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.

Perioperative Mobile Telehealth Program for Post-Prostatectomy Incontinence: A Randomized Clinical Trial.

PURPOSE: Perioperative pelvic floor muscle training can hasten recovery of bladder control and reduce severity of urinary incontinence following radical prostatectomy. Nevertheless, most men undergoing prostatectomy do not receive this training. The purpose of this trial was to test the effectiveness of interactive mobile telehealth (mHealth) to deliver an evidence-based perioperative behavioral training program for post-prostatectomy incontinence. MATERIALS AND METHODS: This was a 3-site, 2-arm, randomized trial (2014-2019). Men with prostate cancer scheduled to undergo radical prostatectomy were randomized to a perioperative behavioral program (education, pelvic floor muscle training, progressive exercises, bladder control techniques) or a general prostate cancer education control condition, both delivered by mHealth for 1-4 weeks preoperatively and 8 weeks postoperatively. The primary outcome was time to continence following surgery measured by the ICIQ (International Consultation on Incontinence Questionnaire) Short-Form. Secondary outcomes measured at 6, 9 and 12 months included Urinary Incontinence Subscale of Expanded Prostate Cancer Index Composite; pad use; International Prostate Symptom Score QoL Question and Global Perception of Improvement. RESULTS: A total of 245 men (ages 42-78 years; mean=61.7) were randomized. Survival analysis using the Kaplan-Meier estimate showed no statistically significant between-group differences in time to continence. Analyses at 6 months indicated no statistically significant between-group differences in ICIQ scores (mean=7.1 vs 7.0, p=0.7) or other secondary outcomes. CONCLUSIONS: mHealth delivery of a perioperative program to reduce post-prostatectomy incontinence was not more effective than an mHealth education program. More research is needed to assess whether perioperative mHealth programs can be a helpful addition to standard prostate cancer care.

Correction to: Patients with Alcoholic Liver Disease Have Worse Functional Status at Time of Liver Transplant Registration and Greater Waitlist and Post-transplant Mortality Which Is Compounded by Older Age.

The original version of the article unfortunately contained an error in Figure 3. X-axis of Figures 3(a-d) should be 'Time in months'. Corrected version of Figure 3 is given.

Patients with Alcoholic Liver Disease Have Worse Functional Status at Time of Liver Transplant Registration and Greater Waitlist and Post-transplant Mortality Which Is Compounded by Older Age.

BACKGROUND: Worse functional status correlates with increased mortality on the liver transplant (LT) waitlist. Whether functional status affects LT outcomes equally across cirrhosis etiologies is unclear. AIMS: We evaluate the impact of functional status on waitlist and post-LT mortality stratified by etiology and age. METHODS: Functional status among US adults from 2005 to 2017 United Network for Organ Sharing LT registry data was retrospectively evaluated using Karnofsky Performance Status Score (KPS-1 = functional status 80-100%, KPS-2 = 60-70%, KPS-3 = 40-50%, KPS-4 = 10-30%). Waitlist and post-LT survival were stratified by KPS and cirrhosis etiology, including alcoholic liver disease (ALD), nonalcoholic steatohepatitis (NASH), hepatitis C (HCV), and HCV/ALD, and evaluated using Kaplan-Meier and multivariate Cox proportional hazard models. RESULTS: Among 94,201 waitlist registrants (69.4% men, 39.5% HCV, 26.7% ALD, 23.2% NASH), ALD patients had worse functional status compared to HCV (KPS-4: 17.2% vs. 8.3%, p < 0.001). Worse functional status at time of waitlist registration was associated with higher 90-day waitlist mortality with the greatest effect in ALD (KPS-4 vs. KPS-1: ALD HR 2.16, 95% CI 1.83-2.55; HCV HR 2.17, 95% CI 1.87-2.51). Similar trends occurred in 5-year post-LT survival with ALD patients the most harmed. Compared to patients < 50 years, patients ≥ 65 years had increased waitlist mortality at 90-days if they had HCV or HCV/ALD, and 5-year post-LT mortality regardless of cirrhosis etiology with ALD patients most severely affected. CONCLUSIONS: In a retrospective cohort study of patients, US ALD patients had disparately worse functional status at time of LT waitlist registration. Worse functional status correlated with higher risk of waitlist and post-LT mortality, affecting ALD and HCV patients the most.

