POMC neurons control fertility through differential signaling of MC4R in Kisspeptin neurons.

Inactivating mutations in the melanocortin 4 receptor (MC4R) gene cause monogenic obesity. Interestingly, female patients also display various degrees of reproductive disorders, in line with the subfertile phenotype of MC4RKO female mice. However, the cellular mechanisms by which MC4R regulates reproduction are unknown. Kiss1 neurons directly stimulate gonadotropin-releasing hormone (GnRH) release through two distinct populations; the Kiss1ARH neurons, controlling GnRH pulses, and the sexually dimorphic Kiss1AVPV/PeN neurons controlling the preovulatory LH surge. Here, we show that Mc4r expressed in Kiss1 neurons is required for fertility in females. In vivo, deletion of Mc4r from Kiss1 neurons in female mice replicates the reproductive impairments of MC4RKO mice without inducing obesity. Conversely, reinsertion of Mc4r in Kiss1 neurons of MC4R null mice restores estrous cyclicity and LH pulsatility without reducing their obese phenotype. In vitro, we dissect the specific action of MC4R on Kiss1ARH vs Kiss1AVPV/PeN neurons and show that MC4R activation excites Kiss1ARH neurons through direct synaptic actions. In contrast, Kiss1AVPV/PeN neurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1AVPV/PeN neurons to induce the LH surge driving ovulation in females. Our findings demonstrate that POMCARH neurons acting through MC4R, directly regulate reproductive function in females by stimulating the "pulse generator" activity of Kiss1ARH neurons and restricting the activation of Kiss1AVPV/PeN neurons to the time of the estradiol-dependent LH surge, and thus unveil a novel pathway of the metabolic regulation of fertility by the melanocortin system.

Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances.

Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1ARH) neurons are responsible for the pulsatile release of Gonadotropin-releasing Hormone (GnRH). In females, the behavior of Kiss1ARH neurons, expressing Kiss1, Neurokinin B (NKB), and Dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17ß-estradiol (E2) reduces peptide expression but increases Vglut2 mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current and that contribute to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of Canonical Transient Receptor Potential (TPRC) 5 and G protein-coupled K+ (GIRK) channels. When TRPC5 channels in Kiss1ARH neurons were deleted using CRISPR, the slow excitatory postsynaptic potential (sEPSP) was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of the Kiss1ARH neuron, suggesting that E2 modifies ionic conductances in Kiss1ARH neurons, enabling the transition from high frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1ARH neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.

Canonical transient receptor potential channels and hypothalamic control of homeostatic functions.

Recent molecular biological and electrophysiological studies have identified multiple transient receptor potential (TRP) channels in hypothalamic neurons as critical modulators of homeostatic functions. In particular, the canonical transient receptor potential channels (TRPCs) are expressed in hypothalamic neurons that are vital for the control of fertility and energy homeostasis. Classical neurotransmitters such as serotonin and glutamate and peptide neurotransmitters such as kisspeptin, neurokinin B and pituitary adenylyl cyclase-activating polypeptide signal through their cognate G protein-coupled receptors to activate TPRC 4, 5 channels, which are essentially ligand-gated calcium channels. In addition to neurotransmitters, circulating hormones like insulin and leptin signal through insulin receptor (InsR) and leptin receptor (LRb), respectively, to activate TRPC 5 channels in hypothalamic arcuate nucleus pro-opiomelanocortin (POMC) and kisspeptin (arcuate Kiss1 [Kiss1ARH]) neurons to have profound physiological (excitatory) effects. Besides its overt depolarizing effects, TRPC channels conduct calcium ions into the cytoplasm, which has a plethora of downstream effects. Moreover, not only the expression of Trpc5 mRNA but also the coupling of receptors to TRPC 5 channel opening are regulated in different physiological states. In particular, the mRNA expression of Trpc5 is highly regulated in kisspeptin neurons by circulating estrogens, which ultimately dictates the firing pattern of kisspeptin neurons. In obesity states, InsRs are "uncoupled" from opening TRPC 5 channels in POMC neurons, rendering them less excitable. Therefore, in this review, we will focus on the critical role of TRPC 5 channels in regulating the excitability of Kiss1ARH and POMC neurons in different physiological and pathological states.

