Hospitalisation and mortality among privately insured individuals with COVID-19 in the United States: The role of intellectual disabilities and Neurogenetic disorders.

BACKGROUND: Individuals with intellectual disabilities (IDs) and neurogenetic conditions (IDNDs) are at greater risk for comorbidities that may increase adverse outcomes for this population when they have coronavirus disease 2019 (COVID-19). The study aims are to examine the population-level odds of hospitalisation and mortality of privately insured individuals with COVID-19 with and without IDNDs IDs, controlling for sociodemographics and comorbid health conditions. METHODS: This is a retrospective, cross-sectional study of 1174 individuals with IDs and neurogenetic conditions within a population of 752 237 de-identified, privately insured, US patients diagnosed with COVID-19 between February 2020 and September 2020. Odds of hospitalisation and mortality among COVID-19 patients with IDNDs adjusted for demographic characteristics, Health Resources and Services Administration region, states with Affordable Care Act and number of comorbid health conditions were analysed. RESULTS: Patients with IDNDs overall had higher rates of COVID-19 hospitalisation than those without IDNDs (35.01% vs. 12.65%, P < .0001) and had higher rates of COVID-19 mortality than those without IDNDs (4.94% vs. .88%, P < .0001). Adjusting for sociodemographic factors only, the odds of being hospitalised for COVID-19 associated with IDNDs was 4.05 [95% confidence interval (CI) 3.56-4.61]. Adjusting for sociodemographic factors and comorbidity count, the odds of hospitalisation for COVID-19 associated with IDNDs was 1.42 (95% CI 1.25-1.61). The odds of mortality from COVID-19 for individuals with IDNDs adjusted for sociodemographic factors only was 4.65 (95% CI 3.47-6.24). The odds of mortality from COVID-19 for patients with IDNDs adjusted for sociodemographic factors and comorbidity count was 2.70 (95% CI 2.03-3.60). A major finding of the study was that even when considering the different demographic structure and generally higher disease burden of patients with IDNDs, having a IDND was an independent risk factor for increased hospitalisation and mortality compared with patients without IDNDs. CONCLUSIONS: Individuals with IDNDs had significantly higher odds of hospitalisation and mortality after adjusting for sociodemographics. Results remained significant with a slight attenuation after adjusting for sociodemographics and comorbidities. Adjustments for comorbidity count demonstrated a dose-response increase in odds of both hospitalisation and mortality, illustrating the cumulative effect of health concerns on COVID-19 outcomes. Together, findings highlight that individuals with IDNDs experience vulnerability for negative COVID-19 health outcomes with implications for access to comprehensive healthcare.

Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder.

Traumatic stress results in hypothalamic pituitary adrenal (HPA) axis abnormalities and an increased risk to both suicidal behaviors and post-traumatic stress disorder (PTSD). Previous work out of our laboratory identified SKA2 DNA methylation associations with suicidal behavior in the blood and brain of multiple cohorts. Interaction of SKA2 with stress predicted suicidal behavior with ~80% accuracy. SKA2 is hypothesized to reduce the ability to suppress cortisol following stress, which is of potentially high relevance in traumatized populations. Our objective was to investigate the interaction of SKA2 and trauma exposure on HPA axis function, suicide attempt and PTSD. SKA2 DNA methylation at Illumina HM450 probe cg13989295 was assessed for association with suicidal behavior and PTSD metrics in the context of Child Trauma Questionnaire (CTQ) scores in 421 blood and 61 saliva samples from the Grady Trauma Project (GTP) cohort. Dexamethasone suppression test (DST) data were evaluated for a subset of 209 GTP subjects. SKA2 methylation interacted with CTQ scores to predict lifetime suicide attempt in saliva and blood with areas under the receiver operator characteristic curve (AUCs) of 0.76 and 0.73 (95% confidence interval (CI): 0.6-0.92, P = 0.003, and CI: 0.65-0.78, P < 0.0001) and to mediate the suppression of cortisol following DST (ß = 0.5 ± 0.19, F = 1.51, degrees of freedom (df) = 12/167, P = 0.0096). Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress.

Latent classes of childhood trauma exposure predict the development of behavioral health outcomes in adolescence and young adulthood.

