Invention of novel 3-aminopiperidin-2-ones as calcitonin gene-related peptide receptor antagonists.

A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.

Exploring Revision Total Ankle Arthroplasty Failures A Comparison Between Failed and Successful Revision Cases.

This study assesses the comorbidities that are associated with failed revision total ankle arthroplasty (TAA) and explores the outcomes following a failed revision TAA. A retrospective analysis was conducted on a cohort of patients who underwent a revision TAA at a single institution from 2008 to 2022. Patients were identified as having revision failure if they required explantation, below-knee amputation (BKA), or a revision of either metal component. Statistical analysis was performed to identify any significant differences and summarize outcomes. The study included a total of 87 patients who underwent revision TAA with 12 patients who subsequently experienced revision failure. The revision TAA failure rate was 13.8%. There were higher rates of former smokers (58.3%; n = 7) and a history of diabetes (33.3%; n = 4) in the failure cohort, although these differences did not reach statistical significance. Limb salvage procedures were achieved in 11 cases (91.7%). Approaches for failed revision TAAs included arthrodesis (n = 5) with 2 isolated ankle arthrodesis (AA) and 3 tibio-talo-calcaneal (TTC) arthrodesis, an additional revision arthroplasty (n = 6), or amputation (n = 1). Ankle arthroplasty retention was successful in 6 cases (50.0%). Our results demonstrate that a second revision approach was chosen in half of the cases, underscoring its viability as a successful intervention according to patient preferences.Level of Evidence: III.

Estimation of Health State Utility Values for Immunoglobulin A Nephropathy: A Time Trade-Off Analysis.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a rare progressive disease that can lead to kidney failure. The current study aimed to estimate health state utility values for IgAN from a UK societal perspective. METHODS: We used the time trade-off (TTO) method to derive utility values for various health states in IgAN, defined based on chronic kidney disease (CKD) stage, proteinuria, dialysis, and nephrotic syndrome (CKD stages 1-4, proteinuria < 1 g/day vs ≥ 1 g/day; CKD stage 5, dialysis vs non-dialysis). We developed health state vignettes to describe typical symptoms and quality-of-life impairments of IgAN. Eligible participants from the UK general public completed a computer-assisted telephone interview. Estimated TTO utility values were reviewed against visual analogue scale (VAS)-derived values. RESULTS: In total, 200 participants were included in the study (mean age, 48.9 years; female, 59.0%). Mean (standard deviation [SD]) utility values were 0.84 (0.17) and 0.71 (0.23) for CKD stage 1/2 with proteinuria < 1 g/day and with proteinuria ≥ 1 g/day, respectively; 0.68 (0.23) and 0.61 (0.25) for CKD stage 3; and 0.55 (0.26) and 0.49 (0.27) for CKD stage 4. Mean (SD) utility of CKD stage 5 with and without dialysis was 0.38 (0.30) and 0.42 (0.28), respectively. The mean (SD) utility value of nephrotic syndrome was 0.43 (0.33). CONCLUSIONS: Our results indicated that various IgAN health states are associated with impaired health status, with substantial utility decrements related to disease progression, elevated proteinuria, and nephrotic syndrome.

Local and whole-body SAR in UHF body imaging: Implications for SAR matrix compression.

PURPOSE: Transmit arrays for body imaging have characteristics of both volume and local transmit coils. This study evaluates two specific absorption rate (SAR) aspects, local and whole-body SAR, of arrays for body imaging at 7 T and also for a 3 T birdcage. METHODS: Simulations were performed for six antenna arrays at 7 T and one 3 T birdcage. Local SAR matrices and the whole-body SAR matrix were computed and evaluated with random shims. A set of reduced local SAR matrices was determined by removing all matrices dominated by the whole-body SAR matrix. RESULTS: The results indicate that all RF transmit coils for body imaging in this study are constrained by the local SAR limit. The ratio between local and whole-body SAR is nevertheless smaller for arrays with large FOV, as these arrays also expose a larger part of the human body. By using the whole-body SAR matrix, the number of local SAR matrices can be reduced (e.g., 33.3% matrices remained for an 8-channel local array and 89.7% for a 30-channel remote array; 12.1% for the 3 T birdcage). CONCLUSION: For transmit antenna arrays used for body imaging at 7 T as well as for the 3 T birdcage, all evaluated cases show that the local SAR limit was reached before reaching the whole-body SAR limit. Nevertheless, the whole-body SAR matrix can be used to reduce the number of local SAR matrices, which is important to reduce memory and computing time for a virtual observation points (VOP) compression. This step can be included as a pre-compression prior to a VOP compression.

