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The eastern Australia coastline is characterized by impressive coastal landforms and an extensive northward-moving longshore drift system that have been influenced by a stable, long-term tectonic history over the Quaternary period. However, the timing and drivers of the formation of two conspicuous landscape features—Fraser Island (K’gari) and the Great Barrier Reef—remain poorly understood. Here we use optically stimulated luminescence and palaeomagnetic dating to constrain the formation of the extensive dunes that make up Fraser Island, the world’s largest sand island, and adjacent Cooloola Sand Mass in southeastern Queensland. We find that both formed between 1.2 Ma and 0.7 Ma, during a global climate reconfiguration across the Middle Pleistocene transition. They formed as a direct result of increased amplitude of sea-level fluctuations associated with increasing global ice volume that redistributed previously stored sediment across the continental shelf. The development of Fraser Island dramatically reduced sediment supply to the continental shelf north of the island. This facilitated widespread coral reef formation in the southern and central Great Barrier Reef and was a necessary precondition for its development. This major reorganization of the coastal sedimentary system is probably not unique to eastern Australia and should be investigated in other passive-margin coastlines.

Objective The aim was to describe the impact of the COVID-19 pandemic upon referral patterns and incident diagnosis of inflammatory rheumatic and musculoskeletal diseases (iRMDs). Methods UK primary care data were used to describe referral patterns for patients with musculoskeletal conditions. Trends in referrals to musculoskeletal services and incident diagnoses of iRMDs (specifically, RA and JIA) were described using Joinpoint Regression and comparisons made between key pandemic time periods. Results The incidence of RA and JIA reduced by −13.3 and −17.4% per month, respectively, between January 2020 and April 2020, then increased by 1.9 and 3.7% per month, respectively, between April 2020 and October 2021. The incidence of all diagnosed iRMDs was stable until October 2021. Referrals decreased between February 2020 and May 2020 by −16.8% per month from 4.8 to 2.4% in patients presenting with a musculoskeletal condition. After May 2020, referrals increased significantly (16.8% per month) to 4.5% in July 2020. The time from first musculoskeletal consultation to RA diagnosis and from referral to RA diagnosis increased in the early pandemic period [rate ratio (RR) 1.11, 95% CI 1.07, 1.15 and RR 1.23, 95% CI 1.17, 1.30, respectively] and remained consistently higher in the late pandemic period (RR 1.13, 95% CI 1.11, 1.16 and RR 1.27, 95% CI 1.23, 1.32, respectively), compared with the pre-COVID-19 pandemic period. Conclusion Patients with underlying RA and JIA that developed during the pandemic might be yet to present or might be in the referral and/or diagnostic process. Clinicians should remain alert to this possibility, and commissioners should be aware of these findings, enabling the appropriate planning and commissioning of services.

Stream restoration, such as channel reconfiguration and riparian zone revegetation, is increasing in response to aquatic impairment in agroecosystems. Though riparian zones effectively remove nitrogen (N), conditions that foster nitrate (NO3−) removal (e.g., soil saturation, low oxygen, available carbon) may facilitate the release of soluble reactive phosphorus (SRP) and greenhouse gases (GHGs—carbon dioxide [CO2], methane [CH4], and nitrous oxide [N2O]). In this study, water quality and GHG fluxes were quantified seasonally at agricultural restored, unrestored, and forested riparian zones via networks of wells and static chambers. Carbon dioxide comprised the majority of GHG emissions, and CO2 fluxes were lower at the restored site than the forested site (medians: 0.71 g C m−2 day−1 and 1.29 g C m−2 day−1, respectively). The restored site was a net CH4 source (median: 1.20 mg C m−2 day−1), while the other sites were net CH4 sinks (medians: − 1.00 to − 1.76 mg C m−2 day−1). Sites had comparable N2O emissions. Subsurface SRP was lower at the restored than unrestored agricultural sites, while median NO3− removal efficiency was higher (restored: 91%, unrestored: 35–66%). Over time, NO3− removal and CO2 fluxes increased post-restoration. Methane emissions were elevated when the restored riparian zone was a CO2 and N2O sink and NO3− removal was high. Despite variability within and between sites, seasonal conditions (temperature, water table height, precipitation) and site characteristics (geomorphology, soils) remained key explanatory variables for riparian N removal and GHG release. Overall, riparian restoration may promote N removal without increasing total GHG emissions.