BACKGROUND: To develop latent classes of exposure to traumatic experiences before the age of 13 years in an urban community sample and to use these latent classes to predict the development of negative behavioral outcomes in adolescence and young adulthood. METHOD: A total of 1815 participants in an epidemiologically based, randomized field trial as children completed comprehensive psychiatric assessments as young adults. Reported experiences of nine traumatic experiences before age 13 years were used in a latent class analysis to create latent profiles of traumatic experiences. Latent classes were used to predict psychiatric outcomes at age ⩾13 years, criminal convictions, physical health problems and traumatic experiences reported in young adulthood. RESULTS: Three latent classes of childhood traumatic experiences were supported by the data. One class (8% of sample), primarily female, was characterized by experiences of sexual assault and reported significantly higher rates of a range of psychiatric outcomes by young adulthood. Another class (8%), primarily male, was characterized by experiences of violence exposure and reported higher levels of antisocial personality disorder and post-traumatic stress. The final class (84%) reported low levels of childhood traumatic experiences. Parental psychopathology was related to membership in the sexual assault group. CONCLUSIONS: Classes of childhood traumatic experiences predict specific psychiatric and behavioral outcomes in adolescence and young adulthood. The long-term adverse effects of childhood traumas are primarily concentrated in victims of sexual and non-sexual violence. Gender emerged as a key covariate in the classes of trauma exposure and outcomes.

Use of triphenyltetrazolium chloride in preservative efficacy testing.

Preservative efficacy testing without counting colonies was done by determining growth in dilutions of inoculated product following enrichment in Letheen broth with 0.001% triphenyltetrazolium chloride (TTC) in 96-well microtiter plates. Bacterial growth was indicated by the development of a red/pink color in the enrichment broth. The method was used to determine log reductions of bacteria at specified times after inoculation, and D-values were calculated using the reciprocal of the highest dilution showing growth (pink color) as the log CFU/ml bacteria at each time point. The method using TTC was validated by demonstrating that D-values for Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, and Escherichia coli in 44 aqueous cosmetic and OTC-drug products were virtually identical to those obtained when using Alamar Blue in the miniaturized system. Plotting D-values obtained using TTC as a function of D-values obtained using Alamar Blue gave a line with a slope of 0.98, which shows excellent agreement of results obtained by the two methods. This miniaturized assay system has been used for more than three years for preservative efficacy testing of several hundred cosmetic and OTC-drug product samples in our laboratory. It is recommended for laboratories that conduct large numbers of preservative efficacy tests.

Complications and results of long adult deformity fusions down to l4, l5, and the sacrum.

STUDY DESIGN: This is a consecutive study of patients having undergone surgical treatment of adult lumbar scoliosis. Follow-up ranged from 2 to 13 years (average 5 years). OBJECTIVES: To assess the complications and outcomes of patients with long fusions to L4 (n=23), L5 (n=21), or the sacrum (n=15) and determine if a "deeply seated" L5 segment is protective. SUMMARY OF BACKGROUND DATA: Few studies assess outcomes and complications in adults fused from the thoracic spine to L4, L5, or the sacrum with minimum 2-year follow-up. METHODS: Fifty-eight patients (59 cases; average age 43 years; range 21 to 60) with minimum 2-year follow-up were analyzed for subsequent spinal degeneration and complications. Outcomes were assessed from questionnaires administered at latest follow-up. RESULTS: Sixteen percent of cases (7 of 44) fused short of the sacrum displayed subsequent postoperative distal spinal degeneration, although only three patients were symptomatic. Compared with the group with no subsequent degeneration, this group had a lower improvement in function and pain relief. Other complications for patients fused short of the sacrum included two cases with crosslink breakage, one with neurologic deficit, three with pseudarthroses, one with hook pullout, and one with L5 screw pullout. For cases fused to the sacrum, two cases with deep wound infections and one with loose iliac screw requiring removal were observed. Because two of four cases fused to L5 with subsequent degeneration at L5-S1 were observed to have "deeply seated" L5 segments and two of the four did not, the authors could conclude only that "deep seating" of L5 is not absolute protection. CONCLUSIONS: Fusions short of the sacrum did not have predictable long-term results. Those fused short of the sacrum who developed distal spinal degeneration had worse outcomes. Patients fused to the sacrum did not have a higher complication rate. A "deeply seated" L5 segment does not necessarily protect the L5-S1 disc.

Long-term complications in adult spinal deformity patients having combined surgery a comparison of primary to revision patients.