Functional Outcomes of Congenital Scoliosis at a Mean 35-Year Follow-up Post In Situ Fusion. Revisiting Patients From the 2002 Goldberg et al Study.

BACKGROUND: The management of congenital scoliosis poses a significant challenge for treating surgeons. The aim of our study was to provide insight into the long-term clinical results of spinal fusion in congenital scoliosis. METHODS: We performed a retrospective review of the scoliosis database in our institution for the period 1976 until 2002 identifying 43 patients with congenital scoliosis who underwent spinal fusion. Patient demographics, diagnosis, levels fused, and radiographs were evaluated. Patients were evaluated for unplanned return to the operating room (UPROR) via SRS 22, EQ5D-5L, and Oswestry Disability Index (ODI). RESULTS: Of the 43 patients who fulfilled the inclusion criteria, 22 patients agreed to participate, 3 patients were known to be deceased and 18 patients were lost to follow-up or declined to participate and were excluded. The mean age of the respondents was 40.7 years (range, 30 to 47 y) with a mean follow-up from index surgery of 35 years (range, 20 to 44 y). At most recent follow-up, 12 patients (54%) underwent UPROR. The mean age at diagnosis was 3.4 years (range, birth to 11.5 y), and the mean age for first surgery was 5.8 years (range, 1 to 13 y). As regards radiologic follow-up; the mean number of levels fused was 5.2 (range, 2 to 12). Thoracic fusion was performed in 17 patients (77%). The mean T1 to T12 height at index surgery and maturity was 166 mm (range, 130 to 240 mm) and 202 mm (range, 125 to 270 mm), respectively. The mean functional scores at follow-up were SRS 22: 4.5 (range, 2.4 to 5), cumulative EQ5D-5L score 7.2 (range, 5 to 15), and ODI: 8% (range, 2 to 30%). All respondents completed high school, 10 patients (45%) completed university, and 2 patients were awarded doctorates. Currently, 17 patients (77%) are in paid employment. CONCLUSIONS: This report constitutes the largest series of patients treated by spinal arthrodesis for congenital scoliosis followed into maturity. We demonstrate the thorax continues to grow after index fusion, patient-reported outcomes were satisfactory with superior educational and employment rates and unplanned return to theatre is rare in adult life. LEVEL OF EVIDENCE: Therapeutic Level IV.

Genomic, Proteomic, and Phenotypic Biomarkers of COVID-19 Severity: Protocol for a Retrospective Observational Study.

