting to both CDh and CDt across the brain. These data suggest that CDh and CDt can control separate functions using anatomically separate circuits. Understanding the roles of these striatal projections will be important for understanding how value memories are created and stored.

Do iatrogenic serosal injuries result in small bowel perforation in a rabbit model?

BACKGROUND: Surgical dogma dictates that serosal injuries should be repaired during laparotomy as these injuries may result in localised areas of bowel ischaemia and may perforate. No study has investigated whether there is a correlation between the extent of serosal injuries and the risk for perforation under normal physiological conditions. We hypothesized that small bowel serosal injuries do not result in early or late perforation at physiological intraluminal pressures regardless of their size. METHOD: An in-vivo rabbit small bowel serosal injury model was developed and two experiments were conducted. The first - to determine whether and at which pressures various lengths and circumferences of serosal injuries in small bowel result in immediate bowel perforation - was performed infusing saline into isolated bowel segments with or without a variety of serosal injuries. In the second study - to determine whether or not serosal injuries result in delayed perforation - a range of injuries was created in rabbits and the effect assessed at re-laparotomy 5 days after the creation of the injury. RESULTS: No perforations were observed at the site of serosal injuries at physiological intraluminal pressures. Perforations occurred at 43.7+ 18.6 cmH2O, 23.3+ 14.4 cmH2O, and 24.4+ 23.9 cmH2O for controls, 4 cm long and 100% circumference serosal injuries respectively (p-value = 0.18 for various lengths and 0.71 for various circumferences). No serosal injuries perforated within 72 or 120 hours after creation. CONCLUSION: Small bowel serosal injuries do not perforate or leak at physiological intraluminal pressures, either at the time of creation or up to 120 hours thereafter.