STUDY DESIGN: This is a comparison of primary (N = 18) to revision (N = 26) combined (anterior and posterior surgery) adult spinal deformity patients with regard to late (>6 months) complications and radiographic/functional outcomes at a minimum 2-year follow-up. OBJECTIVES: To determine whether revision status increases the risk of late complications or offers a poor prognosis for functional outcome in adult deformity patients. SUMMARY OF BACKGROUND DATA: It is known that patients who have combined surgery for adult deformity have a high incidence of perioperative complications. Long-term complications and the effect of revision status have not been clarified in the literature. The functional outcomes for these patients are unclear as to whether or not there is a difference between primary and revision patients. Outside the arena of adult spinal deformity the functional outcomes for revision cases have been disappointing. METHODS: A consecutive series of 44 patients who underwent combined procedures for adult spinal deformity were followed for a minimum of 2 years (average follow-up 42 months). Clinical data were obtained by chart and radiographic review. Major complications were considered to be deep wound infection, pseudarthrosis, transition syndrome, neurologic deficit, and death. Minor complications considered were asymptomatic instrumentation failure (without loss of correction), instrumentation prominence requiring removal, and proximal or distal junctional segmental kyphosis (5-10 degrees ) or subsequent disc space narrowing of 2-5 mm without clinical symptoms. The patients also completed the AAOS Lumbar/Scoliosis MODEMS questionnaires aimed at assessing pain, function, and satisfaction. RESULTS: Minor complications were comparable in both groups: 4 of 18 (22%) in the primary group and 6 of 26 (23%) in the revision group. Major complications were slightly more frequent in the primary group with five complications in 4 patients (4 of 18 patients) (22%) compared with 3 of 26 patients (12%) in the revision group. The incidence of pseudarthrosis was 22% (4 of 18) for the primary group and 4% (1 of 26) for the revision group (P< 0.14). Forty of 44 patients completed the questionnaires. The primary patients functioned at a slightly higher level after surgery than the revision group. The level of pain was also slightly lower at final follow-up in the primary group. Despite these differences, the revision group had a higher level of patient satisfaction. CONCLUSION: At a minimum 2-year follow-up the late complications were not higher in the revision patients than in the primary group. The rate of major long-term complications, specifically pseudarthroses, was higher in the primary group. Patient satisfaction was higher in the revision patients, probably because they were experiencing a greater level of perceived pain and dysfunction at the time of their reconstruction.

Deep wound infections after neuromuscular scoliosis surgery: a multicenter study of risk factors and treatment outcomes.

STUDY DESIGN: A retrospective case-control study evaluating risk factors for infection, causative organisms, and results of treatment in patients with cerebral palsy or myelomeningocele who underwent fusion for scoliosis was performed. OBJECTIVES: To identify risk factors for infection, and to characterize the infections in terms of infecting organisms and response to treatment. SUMMARY OF BACKGROUND DATA: No previous studies have analyzed risk factors or causative organisms, nor have they indicated results of treatment for infections in this group of patients. METHODS: After a 10-year retrospective review of 210 surgically treated patients, deep wound infections developed in 16 patients with myelomeningocele and 9 patients with cerebral palsy. These patients were studied extensively for possible risk factors, along with 50 uninfected patients matched for age, diagnosis, and year of surgery. Statistical testing was performed to identify risk factors. The courses of the infections were characterized in terms of organisms isolated and response to treatment. Treatment was performed in a stepwise fashion and classified in terms of the most successful step: debridement and closure, granulation over rods, or instrumentation removal. RESULTS: Of the 10 risk factors tested, 2 were found to be significant: degree of cognitive impairment and use of allograft. Findings showed that 52% of the infections were polymicrobial. Gram-negative organisms were isolated as commonly as gram-positive organisms. The most common organisms were coagulase-negative Staphylococcus, Enterobacter, Enterococcus, and Escherichia coli.- Debridement and closure were successful in 11 of 25 patients with deep wound infection. Of the 14 patients with infection not resolved by serial debridements and closure, 2 were managed successfully by allowing the wound to granulate over rods, and 7 required rod removal for persistent wound drainage. There were three symptomatic pseudarthroses. Infections resulting from gram-positive organisms were most often managed successfully with debridement and closure (P = 0.012). CONCLUSIONS: Patients with cerebral palsy or myelomeningocele who have severe cognitive impairment, and those who received allograft may be at increased risk for infection. Infections are more often polymicrobial and caused by gram-negative organisms than is typical for elective orthopedic procedures. This suggests an enteric source. Treatment with debridement and closure was not always successful. Patients in whom infection develops are then at increased risk for pseudarthrosis.

Pedicle morphology in thoracic adolescent idiopathic scoliosis: is pedicle fixation an anatomically viable technique?

