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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.

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.

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

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.

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.

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.

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.

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.

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.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patients, we measured circadian rhythms in fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-R patients were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD. © 2018. This is the authors’ accepted and refereed manuscript to the article. Locked until 16.5.2019 due to copyright restrictions.

Background Major depressive disorder is associated with disturbed circadian rhythms. To investigate the causal relationship between mood disorders and circadian clock disruption, previous studies in animal models have employed light/dark manipulations, global mutations of clock genes, or brain area lesions. However, light can impact mood by noncircadian mechanisms; clock genes have pleiotropic, clock-independent functions; and brain lesions not only disrupt cellular circadian rhythms but also destroy cells and eliminate important neuronal connections, including light reception pathways. Thus, a definitive causal role for functioning circadian clocks in mood regulation has not been established. Methods We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain's master circadian pacemaker, the suprachiasmatic nucleus (SCN). Results In these SCN-specific Bmal1 -knockdown (SCN- Bmal1 -KD) mice, circadian rhythms were greatly attenuated in the SCN, while the mice were maintained in a standard light/dark cycle, SCN neurons remained intact, and neuronal connections were undisturbed, including photic inputs. In the learned helplessness paradigm, the SCN- Bmal1 -KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN- Bmal1 -KD mice also showed greater weight gain, an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress. Conclusions Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair, and anxiety-like behavior in mice, establishing SCN- Bmal1 -KD mice as a new animal model of depression.

Bipolar disorder (BD) is characterized by depression, mania, and circadian rhythm abnormalities. Lithium, a treatment for BD stabilizes mood and increases circadian rhythm amplitude. However, in fibroblasts grown from BD patients, lithium has weak effects on rhythm amplitude compared to healthy controls. To understand the mechanism by which lithium differentially affects rhythm amplitude in BD cells, we investigated the extracellular-signal-regulated kinase (ERK) and related signaling molecules linked to BD and circadian rhythms. In fibroblasts from BD patients, controls and mice, we assessed the contribution of the ERK pathway to lithium-induced circadian rhythm amplification. Protein analyses revealed low phospho-ERK1/2 (p-ERK) content in fibroblasts from BD patients vs. controls. Pharmacological inhibition of ERK1/2 by PD98059 attenuated the rhythm amplification effect of lithium, while inhibition of two related kinases, c-Jun N-terminal kinase (JNK), and P38 did not. Knockdown of the transcription factors CREB and EGR-1, downstream effectors of ERK1/2, reduced baseline rhythm amplitude, but did not alter rhythm amplification by lithium. In contrast, ELK-1 knockdown amplified rhythms, an effect that was not increased further by the addition of lithium, suggesting this transcription factor may regulate the effect of lithium on amplitude. Augmentation of ERK1/2 signaling through DUSP 6 knockdown sensitized NIH3T3 cells to rhythm amplification by lithium. In BD fibroblasts, DUSP 6 knockdown reversed the BD rhythm phenotype, restoring the ability of lithium to increase amplitude in these cells. We conclude that the inability of lithium to regulate circadian rhythms in BD may reflect reduced ERK activity, and signaling through ELK-1.

