Navigating the seas of co-submission: A chat with Steven West and Torben Heick Jensen.

Molecular Cell talks with corresponding authors Steven West and Torben Heick Jensen about the journey toward back-to-back publication of their recent Molecular Cell papers, and they share their advice for coordinating the steps along the way.

Disordered eating is not associated with musculoskeletal injury in university athletes.

TAKE HOME MESSAGE: Musculoskeletal injuries and disordered eating are prevalent in varsity-level athletes but are not associated in our participants.

The first patients treated with MR-CBCT soft-tissue matching in a MR-only prostate radiotherapy pathway.

INTRODUCTION: Magnetic Resonance (MR)-only radiotherapy for prostate cancer has previously been reported using fiducial markers for on-treatment verification. MR-Cone Beam Computed Tomography (CBCT) soft-tissue matching does not require invasive fiducial markers and enables MR-only treatments to other pelvic cancers. This study evaluated the first clinical implementation of MR-only prostate radiotherapy using MR-CBCT soft-tissue matching. METHODS: Twenty prostate patients were treated with MR-only radiotherapy using a synthetic (s)CT-optimised plan with MR-CBCT soft-tissue matching. Two MR sequences were acquired: small Field Of View (FOV) for target delineation and large FOV for organs at risk delineation, sCT generation and on-treatment verification. Patients also received a CT for validation. The prostate was independently contoured on the small FOV MR, copied to the registered CT and modified if there were MR-CT soft-tissue alignment differences (MR-CT volume). This was compared to the MR-only volume with a paired t-test. The treatment plan was recalculated on CT and the doses compared. Independent offline CT-CBCT matches for 5/20 fractions were performed by three therapeutic radiographers using the MR-only contours and compared to the online MR-CBCT matches using two one-sided paired t-tests for equivalence within ±1 mm. RESULTS: The MR-only volumes were significantly smaller than MR-CT (p = 0.003), with a volume ratio 0.92 ± 0.02 (mean ± standard error). The sCT isocentre dose difference to CT was 0.2 ± 0.1%. MR-CBCT soft-tissue matching was equivalent to CT-CBCT (p < 0.001), with differences of 0.1 ± 0.2 mm (vertical), -0.1 ± 0.2 mm (longitudinal) and 0.0 ± 0.1 mm (lateral). CONCLUSIONS: MR-only radiotherapy with soft-tissue matching has been successfully clinically implemented. It produced significantly smaller target volumes with high dosimetric and on-treatment matching accuracy. IMPLICATIONS FOR PRACTICE: MR-only prostate radiotherapy can be safely delivered without using invasive fiducial markers. This enables MR-only radiotherapy to be extended to other pelvic cancers where fiducial markers cannot be used.

Four cases of acute comitant esotropia associated with diffuse intrinsic pontine glioma in children.

BACKGROUND: Acute acquired concomitant esotropia (AACE) is usually a benign form of strabismus that infrequently is associated with intracranial pathology. Clinicians have noted an increase in its incidence and theorize that it may be related to public health "lockdown" measures taken in response to the COVID-19 pandemic. With an increased incidence of AACE clinicians must firstly differentiate AACE from common accommodative esotropia and secondly recognize AACE as a possible sign of serious neuropathology.Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating diagnosis for affected families. Children typically present at age 6-7 years with cranial nerve palsies, long tract signs, and/or cerebellar signs. Diagnosis is made from characteristic findings on magnetic resonance brain imaging (MRI brain) and treatment includes radiotherapy and palliative care. Two years from diagnosis, 90% of affected children will have died from their disease. CASE SERIES: We present four cases that attended our pediatric ophthalmology clinic with AACE either as a presenting sign of DIPG or as a clinical finding following a DIPG diagnosis. Patient A (age 5 years) presented to the emergency eye clinic with sudden onset diplopia and intermittent esotropia. Suppression later developed, they had 0.00 logMAR visual acuity either eye, and bilateral physiological hypermetropia. MRI brain imaging requested as a result of the unusual presentation led to the DIPG diagnosis. The other 3 cases (ages 11, 5 & 5 years) were assessed post DIPG diagnosis and found to have an esotropia measuring bigger on 1/3-meter fixation than 6-meter fixation, full ocular motility, physiological hypermetropia or emmetropia, and visual acuity normal for age. Other than patient B (age 11 years), who had papilledema and gaze evoked nystagmus when they were assessed 2 weeks prior to death, no patient had any other clinical eye findings. CONCLUSIONS: This small series of 4 patients attending our clinic within a 12-month period supports the notion that children presenting with AACE should routinely be offered brain MRI. Not all children with DIPG-associated AACE have significant ophthalmic findings indicative of intracranial pathology. With the potential for increased incidence of AACE related to lockdowns, clinicians should be reminded of the infrequent possibility their patient has a more serious condition.