More Severe Deficits in Performance Status at Time of Liver Transplant is Associated With Significantly Higher Risk of Death Following Liver Transplantation.

GOAL: To evaluate the impact of Karnofsky Performance Status score (KPSS) at the time of liver transplantation (LT) on post-LT survival. BACKGROUND: While the Model for End-Stage Liver Disease (MELD) score is used to prioritize individuals for LT, it does not specifically incorporate functional status into patient assessment for LT. METHODS: Using 2005 to 2016 United Network for Organ Sharing data, all adults (age 18 y and above) undergoing LT were identified. The association of KPSS at the time of LT (KPSS 1: functional status 80% to 100%, KPSS 2: 60% to 70%, KPSS 3: 40% to 50%, KPSS 4: 10% to 30%) with post-LT survival was evaluated using Kaplan-Meier methods and adjusted multivariate logistic regression models. RESULTS: Among 66,397 LT recipients (68% male, 72% non-Hispanic white, 22% hepatocellular carcinoma, median age: 55 to 57), women were more likely to be KPSS 4 at the time of LT compared with men (27.95% vs. 22.79%; P<0.001) and African Americans (25.43% vs. 23.03%; P<0.001) and Hispanics (31.69% vs. 23.03%; P<0.001) were more likely to be KPSS 4 than non-Hispanic whites. Worse KPSS at LT correlated with higher post-LT mortality [compared with KPSS 1: Hazard Ratio (HR) for KPSS 2: 1.16, 95% confidence interval (CI): 1.10-1.22; HR for KPSS 3: 1.40; 95% CI: 1.32-1.49; HR for KPSS 4: 1.67; 95% CI: 1.55-1.79]. This increased mortality seen with worse KPSS was observed among all liver disease etiologies and in patients with and without hepatocellular carcinoma. CONCLUSIONS: Worse functional status at the time of LT is strongly associated with higher risk of mortality following LT, emphasizing the importance of optimizing performance status in the preoperative period.

Autonomic neurophysiologic implications of disorders comorbid with bladder pain syndrome vs myofascial pelvic pain.

AIMS: The neuropathophysiology of a debilitating chronic urologic pain condition, bladder pain syndrome (BPS), remains unknown. Our recent data suggests withdrawal of cardiovagal modulation in subjects with BPS, in contrast to sympathetic nervous system dysfunction in another chronic pelvic pain syndrome, myofascial pelvic pain (MPP). We evaluated whether comorbid disorders differentially associated with BPS vs MPP shed additional light on these autonomic differences. METHODS: We compared the presence and relative time of onset of 27 other medical conditions in women with BPS, MPP, both syndromes, and healthy subjects. Analysis included an adjustment for multiple comparisons. RESULTS: Among 107 female subjects (BPS alone = 32; BPS with MPP = 36; MPP alone = 9; healthy controls = 30), comorbidities differentially associated with BPS included irritable bowel syndrome (IBS), dyspepsia, and chronic nausea, whereas those associated with MPP included migraine headache and dyspepsia, consistent with the distinct autonomic neurophysiologic signatures of the two disorders. PTSD (earliest), anxiety, depression, migraine headache, fibromyalgia, chronic fatigue, and IBS usually preceded BPS or MPP. PTSD and the presence of both pelvic pain disorders in the same subject correlated with significantly increased comorbid burden. CONCLUSIONS: Our study suggests a distinct pattern of comorbid conditions in women with BPS. These findings further support our hypothesis of primary vagal defect in BPS as compared with primary sympathetic defect in MPP, suggesting a new model for chronic these pelvic pain syndromes. Chronologically, PTSD, migraine, dysmenorrhea, and IBS occurred early, supporting a role for PTSD or its trigger in the pathophysiology of chronic pelvic pain.

Sex differences in the circadian regulation of sleep and waking cognition in humans.