Octogenarians unable to return home by postoperative-day 30.

BACKGROUND: For older adults undergoing surgery, returning home is instrumental for functional independence. We quantified octogenarians unable to return home by POD-30, assessed geriatric factors in a predictive model, and identified risk factors to inform decision-making and quality improvement. METHODS: This retrospective cohort study examined patients ≥80 years old from the ACS NSQIP Geriatric Surgery Pilot, using sequential logistic regression modelling. The primary outcome was non-home living location at POD-30. RESULTS: Of 4946 patients, 19.8 â€‹% lived in non-home facilities at POD-30. Increased odds of non-home living location were seen in patients with preoperative fall history (OR 2.92, 95%CI 2.06-4.14) and new postoperative pressure ulcer (OR 2.66, 95%CI 1.50-4.71) Other significant geriatric-specific risk factors included mobility aid use, surrogate-signed consent, and postoperative delirium, with odds ratios ranging from 1.42 (1.19-1.68) to 1.97 (1.53-2.53). CONCLUSIONS: These geriatric-specific risk factors highlight the importance of preoperative vulnerability screening and intervention to inform surgical decision-making.

Refractive Error in Inherited Retinal Disease.

PURPOSE: Inherited retinal dystrophies (IRDs) lead to significant vision impairment. Refractive errors (RE) are also associated with vision impairment and an increased risk of ocular comorbidities and may compound impairment caused by IRDs. Identifying the pattern of RE in IRDs may assist in the better management of patients with IRD and provide insights into understanding genetic associations with RE. The aim of this study was to investigate the patterns of RE in patients with IRD from three academic ophthalmology referral centers. DESIGN: Retrospective tri-center cohort study. METHODS: Chart review of clinically and molecularly confirmed IRD cases seen at the University of California San Diego, Oregon Health & Science University, and Children's Hospital Los Angeles. Data retrieved included: demographics, disease phenotype, genotype, best-corrected visual acuity, objective, and/or subjective refraction. RESULTS: A total of 1942 patient notes were reviewed, of these 634 patients (1255 eyes) had refractive data. For genes associated with myopia, NYX (n=14 [1%]) was associated with the highest SER of myopia (mean -9.26 diopters (D) [95% CI -11.867, -6.651], P<0.001) followed by IMPG2 (n=16 [1.1%]) (mean -4.062 D [95% CI -6.254, -1.871], P=0.002), then RPGR (n=104 [7.2%]) (mean -2.664 D [95% CI [-3.618, -1.710], P=0.016) and for genes associated with hyperopia, BEST1 (n= 38 [2.6%]) had the highest SER for hyperopia (mean 2.996 D [95% CI 1.830, 4.162], P<0.001) followed by RS1 (n=26 [1.8%]) (mean 2.562 D [95% CI 1.454, 3.671], P<0.001), then CNGA3 (n=28 [1.9%]) (mean 0.603 D [(95% CI -0.48, 1.686]), P=0.009). Overall patients with IRD were significantly more myopic than age matched population controls. (n=eyes) CONCLUSION: By combining genetic testing with refraction data from a large cohort of patients, we identify IRD genes associated with myopia and hyperopia. However, we find that the pattern of ametropia varies widely not only by gene but also within a gene cohort. The genes identified to be associated with RE are candidates for further in-depth investigation to understand their functional role in RE.

Brain hemodynamic responses and fall prediction in older adults with multiple sclerosis.