Bipolar disorder (BD) is associated with mood episodes and low amplitude circadian rhythms. Previously, we demonstrated that fibroblasts grown from BD patients show weaker amplification of circadian rhythms by lithium compared to control cells. Since calcium signals impact upon the circadian clock, and L-type calcium channels (LTCC) have emerged as genetic risk factors for BD, we examined whether loss of function in LTCCs accounts for the attenuated response to lithium in BD cells. We used fluorescent dyes to measure Ca2+ changes in BD and control fibroblasts after lithium treatment, and bioluminescent reporters to measure Per2::luc rhythms in fibroblasts from BD patients, human controls, and mice while pharmacologically or genetically manipulating calcium channels. Longitudinal expression of LTCC genes (CACNA1C, CACNA1D and CACNB3) was then measured over 12–24 h in BD and control cells. Our results indicate that independently of LTCCs, lithium stimulated intracellular Ca2+ less effectively in BD vs. control fibroblasts. In longitudinal studies, pharmacological inhibition of LTCCs or knockdown of CACNA1A, CACNA1C, CACNA1D and CACNB3 altered circadian rhythm amplitude. Diltiazem and knockdown of CACNA1C or CACNA1D eliminated lithium's ability to amplify rhythms. Knockdown of CACNA1A or CACNB3 altered baseline rhythms, but did not affect rhythm amplification by lithium. In human fibroblasts, CACNA1C genotype predicted the amplitude response to lithium, and the expression profiles of CACNA1C, CACNA1D and CACNB3 were altered in BD vs. controls. We conclude that in cells from BD patients, calcium signaling is abnormal, and that LTCCs underlie the failure of lithium to amplify circadian rhythms.

Disruption of circadian clocks is strongly associated with mood disorders. Chronotherapies targeting circadian rhythms have been shown to be very effective treatments of mood disorders, but still are not widely used in clinical practice. The mechanisms by which circadian disruption leads to mood disorders are poorly characterized and, therefore, may not convince clinicians to apply chronotherapies. Hence, in this review, we describe specific potential mechanisms, in order to make this connection more credible to clinicians. We believe that four major features of disrupted clocks may contribute to the development of mood disorders: (1) loss of synchronization to environmental 24-h rhythms, (2) internal desynchronization among body clocks, (3) low rhythm amplitude, and (4) changes in sleep architecture. Discussing these attributes and giving plausible examples, we will discuss prospects for relatively simple chronotherapies addressing these features that are easy to implement in clinical practice. Key messages In this review, we describe specific potential mechanisms by which disrupted clocks may contribute to the development of mood disorders: (1) loss of synchronization to environmental 24-h rhythms, (2) internal desynchronization among body clocks, (3) low rhythm amplitude, and (4) changes in sleep architecture. We provide prospects for relatively simple chronotherapies addressing these features that are easy to implement in clinical practice.

Flash glucose monitoring is proven in randomized clinical trials to reduce the amount of time that people with type 1 or type 2 diabetes spend in hypoglycemia, with glucose below 3.9 mmol/L (70 mg/dL). Here we report a meta-analysis of real world observational studies on the impact of flash glucose monitoring on glycemic control as measured by HbA1c. A series of 17 studies were identified as reporting longitudinal HbA1c data in a total 1338 participants with type 1 (n=1112) or type 2 diabetes (n=226) using the FreeStyle Libre flash glucose monitoring system. Data included observations on children, adolescents and adults. The studies were reported in peer-reviewed published manuscripts, congress poster presentations and in-press data. Meta-analysis of change in HbA1c was performed using trial as a random effect and weighting with the inverse of the within trial variance. Overall mean change in HbA1c was -0.56, 95% CI (-0.76, -0.36), with substantial heterogeneity between trials (I2=92.6%). Meta-regression was performed with the covariate initial HbA1c and treating trial as a random effect (Figure). No significant differences were detected based on length of study, type of diabetes (type 1 vs. type 2) or children vs. adults. Disclosure A. Seibold: Employee; Self; Abbott. Stock/Shareholder; Self; Abbott. Z.K. Welsh: Employee; Self; Abbott. Stock/Shareholder; Self; Abbott, AbbVie Inc. S. Ells: Employee; Self; Abbott. Stock/Shareholder; Self; Abbott. C. Schlaeger: Employee; Self; Abbott. Stock/Shareholder; Self; Roche Pharma.