Practice variation in the diagnosis of acute rejection among pediatric heart transplant centers: An analysis of the pediatric heart transplant society (PHTS) registry.

BACKGROUND: Freedom from rejection in pediatric heart transplant recipients is highly variable across centers. This study aimed to assess the center variation in methods used to diagnose rejection in the first-year post-transplant and determine the impact of this variation on patient outcomes. METHODS: The PHTS registry was queried for all rejection episodes in the first-year post-transplant (2010-2019). The primary method for rejection diagnosis was determined for each event as surveillance biopsy, echo diagnosis, or clinical. The percentage of first-year rejection events diagnosed by surveillance biopsy was used to approximate the surveillance strategy across centers. Methods of rejection diagnosis were described and patient outcomes were assessed based on surveillance biopsy utilization among centers. RESULTS: A total of 3985 patients from 56 centers were included. Of this group, 873 (22%) developed rejection within the first-year post-transplant. Surveillance biopsy was the most common method of rejection diagnosis (71.7%), but practices were highly variable across centers. The majority (73.6%) of first rejection events occurred within 3-months of transplantation. Diagnosis modality in the first-year was not independently associated with freedom from rejection, freedom from rejection with hemodynamic compromise, or overall graft survival. CONCLUSIONS: Rejection in the first-year after pediatric heart transplant occurs in 22% of patients and most commonly in the first 3 months post-transplant. Significant variation exists across centers in the methods used to diagnose rejection in pediatric heart transplant recipients, however, these variable strategies are not independently associated with freedom from rejection, rejection with hemodynamic compromise, or overall graft survival.

Corrigendum to "Regional anaesthesia in patients at risk of bleeding" [BJA Educ 21 (2021) 84-94].

[This corrects the article DOI: 10.1016/j.bjae.2020.11.004.].

Training and match load in professional rugby union: Do contextual factors influence the training week?

Background: Rugby union demands a multifaceted approach to training, given the multiple physical and technical attributes required to play the sport. Objectives: The aim of this study is to describe the distribution of training throughout the week and investigate how this may be influenced by match-related factors. Methods: Training load data (session Rating of Perceived Exertion [sRPE], total distance and high-speed running [HSR]) were collected from six professional English rugby teams during the 2017/18 season. Five contextual factors were also recorded including: standard of opposition, competition type, result of previous fixture, surface type, and match venue. Results: The day prior to matches demonstrated the lowest training load (101 AU (95% CIs: 0-216 AU), 1 047 m (95% CIs:1 128-1 686 m) and 59 m (95% CIs: 0-343 m), respectively), while four days prior to the match demonstrated the highest training load (464 AU (95% CIs: 350-578), 2 983 m (95% CIs: 2 704-3 262m) and 234m (95% CIs: 0-477m), respectively). Of the five contextual factors, competition type was the only variable that demonstrated greater than trivial findings, with training before European fixtures the lowest stimulus across the four different competition types. Standard of opposition, previous result, surface type and venue had only trivial effects on training load (effect sizes = -0.13 to 0.15). Conclusion: Future studies should outline the distribution of other training metrics, including contact and collision training. This study provides a multi-club evaluation that demonstrates the variety of loading strategies prior to competitive match play and highlights competition type as the most influential contextual factor impacting the average training load.

Induced prostaglandin release alters steroid concentrations but not pregnancy survival in cows.