BACKGROUND: Health organizations and countries around the world have found it difficult to control the spread of COVID-19. To minimize the future impact on the UK National Health Service and improve patient care, there is a pressing need to identify individuals who are at a higher risk of being hospitalized because of severe COVID-19. Early targeted work was successful in identifying angiotensin-converting enzyme-2 receptors and type II transmembrane serine protease dependency as drivers of severe infection. Although a targeted approach highlights key pathways, a multiomics approach will provide a clearer and more comprehensive picture of severe COVID-19 etiology and progression. OBJECTIVE: The COVID-19 Response Study aims to carry out an integrated multiomics analysis to identify biomarkers in blood and saliva that could contribute to host susceptibility to SARS-CoV-2 and the development of severe COVID-19. METHODS: The COVID-19 Response Study aims to recruit 1000 people who recovered from SARS-CoV-2 infection in both community and hospital settings on the island of Ireland. This protocol describes the retrospective observational study component carried out in Northern Ireland (NI; Cohort A); the Republic of Ireland cohort will be described separately. For all NI participants (n=519), SARS-CoV-2 infection has been confirmed by reverse transcription-quantitative polymerase chain reaction. A prospective Cohort B of 40 patients is also being followed up at 1, 3, 6, and 12 months postinfection to assess longitudinal symptom frequency and immune response. Data will be sourced from whole blood, saliva samples, and clinical data from the electronic care records, the general health questionnaire, and a 12-item general health questionnaire mental health survey. Saliva and blood samples were processed to extract DNA and RNA before whole-genome sequencing, RNA sequencing, DNA methylation analysis, microbiome analysis, 16S ribosomal RNA gene sequencing, and proteomic analysis were performed on the plasma. Multiomics data will be combined with clinical data to produce sensitive and specific prognostic models for severity risk. RESULTS: An initial demographic and clinical profile of the NI Cohort A has been completed. A total of 249 hospitalized patients and 270 nonhospitalized patients were recruited, of whom 184 (64.3%) were female, and the mean age was 45.4 (SD 13) years. High levels of comorbidity were evident in the hospitalized cohort, with cardiovascular disease and metabolic and respiratory disorders being the most significant (P<.001), grouped according to the International Classification of Diseases 10 codes. CONCLUSIONS: This study will provide a comprehensive opportunity to study the mechanisms of COVID-19 severity in recontactable participants. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50733.

Demonstrating the learning and impact of embedding participant involvement in a pandemic research study: the experience of the SARS-CoV-2 immunity & reinfection evaluation (SIREN) study UK, 2020-2023.

BACKGROUND: Participant involvement in research studies is not a new concept, yet barriers to implementation remain and application varies. This is particularly true for pandemic response research studies, where timeframes are condensed, pressure is high and the value and inclusion of participant involvement can be overlooked. The SIREN Participant Involvement Panel (PIP) provides a case study for participant involvement in pandemic research, working in partnership with people who the research is for and about. METHODS: SIREN and the British Society for Immunology (BSI) recruited and ran two phases of the PIP, involving 15 members in total over a 16-month period. Phase 1 ran between January and August 2022 and Phase 2 between October 2022 and March 2023. Activity figures including recruitment interest and PIP meeting attendance were recorded. To evaluate how the PIP has influenced SIREN, feedback was collected from (a) researchers presenting at the PIP and (b) PIP members themselves. Evaluation at the end of Phase 1 informed our approach to Phase 2. Thematic grouping was planned to identify key lessons learned. RESULTS: Applications increased from n = 30 to n = 485 between Phase 1 and Phase 2 of the PIP, a more than 15-fold increase. The SIREN PIP positively impacted the design, implementation and evaluation phases of the study and sub-studies. Feedback from PIP members themselves was positive, with members highlighting that they found the role rewarding and felt valued. Learnings from the PIP have been condensed into five key themes for applying to future pandemic response research studies: the importance of dedicated resources; recruiting the right panel; understanding motivations for participant involvement; providing flexible options for involvement and enabling the early involvement of participants. CONCLUSIONS: The SIREN PIP has demonstrated the value of actively involving people who research is for and about. The PIP has provided an active feedback mechanism for research and demonstrated a positive influence on both SIREN study researchers and PIP members themselves. This paper makes the case for participant involvement in future pandemic research studies. Future work should include improved training for researchers and we would support the development of a national PIP forum as part of future pandemic research preparedness.

The SARS-Cov2 Immunity & Reinfection Evaluation (SIREN) study was set-up at speed during the early stages of the pandemic to help answer key questions about COVID-19 and inform the national pandemic response. It has provided valuable insight into COVID-19 infections, reinfections, and how well the vaccines work. SIREN helped to find these answers by regularly testing over 44,000 healthcare staff working at 135 NHS organisations. To support participant retention, SIREN established a Participant Involvement Panel (PIP) involving 15 SIREN participants to date. PIP members provide guidance and feedback to SIREN researchers on key research priorities, changes to the study and strategies for maximising participant engagement. This paper provides insight into how the PIP was set-up, run and the resources required from the perspective of the PIP and SIREN researchers. Lessons learned from establishing the PIP are summarised to help inform future pandemic response research studies. The paper adds to the evidence base, and makes the case for, the valuable role participant involvement can play in pandemic response research studies.

Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun): a multicentre, single-blinded, randomised clinical trial.

BACKGROUND: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods. METHODS: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete. FINDINGS: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 µg daily to 1000 µg daily (500 µg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 µg once daily to 500 µg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA. INTERPRETATION: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden. FUNDING: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.

A Framework for Authentic Ethical Decision Making in the Face of Grand Challenges: A Lonerganian Gradation.

This paper contributes to the contemporary business ethics narrative by proposing an approach to corporate ethical decision making (EDM) which serves as an alternative to the imposition of codes and standards to address the ethical consequences of grand challenges, like COVID-19, which are impacting today's society. Our alternative approach to EDM embraces the concept of reflexive thinking and ethical consciousness among the individual agents who collectively are the corporation and who make ethical decisions, often in isolation, removed from the collocated corporate setting. We draw on the teachings of the Canadian philosopher and theologian, Fr. Bernard Lonergan, to conceptualize an approach to EDM which focuses on the ethics of the corporate agent by nurturing the universal and invariant structure that is operational in all human beings. Embracing Lonergan's dynamic cognitive structure of human knowing, and the structure of the human good, we advance a paradigm of EDM in business which emboldens authentic ethical thought, decision making, and action commensurate with virtuous living and germane to human flourishing. Lonergan's philosophy guides us away from the imposition of over-arching corporate codes of ethics and inspires us, as individual agents, to attend to the data of our own consciousness in our ethical decision making. Such cognitional endowment leads us out of the ethics of the 'timeless present' (Islam and Greenwood in Journal of Business Ethics 170: 1-4, 2021) towards ethical authenticity in business, leaving us better placed to reflect upon and address the ethical issues emanating from grand challenges like COVID-19.

Large Intra-Abdominal Desmoid Tumor in a Deployed Soldier Initially Presented With Chronic Diarrhea.

Diarrhea is a common condition seen among soldiers in both garrison and deployed environments. Although the vast majority of soldiers with diarrhea will recover uneventfully with supportive care, clinicians should also maintain suspicion for less common causes and perform a thorough physical exam. We report the case of a young, healthy soldier with chronic diarrhea and progressively worsening abdominal distention that began during his deployment to Honduras who was subsequently found to have a large intra-abdominal desmoid tumor. Desmoid tumor is a rare and benign neoplasm that typically appears on the extremity, abdominal wall, intra-abdominal space, and occasionally in the chest wall. This tumor may be associated with abdominal distension and gastrointestinal complaints. A large tumor can compress organs, causing local tissue damage and, in rare cases, death.

CRISPR/SaCas9 mutagenesis of stromal interaction molecule 1 in proopiomelanocortin neurons increases glutamatergic excitability and protects against diet-induced obesity.