© 2018 National Academy of Sciences. All Rights Reserved. Endogenous circadian clocks control 24-h physiological and behavioral rhythms in mammals. Here, we report a real-time in vivo fluorescence recording system that enables long-term monitoring of circadian rhythms in the brains of freely moving mice. With a designed reporter of circadian clock gene expression, we tracked robust Cry1 transcription reporter rhythms in the suprachiasmatic nucleus (SCN) of WT, Cry1−/−, and Cry2−/− mice in LD (12 h light, 12 h dark) and DD (constant darkness) conditions and verified that signals remained stable for over 6 mo. Further, we recorded Cry1 transcriptional rhythms in the subparaventricular zone (SPZ) and hippocampal CA1/2 regions of WT mice housed under LD and DD conditions. By using a Cre-loxP system, we recorded Per2 and Cry1 transcription rhythms specifically in vasoactive intestinal peptide (VIP) neurons of the SCN. Finally, we demonstrated the dynamics of Per2 and Cry1 transcriptional rhythms in SCN VIP neurons following an 8-h phase advance in the light/dark cycle.

No single biomarker can reliably represent the complexity of aging. One way to overcome this shortcoming is to aggregate multiple biomarkers into a composite index. The frailty index (FI), which is simply the proportion of accumulated deficits among a set of various health markers, reflects functional abilities and risks of adverse outcomes. Furthermore, the FI accounts for the variation in mortality among individuals of the same chronological age (CA). Thus, the FI is a reliable measure of biological age (BA). Unlike the FI, other popular BA-estimating algorithms use CA directly as a biomarker or indirectly to derive model parameters. However, genetic, pharmaceutical, and intervention studies have shown that aging is delayable or reversible, indicating that CA is not the direct cause of aging. The popular Klemera-Doubal (K-D) method proposes two equations for BA estimation: BE uses CA to derive equation parameters, and BEC directly incorporates CA as an additional biomarker. BA estimates by the K-D method, especially by BEC, have been shown to outperform CA. Using Louisiana Healthy Aging Study (LHAS) data, we constructed an FI from a battery of health items selected using machine learning methods for their ability to predict mortality. We compared the FI with CA and the two K-D BA estimates and found that the FI was the better predictor of mortality, especially among nonagenarians. The results were replicable with the FI calculated from different sets of selected health items using NHANES and HRS datasets. These results demonstrate the FI as the best-performing measure of BA.

An association between circadian rhythms and mood regulation is well established, and disturbed circadian clocks are believed to contribute to the development of mood disorders, including major depressive disorder. The circadian system is coordinated by the suprachiasmatic nucleus (SCN), the master pacemaker in the hypothalamus that receives light input from the retina and synchronizes circadian oscillators in other brain regions and peripheral tissues. Lacking the tight neuronal network that couples single-cell oscillators in the SCN, circadian clocks outside the SCN may be less stable and more susceptible to disturbances, for example by clock gene mutations or uncontrollable stress. However, non-SCN circadian clocks have not been studied extensively in rodent models of mood disorders. In the present study, it was hypothesized that disturbances of local circadian clocks in mood-regulating brain areas are associated with depression-like behaviour in mice. Using the learned helplessness procedure, depression-like behaviour was evoked in mice bearing the PER2::LUC circadian reporter, and then circadian rhythms of PER2 expression were examined in brain slices from these mice using luminometry and bioluminescence imaging. It was found that helplessness is associated with absence of circadian rhythms in the nucleus accumbens and the periaqueductal grey, two of the most critical brain regions within the reward circuit. The current study provides evidence that susceptibility of mice to depression-like behaviour is associated with disturbed local circadian clocks in a subset of mood-regulating brain areas, but the direction of causality remains to be determined.