Embryonic mortality (EM) is a major factor limiting reproductive efficiency in cattle, and despite negative connotations related to reproductive performance, prostaglandin F2α (PGF2α) is capable of being released by the uterus by Day 30 of gestation. Therefore, the objective was to evaluate differences in PGF2α release after an oxytocin challenge between cows with high circulating concentrations of pregnancy-associated glycoproteins (PAGs) vs low PAG because of the association of increased PAG concentrations with pregnancy success. At Day 30 of gestation, pregnant cows were divided into oxytocin treatment (OT; n = 13) and control (CON; n = 12) groups. Treatment cows were further subdivided by circulating PAG concentration (high PAG, n = 7; and low PAG, n = 6). Blood samples were collected every 30 min beginning 1 h before oxytocin administration and continuing for 4 h. Prostaglandin F2α metabolite (PGFM), progesterone, estradiol-17ß (E2), and PAG concentrations were quantified. The peak concentration of PGFM occurred 2 h after oxytocin injection in treatment animals and returned to baseline levels by 4 h. No correlations were observed between PAG and PGFM, progesterone, or E2 concentrations (P > 0.05). There was no difference in initial or final PGFM concentrations between groups (P > 0.05). Progesterone and E2 concentrations decreased in cows after treatment of oxytocin (P < 0.05); however, only progesterone returned to basal concentrations by the end of the sampling period. In summary, cows with high vs low PAG concentrations at Day 30 of gestation have a similar PGFM response to oxytocin challenge.

Nutritional control of puberty in the bovine female: prenatal and early postnatal regulation of the neuroendocrine system.

Puberty is a complex biological event that requires maturation of the reproductive neuroendocrine axis and subsequent initiation of high-frequency, episodic release of GnRH and LH. Nutrition is a critical factor affecting the neuroendocrine control of puberty. Although nutrient restriction during juvenile development delays puberty, elevated rates of body weight gain during this period facilitate pubertal maturation by programming hypothalamic centers that underlie the pubertal process. Recent findings suggest that maternal nutrition during gestation can also modulate the development of the fetal neuroendocrine axis, thus influencing puberty and subsequent reproductive function. Among the several metabolic signals, leptin plays a critical role in conveying metabolic information to the brain and, consequently, controlling puberty. The effects of leptin on GnRH secretion are mediated via an upstream neuronal network because GnRH neurons do not express the leptin receptor. Two neuronal populations located in the arcuate nucleus that express the orexigenic peptide neuropeptide Y (NPY), and the anorexigenic peptide alpha melanocyte-stimulating hormone (αMSH), are key components of the neurocircuitry that conveys inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. In addition, neurons in the arcuate nucleus that coexpress kisspeptin, neurokinin B, and dynorphin (termed KNDy neurons) are also involved in the metabolic control of puberty. Our studies in the bovine female demonstrate that increased planes of nutrition during juvenile development lead to organizational and functional changes in hypothalamic pathways comprising NPY, proopiomelanocortin (POMC, the precursor of αMSH), and kisspeptin neurons. Changes include alterations in the abundance of NPY, POMC, and Kiss1 mRNA and in plasticity of the neuronal projections to GnRH neurons. Our studies also indicate that epigenetic mechanisms, such as modifications in the DNA methylation pattern, are involved in this process. Finally, our most recent data demonstrate that maternal nutrition during gestation can also induce morphological and functional changes in the hypothalamic NPY system in the heifer offspring that are likely to persist long after birth. These organizational changes occurring during fetal development have the potential to not only impact puberty but also influence reproductive performance throughout adulthood in the bovine female.

The acute influence of sucrose consumption with and without vitamin C co-ingestion on microvascular reactivity in healthy young adults.

BACKGROUND: Sugar sweetened beverages (SSB) are a major source of dietary sugar and a public health concern. Glucose consumption acutely influences microvascular reactivity in healthy adults, possibly via oxidative stress. The purpose of this study was to observe the acute influence of a more relevant dose of sucrose on microvascular reactivity, and to identify whether this response is influenced by the amount of vitamin C typically contained in SSB. METHODS: Thirteen ostensibly healthy adults (8 male, 5 female) performed three 1-day trials in a randomized order; the consumption of 300 ml water (control; CON), or 300 ml water with 50 g sucrose (SUGAR) or 50 g sucrose with 160 mg of vitamin C (VITC). Near infrared spectroscopy was used to determine peak reactive hyperaemia (PRH), the rate of desaturation (Slope 1) and reperfusion (Slope 2), and the total area under the reperfusion curve versus time (TRH) following 5 min of forearm cuff occlusion before and 30, 60, 90 and 120 min after test drink consumption. RESULTS: SUGAR and VITC significantly increased the total area under the curve versus time for plasma glucose (P < 0.05 for both). No changes in microvascular reactivity were observed between trials, although VITC increased Slope 1 compared to both SUGAR and CON 30 and 60 min post drink (P < 0.05 for both). CONCLUSION: The consumption of a sugar load representative of commercially available SSB did not influence microvascular reactivity. The co-ingestion of Vitamin C also failed to influence microvascular reactivity, but did increase the rate of oxygen extraction.