OBJECTIVE: Proopiomelanocortin (POMC) neurons are the key anorexigenic hypothalamic neuron for integrating metabolic cues to generate the appropriate output for maintaining energy homeostasis and express the requisite channels as a perfect synaptic integrator in this role. Similar to the metabolic hormones leptin and insulin, glutamate also excites POMC neurons via group I metabotropic glutamate receptors (mGluR1 and 5, mGluR1/5) that activate Transient Receptor Potential Canonical (TRPC 5) Channels to cause depolarization. A key modulator of TRPC 5 channel activity is stromal interaction molecule 1 (STIM1), which is involved in recruitment of TRPC 5 channels from receptor-operated to store-operated calcium entry following depletion of calcium from the endoplasmic reticulum. METHODS: We used a single adeno-associated viral (AAV) vector containing a recombinase-dependent Staphylococcus aureus Cas9 (SaCas) and a single guide RNA (sgRNA) to mutate Stim1 in POMCCre neurons in male mice, verified by qPCR of Stim1 mRNA expression in single POMC neurons. Whole-cell patch clamp experiments were conducted to validate the effects of Stim1 mutagenesis. Body weight and food intake were measured in male mice to assess disruptions in energy balance. RESULTS: Reduced Stim1 expression augmented the efficacy of the mGluR1/5 agonist 3, 5-Dihydroxyphenylglycine (DHPG) to depolarize POMC neurons via a Gαq-coupled signaling pathway, which is an essential part of excitatory glutamatergic input in regulating energy homeostasis. The TRPC 5 channel blockers HC070 and Pico145 antagonized the excitatory effects of DHPG. As proof of principle, mutagenesis of Stim1 in POMC neurons reduced food intake, attenuated weight gain, reduced body fat and fat pad mass in mice fed a high fat diet. CONCLUSIONS: Using CRISPR technology we have uncovered a critical role of STIM1 in modulating glutamatergic activation of TRPC 5 channels in POMC neurons, which ultimately is important for maintaining energy balance.

The novel estrogen receptor modulator STX attenuates Amyloid-ß neurotoxicity in the 5XFAD mouse model of Alzheimer's disease.

Based on previous evidence that the non-steroidal estrogen receptor modulator STX mitigates the effects of neurotoxic Amyloid-ß (Aß) in vitro, we have evaluated its neuroprotective benefits in a mouse model of Alzheimer's disease. Cohorts of 5XFAD mice, which begin to accumulate cerebral Aß at two months of age, were treated with orally-administered STX starting at 6 months of age for two months. After behavioral testing to evaluate cognitive function, biochemical and immunohistochemical assays were used to analyze key markers of mitochondrial function and synaptic integrity. Oral STX treatment attenuated Aß-associated mitochondrial toxicity and synaptic toxicity in the brain, as previously documented in cultured neurons. STX also moderately improved spatial memory in 5XFAD mice. In addition, STX reduced markers for reactive astrocytosis and microgliosis surrounding amyloid plaques, and also unexpectedly reduced overall levels of cerebral Aß in the brain. The neuroprotective effects of STX were more robust in females than in males. These results suggest that STX may have therapeutic potential in Alzheimer's Disease.

The addition of oral Tranexamic acid to knee arthroplasty patients does not further improve blood loss: a double blinded randomized control trial.

Perioperative intravenous (IV) TA has become routine in knee and hip arthroplasty. Less evidence exists on the administration of oral TA in the post- operative period. Our study aims to identify the efficacy and safety of combined perioperative IV and post-operative oral TA on blood loss and Hemoglobin (Hb) drop compared to perioperative IV TA alone. Patients undergoing primary elective knee arthro- plasty at our institution were invited to participate in the study (n=50). A computer-generated randomisation sequence was created online (www.randomization. org), with an allocation ratio of 1:1 and a block size of 50. Group A received perioperative IV TA alone and post-operative oral TA (n= 26) and Group B received perioperative IV TA plus 48 hours additional oral placebo (n= 24). Day 3 total blood loss and Hb drop was calculated. Continuous, normally distributed data (total blood loss) was compared utilising using one-way analysis of variance with post hoc Tukey test. Continuous skewed data (Hb drop) was compared using the Kruskal-Wallis test. P <0.05 was considered statistically significant. Group A demonstrated a trend in decreased total blood loss that was close to statistical significance ( p = 0.072). No difference in Hb drop was identified between the 2 groups. Increased nausea was also observed in Group A. The administration of oral TA to post-operative knee arthroplasty patients does not improve further blood loss compared to patients receiving perioperative IV TA pre-operatively and at wound closure.

Estrogenic regulation of reproduction and energy homeostasis by a triumvirate of hypothalamic arcuate neurons.