Alzheimer’s disease (AD) is a tragic neurodegenerative disease affecting more than 5 million Americans. Circadian disruptions impact nearly all AD patients, with reversal of sleep/wake cycles and agitation in the evening being common disturbances that manifest early in disease. These alterations support a role for circadian dysfunction as a driver of AD, emphasizing a critical need to investigate the therapeutic potential of circadian-modulating interventions. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. Here we show that time-restricted feeding (TRF) without caloric restriction, improved key disease components including behavior, disease pathology and transcription in the APP23 mouse model of Alzheimer’s disease. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and hyperactivity, and normalizing transcription of circadian, AD and neuroinflammation-associated genes in APP23 mice. Thus, our study unveils for the first time that circadian modulation through timed feeding has far-reaching effects beyond metabolism and affects the brain as the substrate for neurodegeneration. Since the pleiotropic effects of TRF can substantially modify disease trajectory, this intervention has immediate translational value, addressing the crucial need for accessible approaches to reduce or halt AD progression.

Seasonal changes in day length (photoperiod) affect numerous physiological functions. The suprachiasmatic nucleus (SCN)–paraventricular nucleus (PVN) axis plays a key role in processing photoperiod-related information. Seasonal variations in SCN and PVN neurotransmitter expression have been observed in humans and animal models. However, the molecular mechanisms by which the SCN-PVN network responds to altered photoperiod is unknown. Here, we show in mice that neuromedin S (NMS) and vasoactive intestinal polypeptide (VIP) neurons in the SCN display photoperiod-induced neurotransmitter plasticity. In vivo recording of calcium dynamics revealed that NMS neurons alter PVN network activity in response to winter-like photoperiod. Chronic manipulation of NMS neurons is sufficient to induce neurotransmitter switching in PVN neurons and affects locomotor activity. Our findings reveal previously unidentified molecular adaptations of the SCN-PVN network in response to seasonality and the role for NMS neurons in adjusting hypothalamic function to day length via a coordinated multisynaptic neurotransmitter switching affecting behavior.

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

Objective: Retrospective case-matched comparison of magnetic liver retraction to a bedrail-mounted liver retractor in bariatric surgery specifically targeting short-term postoperative outcomes, including pain and resource utilization. Background: Retraction of the liver is essential to ensure appropriate visualization of the hiatus in bariatric surgery. Externally mounted retractors require a dedicated port or an additional incision. Magnetic devices provide effective liver retraction without the need of an incision. Methods: The sample consisted of primary and revisional bariatric surgery patients, including Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and biliopancreatic diversion with duodenal switch (BPD-DS) operations. Propensity score analysis was used to match patients with magnetic retraction to patients with a bedrail-mounted retractor with a 1:2 ratio using preoperative characteristics. Baseline characteristics and postprocedure outcomes were compared using two-sample t-tests or Wilcoxon rank sum tests and chi-square or Fisher's exact test as appropriate. Results: One hundred patients met inclusion criteria for the use of magnetic liver retraction (45 RYGB, 35 SG, 20 BPD-DS) with 196 suitable matched external retractor patients identified. Patients were matched and comparable for all preoperative characteristics except for transversus abdominus plane block (27% versus 47%). Patients in the magnet cohort had significantly decreased mean 12-hour postoperative pain scores (2.9 versus 4.2, P = .004) and decreased hospital length of stay (LOS) (1.5 versus 1.9 days, P = .005) while operating room supply were higher in the magnet cohort ($4600 versus $4213, P = .0001). Conclusions: Magnetic liver retraction in bariatric surgery is associated with decreased postoperative pain scores, decreased hospital LOS, and increased operating supply costs.

Asthma is characterized by reversible pulmonary symptoms, frequent hospitalizations, poor quality of life, and varied treatment. Parents with low health literacy (HL) is linked to poor asthma outcomes in children. Recent practice updates recommended inhaled corticosteroids for the management of persistent asthma, but guideline-concordant care is suboptimal. Our aim was to develop and assess an Asthma Action Plan (AAP) that could serve as an individualized plan for low HL families and facilitate guideline-concordant care for clinicians.We followed the National Institute of Health 5-step "ClearSimple" approach to develop the Uniformed Services AAP. Our AAP included symptom pictographs (dyspnea, cough, sleep, activity) and guideline-concordant clinical automation tools. Caregivers assessed the pictograms for validity (transparency of ≥ 85%; translucency score ≥ 5; and ≥ 85% recall). Readability was assessed using 7 formulas. (6th Grade was acceptable). Comprehensibility, design quality, and usefulness was assessed by caregivers using the Consumer Information Rating Form (CIRF) (80% was acceptable). Understandability and actionability was assessed by medical librarians using the Patient Education Materials Assessment Tool-Printable (80% was acceptable). Suitability was assessed by clinicians using the modified Suitability Assessment of Materials (SAM) instrument (70% was superior).All 12 pictograms were validated (Our AAP was formally endorsed by the AllergyAsthma Network. The Uniformed Services AAP is a novel tool with embedded clinical automation that can address low HL and enhance guideline-concordant care.