STUDY DESIGN: A radiographic study of thoracic pedicle anatomy in a group of adolescent idiopathic scoliosis (AIS) patients. OBJECTIVE: To investigate the anatomic constraints of the thoracic pedicles and determine whether the local anatomy would routinely allow pedicle screw insertion at every level. SUMMARY OF BACKGROUND DATA: In spite of the clinical successes reported with limited thoracic pedicle screw-rod constructs for thoracic AIS, controversy exists as to the safety of this technique. MATERIAL AND METHODS: Twenty-nine patients with right thoracic AIS underwent preoperative thoracic CT scans and plain radiographs. Anatomic parameters were measured from T1 to T12. RESULTS: Information on 512 pedicles was obtained. The transverse width of the pedicles from T1 through T12 ranged from 4.6-8.25 mm. The medial pedicle to lateral rib wall transverse width from T1 through T2 ranged from 12.6 to 17.9 mm. Measured dimensions from the CT scans showed the actual pedicle width to be 1-2 mm larger than would have been predicted from the plain radiographs. Age, Risser grade, curve magnitude, and the amount of segmental axial rotation did not correlate with the morphology or size of the thoracic pedicles investigated. In no case would pedicle morphology have precluded the passage of a pedicle screw. CONCLUSION: Based on the data identified in this group of adolescent patients, it is reasonable to consider pedicle screw insertion at most levels and pedicle-rib fixation at all levels of the thoracic spine during the treatment of thoracic AIS.

Analysis of titanium mesh cages in adults with minimum two-year follow-up.

STUDY DESIGN: This is a study of 66 consecutive adult patients (ages 20-81 years) with sagittal deformities who underwent surgery in which structural titanium mesh cages were implanted into the anterior column during posterior instrumentation and fusion. Follow-up ranged from 24 to 62 months (mean, 33 months). OBJECTIVES: To assess the complications and outcomes of patients with structural cages implanted into the anterior column. SUMMARY OF BACKGROUND DATA: Structural cages for the anterior column are popular in the treatment of adult spinal disorders. Few studies to determine their efficacy have a minimum 2-year follow-up. METHODS: Sixty-six patients with minimum 2-year follow-up were analyzed for cage, spinal fusion, and instrumentation status. Outcomes were assessed by analysis of responses to questionnaires administered to the patients at latest follow-up. RESULTS: No cage failure or extrusion was observed. The average segmental improvement in lordosis with cage implantation was 11 degrees with a loss of correction of less than 1 degrees at latest follow-up. The readability of plain radiographs for assessment of anterior fusions was better than for posterior fusions. The agreement level for judging spines to be fused was two of three for 78% of the anterior levels and 47% of the posterior levels. The remaining posterior fusion levels were unassessable. No statistical difference was found in outcome between the group of patients with suspected nonfused anterior levels and the group with all levels fused. CONCLUSIONS: Structural titanium mesh cages implanted into the anterior column function appropriately to maintain sagittal correction, with rare radiographic complications. Seventy-eight percent of the anterior levels were judged to be fused by observers examining plain radiographs. The outcome at latest follow-up for patients with suspected nonfused anterior levels was similar to that in the group of patients with fusions rated solid at every level.

Radiographic assessment of anterior titanium mesh cages.

Carbon fiber and titanium cage implantation for anterior column support during spinal fusions is an alternative to the use of more traditional structural allografts and autografts. The authors report instrumentation and cage failure for patients who underwent spinal fusion with structural titanium mesh cages implanted into the anterior column a minimum of 2 years after surgery. They wanted to determine whether plain radiographic techniques can be used to critically assess disk space and corpectomy fusions after implantation of these radioopaque cages. Fifty patients having undergone spinal fusions using structural titanium mesh cages in the anterior column had 99 anterior levels fused with at least 1 (maximum of 2) titanium mesh cage, resulting in a total of 131 cages used. The cages were examined for evidence of settling, migration, or failure. The anterior and posterior instrumentation was assessed for evidence of failure, and the spine was examined for evidence of successful fusion. Radiographic cage settling (>2 mm) into the vertebral body end plates was observed, but cage migration or failure were not. An average lordotic correction of 10 degrees was observed, with loss of correction into kyphosis from immediately after operation to final follow-up averaging 2 degrees. As an average of all reviewers, using a strict radiographic fusion assessment, definite or probable anterior fusion was graded at 81% of the levels, probably not or no at 5% of the levels, and could not be assessed at 14% of the levels. Definite or probable posterior fusion as an average of all reviewers was graded at 44% of the posterior fusion levels, questionable at 4%, no at 5%, and could not be assessed at 47%. The use of anterior-only, posterior-only, or anterior and posterior instrumentation with structural titanium mesh cages in the anterior spine along with proper autogenous bone grafting techniques provided anterior column support with a low rate of radiographic complications. Acceptable anterior spinal fusion rates, as assessed by a consensus agreement of reviewers, were observed primarily by evaluation of the fusion mass around the cages (extracage fusion), because intracage fusion was difficult to assess.