OBJECTIVE: We examined whether brain hemodynamic responses, gait, and cognitive performances under single- and dual-task conditions predict falls during longitudinal follow-up in older adults with multiple sclerosis (OAMS) with relapsing-remitting and progressive subtypes. METHODS: Participants with relapsing-remitting (n = 53, mean age = 65.02 ± 4.17 years, %female = 75.5) and progressive (n = 28, mean age = 64.64 ± 4.31 years, %female = 50) multiple sclerosis (MS) subtypes completed a dual-task-walking paradigm and reported falls during longitudinal follow-up using a monthly structured telephone interview. We used functional near-infrared spectroscopy (fNIRS) to assess oxygenated hemoglobin (HbO) in the prefrontal cortex during active walking and while performing a cognitive test under single- and dual-task conditions. RESULTS: Adjusted general estimating equations models indicated that higher HbO under dual-task walking was significantly associated with a reduction in the odds of reporting falls among participants with relapsing-remitting (odds ratio (OR) = 0.472, p = 0.004, 95% confidence interval (CI) = 0.284-0.785), but not progressive (OR = 1.056, p = 0.792, 95% CI = 0.703-1.588) MS. In contrast, faster stride velocity under dual-task walking was significantly associated with a reduction in the odds of reporting falls among progressive (OR = 0.658, p = 0.004, 95% CI = 0.495-0.874), but not relapsing-remitting (OR = 0.998, p = 0.995, 95% CI = 0.523-1.905) MS. CONCLUSION: Findings suggest that higher prefrontal cortex activation levels during dual-task walking, which may represent compensatory reallocation of brain resources, provide protection against falls for OAMS with relapsing-remitting subtype.

Within-hospital Temporal Clustering of Postoperative Complications and Implications for Safety Monitoring and Benchmarking Using ACS-NSQIP Data.

Objective: To determine the extent to which within-hospital temporal clustering of postoperative complications is observed in the American College of Surgeons, National Surgical Quality Improvement Program (ACS-NSQIP). Background: ACS-NSQIP relies on periodic and on-demand reports for quality benchmarking. However, if rapid increases in postoperative complication rates (clusters) are common, other reporting methods might be valuable additions to the program. This article focuses on estimating the incidence of within-hospital temporal clusters. Methods: ACS-NSQIP data from 1,547,440 patients, in 425 hospitals, over a 2-year period was examined. Hospital-specific Cox proportional hazards regression was used to estimate the incidence of mortality, morbidity, and surgical site infection (SSI) over a 30-day postoperative period, with risk adjustment for patient and procedure and with additional adjustments for linear trend, day-of-week, and season. Clusters were identified using scan statistics, and cluster counts were compared, using unpaired and paired t tests, for different levels of adjustment and when randomization of cases across time eliminated all temporal influences. Results: Temporal clusters were rarely observed. When clustering was adjusted only for patient and procedure risk, an annual average of 0.31, 0.85, and 0.51 clusters were observed per hospital for mortality, morbidity, and SSI, respectively. The number of clusters dropped after adjustment for linear trend, day-of-week, and season (0.31-0.24; P = 0.012; 0.85-0.80; P = 0.034; and 0.51-0.36; P < 0.001; using paired t tests) for mortality, morbidity, and SSI, respectively. There was 1 significant difference in the number of clusters when comparing data with all adjustments and after data were randomized (0.24 and 0.25 for mortality; P = 0.853; 0.80 and 0.82 for morbidity; P = 0.529; and 0.36 and 0.46 [randomized data had more clusters] for SSI; P = 0.001; using paired t tests) for mortality, morbidity, and SSI, respectively. Conclusions: Temporal clusters of postoperative complications were rarely observed in ACS-NSQIP data. The described methodology may be useful in assessing clustering in other surgical arenas.

HIF-2α-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis.

Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation.

Whose Job is it Anyway? A Qualitative Study of Providers' Perspectives on Diagnosing Anxiety Disorders in Integrated Health Settings.