The abdominal wall and musculoskeletal tendons share many anatomic, physiologic, and functional characteristics. This review aims to highlight these similar characteristics and to present a rationale why the treatment principles of successful musculoskeletal tendon reconstruction, including principles of surgical technique and physical therapy, can be used in the treatment of complex abdominal wall reconstruction or ventral hernia repair. The MEDLINE/PubMed database was used to identify published literature relevant to the purpose of this review. There are several anatomical and functional similarities between the linea alba and musculoskeletal tendons. Because of this reason, many of the surgical principles for musculoskeletal tendon repair and ventral hernia repair overlap. Distribution of tension is the main driving principle for both procedures. Suture material and configuration are chosen to maximize tension distribution among the tissue edges, as seen in the standard of care multistrand repairs for musculoskeletal tendons, as well as in the small bites for laparotomy technique described in the STITCH trial. Physical therapy is also one of the mainstays of tendon repair, but surprisingly, is not routine in ventral hernia repair. The evidence surrounding physical therapy prehabilitation and rehabilitation protocols in other disciplines is significant. This review challenges the fact that these protocols are not routinely implemented for ventral hernia repair, and presents the rationale and feasibility for the routine practice of physical therapy in ventral hernia repair.

Introduction:In prostate surgery retraction of the prostate is essential to ensure appropriate visualization of the surgical field. In the past improvement in exposure would require the ded...

Background Racial disparities in postoperative complications have been demonstrated in bariatric surgery, yet the relationship of race to complication severity is unknown. Study Design Adult laparoscopic primary bariatric procedures were queried from the 2015 and 2016 MBSAQIP registry. Adjusted logistic and multinomial regressions were used to examine the relationships between race and 30-day complications categorized by the Clavien-Dindo grading system. Results A total of 212,970 patients were included in the regression analyses. For Black patients, readmissions were higher (OR = 1.39, p

HighlightsDenitrification enzyme activity (DEA) was measured in stream sediments of restored and unrestored agricultural streams.Nitrate, sediment characteristics, riparian vegetation, and geomorphology influenced DEA.Pools at restored sites had lower organic carbon, coarser sediment textures, and lower denitrification potential.Restoration strategies should increase organic carbon and residence times through complex flowpaths.Abstract. Agricultural land use, channel modifications, and riparian vegetation composition can affect instream denitrification by altering geomorphic features, such as sediment texture, organic matter, retention time, and hyporheic exchange. Stream and riparian restoration is widely implemented in agricultural watersheds to mitigate excess nutrient export to sensitive downstream waters; however, the cumulative impact of channel reconstruction and altered channel and near-stream morphology on nitrogen dynamics remains poorly understood. We measured denitrification enzyme activity (DEA) and environmental variables (e.g., water chemistry, sediment texture, and organic matter) in different geomorphic features in agriculturally influenced streams in North Carolina with varied channel and riparian zone characteristics. Our results indicate that denitrification is primarily influenced by increased transport of nitrate (NO3-) to the streams in wetter months. Secondarily, structural factors, including riparian vegetation and stream geomorphology, impact denitrification by controlling the distribution of sediment texture and organic carbon. In the newly restored stream, we observed coarser streambed sediments and low sediment organic carbon, especially in scour pools constructed downstream from cross-vanes. Lower DEA was observed in restored pools (39.1 ng N g-1 dry mass h-1) compared to naturally occurring pools (70.7 to 278.1 ng N g-1 dry mass h-1). These results highlight the need for restoration strategies to be directed at increasing organic carbon and residence times through complex flowpaths (e.g., meanders, root wads, artificial woody debris dams). Keywords: Denitrification, Freshwater, Nitrogen, Restoration, Riparian, Stream, Water quality.

Endoscopy is essential in the assessment and treatment of the bariatric patient, especially in the postoperative state. Since bariatric surgery is increasing exponentially, endoscopists should be familiar with the anatomy and how to manage possible complications. New less invasive therapeutic tools will have a major impact on the prognosis of these patients. Dreaded complications such as leaks, stenosis or weight regain can be successfully assessed and treated by endoscopy. Postoperative evaluation of symptoms requires the precise search of details that can change patient's management.

Background: Appropriate tissue retraction is essential in laparoscopic surgery, and colorectal operations often require an additional incision and trocar that can disturb visualization and maneuverability. Each incision carries an increased risk for complications as well as increased pain and cosmetic issues. Magnetic devices have been developed for a less invasive retraction. The objective of this study is to report our initial experience using magnet retraction. Methods: Ten consecutive patients who underwent laparoscopic colorectal procedures by a single surgeon using a magnetic retractor (Levita Magnetics® Surgical System, San Mateo, CA) between October 2017 and June 2018 at Duke Regional Hospital in Durham, NC, were included. Results: The cases included four single-port right colectomies, one sigmoidectomy, and five rectopexies. Nine cases were completed laparoscopically, as one right colectomy required conversion due to adhesions and bulky specimen. Indications included adenocarcinoma, diverticular disease, and rectal prolapse. The magnet was successfully used for uterus, colon, or colonic pedicle retraction. No intraoperative or 30-day complications were observed. Conclusion: Magnetic surgical retractors are a safe, dynamic, and incision-less option for surgical field exposure during laparoscopic colorectal surgery. Reduced trocars decrease tissue trauma, enhances maneuverability, and potentially improves outcomes; however, further studies are required.