Magnetic resonance imaging as a tool to predict meniscal reparability.

One hundred six patients who underwent high field strength magnetic resonance imaging and subsequent arthroscopy of the knee were evaluated to determine the accuracy of magnetic resonance imaging in predicting meniscal tear reparability. Each scan was independently read by three examiners with varying degrees of expertise: a musculoskeletal radiologist, a senior orthopaedic surgeon, and a general radiologist. Each suspected tear was characterized by its morphologic type, maximum length, and minimum distance from the meniscosynovial junction. A prediction was then made of whether the tear was reparable. There were 115 meniscal tears noted in the 106 patients studied. The examiners' ability to correctly estimate tear type was only fair, with correct estimates made only 14% to 67% of the time. The overall correlation of the three examiners to correctly predict the method of treatment was fair. The average accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of magnetic resonance imaging in predicting meniscal reparability were 74%, 29%, 89%, 50%, and 80%, respectively; for predicting meniscectomy, these values were 69%, 68%, 75%, 90%, and 43%, respectively. There were no significant differences between the three examiners in the accuracy of their treatment predictions. The results of this study suggest that magnetic resonance imaging is only moderately reliable for the prediction of meniscus reparability. In addition, the training of the reader does not appear to significantly influence the results.

A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells.

Neoplastic events are marked by uncontrolled cell proliferation. One major focus of cancer research has been to identify treatments that reduce or inhibit cell growth. Over the years, various compounds, both naturally occurring and chemically synthesized, have been used to inhibit neoplastic cell proliferation. Two such oncostatic agents, melatonin and retinoic acid, have been shown to suppress the growth of hormone-responsive breast cancer. Currently, separate clinical protocols exist for the administration of retinoids and melatonin as adjuvant therapies for cancer. Using the oestrogen receptor (ER)-positive MCF-7 human breast tumour cell line, our laboratory has studied the effects of a sequential treatment regimen of melatonin followed by all-trans retinoic acid (atRA) on breast tumour cell proliferation in vitro. Incubation of hormonally responsive MCF-7 and T47D cells with melatonin (10(-9) M) followed 24 h later by atRA (10(-9) M) resulted in the complete cessation of cell growth as well as a reduction in the number of cells to below the initial plating density. This cytocidal effect is in contrast to the growth-suppressive effects seen with either hormone alone. This regimen of melatonin followed by atRA induced cytocidal effects on MCF-7 cells by activating pathways leading to apoptosis (programmed cell death) as evidenced by decreased ER and Bcl-2 and increased Bax and transforming growth factor beta 1 (TGF-beta1) expression. Apoptosis was reflected morphologically by an increase in the number of lysosomal bodies and perinuclear chromatin condensation, cytoplasmic blebbing and the presence of apoptotic bodies. The apoptotic effect of this sequential treatment with melatonin and atRA appears to be both cell and regimen specific as (a) ER-negative MDA-MB-231 and BT-20 breast tumour cells were unaffected, and (b) the simultaneous administration of melatonin and atRA was not associated with apoptosis in any of the breast cancer cell lines studied. Taken together, the results suggest that use of an appropriate regimen of melatonin and atRA should be considered for preclinical and clinical evaluation against ER-positive human breast cancer.

Isocitrate dehydrogenase kinase/phosphatase exhibits an intrinsic adenosine triphosphatase activity.

In Escherichia coli, isocitrate dehydrogenase (IDH) is regulated by reversible phosphorylation. The bifunctional enzyme which catalyzes this phosphorylation cycle, IDH kinase/phosphatase, also exhibits a specific ATPase activity. Mutant derivatives of this protein which are nearly devoid of IDH phosphatase activity retain both IDH kinase and ATPase activity, indicating that ATP hydrolysis does not result from the cyclic phosphorylation of IDH. However, the IDH kinase and ATPase activities of these mutant proteins differ significantly from those of the wild-type IDH kinase/phosphatase expressed from the parental allele. This observation suggest that IDH kinase and IDH phosphatase do not reside on structurally independent domains. In contrast to many enzymes which catalyze kinetically unfavorable side reactions, the maximum velocity of the ATPase substantially exceeded those of IDH kinase and IDH phosphatase. ATP hydrolysis was only partially inhibited by phospho- and dephospho-IDH, with saturating levels of phospho-IDH decreasing the rate of ATP hydrolysis by a factor of approximately 5. Even in the presence of near-saturating concentrations of phospho-IDH, the rate of ATP hydrolysis was 4-fold greater than the rate of the cyclic phosphorylation of IDH.