The sleep-wake cycle and circadian rhythmicity both contribute to brain function, but whether this contribution differs between men and women and how it varies across cognitive domains and subjective dimensions has not been established. We examined the circadian and sleep-wake-dependent regulation of cognition in 16 men and 18 women in a forced desynchrony protocol and quantified the separate contributions of circadian phase, prior sleep, and elapsed time awake on cognition and sleep. The largest circadian effects were observed for reported sleepiness, mood, and reported effort; the effects on working memory and temporal processing were smaller. Although these effects were seen in both men and women, there were quantitative differences. The amplitude of the circadian modulation was larger in women in 11 of 39 performance measures so that their performance was more impaired in the early morning hours. Principal components analysis of the performance measures yielded three factors, accuracy, effort, and speed, which reflect core performance characteristics in a range of cognitive tasks and therefore are likely to be important for everyday performance. The largest circadian modulation was observed for effort, whereas accuracy exhibited the largest sex difference in circadian modulation. The sex differences in the circadian modulation of cognition could not be explained by sex differences in the circadian amplitude of plasma melatonin and electroencephalographic slow-wave activity. These data establish the impact of circadian rhythmicity and sex on waking cognition and have implications for understanding the regulation of brain function, cognition, and affect in shift-work, jetlag, and aging.

Pretibial Panniculitis Ossificans-A Rare but Significant Diagnosis.

Pretibial panniculitis ossificans is a rare condition. In this report, we describe a 67-year-old male localized to his right pretibial tissue, approximately 20 years after contusion to the same area.

Crystal structure prediction of flexible pharmaceutical-like molecules: density functional tight-binding as an intermediate optimisation method and for free energy estimation.

Successful methodologies for theoretical crystal structure prediction (CSP) on flexible pharmaceutical-like organic molecules explore the lattice energy surface to find a set of plausible crystal structures. The initial search stages of CSP studies use relatively simple lattice energy approximations as hundreds of thousands of minima have to be considered. These generated crystal structures often have poor molecular geometries, as well as inaccurate lattice energy rankings, and performing reasonably accurate but computationally affordable optimisations of the crystal structures generated in a search would be highly desirable. Here, we seek to explore whether semi-empirical quantum-mechanical methods can perform this task. We employed the dispersion-corrected tight-binding Hamiltonian (DFTB3-D3) to relax all the inter- and intra-molecular degrees of freedom of several thousands of generated crystal structures of five pharmaceutical-like molecules, saving a large amount of computational effort compared to earlier studies. The computational cost scales better with molecular size and flexibility than other CSP methods, suggesting that it could be extended to even larger and more flexible molecules. On average, this optimisation improved the average reproduction of the eight experimental crystal structures (RMSD15) and experimental conformers (RMSD1) by 4% and 23%, respectively. The intermolecular interactions were then further optimised using distributed multipoles, derived from the molecular wave-functions, to accurately describe the electrostatic components of the intermolecular energies. In all cases, the experimental crystal structures are close to the top of the lattice energy ranking. Phonon calculations on some of the lowest energy structures were also performed with DFTB3-D3 methods to calculate the vibrational component of the Helmholtz free energy, providing further insights into the solid-state behaviour of the target molecules. We conclude that DFTB3-D3 is a cost-effective method for optimising flexible molecules, bridging the gap between the approximate methods used in CSP searches for generating crystal structures and more accurate methods required in the final energy ranking.

More severe deficits in functional status associated with higher mortality among adults awaiting liver transplantation.

The impact of functional status on liver transplant (LT) waitlist outcomes is not well studied. Early evidence suggests frailty portends increased mortality. We aim to evaluate the association of functional status with LT waitlist survival and the probability of receiving LT among adults with cirrhosis. Using 2005-2016 United Network for Organ Sharing (UNOS) data, we retrospectively assessed the association of functional status, as determined by Karnofsky Performance Status Score (KPSS) with LT waitlist survival and the probability of receiving LT using Kaplan-Meier and multivariate Cox proportional hazard models. Among 118 954 patients listed for LT, patients with worse Karnofsky scores, indicating poor functional status, were progressively more likely to receive liver transplantation compared to patients with better scores, with the most functionally disabled group having 68% higher probability of receiving LT (HR 1.68; 95% CI 1.61-1.75, P < 0.001). Worse functional status was associated with increased waitlist mortality, with the most functionally disabled group 97% more likely to die on the waitlist (HR 1.97; 95% CI 1.81-2.16, P < 0.001). In conclusion, among patients awaiting LT, worse functional status was associated with significantly higher waitlist mortality.

Knowledge-Based Conformer Generation Using the Cambridge Structural Database.

Fast generation of plausible molecular conformations is central to molecular modeling. This paper presents an approach to conformer generation that makes extensive use of the information available in the Cambridge Structural Database. By using geometric distributions derived from the Cambridge Structural Database, it is possible to create biologically relevant conformations in the majority of cases analyzed. The paper compares the performance of the approach with previously published evaluations, and presents some cases where the method fails. The method appears to show significantly improved performance in reproduction of the conformations of structures observed in the Cambridge Structural Database and the Protein Data Bank as compared to other published methods of a similar speed.