Up to 33% of American adults will experience a diagnosable anxiety disorder in their lifetime. Approximately one-third of anxiety diagnoses assigned by mental health providers in outpatient settings are unspecified. The tendency of many providers to use an unspecified anxiety diagnosis may negatively impact the provision of evidence-based treatments for specific anxiety disorders. This study examines the perspectives of mental health providers working in an integrated and stepped health care system, asking how their roles and responsibilities shape their practices related to diagnosing specific anxiety disorders. The authors conducted semi-structured interviews with 32 Veteran Health Administration (VHA) mental health providers to understand their perspectives on diagnosing anxiety disorders. Matrix analysis was used to identify different roles and responsibilities articulated. Thematic analysis was used to highlight themes across providers' discussion of their roles in diagnosing and treating patients. The results show that, for most providers, assigning a specific diagnosis is a component of duties but rarely their focus. Second, it is unclear in which clinic setting a specific anxiety diagnosis should be made. Finally, among different types of mental health professionals, there is no clear designation on who should be providing a specific anxiety diagnosis. Altogether, results indicate that many providers feel making a specific diagnosis for anxiety is the responsibility of others-either those in other clinic settings or with other credentials. Findings call for clearer guidelines that specify individual clinician accountability for obtaining a specific anxiety diagnosis in a team-based environment.

Can TK-TD modelling bridge the gap between in vitro and in vivo mammalian toxicity data?

Repeated dietary dose testing is used to assess longer term toxicity of chemicals, such as pesticides, to mammals. However, the internal pesticide concentration varies significantly as feeding rate relative to body size fluctuates over time. Toxicokinetic-toxicodynamic (TK-TD) models can estimate internal toxicant concentration over time and link this directly to observed effects on endpoints such as the growth rate of laboratory rats. Using TK-TD models it is therefore possible to predict the effects that would result from a constant internal concentration of a pesticide. This presents the possibility of comparison with data from in vitro experiments, potentially facilitating quantitative in vitro to in vivo extrapolation (QIVIVE). We used in vivo TK-TD models to identify relevant internal concentrations and then estimated the experimental conditions required to replicate these in cultured cells, using in vitro TK models. Cell population growth was measured, with a view to extrapolating through time and comparing effect sizes with in vivo predictions. However, observed cell proliferation was not significantly affected by the tested concentrations of any of the five pesticides in this study and so extrapolation was not possible. In light of this negative result, we highlight areas for future work towards QIVIVE of graded sublethal effects in mammals. The most pressing objective is improving the accuracy of in vivo TK predictions, which could be achieved with dietary dosing in TK studies.

Changes in use of acute and preventive medications for migraine after erenumab initiation over 12 months: A United States retrospective cohort study.

OBJECTIVE: To assess changes in real-world use of acute and preventive medications for migraine over a 12-month follow-up period in the United States following initiation of the anti-calcitonin gene-related peptide (CGRP) pathway monoclonal antibody (mAb) erenumab. BACKGROUND: Early assessments of real-world use of acute and preventive medications for migraine after initiation of erenumab have been limited to 6 months of follow-up. METHODS: This retrospective cohort study used data from the IQVIA open-source longitudinal prescription (LRx) and medical (Dx) claims databases. Adult patients with an initial claim (index date) for erenumab between May 2018 and April 2020 were identified. RESULTS: Among 201,176 patients who met inclusion criteria, the mean (standard deviation [SD]) age was 47.5 (13.8) years and 85.6% (n = 172,153) were female. Most patients used one or more acute (88.4%; n = 177,795) and one or more traditional preventive (86.1%; n = 173,225) medications during the 12-month pre-index period. Adherence to erenumab (proportion of days covered [PDC] ≥0.80) was 40.2% (n = 80,927) with an overall mean (SD) PDC of 0.60 (0.34). Among all patients, 70.0% (n = 140,809) discontinued erenumab. After accounting for 24.7% (n = 49,720) of patients who restarted erenumab, discontinuation without reinitiation was observed in 45.3% (n = 91,089) of total patients. Switching to a different anti-CGRP pathway mAb was observed in 13.1% (n = 26,446) of total patients. Among 177,795 patients with pre-index use of one or more acute migraine medication class, 86.5% (n = 153,788) had post-index use of the same class, and 56.7% (87,134/153,788) of them discontinued one or more class of acute medication in the 12-month follow-up period. Similarly, among 173,225 patients with pre-index use of one or more traditional migraine preventive medication class, 67.7% (n = 117,274) had post-index use of the same class, and 46.7% (54,790/117,274) of them discontinued one or more class of traditional preventive medication in the 12-month follow-up period. CONCLUSIONS: In this long-term study, we observed the discontinuation of both acute and preventive medications for migraine post-erenumab initiation.