Alcohol use results in changes in intestinal epithelial cell turnover and microbial translocation, yet less is known about the consequences on intestinal lymphocytes in the gut. Here, we compared T-cell subsets in the intestine of macaques before and after 3 months of chronic alcohol administration to examine the effects of alcohol on intestinal T-cell subsets.Rhesus macaques received either alcohol or isocaloric sucrose as a control treatment daily over a 3-month period via indwelling gastric catheters. Intestinal lymphocyte subsets were identified in biopsy samples by flow cytometry. Twenty-four hours prior to sampling, animals were inoculated with bromo-deoxyuridine (BrdU) to assess lymphocyte proliferation. Immunohistochemistry was performed on tissue samples to quantitate CD3+ cells.Animals receiving alcohol had increased rates of intestinal T-cell turnover of both CD4+ and CD8+ T cells as reflected by increased BrdU incorporation. However, absolute numbers of T cells were decreased in intestinal tissues as evidenced by immunohistochemistry for total CD3 expression per mm(2) intestinal lamina propria in tissue sections. Combining immunohistochemistry and flow cytometry data showed that the absolute numbers of CD8+ T cells were significantly decreased, whereas absolute numbers of total CD4+ T cells were minimally decreased.Collectively, these data indicate that alcohol exposure to the small intestine results in marked loss of CD3+ T cells, accompanied by marked increases in CD4+ and CD8+ T-cell proliferation and turnover, which we speculate is an attempt to maintain stable numbers of T cells in tissues. This suggests that alcohol results in accelerated T-cell turnover in the gut, which may contribute to premature T-cell senescence. Further, these data indicate that chronic alcohol administration results in increased levels of HIV target cells (proliferating CD4+ T cells) that may support higher levels of HIV replication in intestinal tissues.

Shift-work and jet-lag-related disorders are caused by the limited flexibility of the suprachiasmatic nucleus (SCN), a master circadian clock in the hypothalamus, to adjust to new light-dark (LD) cycles. Recent findings confirmed here establish that behavioral jet lag after simulated time-zone travel is virtually eliminated following bifurcated circadian entrainment under a novel and atypical 24-h light:dark:light:dark (LDLD) cycle. To investigate the mechanisms of this fast resetting, we examined the oscillatory stability of the SCN and peripheral tissues in LDLD-bifurcated mice employing the dissection procedure as a perturbing resetting stimulus. SCN, lung, liver, and adrenal tissue were extracted at times throughout the day from female and male PER2::Luciferase knock-in mice entrained to either LDLD or a normal LD cycle. Except for adrenals, the phase of the cultured explants was more strongly set by dissection under LDLD than under normal LD. Acute bioluminescence levels of SCN explants indicate that the rhythm amplitude of PER2 is reduced and phase is altered in LDLD. Real-time quantitative PCR suggests that amplitude and rhythmicity of canonical clock genes in the lung, liver, and kidney are also significantly reduced in LDLD in vivo. Furthermore, spatiotemporal patterns of PER2 peak time in cultured SCN were altered in LDLD. These results suggest that altered gene expression patterns in the SCN caused by bifurcation likely result in fast resetting of behavior and cultured explants, consistent with previously reported mathematical models. Thus, non-invasive, simple light manipulations can make circadian rhythms more adaptable to abrupt shifts in the environmental LD cycle.

Background Circadian clocks control cell cycle factors, and circadian disruption promotes cancer. To address whether enhancing circadian rhythmicity in tumor cells affects cell cycle progression and reduces proliferation, we compared growth and cell cycle events of B16 melanoma cells and tumors with either a functional or dysfunctional clock. Results We found that clock genes were suppressed in B16 cells and tumors, but treatments inducing circadian rhythmicity, such as dexamethasone, forskolin and heat shock, triggered rhythmic clock and cell cycle gene expression, which resulted in fewer cells in S phase and more in G1 phase. Accordingly, B16 proliferation in vitro and tumor growth in vivo was slowed down. Similar effects were observed in human colon carcinoma HCT-116 cells. Notably, the effects of dexamethasone were not due to an increase in apoptosis nor to an enhancement of immune cell recruitment to the tumor. Knocking down the essential clock gene Bmal1 in B16 tumors prevented the effects of dexamethasone on tumor growth and cell cycle events. Conclusions Here we demonstrated that the effects of dexamethasone on cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock. Thus, our work reveals that enhancing circadian clock function might represent a novel strategy to control cancer progression. Electronic supplementary material The online version of this article (doi:10.1186/s12915-017-0349-7) contains supplementary material, which is available to authorized users.