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Significance Because of the tight fit of the large human neonate through the narrow maternal birth canal, childbirth is remarkably difficult. In this study we show that the dimensions of head, stature, and pelvis in a human body are linked in a complex way that was not recognized before and that contributes to ameliorate this tight fit. We show that females with a large head possess a birth canal that can better accommodate large-headed neonates. Because mothers with large heads usually give birth to neonates with large heads, the detected pattern of covariation contributes to ease childbirth and has likely evolved in response to strong selection. Compared with other primates, childbirth is remarkably difficult in humans because the head of a human neonate is large relative to the birth-relevant dimensions of the maternal pelvis. It seems puzzling that females have not evolved wider pelvises despite the high maternal mortality and morbidity risk connected to childbirth. Despite this seeming lack of change in average pelvic morphology, we show that humans have evolved a complex link between pelvis shape, stature, and head circumference that was not recognized before. The identified covariance patterns contribute to ameliorate the “obstetric dilemma.” Females with a large head, who are likely to give birth to neonates with a large head, possess birth canals that are shaped to better accommodate large-headed neonates. Short females with an increased risk of cephalopelvic mismatch possess a rounder inlet, which is beneficial for obstetrics. We suggest that these covariances have evolved by the strong correlational selection resulting from childbirth. Although males are not subject to obstetric selection, they also show part of these association patterns, indicating a genetic–developmental origin of integration.

Intratumor heterogeneity may contribute to the ambiguous clinical results on PD-L1 status as a predictor for immunotherapy response in patients with HNSCC. This decreases the utility of PD-L1 expression from single tumour biopsies as a predictive biomarker. In this prospective study, intratumor heterogeneity of PD-L1 expression in HNSCC was investigated with both Tumour Proportion Score (TPS) and Combined Positive Score (CPS). Thirty-three whole surgical specimens from 28 patients with HNSCC were included. PD-L1 expression in six random core biopsies from each surgical specimen was used to assess the concordance between multiple biopsies and the negative predictive value of a single negative core biopsy. With 1% cut off, 36% of the specimens were concordant with TPS and 52% with CPS. With a 50% cut-off value the concordance was 70% with TPS and 55% with CPS. Defining a tumour as positive if just a single-one of the biopsies was positive, the negative predictive value (NPV) of a single negative core biopsy was 38.9 and 0% (1% cut off), and 79.9% and 62.8% (50% cut off) for TPS and CPS, respectively. In conclusion, PD-L1 positivity varies markedly within the tumour, both with TPS and CPS, challenging the utility of this biomarker.

Background Although mentoring is acknowledged as a key to successful and satisfying careers in medicine, formal mentoring programs for medical students are lacking in most countries. Within the framework of planning a mentoring program for medical students at Zurich University, an investigation was carried out into what types of programs exist, what the objectives pursued by such programs are, and what effects are reported. Methods A PubMed literature search was conducted for 2000 - 2008 using the following keywords or their combinations: mentoring, mentoring program, medical student, mentor, mentee, protégé, mentorship. Although a total of 438 publications were identified, only 25 papers met the selection criteria for structured programs and student mentoring surveys. Results The mentoring programs reported in 14 papers aim to provide career counseling, develop professionalism, increase students' interest in research, and support them in their personal growth. There are both one-to-one and group mentorships, established in the first two years of medical school and continuing through graduation. The personal student-faculty relationship is important in that it helps students to feel that they are benefiting from individual advice and encourages them to give more thought to their career choices. Other benefits are an increase in research productivity and improved medical school performance in general. Mentored students also rate their overall well-being as higher. - The 11 surveys address the requirements for being an effective mentor as well as a successful mentee. A mentor should empower and encourage the mentee, be a role model, build a professional network, and assist in the mentee's personal development. A mentee should set agendas, follow through, accept criticism, and be able to assess performance and the benefits derived from the mentoring relationship. Conclusion Mentoring is obviously an important career advancement tool for medical students. In Europe, more mentoring programs should be developed, but would need to be rigorously assessed based on evidence of their value in terms of both their impact on the career paths of juniors and their benefit for the mentors. Medical schools could then be monitored with respect to the provision of mentorships as a quality characteristic.