A Systematic Review of the Current Status of Safer Conception Strategies for HIV Affected Heterosexual Couples in Sub-Saharan Africa.

We conducted a systematic review of safer conception strategies (SCS) for HIV-affected couples in sub-Saharan Africa to inform evidence-based safer conception interventions. Following PRISMA guidelines, we searched fifteen electronic databases using the following inclusion criteria: SCS research in HIV-affected couples; published after 2007; in sub-Saharan Africa; primary research; peer-reviewed; and addressed a primary topic of interest (SCS availability, feasibility, and acceptability, and/or education and promotion). Researchers independently reviewed each study for eligibility using a standardized tool. We categorize studies by their topic area. We identified 41 studies (26 qualitative and 15 quantitative) that met inclusion criteria. Reviewed SCSs included: antiretroviral therapy (ART), pre-exposure prophylaxis, timed unprotected intercourse, manual/self-insemination, sperm washing, and voluntary male medical circumcision (VMMC). SCS were largely unavailable outside of research settings, except for general availability (i.e., not specifically for safer conception) of ART and VMMC. SCS acceptability was impacted by low client and provider knowledge about safer conception services, stigma around HIV-affected couples wanting children, and difficulty with HIV disclosure in HIV-affected couples. Couples expressed desire to learn more about SCS; however, provider training, patient education, SCS promotions, and integration of reproductive health and HIV services remain limited. Studies of provider training and couple-based education showed improvements in communication around fertility intentions and SCS knowledge. SCS are not yet widely available to HIV-affected African couples. Successful implementation of SCS requires that providers receive training on effective SCS and provide couple-based safer conception counseling to improve disclosure and communication around fertility intentions and reproductive health.

Temperature regulates NF-κB dynamics and function through timing of A20 transcription.

NF-κB signaling plays a pivotal role in control of the inflammatory response. We investigated how the dynamics and function of NF-κB were affected by temperature within the mammalian physiological range (34 °C to 40 °C). An increase in temperature led to an increase in NF-κB nuclear/cytoplasmic oscillation frequency following Tumor Necrosis Factor alpha (TNFα) stimulation. Mathematical modeling suggested that this temperature sensitivity might be due to an A20-dependent mechanism, and A20 silencing removed the sensitivity to increased temperature. The timing of the early response of a key set of NF-κB target genes showed strong temperature dependence. The cytokine-induced expression of many (but not all) later genes was insensitive to temperature change (suggesting that they might be functionally temperature-compensated). Moreover, a set of temperature- and TNFα-regulated genes were implicated in NF-κB cross-talk with key cell-fate-controlling pathways. In conclusion, NF-κB dynamics and target gene expression are modulated by temperature and can accurately transmit multidimensional information to control inflammation.

Signalling of information that is neither cryptic nor private.

It is commonly assumed that in order for animal signals to be advantageous, the information being signalled could not have been obtained otherwise, and is therefore 'cryptic' or 'private'. Here, we suggest a scenario in which individuals can gain an advantage by signalling 'public' information that is neither cryptic nor private. In that scenario, signalling increases the efficiency with which that 'public' information is transmitted. We formalize our idea with a game in which offspring can signal their condition to their parents. Specifically, we consider a resource-strapped parent who can only invest in one of its two offspring, and we allow offspring the chance to influence parental investment through a signal. A parent in the game seeks to invest in the higher-quality offspring, which it could identify either through a publicly available cue, such as body size, or by relying on a signal provided by the offspring. We find that if the signal can convey information about offspring quality more efficiently than cues, then signalling of condition between offspring and parents can be favoured by selection, even though parents could potentially have acquired the same information from the cue. Our results suggest that the biological function of signals may be broader than currently considered, and provide a scenario where low cost signalling can be favoured. More generally, efficiency benefits could explain signalling across a range of biological and economic scenarios.

Bacteriocins and the assembly of natural Pseudomonas fluorescens populations.