Riparian zones have been used for water quality management with respect to NO in subsurface flow and total P (TP), sediments, and pesticides in overland flow for decades. Only recently has the fate and transport of soluble reactive P (SRP), Hg, emerging contaminants, and greenhouse gas (GHG) fluxes (NO, CO, and CH) been examined in riparian zones. Overall, riparian zones are efficient at reducing emerging contaminants in subsurface flow and only function as hot spots of methylmercury production in the landscape when dominated by Hg-rich wet organic soils. However, riparian zones do not provide consistent benefits with respect to SRP removal or GHG emissions. Although most existing riparian models almost exclusively focus on NO removal, recent developments in riparian models demonstrate the potential for using easily accessible digital environmental datasets to simulate and scale up riparian functions beyond NO removal to include SRP, TP, and GHG dynamics. To further inform integrated watershed management efforts, more research should be conducted on how various practices, including stream restoration, subsurface drainage, two-stage ditches, beaver dam analogues, denitrification bioreactors and permeable reactive barriers, artificial wetlands, and short-rotation forestry crops affect riparian water and air quality functions. Riparian zone benefits should be discussed not only with respect to water and air quality, but also in terms of recreation, habitat for wildlife, and other ecosystem services. More research is needed to fully address potential water quality or air quality tradeoffs associated with riparian zone management in a multicontaminant-multiuse landscape context.

Bipolar disorder (BD) is a neuropsychiatric disorder with genetic risk factors defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. While lithium is an effective drug for BD, 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of clock genes and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, rhythm abnormalities in BD have not been evaluated in neurons and it is unknown if neuronal rhythms differ between Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients and controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R. NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low-amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein expression was higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

Circadian rhythms in cellular function can be monitored in real time with bioluminescence imaging. In this approach, bioluminescence is produced by an enzymatic reaction, which can be used to report dynamic changes in gene or protein expression in living cells. Bioluminescence imaging in circadian experiments typically uses an ex vivo slice preparation, with the most commonly studied structure being the master clock in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Here we describe procedures for dissecting and collecting SCN slices for bioluminescence imaging experiments.

The homeodomain transcription factors sine oculis homeobox 3 (Six3) and ventral anterior homeobox 1 (Vax1) are required for brain development. Their expression in specific brain areas is maintained in adulthood, where their functions are poorly understood. To identify the roles of Six3 and Vax1 in neurons, we conditionally deleted each gene using Synapsin(cre), a promoter targeting maturing neurons, and generated Six3(syn) and Vax1(syn) mice. Six3(syn) and Vax1(syn) females, but not males, had reduced fertility, due to impairment of the luteinizing hormone (LH) surge driving ovulation. In nocturnal rodents, the LH surge requires a precise timing signal from the brain’s circadian pacemaker, the suprachiasmatic nucleus (SCN), near the time of activity onset. Indeed, both Six3(syn) and Vax1(syn) females had impaired rhythmic SCN output, which was associated with weakened Period 2 molecular clock function in both Six3(syn) and Vax1(syn) mice. These impairments were associated with a reduction of the SCN neuropeptide vasoactive intestinal peptide in Vax1(syn) mice and a modest weakening of SCN timekeeping function in both Six3(syn) and Vax1(syn) mice. Changes in SCN function were associated with mistimed peak PER2::LUC expression in the SCN and pituitary in both Six3(syn) and Vax1(syn) females. Interestingly, Six3(syn) ovaries presented reduced sensitivity to LH, causing reduced ovulation during superovulation. In conclusion, we have identified novel roles of the homeodomain transcription factors SIX3 and VAX1 in neurons, where they are required for proper molecular circadian clock function, SCN rhythmic output, and female fertility.