The strikingly high incidence of obstructed labor due to the disproportion of fetal size and the mother’s pelvic dimensions has puzzled evolutionary scientists for decades. Here we propose that these high rates are a direct consequence of the distinct characteristics of human obstetric selection. Neonatal size relative to the birth-relevant maternal dimensions is highly variable and positively associated with reproductive success until it reaches a critical value, beyond which natural delivery becomes impossible. As a consequence, the symmetric phenotype distribution cannot match the highly asymmetric, cliff-edged fitness distribution well: The optimal phenotype distribution that maximizes population mean fitness entails a fraction of individuals falling beyond the “fitness edge” (i.e., those with fetopelvic disproportion). Using a simple mathematical model, we show that weak directional selection for a large neonate, a narrow pelvic canal, or both is sufficient to account for the considerable incidence of fetopelvic disproportion. Based on this model, we predict that the regular use of Caesarean sections throughout the last decades has led to an evolutionary increase of fetopelvic disproportion rates by 10 to 20%.

The overall aim was to investigate the change over time in circulating cell free DNA (cfDNA) in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemo-radiotherapy. Furthermore, to assess the possibility of detecting circulating cell free tumor DNA (ctDNA) using shallow whole genome sequencing (sWGS) and size selection. Ten patients were included in a two-phase study. The first four patients had blood samples taken prior to a radiation therapy (RT) dose fraction and at 30 minutes, 1 hour and 2 hours after RT to estimate the short-term dynamics of cfDNA concentration after irradiation. The remaining six patients had one blood sample taken on six treatment days 30 minutes post treatment to measure cfDNA levels. Presence of ctDNA as indicated by chromosomal aberrations was investigated using sWGS. The sensitivity of this method was further enhanced using in silico size selection. cfDNA concentration from baseline to 120 min after therapy was stable within 95% tolerance limits of +/- 2 ng/ml cfDNA. Changes in cfDNA were observed during therapy with an apparent qualitative difference between adenocarcinoma (average increase of 0.69 ng/ml) and squamous cell carcinoma (average increase of 4.0 ng/ml). Tumor shrinkage on daily cone beam computer tomography scans during radiotherapy did not correlate with changes in concentration of cfDNA. Concentrations of cfDNA remain stable during the first 2 hours after an RT fraction. However, based on the sWGS profiles, ctDNA represented only a minor fraction of cfDNA in this group of patients. The detection sensitivity of genomic alterations in ctDNA strongly increases by applying size selection.

Maternal effects on offspring size can have a strong effect on fitness, as larger offspring often survive better under harsh environmental conditions. Selection should hence favour mothers that find an optimal solution to the offspring size versus number tradeoff. If environmental conditions are variable, there will not be a single optimal offspring size, as predicted in a constant environment, but plastic responses can be favoured. To be able to adjust offspring size in an adaptive manner, mothers have to use environmental cues to predict offspring environmental conditions. Cues can be unreliable, however, particularly in species where individuals occupy different niches at different life stages. Here we model the evolution of plasticity of offspring size when the environmental cues mothers use to predict the conditions experienced by their offspring are not perfectly reliable. Our results show that plastic strategies are likely to be superior to fixed strategies in a stochastically varying environment when the environmental cues are at least moderately reliable, with the threshold depending on plasticity costs and the difference of resources available to mothers. Plasticity is more likely to occur if resource availability is not too different between environments. For any given scenario, plasticity in offspring size is favoured if offspring survival varies greatly between environmental states. Whenever plastic strategies are optimal, the occurring switches performed by mothers between small and large offspring are predicted to be substantial, as small adjustments are unlikely to reap fitness benefits great enough to overcome the costs of plasticity.

The aim of the study was to assess healthy tissue metabolism (HTM) using 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) positron emission tomography/computed tomography (PET/CT) during chemotherapy in Hodgkin lymphoma (HL) and the association of HTM with baseline metabolic tumour volume (MTV), haematological parameters, adverse events (AEs), early response and progression-free survival (PFS). We retrospectively identified 200 patients with advanced HL from the RATHL trial with [ 18 F]FDG-PET/CT before (PET0) and following 2 cycles of chemotherapy (PET2). [ 18 F]FDG-uptake was measured in bone marrow (BM), spleen, liver and mediastinal blood pool (MBP). Deauville score (DS) 1–3 was used to classify responders and DS 4–5, non-responders. [ 18 F]FDG-uptake decreased significantly in BM and spleen and increased in liver and MBP at PET2 (all p  < 0.0001), but was not associated with MTV. Higher BM uptake at PET0 was associated with lower baseline haemoglobin and higher absolute neutrophil counts, platelets, and white blood cells. High BM, spleen, and liver uptake at PET0 was associated with neutropenia after cycles 1–2. BM uptake at PET0 was associated with treatment failure at PET2 and non-responders with higher BM uptake at PET2 had significantly inferior PFS ( p  = 0.023; hazard ratio = 2.31). Based on these results, we concluded that the change in HTM during chemotherapy was most likely a direct impact of chemotherapy rather than a change in MTV. BM uptake has prognostic value in HL.