Younger age correlates with increased gutter impingement rates after total ankle arthroplasty.

BACKGROUND: While total ankle arthroplasty (TAA) has evolved over the years with improved designs and enhanced bony fixation methods, it remains a technically demanding procedure with a risk of early postoperative complications. One of the most common complications associated with TAA is medial and lateral gutter ankle impingement, which can lead to issues such as increased pain and decreased range of motion (ROM). However, there is a paucity of information in the literature discussing the impact of certain risk factors on gutter impingement complications. METHODS: A retrospective analysis was conducted on a cohort of patients who underwent a TAA at a single institution from 2003 to 2019 with a minimum of 2-year follow-up. Patient were identified as having gutter impingement based on diagnostic imaging and/or clinical examination. Data collection included demographics, implant type, follow-up time, and co-morbidities. Multivariate odds ratios (OR) of experiencing gutter impingement were calculated for perioperative variables. RESULTS: The study included a total of 908 patients who underwent TAA with a minimum of 2 year follow up and 121 patients (13.3 %) who subsequently experienced gutter impingement. The average follow-up time was 5.84 + /- 3.07 years. There were 178 patients under 55 years old, 495 patients aged 55 to 70, and 235 patients over 70 years old. A higher rate of gutter impingement was observed in patients under 55 years of age compared to those aged 55 to 70 and over 70 (20.8 % vs. 13.5 % vs. 7.2 %; p < 0.01). Multivariable logistic regression revealed that patient age was significantly correlated with gutter impingement following TAA, with an OR of 0.94 (CI: 0.91-0.98; p < 0.01). CONCLUSION: This study demonstrated increased incidence of gutter impingement in younger patients who underwent TAA. Propensity for scar tissue formation may be higher in this population. Scar tissue deposition following TAA can cause narrowing of the medial and lateral clear spaces, potentially leading to gutter impingement. Additionally, younger patients may have increased activity demands, which subsequently may cause higher rates of symptomatic impingement. As increased impingement after TAA may require the need for additional debridement surgeries, it is important to understand the intricate relationship between age and gutter impingement for managing patient expectations following TAA. LEVEL OF EVIDENCE: Level III.

Gain-of-Function Variants in SMAD4 Compromise Respiratory Epithelial Function.

BACKGROUND: Myhre syndrome (MIM #139210) is an exceedingly rare yet increasingly diagnosed genetic disorder arising from germline variants in the SMAD4 gene. Its core manifestation is the progression of stiffness and fibrosis across multiple organs. Individuals with Myhre syndrome exhibit a propensity for upper respiratory remodeling and infections. The molecular and cellular mechanisms underlying this phenotype remain unclear. OBJECTIVE: We aim to investigate how SMAD4 pathogenic variants associated with Myhre syndrome impact SMAD4 protein levels, activation, and physiological functions in patient-derived nasal epithelial cells. METHODS: Clinical observations were conducted on a cohort of 47 patients recruited at MGH from 2016 to 2023. Nasal epithelial basal cells were isolated and cultured from inferior turbinate brushings of healthy subjects (n=8) and Myhre syndrome patients (n=3, SMAD4-Ile500Val, Arg496Cys, and Ile500Thr). Transcriptomic analysis and functional assays were employed to assess SMAD4 levels, transcriptional activity, and epithelial cell host defense functions, including cell proliferation, mucociliary differentiation, and bacterial elimination. RESULTS: Clinical observations revealed a prevalent history of otitis media and sinusitis among most individuals with Myhre syndrome. Analyses of nasal epithelial cells indicated that SMAD4 mutations do not alter SMAD4 protein stability or upstream regulatory SMAD phosphorylation but enhance signaling transcriptional activity, supporting a gain-of-function mechanism, likely attributable to increased protein-protein interaction of the SMAD complex. Consequently, Myhre syndrome nasal basal cells exhibit reduced potential in cell proliferation and mucociliary differentiation. Furthermore, Myhre syndrome nasal epithelia are impaired in bacterial killing. CONCLUSIONS: Compromised innate immunity originating from epithelial cells in Myhre syndrome may contribute to increased susceptibility to upper respiratory infections.