Light, circadian clocks, and rhythmic behaviors interact closely to produce a temporal order that is essential for the survival of most living organisms. In mammals, the principal circadian pacemaker in the brain is the suprachiasmatic nucleus (SCN), which receives direct retinal input and synchronizes itself and other brain regions to the external light-dark cycle. Altered day length (photoperiod) and disrupted circadian rhythms are associated with impaired memory and mood in both humans and animal models. Prior work demonstrated that altering photoperiod can change neurotransmitter (NT) expression in the periventricular nucleus (PeVN) of the hypothalamus in adult rat brain. Here we show that neuromedin S-(NMS-) and vasoactive intestinal polypeptide-(VIP-) expressing neurons in the SCN also display photoperiod-induced neurotransmitter switching. Such photoperiod-dependent NT plasticity is retained in Bmal1-KO mice, indicating that NT plasticity in the SCN does not require a functional circadian clock. Utilizing a conditional viral DO-DIO vector as an historical marker of NT expression in the SCN, we further reveal that short-day photoperiod induces a cluster of non-NMS-expressing neurons to undergo NT switching and acquire the NMS phenotype. Selective chemogenetic activation of NMS neurons, but not VIP neurons, during the dark phase induces a significant delay in the timing of locomotor activity onset and is sufficient to increase the number of dopaminergic neurons in the PeVN. Our findings provide novel insights into molecular adaptations of the SCN neuronal network in response to altered photoperiod that affect neuronal circuit function in the hypothalamus and lead to changes in circadian behavior.

The nucleus accumbens (NAc), a central component of the midbrain dopamine reward circuit, exhibits disturbed circadian rhythms in the postmortem brains of depressed patients. We hypothesized that normal mood regulation requires proper circadian timing in the NAc, and that mood disorders are associated with dysfunctions of the NAc cellular circadian clock. In mice exhibiting stress-induced depression-like behavior (helplessness), we found altered circadian clock function and high nighttime expression of the core circadian clock component CRYPTOCHROME (CRY) in the NAc. In the NAc of helpless mice, we found that higher expression of CRY is associated with decreased activation of dopamine 1 receptor-expressing medium spiny neurons (D1R-MSNs). Furthermore, D1R-MSN-specific CRY-knockdown in the NAc reduced susceptibility to stress-induced helplessness and increased NAc neuronal activation at night. Finally, we show that CRY inhibits D1R-induced G protein activation, likely by interacting with the Gs protein. Altered circadian rhythms and CRY expression were also observed in human fibroblasts from major depressive disorder patients. Our data reveal a causal role for CRY in regulating the midbrain dopamine reward system, and provide a mechanistic link between the NAc circadian clock and vulnerability to depression.

The abdominal wall and musculoskeletal tendons share many anatomic, physiologic, and functional characteristics. This review aims to highlight these similar characteristics and to present a rationale why the treatment principles of successful musculoskeletal tendon reconstruction, including principles of surgical technique and physical therapy, can be used in the treatment of complex abdominal wall reconstruction or ventral hernia repair.The MEDLINE/PubMed database was used to identify published literature relevant to the purpose of this review.There are several anatomical and functional similarities between the linea alba and musculoskeletal tendons. Because of this reason, many of the surgical principles for musculoskeletal tendon repair and ventral hernia repair overlap. Distribution of tension is the main driving principle for both procedures. Suture material and configuration are chosen to maximize tension distribution among the tissue edges, as seen in the standard of care multistrand repairs for musculoskeletal tendons, as well as in the small bites for laparotomy technique described in the STITCH trial. Physical therapy is also one of the mainstays of tendon repair, but surprisingly, is not routine in ventral hernia repair. The evidence surrounding physical therapy prehabilitation and rehabilitation protocols in other disciplines is significant. This review challenges the fact that these protocols are not routinely implemented for ventral hernia repair, and presents the rationale and feasibility for the routine practice of physical therapy in ventral hernia repair.

IntroductionRadiogenomic analysis of patients being considered for liver resection is seldom performed in the clinic despite recent evidence indicating that quantitative MRI could improve posthepatectomy outcomes. Meanwhile, the increasingly accessible results from whole genome sequencing reporting on clinically actionable genetic biomarkers are yet to be fully integrated into the clinical care pathway.Methods and analysisA prospective observational cohort study of up to 200 participants is planned, recruiting adults with primary or secondary liver cancer being considered for liver resection at Hampshire Hospitals NHS Foundation Trust. The data will be evaluated to address the primary endpoint to calculate the proportion of participants in which the results from whole genome sequencing would have resulted in a change in clinical management. Participants will be offered an additional non-invasive quantitative MRI scan prior to the operation and the impact of the imaging results on treatment decision-making will be evaluated.Ethics and disseminationThis study was reviewed by the NHS Health Research Authority and given favourable opinion by the Brighton and Sussex Research Ethics Committee (REC reference: 20/PR/0222). Research findings will be discussed with a patient and public involvement and engagement group, presented at relevant scientific conferences and published in open access journals.Trial registration numberNCT04597710