An age-dependent decline in skeletal muscle mass, strength, and endurance during the aging process is a physiological development, but several factors may exacerbate this process, leading to the threatening state of sarcopenia, frailty, and eventually higher mortality rates. Obesity appears to be such a promoting factor and has been linked in several studies to sarcopenia. The reason for this causal association remains poorly understood. Notwithstanding the fact that a higher body mass might simply lead to diminished physical activity and therefore contribute to a decline in skeletal muscle, several molecular mechanisms have been hypothesized. There could be an obesity derived intracellular lipotoxicity (i.e., elevated intramuscular levels of lipids and their derivatives), which induces apoptosis by means of an elevated oxidative stress. Paracrine mechanisms and inflammatory cytokines, such as CRP and IL-6 could be confounders of the actual underlying pathological mechanism. Due to a cross-talk of the hypothalamo-pituitary axis with nutritional status, obese subjects are more in a catabolic state of metabolism, with a higher susceptibility to muscle wasting under energy restriction. Obesity induces insulin resistance in the skeletal muscle, which consequently leads to perturbed metabolism, and misrouted signaling in the muscle cells. In obesity, muscle progenitor cells could differentiate to an adipocyte-like phenotype as a result of paracrine signals from (adipo)cytokines leading to a reduced muscular renewal capacity. The present review outlines current knowledge concerning possible pathways, which might be involved in the molecular pathogenesis of sarcopenic obesity.

Purpose New total-body PET scanners with a long axial field of view (LAFOV) allow for higher temporal resolution due to higher sensitivity, which facilitates perfusion estimation by model-free deconvolution. Fundamental tracer kinetic theory predicts that perfusion can be estimated for all tracers despite their different fates given sufficiently high temporal resolution of 1 s or better, bypassing the need for compartment modelling. The aim of this study was to investigate whether brain perfusion could be estimated using model-free Tikhonov generalized deconvolution for five different PET tracers, [ 15 O]H 2 O, [ 11 C]PIB, [ 18 F]FE-PE2I, [ 18 F]FDG and [ 18 F]FET. To our knowledge, this is the first example of a general model-free approach to estimate cerebral blood flow (CBF) from PET data. Methods Twenty-five patients underwent dynamic LAFOV PET scanning (Siemens, Quadra). PET images were reconstructed with an isotropic voxel resolution of 1.65 mm 3 . Time framing was 40 × 1 s during bolus passage followed by increasing framing up to 60 min. AIF was obtained from the descending aorta. Both voxel- and region-based calculations of perfusion in the thalamus were performed using the Tikhonov method. The residue impulse response function was used to estimate the extraction fraction of tracer leakage across the blood–brain barrier. Results CBF ranged from 37 to 69 mL blood min −1  100 mL of tissue −1 in the thalamus. Voxelwise calculation of CBF resulted in CBF maps in the physiologically normal range. The extraction fractions of [ 15 O]H 2 O, [ 18 F]FE-PE2I, [ 11 C]PIB, [ 18 F]FDG and [ 18 F]FET in the thalamus were 0.95, 0.78, 0.62, 0.19 and 0.03, respectively. Conclusion The high temporal resolution and sensitivity associated with LAFOV PET scanners allow for noninvasive perfusion estimation of multiple tracers. The method provides an estimation of the residue impulse response function, from which the fate of the tracer can be studied, including the extraction fraction, influx constant, volume of distribution and transit time distribution, providing detailed physiological insight into normal and pathologic tissue.

Background The human foetus typically needs to rotate when passing through the tight birth canal because of the complex shape of the pelvis. In most women, the upper part, or inlet, of the birth canal has a round or mediolaterally oval shape, which is considered ideal for parturition, but it is unknown why the lower part of the birth canal has a pronounced anteroposteriorly oval shape. Results Here, we show that the shape of the lower birth canal affects the ability of the pelvic floor to resist the pressure exerted by the abdominal organs and the foetus. Based on a series of finite element analyses, we found that the highest deformation, stress, and strain occur in pelvic floors with a circular or mediolaterally oval shape, whereas an anteroposterior elongation increases pelvic floor stability. Conclusions This suggests that the anteroposterior oval outlet shape is an evolutionary adaptation for pelvic floor support. For the pelvic inlet, by contrast, it has long been assumed that the mediolateral dimension is constrained by the efficiency of upright locomotion. But we argue that the mediolateral elongation has evolved because of the limits on the anteroposterior diameter imposed by upright posture. We show that an anteroposteriorly deeper inlet would require greater pelvic tilt and lumbar lordosis, which compromises spine health and the stability of upright posture. These different requirements of the pelvic inlet and outlet likely have led to the complex shape of the pelvic canal and to the evolution of rotational birth characteristic of humans.