Sensory mapping of pelvic dermatomes in women with interstitial cystitis/bladder pain syndrome.

AIM: To describe a sensory map of pelvic dermatomes in women with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). We hypothesized that if IC/BPS involves changes in central processing, then women with IC/BPS will exhibit sensory abnormalities in neurologic pelvic dermatomes. METHODS: Women with IC/BPS and healthy controls underwent neurologic examination that included evaluation of sharp pain sensitivity and vibration in dermatomes T12, L1, L2, S1-5. Peripheral nervous system sensitivity to pressure, vibration, and pinprick were scored using numeric rating scales (NRS). Bilateral comparisons were made with Wilcoxon signed-rank test and comparisons between groups were made by the Mann-Whitney U-test. RESULTS: Total of 74 women with IC/BPS and 36 healthy counterparts were included. IC/BPS and control groups had similar age (43.0 ± 14.1 and 38.6 ± 15.3 years, P = 0.14) and BMI (28.9 ± 8.0 kg/m2 and 26.9 ± 8.4 kg/m2 , P = 0.24), respectively. Women with IC/BPS reported hyperalgesia (elevated bilateral NRS pain intensity) in all pelvic dermatomes compared to healthy controls. S4-S5 region had the highest pain intensity in all participants. All IC/BPS participants exhibited vibration sensation hypoesthesia, at least unilaterally, in all of the pelvic dermatomes except L1 compared to healthy controls. CONCLUSION: This detailed map of neurologic pelvic dermatomes in women with IC/BPS found hyperalgesia in all pelvic dermatomes, and some evidence of vibration sensation hypoesthesia, compared to healthy controls. These findings support the hypothesis that IC/BPS may involve changes in central signal processing biased towards nociception.

SYMPTOM AND FUNCTIONAL TRAITS OF BRIEF MAJOR DEPRESSIVE EPISODES AND DISCRIMINATION OF BEREAVEMENT.

BACKGROUND: Despite the removal of the bereavement exclusion from DSM-5, clinicians may feel uncertain on how to proceed when caring for a patient who presents with depressive symptoms following the death of someone close. The ability to better distinguish, on a symptom and functional level, between patients who experience depression in the context of bereavement and those with nonbereavement-related depression, could help guide clinical decision making. METHOD: Individual and clustered depressive symptom and impairment measures were used for modeling bereavement status within a nationally representative longitudinal cohort. Deviance, linear shrinkage factor, and bias-corrected c-statistic were used for identifying a well-calibrated and discriminating final model. RESULTS: Of the 450 (1.2%) respondents with a single brief major depressive episode, 162 (38.4%) reported the episode as bereavement-related. The bereaved were less likely to endorse worthlessness (P < .001), social conflict (P < .001), distress (P < .001), thoughts of suicide (P = .001), wanting to die (P = .01), self-medicating (P = .01), and being withdrawn (P = .04). In a multivariate model, the bereaved were more likely to have thoughts of their own death (P = .003), guilt coupled with weight or appetite loss (P = .013), and were less likely to report social conflict (P < .001), worthlessness coupled with difficulty making decisions (P < .001), thoughts of suicide (P = .006), distress coupled with weight or appetite gain (P = .022), and self-medicating (P = .045). CONCLUSIONS: Traits and trait combinations differentiate individuals who experience brief depressive episodes following the death of a loved one from other brief episodes. These differences can help guide clinical care of patients who present with depressive symptoms shortly after a loved one's death.

Knowledge-Based Optimization of Molecular Geometries Using Crystal Structures.

This paper describes a novel way to use the structural information contained in the Cambridge Structural Database (CSD) to drive geometry optimization of organic molecules. We describe how CSD structural information is transformed into objective functions for gradient-based optimization to provide good quality geometries for a large variety of organic molecules. Performance is assessed by minimizing different sets of organic molecules reporting RMSD movements for bond lengths, valence angles, torsion angles, and heavy atom positions.

Kernel density estimation applied to bond length, bond angle, and torsion angle distributions.