Pregnancy is energetically demanding and therefore, by necessity, reproduction and energy balance are inextricably linked. With insufficient or excessive energy stores a female is liable to suffer complications during pregnancy or produce unhealthy offspring. Gonadotropin-releasing hormone neurons are responsible for initiating both the pulsatile and subsequent surge release of luteinizing hormone to control ovulation. Meticulous work has identified two hypothalamic populations of kisspeptin (Kiss1) neurons that are critical for this pattern of release. The involvement of the hypothalamus is unsurprising because its quintessential function is to couple the endocrine and nervous systems, coordinating energy balance and reproduction. Estrogens, more specifically 17ß-estradiol (E2 ), orchestrate the activity of a triumvirate of hypothalamic neurons within the arcuate nucleus (ARH) that govern the physiological underpinnings of these behavioral dynamics. Arising from a common progenitor pool, these cells differentiate into ARH kisspeptin, pro-opiomelanocortin (POMC), and agouti related peptide/neuropeptide Y (AgRP) neurons. Although the excitability of all these subpopulations is subject to genomic and rapid estrogenic regulation, Kiss1 neurons are the most sensitive, reflecting their integral function in female fertility. Based on the premise that E2 coordinates autonomic functions around reproduction, we review recent findings on how Kiss1 neurons interact with gonadotropin-releasing hormone, AgRP and POMC neurons, as well as how the rapid membrane-initiated and intracellular signaling cascades activated by E2 in these neurons are critical for control of homeostatic functions supporting reproduction. In particular, we highlight how Kiss1 and POMC neurons conspire to inhibit AgRP neurons and diminish food motivation in service of reproductive success.

Readability and quality assessment of internet-based patient education materials related to deep vein thrombosis.

Access to health-related internet information has increased dramatically during the past decade. A significant proportion of this information has been demonstrated to be set at too high a level for general comprehension. The goal of this study was to evaluate the readability and quality of information available on the internet relating to deep vein thrombosis (DVT). A search for 'DVT' and 'Deep Vein Thrombosis' was performed on five most commonly accessed search engines. Top hundred websites were reviewed. Website authorship was classified. Each site was assessed using the recognized quality and readability scoring systems. The presence of the health on the net foundation code of conduct (HON-code), a reported quality-assurance marker, was noted. The majority of web sites (45%) were academic or physician compiled. Only 36% of the websites were HON-code certified. HON-code certified sites achieved significantly greater DISCERN and Journal of the American Medical Association (JAMA) scores. Seventy-three percent of the websites were above the recommended sixth-grade readability level. Flesch--Kincaid readability test (FRES) of more than half of the websites (56%) was below 60, which makes them fairly difficult to read by general public. Internet information relating to DVT is of variable quality and largely set at an inappropriate readability level. Given this variability in quality, healthcare providers should direct patients to known sources of reliable, readable online information. Identification of reliable sources may be aided by known markers of quality such as HONcode certification and to educate them to use academic and physician-provided sites which have been shown to contain better-quality information. Moreover, academic and physician-compiled websites should be written in a fashion appropriate for general public consumption.

Hypothalamic Kisspeptin Neurons and the Control of Homeostasis.

Hypothalamic kisspeptin (Kiss1) neurons provide indispensable excitatory transmission to gonadotropin-releasing hormone (GnRH) neurons for the coordinated release of gonadotropins, estrous cyclicity, and ovulation. But maintaining reproductive functions is metabolically demanding so there must be a coordination with multiple homeostatic functions, and it is apparent that Kiss1 neurons play that role. There are 2 distinct populations of hypothalamic Kiss1 neurons, namely arcuate nucleus (Kiss1ARH) neurons and anteroventral periventricular and periventricular nucleus (Kiss1AVPV/PeN) neurons in rodents, both of which excite GnRH neurons via kisspeptin release but are differentially regulated by ovarian steroids. Estradiol (E2) increases the expression of kisspeptin in Kiss1AVPV/PeN neurons but decreases its expression in Kiss1ARH neurons. Also, Kiss1ARH neurons coexpress glutamate and Kiss1AVPV/PeN neurons coexpress gamma aminobutyric acid (GABA), both of which are upregulated by E2 in females. Also, Kiss1ARH neurons express critical metabolic hormone receptors, and these neurons are excited by insulin and leptin during the fed state. Moreover, Kiss1ARH neurons project to and excite the anorexigenic proopiomelanocortin neurons but inhibit the orexigenic neuropeptide Y/Agouti-related peptide neurons, highlighting their role in regulating feeding behavior. Kiss1ARH and Kiss1AVPV/PeN neurons also project to the preautonomic paraventricular nucleus (satiety) neurons and the dorsomedial nucleus (energy expenditure) neurons to differentially regulate their function via glutamate and GABA release, respectively. Therefore, this review will address not only how Kiss1 neurons govern GnRH release, but how they control other homeostatic functions through their peptidergic, glutamatergic and GABAergic synaptic connections, providing further evidence that Kiss1 neurons are the key neurons coordinating energy states with reproduction.