Objective: Accurate measurement of steroid hormones remains challenging. Mass spectrometry affords a reliable means for quantitating steroid profiles accurately. Our objective was to establish and define (1) the extent of diurnal fluctuations in steroid concentrations that potentially necessitate strict adherence to time of sample acquisition and (2) time-dependent steroid reference intervals. Design: Nine steroid markers were examined in couplets in males and females. Methods: Using isotope dilution high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis, we developed a multi-steroid profile requiring only a minimal volume of serum (0.1 mL). Couplet (AM and PM) measurements of steroid hormones for 120 healthy females (F) and 62 healthy males (M) were obtained. Patients were recruited from several participating centers. Results: The following diurnal values were noted to be significantly different in both females and males: cortisone, cortisol, corticosterone, 11 deoxycortisol (11 DOC), androstenedione, 17a-hydroxyprogesterone (17 OHP) and dehydroepiandrosterone (DHEA). Testosterone was only found to have significant diurnal variance in males. Progesterone showed no significant difference in AM and PM values for either groups and thus may provide an internal control. Conclusions: When diagnosing endocrine disorders, it is imperative to acknowledge the 24-h diurnal variation of the biochemical steroid markers. We highlight the importance of standardization of collection times and appropriate implementation of reference intervals. Precis: We identify diurnal fluctuations in steroid concentrations with time of day and emphasize the importance of adhering to firm time of sample acquisition. National Center for Advancement of Translational Science (UL1TR001409) United States Department of Health & Human Services National Institutes of Health (NIH) - USA (NCT00428987) National Center for Advancement of Translational Science NIH Intramural Research Grant United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) (ZIEHD008737) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Center for Advancing Translational Sciences (NCATS) (UL1TR001409) CLINICAL CENTER (ZIACL010355)

Seasonal changes in light exposure have profound effects on behavioral and physiological functions in many species, including effects on mood and cognitive function in humans. The mammalian brain’s master circadian clock, the suprachiasmatic nucleus (SCN), transmits information about external light conditions to other brain regions, including some implicated in mood and cognition. Although the detailed mechanisms are not yet known, the SCN undergoes highly plastic changes at the cellular and network levels under different light conditions. We therefore propose that the SCN may be an essential mediator of the effects of seasonal changes of day length on mental health. In this review, we explore various forms of neuroplasticity that occur in the SCN and other brain regions to facilitate seasonal adaptation, particularly altered phase distribution of cellular circadian oscillators in the SCN and changes in hypothalamic neurotransmitter expression.

Although floodplain restoration may improve stream-riparian connectivity and increase channel stability through cross-vane installation, stream bank regrading, and buffer revegetation, the impact of these geomorphic alterations on denitrification across the aquatic-terrestrial interface is poorly understood. Seasonal denitrification enzyme activity (DEA) was compared in stream-riparian ecotones of four streams with varying hydrologic connection, riparian vegetation composition, and agricultural influence. Riparian and stream DEA was generally higher in sites adjacent to agricultural fields due to proximity to nitrate source. Mean DEA was higher in the dormant season (riparian: 928 ± 116 ng N g⁻¹ dry mass [DM] h⁻¹, stream: 108 ± 149 ng N g⁻¹ DM h⁻¹) than in the growing season (riparian: 355 ± 55 ng N g⁻¹ DM h⁻¹, stream: 45 ± 40 ng N g⁻¹ DM h⁻¹) and was influenced by antecedent precipitation, soil texture, and landscape characteristics (land use, vegetation type, topography) in multivariate models. Hot spots of denitrification occurred at the confluence of fine soil textures with high organic matter and moisture, often at low-lying areas of the landscape. At the restored site, we observed enhanced denitrification in the reconnected floodplain but decreased stream denitrification capacity in pools. Across all sites, streams had lower DEA than riparian zones, stressing the importance of restoration approaches designed to conserve riparian areas and maintain hydrologic connectivity. Easily obtainable data including precipitation, adjacent land use, vegetation, and stream and floodplain geomorphology reasonably predicted denitrification potential compared with more complex models, showing potential for application in water resources and nitrogen management.

In mammals, the master circadian clock resides in the suprachiasmatic nucleus (SCN). The SCN is characterized by robust circadian oscillations of clock gene expression and neuronal firing. The synchronization of circadian oscillations among individual cells in the SCN is attributed to intercellular coupling. Previous studies have shown that gap junctions, specifically those composed of connexin-36 (Cx36) subunits, are required for coupling of electrical firing among SCN neurons at a time scale of milliseconds. However, it remains unknown whether Cx36 gap junctions also contribute to coupling of circadian (~24 h) rhythms of clock gene expression. Here, we investigated circadian expression patterns of the clock gene Period 2 (Per2) in the SCN of Cx36-deficient mice using luminometry and single-cell bioluminescence imaging. Surprisingly, we found that synchronization of circadian PER2 expression rhythms is maintained in SCN explants from Cx36-deficient mice. Since Cx36 expression levels change with age, we also tested circadian running-wheel behavior of juvenile (3–4 weeks old) and adult (9–30 weeks old) Cx36-deficient mice. We found that impact of connexin-36 expression on circadian behavior changes greatly during postnatal development. However, consistent with the intact synchrony among SCN cells in cultured explants, Cx36-deficient mice had intact locomotor circadian rhythms, although adults displayed a lengthened period in constant darkness. Our data indicate that even though Cx36 may be required for electrical coupling of SCN cells, it does not affect coupling of molecular clock gene rhythms. Thus, electrical coupling of neurons and coupling of circadian clock gene oscillations can be regulated independently in the SCN.