Comparative analysis of patient-reported outcomes in myelopathy and myeloradiculopathy: a Quality Outcomes Database study.

OBJECTIVE: Myelopathy in the cervical spine can present with diverse symptoms, many of which can be debilitating for patients. Patients with radiculopathy symptoms demonstrate added complexity because of the overlapping symptoms and treatment considerations. The authors sought to assess outcomes in patients with myelopathy presenting with or without concurrent radiculopathy. METHODS: The Quality Outcomes Database, a prospectively collected multi-institutional database, was used to analyze demographic, clinical, and surgical variables of patients presenting with myelopathy or myeloradiculopathy as a result of degenerative pathology. Outcome measures included arm (VAS-arm) and neck (VAS-neck) visual analog scale (VAS) scores, modified Japanese Orthopaedic Association (mJOA) scale score, EuroQol VAS (EQ-VAS) score, and Neck Disability Index (NDI) at 3, 12, and 24 months compared with baseline. RESULTS: A total of 1015 patients were included in the study: 289 patients with myelopathy alone (M0), 239 with myeloradiculopathy but no arm pain (MRAP-), and 487 patients with myeloradiculopathy and arm pain (MRAP+). M0 patients were older than the myeloradiculopathy cohorts combined (M0 64.2 vs MRAP- + MRAP+ 59.5 years, p < 0.001), whereas MRAP+ patients had higher BMI and a greater incidence of current smoking compared with the other cohorts. There were more anterior approaches used in in MRAP+ patients and more posterior approaches used in M0 patients. In severely myelopathic patients (mJOA scale score ≤ 10), posterior approaches were used more often for M0 (p < 0.0001) and MRAP+ (p < 0.0001) patients. Patients with myelopathy and myeloradiculopathy both exhibited significant improvement at 1 and 2 years across all outcome domains. The amount of improvement did not vary based on surgical approach. In comparing cohort outcomes, postoperative outcome differences were associated with patient-reported scores at baseline. CONCLUSIONS: Patients with myelopathy and those with myeloradiculopathy demonstrated significant and similar improvement in arm and neck pain scores, myelopathy, disability, and quality of life at 3 months that was sustained at 1- and 2-year follow-up intervals. More radicular symptoms and arm pain increased the likelihood of a surgeon choosing an anterior approach, whereas more severe myelopathy increased the likelihood of approaching posteriorly. Surgical approach itself was not an independent predictor of outcome.

Does comorbid depression and anxiety portend poor long-term outcomes following surgery for lumbar spondylolisthesis? Five-year analysis of the Quality Outcomes Database.