Acetabular Lip Augmentation Devices for the Unstable Total Hip Replacement-A Systematic Review.

BACKGROUND: The optimal management strategy for instability afte total hip arthroplasty remains unclear. Acetabular lip augmentation devices may offer an operative solution for recurrent instability. This systematic review reports the clinical outcomes of acetabular lip augmentation devices in comparison to other treatment options. METHODS: A literature search strategy was performed of Medline, EMBASE, and CENTRAL on September 19, 2020, for all studies reporting outcomes of acetabular lip augmentation devices for recurrent dislocation after total hip arthroplasty. Non-English language articles were excluded. Clinical and survivorship data were collated and analyzed. RESULTS: Thirteen studies describing acetabular augmentation were included for analysis. A total of 644 hips in 636 patients were augmented with a mean age of 75 years (39 to 103). Five different augmentation devices were used. The posterior lip augmentation device (PLAD, DePuy) was the most used (406 hips). Overall, acetabular lip augmentation devices had a 10% postoperative dislocation rate at a mean follow-up of 49 months (0.2 to 132). The PLAD had a 3.9% subsequent dislocation rate with a mean follow-up of 51 months (0.2 to 132). Only one study compared the PLAD to a dual-mobility cup, which demonstrated shorter operative times with the PLAD but higher rates of dislocation and revision surgery. CONCLUSION: The quality of literature on lip acetabular augmentation devices is poor. In these studies, the postoperative dislocation rate after lip acetabular augmentation was relatively high. The PLAD (DePuy) has the most evidence and may offer a therapeutic option for recurrent instability, in very specific clinical situations.

Nasopharyngeal Swabs vs. Nasal Aspirates for Respiratory Virus Detection: A Systematic Review.

Nasal pathogen detection sensitivities can be as low as 70% despite advances in molecular diagnostics. This may be linked to the choice of sampling method. A diagnostic test accuracy review for sensitivity was undertaken to compare sensitivity of swabbing to the nasopharynx and extracting nasal aspirates, using the PRISMA protocol, Cochrane rapid review methodology, and QUADAS-2 risk of bias tools, with meta-analysis of included studies. Sensitivities were calculated by a consensus standard of positivity by either method as the 'gold standard.' Insufficient sampling methodology, cross sectional study designs, and studies pooling samples across anatomical sites were excluded. Of 13 subsequently eligible studies, 8 had 'high' risk of bias, and 5 had 'high' applicability concerns. There were no statistical differences in overall sensitivities between collection methods for eight different viruses, and this did not differ with use of PCR, immunofluorescence, or culture. In one study alone, Influenza H1N1(2009) favored nasopharyngeal swabs, with aspirates having 93.3% of the sensitivity of swabs (p > 0.001). Similarly equivocal sensitivities were noted in reports detecting bacteria. The chain of sampling, from anatomical site to laboratory results, features different potential foci along which sensitivity may be lost. A fair body of evidence exists that use of a different sampling method will not yield more respiratory pathogens.