While the influence of stream restoration on vertical and lateral hyporheic exchange has been documented, impacts on broader riparian zone hydrology have not been thoroughly investigated. We quantified riparian water table dynamics, hydraulic gradient, and groundwater flow paths and fluxes across a range of hydrologic conditions following natural channel design restoration (riparian regrading, in-channel cross-vane structure installation). Water table measurements were collected at least once per season for 2.5 years to capture water levels during baseflow conditions from networks of wells and piezometers at sites with different stream morphology (created riffle-cross-vane-scour pool complexes versus natural pools and riffles), restoration status (agricultural restored, unrestored, forested reference), and riparian characteristics (slope, soils, topography) in North Carolina, USA. The regraded riparian zone had higher near-stream water tables (< 0.5 m below ground surface) than the unrestored site. Riffle-cross-vane complexes induced a zone of low hydraulic gradient that spanned 30–40% of the riparian area, similar to groundwater dynamics near beaver dams. This effect persisted regardless of hydrologic condition (wet or dry) or scour pool status (functioning or filled-in). Riffles also promoted a lower near-stream hydraulic gradient at the forested site. Conversely, the influence of stream features on riparian groundwater was minimal at the unrestored site, where groundwater fluxes were controlled by hillslope inputs and riparian geomorphology. Overall, restoration enhanced stream-riparian zone hydrologic interaction beyond the immediate hyporheic zone. Our work stresses that cross-vanes, even when partially buried by sediments post-restoration, impact whole floodplain hydrology in a more significant way than shown by prior stream restoration studies.

Background and study aims Sleeve gastrectomy (LSG) is the most commonly performed bariatric procedure in the world. Leaks are the most feared complications after this procedure. Endoscopic septotomy has been described as a resolution technique that could be useful in the setting of late and chronic leaks. We present our experience in the management of gastric leaks with this advanced endoscopic technique. Patients and methods Retrospective review of patients who have been admitted to our hospital from January 2016 to December 2018. Results Five patients were found. All had their index surgery in outside hospitals. The average age was 51 years (range 40 – 69), and four patients were female. Mean time from LSG to leak presentation was 15 days (range 7 – 25). Mean time from leak presentation to septotomy procedure was 61 days (range 21 – 110). All patients were treated with sleeve dilatation before septotomy using endoscopic achalasia balloons. Mean procedure time was 79 minutes (range 55 – 125). Success was achieved in 80 % of patients, and no complications related to the procedure were identified. One patient underwent total gastrectomy for definitive management. Mean follow-up time was 14.25 months (range 6 – 26), and the average time for fistula closure was 60.25 days. Conclusion Endoscopic septotomy is safe and effective for management of chronic leaks after LSG. Associated non-selective dilatation may be a crucial step to allow distal patency and axis rectification for appropriate leak closure.

Human circadian timing—most visibly, the sleep-wake cycle—is constantly calibrated to match changing environmental conditions, through a complex system that responds mainly to ambient light. For psychiatrists, the most familiar clinical manifestations of disordered circadian timing are sleep disorders, that is, impaired intrinsic circadian cycling or a persistent mismatch between an individual’s sleep timing and societal expectations, and this chapter discusses their psychopathology. However, the physiological significance of circadian functions extends far beyond sleep, to include mood, hormonal function, and metabolism. We will also discuss how techniques to directly influence circadian timing can be used by psychiatrists to treat mood disorders.

Obesity is the most prevalent chronic disease in the United States and bariatric surgery stands as the best treatment. Laparoscopic sleeve gastrectomy (LSG) is the most common bariatric operation performed in the United States. Leaks after LSG are rare but represent the most serious complication. The majority of leaks occur in the proximal third of the stomach near the angle of His, and ischemia is the most likely etiology. Indocyanine green (ICG) is an ideal compound to assess tissue perfusion intraoperatively, and ICG fluorescence angiography during LSG can be used to identify blood supply patterns. Confirming adequate perfusion of the remnant sleeve stomach minimizes perfusion compromise and prevents potential serious postoperative complications including leaks and strictures. ICG can also be used in anastomotic operations such as gastric bypass and biliopancreatic diversion with duodenal switch with many potential future applications.