When competing for space and resources, bacteria produce toxins known as bacteriocins to gain an advantage over competitors. Recent studies in the laboratory have confirmed theoretical predictions that bacteriocin production can determine coexistence, by eradicating sensitive competitors or driving the emergence of resistant genotypes. However, there is currently limited evidence that bacteriocin-mediated competition influences the coexistence and distribution of genotypes in natural environments, and what factors drive interactions towards inhibition remain unclear. Using natural soil populations of Pseudomonas fluorescens, we assessed the ability of the isolates to inhibit one another with respect to spatial proximity in the field, genetic similarity and niche overlap. The majority of isolates were found to produce bacteriocins; however, widespread resistance between coexisting isolates meant relatively few interactions resulted in inhibition. When inhibition did occur, it occurred more frequently between ecologically similar isolates. However, in contrast with results from other natural populations, we found no relationship between the frequency of inhibition and the genetic similarity of competitors. Our results suggest that bacteriocin production plays an important role in mediating competition over resources in natural settings and, by selecting for isolates resistant to local bacteriocin production, can influence the assembly of natural populations of P. fluorescens.

Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus-a prospective, population-based cohort study.

STUDY QUESTION: What are the respective roles of polycystic ovary syndrome (PCOS), long-term weight gain and obesity for the development of prediabetes or Type 2 diabetes mellitus (T2DM) by age 46 years? SUMMARY ANSWER: The risk of T2DM in women with PCOS is mainly due to overweight and obesity, although these two factors have a synergistic effect on the development of T2DM. WHAT IS KNOWN ALREADY: PCOS is associated with an increased risk of prediabetes and T2DM. However, the respective roles of PCOS per se and BMI for the development of T2DM have remained unclear. STUDY DESIGN, SIZE, DURATION: In a prospective, general population-based follow-up birth cohort 1966 (n = 5889), postal questionnaires were sent at ages 14 (95% answered), 31 (80% answered) and 46 years (72% answered). Questions about oligoamenorrhoea and hirsutism were asked at age 31 years, and a question about PCOS diagnosis at 46 years. Clinical examination and blood sampling were performed at 31 years in 3127 women, and at 46 years in 3280 women. A 2-h oral glucose tolerance test (OGTT) was performed at 46 years of age in 2780 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women reporting both oligoamenorrhoea and hirsutism at age 31 years and/or diagnosis of PCOS by 46 years were considered as women with PCOS (n = 279). Women without any symptoms at 31 years and without PCOS diagnosis by 46 years were considered as controls (n = 1577). The level of glucose metabolism was classified according to the results of the OGTT and previous information of glucose metabolism status from the national drug and hospital discharge registers. MAIN RESULTS AND THE ROLE OF CHANCE: PCOS per se significantly increased the risk of T2DM in overweight/obese (BMI ≥ 25.0 kg/m2) women with PCOS when compared to overweight/obese controls (odds ratio: 2.45, 95% CI: 1.28-4.67). Normal weight women with PCOS did not present with an increased risk of prediabetes or T2DM. The increase in weight between ages 14, 31 and 46 years was significantly greater in women with PCOS developing T2DM than in women with PCOS and normal glucose tolerance, with the most significant increase occurring in early adulthood (between 14 and 31 years: median with [25%; 75% quartiles]: 27.25 kg [20.43; 34.78] versus 13.80 kg [8.55; 20.20], P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The diagnosis of PCOS was based on self-reporting, and the questionnaire at 46 years did not distinguish between polycystic ovaries only in ultrasonography and the syndrome. Ovarian ultrasonography was not available to aid the diagnosis of PCOS. WIDER IMPLICATIONS OF THE FINDINGS: These results emphasize weight management already during adolescence and early adulthood to prevent the development of T2DM in women with PCOS, as the period between 14 and 31 years seems to be a crucial time-window during which the women with PCOS who are destined to develop T2DM by 46 years of age experience a dramatic weight gain. Furthermore, our results support the view that, particularly in times of limited sources of healthcare systems, OGTT screening should be targeted to overweight/obese women with PCOS rather than to all women with PCOS. STUDY FUNDING/COMPETING INTERESTS: Finnish Medical Foundation; North Ostrobothnia Regional Fund; Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE); Sigrid Juselius Foundation; Biocenter Oulu; University Hospital Oulu and University of Oulu (75617); Medical Research Center Oulu; National Institute for Health Research (UK); National Heart, Lung, and Blood Institute (grant 5R01HL087679-02) through the STAMPEED program (1RL1MH083268-01); National Institute of Health/National Institute of Mental Health (5R01MH63706:02); ENGAGE project and grant agreement HEALTH-F4-2007-201413; EU FP7 EurHEALTHAgeing-277849 European Commission and Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and Medical Research Center, Centenary Early Career Award. The authors have no conflicts of interests. TRIAL REGISTRATION NUMBER: N/A.