OBJECTIVE: Depression and anxiety are associated with poor outcomes following spine surgery. However, the influence of these conditions on achieving a minimal clinically important difference (MCID) following lumbar spine surgery, as well as the potential compounding effects of comorbid depression and anxiety, is not well understood. This study explores the impact of comorbid depression and anxiety on long-term clinical outcomes following surgical treatment for degenerative lumbar spondylolisthesis. METHODS: This study was a retrospective analysis of the multicenter, prospectively collected Quality Outcomes Database (QOD). Patients with surgically treated grade 1 lumbar spondylolisthesis from 12 centers were included. Preoperative baseline characteristics and comorbidities were recorded, including self-reported depression and/or anxiety. Pre- and postoperative patient-reported outcomes (PROs) were recorded: the numeric rating scale (NRS) score for back pain (NRS-BP), NRS score for leg pain (NRS-LP), Oswestry Disability Index (ODI), and EQ-5D. Patients were grouped into 3 cohorts: no self-reported depression or anxiety (non-SRD/A), self-reported depression or anxiety (SRD/A), or presence of both comorbidities (SRD+A). Changes in PROs over time, satisfaction rates, and rates of MCID were compared. A multivariable regression analysis was performed to establish independent associations. RESULTS: Of the 608 patients, there were 452 (74.3%) with non-SRD/A, 81 (13.3%) with SRD/A, and 75 (12.3%) with SRD+A. Overall, 91.8% and 80.4% of patients had ≥ 24 and ≥ 60 months of follow-up, respectively. Baseline PROs were universally inferior for the SRD+A cohort. However, at 60-month follow-up, changes in all PROs were greatest for the SRD+A cohort, resulting in nonsignificant differences in absolute NRS-BP, NRS-LP, ODI, and EQ-5D across the 3 groups. MCID was achieved for the SRD+A cohort at similar rates to the non-SRD/A cohort. All groups achieved > 80% satisfaction rates with surgery without significant differences across the cohorts (p = 0.79). On multivariable regression, comorbid depression and anxiety were associated with worse baseline PROs, but they had no impact on 60-month PROs or 60-month achievement of MCIDs. CONCLUSIONS: Despite lower baseline PROs, patients with comorbid depression and anxiety achieved comparable rates of MCID and satisfaction after surgery for lumbar spondylolisthesis to those without either condition. This quality-of-life benefit was durable at 5-year follow-up. These data suggest that patients with self-reported comorbid depression and anxiety should not be excluded from consideration of surgical intervention and often substantially benefit from surgery.

Analysis of bigmouth buffalo Ictiobus cyprinellus spawning phenology in Minnesota reveals 50-year recruitment failure and conservation concern.

The bigmouth buffalo Ictiobus cyprinellus (Catostomidae) is a freshwater fish native to North America that is known for its longevity. During the 1970s, the bigmouth buffalo was recorded as declining in Canada, Minnesota, and North Dakota and became a protected species in Canada. In the USA, population declines are exacerbated by wasteful recreational bowfishing, lack of fisheries management, and overall lack of knowledge. However, recent studies have revealed the exceptional lifespan of bigmouth buffalo, their negligible senescence, slow growth, delayed maturity, and episodic recruitment. Yet little is known about the spawning phenology of bigmouth buffalo, nor their age demographics in east central Minnesota. In this 2021-2023 study of bigmouth buffalo from Rice Lake National Wildlife Refuge we found that 99.7% (389 of 390) of the extant population hatched prior to 1972 despite annual spawning in Rice Lake. Moreover, recruitment success declined significantly since water control measures were established (1953). We found males arrive to spawning grounds with females but depart later, that both the midpoint and duration of spawn significantly vary across years, and that more massive females of the same age range invest disproportionately more in ovaries. Extensive post-spawn seining revealed bigmouth buffalo young-of-the-year in low numbers, but by mid-to-late summer they were no longer evident having likely succumbed to predation. Overall, these findings thoroughly reveal one of the oldest populations of vertebrate currently known (median age of 79 years as of 2024) and expose the stark vulnerability of a bigmouth buffalo population for which substantial recruitment has not occurred for more than six decades. Multiple lines of evidence indicate that the long-lived bigmouth buffalo is vulnerable, that a precautionary approach is immediately needed, and that the unlimited and unregulated kill-fishery be closed.

The Effect of Medical Status on Long Term Survival of Dental Implants.

Successful dental implant therapy relies on a bone-implant interface that is mechanically strong and capable of dynamic remodeling in response to functional loads. There are a number of medical conditions or therapies that can affect either bone metabolism or the resistance of bone to infection. However, their effects are often mitigated by local factors or individual responses so the impact of these conditions is not clear-cut. This article will review a number of these conditions and therapies and describe existing studies that have studied these conditions to guide practitioners in their implant practice.

DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain.

BACKGROUND: Plasma growth differentiation factor 15 (GDF15) and N-terminal proB-type natriuretic peptide (NT-proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. RESULTS: In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36-1.41, PFDR < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R2 range of 5.7-12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population. CONCLUSIONS: EpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.