Introduction: Glycated haemoglobin A1c (HbA1c) is the established standard measurement for assessment of glycaemic control in people with diabetes. Here we report on a meta-analysis of real-world observational studies on the impact of flash continuous glucose monitoring on glycaemic control as measured by HbA1c. Methods: A total of 271 studies were identified in our search, of which 29 contained data reporting changes in HbA1c over periods from 1 to 24 months that could be used in a statistical analysis. Our meta-analysis focuses on observed change in HbA1c at either 2, 3 or 4 months, in adult or paediatric subjects, as well as a longitudinal analysis up to 12 months in adult subjects. These data were drawn from 25 of the studies identified in our initial search. These reported HbA1c data up to 12 months in a total of 1723 participants with type 1 diabetes (T1D) or type 2 diabetes (T2D) using the FreeStyle Libre® flash glucose monitoring system. Results: Overall mean change in laboratory HbA1c across study subjects at 2–4 months was − 0.55% (95% CI − 0.70, − 0.39). Amongst the 1023 adults, mean change in HbA1c was − 0.56% (95% CI − 0.76, − 0.36); for the 447 children and adolescents, mean change in HbA1c was − 0.54% (95% CI − 0.84, − 0.23). Based on regression analysis, the degree of change in HbA1c correlated with the initial HbA1c of the study population. A longitudinal analysis in adult subjects (n = 1276) shows that HbA1c fell within the first 2 months and changes were sustained up to 12 months. No significant differences were detected between T1D and T2D. Conclusion: The meta-analysis reported here confirms that starting the FreeStyle Libre system as part of diabetes care results in a significant and sustained reduction in HbA1c for adults and children with T1D and for adults with T2D. Funding: Abbott Diabetes Care.

Background and study aims Sleeve gastrectomy (LSG) is the most commonly performed bariatric procedure in the world. Leaks are the most feared complications after this procedure. Endoscopic septotomy has been described as a resolution technique that could be useful in the setting of late and chronic leaks. We present our experience in the management of gastric leaks with this advanced endoscopic technique. Patients and methods Retrospective review of patients who have been admitted to our hospital from January 2016 to December 2018. Results Five patients were found. All had their index surgery in outside hospitals. The average age was 51 years (range 40 – 69), and four patients were female. Mean time from LSG to leak presentation was 15 days (range 7 – 25). Mean time from leak presentation to septotomy procedure was 61 days (range 21 – 110). All patients were treated with sleeve dilatation before septotomy using endoscopic achalasia balloons. Mean procedure time was 79 minutes (range 55 – 125). Success was achieved in 80 % of patients, and no complications related to the procedure were identified. One patient underwent total gastrectomy for definitive management. Mean follow-up time was 14.25 months (range 6 – 26), and the average time for fistula closure was 60.25 days. Conclusion Endoscopic septotomy is safe and effective for management of chronic leaks after LSG. Associated non-selective dilatation may be a crucial step to allow distal patency and axis rectification for appropriate leak closure.

Non-perennial streams dominate the extent of stream networks worldwide. Intermittent streams can provide ecosystem services to the entire network – including nitrate uptake to alleviate eutrophication of coastal waters – and are threatened by lack of legal protection. We examined 12 intermittent streams in the temperate, humid climate of the Northeast USA. Over three years of monitoring, continuous flow was observed a median of 277 d yr-1, with no-flow conditions from early summer into fall. Estimated median discharge was 2.9 L s-1 or 0.36 mm d-1. All intermittent streams originated from source wetlands (median area: 0.27 ha) and the median length of the intermittent stream from the source wetland to the downstream perennial stream was 344 m. Through regional geospatial analysis with high resolution orthophotography, we estimated that widely available, “high resolution” (1:24,000) hydrography databases (e.g., NHDPlus HR) only displayed 43% of the total number of intermittent streams. Whole-stream gross nitrate-N uptake rates were estimated at six intermittent streams during continuous flow conditions using pulse additions of nitrate and a conservative tracer. These rates displayed high temporal variability (range: no detect to over 6000 mg N m-1 d-1); hot moments were noted in nine of the 65 pulse additions. Whole-stream gross nitrate-N uptake rates were significantly inversely related to discharge, with no measurable rates above 7 L s-1. Temperature was significantly positively correlated with whole-stream gross nitrate-N uptake rates, with more hot moments in the spring. Microbial assays demonstrated that nitrate cycling in intermittent streams are consistent with results from low order, perennial forested streams and highlighted the importance of debris dams and pools – potential locations for transient storage. Our assessment suggests that intermittent streams in our region may annually contribute 24-47% of the flow to perennial streams and potentially remove 4.1 to 80.4 kg nitrate-N km-2 annually. If development in these areas continues, perennial streams are in danger of losing a portion of their headwaters and potential nitrate uptake areas may become nitrate sources to downstream areas. These results argue to manage fluvial systems with a holistic approach that couples intermittent and perennial components.