Deletion of Stim1 in Hypothalamic Arcuate Nucleus Kiss1 Neurons Potentiates Synchronous GCaMP Activity and Protects against Diet-Induced Obesity.

Kisspeptin (Kiss1) neurons are essential for reproduction, but their role in the control of energy balance and other homeostatic functions remains unclear. High-frequency firing of hypothalamic arcuate Kiss1 (Kiss1ARH) neurons releases kisspeptin into the median eminence, and neurokinin B (NKB) and dynorphin onto neighboring Kiss1ARH neurons to generate a slow EPSP mediated by TRPC5 channels that entrains intermittent, synchronous firing of Kiss1ARH neurons. High-frequency optogenetic stimulation of Kiss1ARH neurons also releases glutamate to excite the anorexigenic proopiomelanocortin (POMC) neurons and inhibit the orexigenic neuropeptide Y/agouti-related peptide (AgRP) neurons via metabotropic glutamate receptors. At the molecular level, the endoplasmic reticulum (ER) calcium-sensing protein stromal interaction molecule 1 (STIM1) is critically involved in the regulation of neuronal Ca2+ signaling and neuronal excitability through its interaction with plasma membrane (PM) calcium (e.g., TRPC) channels. Therefore, we hypothesized that deletion of Stim1 in Kiss1ARH neurons would increase neuronal excitability and their synchronous firing, which ultimately would affect energy homeostasis. Using optogenetics in combination with whole-cell recording and GCaMP6 imaging in slices, we discovered that deletion of Stim1 in Kiss1 neurons significantly increased the amplitude and duration of the slow EPSP and augmented synchronous [Ca2+]i oscillations in Kiss1ARH neurons. Deletion of Stim1 in Kiss1ARH neurons amplified the actions of NKB and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting (HFD). Therefore, STIM1 appears to play a critical role in regulating synchronous firing of Kiss1ARH neurons, which ultimately affects the coordination between energy homeostasis and reproduction.SIGNIFICANCE STATEMENT Hypothalamic arcuate kisspeptin (Kiss1ARH) neurons are essential for stimulating the pulsatile release of gonadotropin-releasing hormone (GnRH) and maintaining fertility. However, Kiss1ARH neurons appear to be a key player in coordinating energy balance with reproduction. The regulation of calcium channels and hence calcium signaling is critically dependent on the endoplasmic reticulum (ER) calcium-sensing protein stromal interaction molecule 1 (STIM1), which interacts with the plasma membrane (PM) calcium channels. We have conditionally deleted Stim1 in Kiss1ARH neurons and found that it significantly increased the excitability of Kiss1ARH neurons and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting (HFD).

Management for Bony Mallet Thumb with a Single Extension Blocking Kirschner Wire.

INTRODUCTION: Mallet finger injury is defined by disruption of the terminal extensor tendon distal-to-distal interphalangeal (DIP) joint. While in the fingers, it is a relatively common injury, it is a rarely encountered entity when involving the thumb. Various conservative and operative treatment strategies have been reported for the management of mallet thumb with no consensus by clinicians. CASE REPORT: We present the case of a 27-year-old right hand dominant man with a left bony mallet thumb injury that occurred while playing hurling. Hurling is traditional Irish sport that is one of the fastest field games in the world, involving the use of a wooden Hurley and ball. Clinically, there was loss of active extension at the DIP joint of the non-dominant thumb with radiographs revealing an avulsion fracture involving more than one-third of the articular surface at the base of the distal phalanx. Closed reduction and percutaneous fixation using a single extension block Kirschner wire was performed without a transfixion wire across the DIP joint. Four months postoperatively, the patient had regained that good functional dexterity was able to return to playing hurling. CONCLUSION: A single K-wire technique may be beneficial with theoretical reduction of chance of iatrogenic nail bed, bone fragment rotation, chondral damage, and bone injury. To the best of our knowledge, no previous reports of its application to bony mallet thumb have been described.