We describe the method of kernel density estimation (KDE) and apply it to molecular structure data. KDE is a quite general nonparametric statistical method suitable even for multimodal data. The method generates smooth probability density function (PDF) representations and finds application in diverse fields such as signal processing and econometrics. KDE appears to have been under-utilized as a method in molecular geometry analysis, chemo-informatics, and molecular structure optimization. The resulting probability densities have advantages over histograms and, importantly, are also suitable for gradient-based optimization. To illustrate KDE, we describe its application to chemical bond length, bond valence angle, and torsion angle distributions and show the ability of the method to model arbitrary torsion angle distributions.

Knowledge-based libraries for predicting the geometric preferences of druglike molecules.

We describe the automated generation of libraries for predicting the geometric preferences of druglike molecules. The libraries contain distributions of molecular dimensions based on crystal structures in the Cambridge Structural Database (CSD). Searching of the libraries is performed in cascade fashion to identify the most relevant distributions in cases where precise structural features are poorly represented by existing crystal structures. The libraries are fully comprehensive for bond lengths, valence angles, and rotamers and produce templates for the large majority of unfused and fused rings. Geometry distributions for rotamers and rings take into account any atom chirality that may be present. Library validation has been performed on a set of druglike molecules whose structures were published after the latest CSD entry contributing to the libraries. Hence, the validation gives a true indication of prediction accuracy.

Deep generative models for 3D molecular structure.

Deep generative models have gained recent popularity for chemical design. Many of these models have historically operated in 2D space; however, more recently explicit 3D molecular generative models have become of interest, which are the topic of this article. Dozens of published models have been developed in the last few years to generate molecules directly in 3D, outputting both the atom types and coordinates, either in one-shot or adding atoms or fragments step-by-step. These 3D generative models can also be guided by structural information such as a binding pocket representation to successfully generate molecules with docking score ranges similar to known actives, but still showing lower computational efficiency and generation throughput than 1D/2D generative models and sometimes producing unrealistic conformations. We advocate for a unified benchmark of metrics to evaluate generation and propose perspectives to be addressed in next implementations.

Applying atomistic neural networks to bias conformer ensembles towards bioactive-like conformations.

Identifying bioactive conformations of small molecules is an essential process for virtual screening applications relying on three-dimensional structure such as molecular docking. For most small molecules, conformer generators retrieve at least one bioactive-like conformation, with an atomic root-mean-square deviation (ARMSD) lower than 1 Å, among the set of low-energy conformers generated. However, there is currently no general method to prioritise these likely target-bound conformations in the ensemble. In this work, we trained atomistic neural networks (AtNNs) on 3D information of generated conformers of a curated subset of PDBbind ligands to predict the ARMSD to their closest bioactive conformation, and evaluated the early enrichment of bioactive-like conformations when ranking conformers by AtNN prediction. AtNN ranking was compared with bioactivity-unaware baselines such as ascending Sage force field energy ranking, and a slower bioactivity-based baseline ranking by ascending Torsion Fingerprint Deviation to the Maximum Common Substructure to the most similar molecule in the training set (TFD2SimRefMCS). On test sets from random ligand splits of PDBbind, ranking conformers using ComENet, the AtNN encoding the most 3D information, leads to early enrichment of bioactive-like conformations with a median BEDROC of 0.29 ± 0.02, outperforming the best bioactivity-unaware Sage energy ranking baseline (median BEDROC of 0.18 ± 0.02), and performing on a par with the bioactivity-based TFD2SimRefMCS baseline (median BEDROC of 0.31 ± 0.02). The improved performance of the AtNN and TFD2SimRefMCS baseline is mostly observed on test set ligands that bind proteins similar to proteins observed in the training set. On a more challenging subset of flexible molecules, the bioactivity-unaware baselines showed median BEDROCs up to 0.02, while AtNNs and TFD2SimRefMCS showed median BEDROCs between 0.09 and 0.13. When performing rigid ligand re-docking of PDBbind ligands with GOLD using the 1% top-ranked conformers, ComENet ranked conformers showed a higher successful docking rate than bioactivity-unaware baselines, with a rate of 0.48 ± 0.02 compared to CSD probability baseline with a rate of 0.39 ± 0.02. Similarly, on a pharmacophore searching experiment, selecting the 20% top-ranked conformers ranked by ComENet showed higher hit rate compared to baselines. Hence, the approach presented here uses AtNNs successfully to focus conformer ensembles towards bioactive-like conformations, representing an opportunity to reduce computational expense in virtual screening applications on known targets that require input conformations.