A method for intelligent allocation of diagnostic testing by leveraging data from commercial wearable devices: a case study on COVID-19.

Mass surveillance testing can help control outbreaks of infectious diseases such as COVID-19. However, diagnostic test shortages are prevalent globally and continue to occur in the US with the onset of new COVID-19 variants and emerging diseases like monkeypox, demonstrating an unprecedented need for improving our current methods for mass surveillance testing. By targeting surveillance testing toward individuals who are most likely to be infected and, thus, increasing the testing positivity rate (i.e., percent positive in the surveillance group), fewer tests are needed to capture the same number of positive cases. Here, we developed an Intelligent Testing Allocation (ITA) method by leveraging data from the CovIdentify study (6765 participants) and the MyPHD study (8580 participants), including smartwatch data from 1265 individuals of whom 126 tested positive for COVID-19. Our rigorous model and parameter search uncovered the optimal time periods and aggregate metrics for monitoring continuous digital biomarkers to increase the positivity rate of COVID-19 diagnostic testing. We found that resting heart rate (RHR) features distinguished between COVID-19-positive and -negative cases earlier in the course of the infection than steps features, as early as 10 and 5 days prior to the diagnostic test, respectively. We also found that including steps features increased the area under the receiver operating characteristic curve (AUC-ROC) by 7-11% when compared with RHR features alone, while including RHR features improved the AUC of the ITA model's precision-recall curve (AUC-PR) by 38-50% when compared with steps features alone. The best AUC-ROC (0.73 ± 0.14 and 0.77 on the cross-validated training set and independent test set, respectively) and AUC-PR (0.55 ± 0.21 and 0.24) were achieved by using data from a single device type (Fitbit) with high-resolution (minute-level) data. Finally, we show that ITA generates up to a 6.5-fold increase in the positivity rate in the cross-validated training set and up to a 4.5-fold increase in the positivity rate in the independent test set, including both symptomatic and asymptomatic (up to 27%) individuals. Our findings suggest that, if deployed on a large scale and without needing self-reported symptoms, the ITA method could improve the allocation of diagnostic testing resources and reduce the burden of test shortages.

A Method for Intelligent Allocation of Diagnostic Testing by Leveraging Data from Commercial Wearable Devices: A Case Study on COVID-19.

Mass surveillance testing can help control outbreaks of infectious diseases such as COVID-19. However, diagnostic test shortages are prevalent globally and continue to occur in the US with the onset of new COVID-19 variants, demonstrating an unprecedented need for improving our current methods for mass surveillance testing. By targeting surveillance testing towards individuals who are most likely to be infected and, thus, increasing testing positivity rate (i.e., percent positive in the surveillance group), fewer tests are needed to capture the same number of positive cases. Here, we developed an Intelligent Testing Allocation (ITA) method by leveraging data from the CovIdentify study (6,765 participants) and the MyPHD study (8,580 participants), including smartwatch data from 1,265 individuals of whom 126 tested positive for COVID-19. Our rigorous model and parameter search uncovered the optimal time periods and aggregate metrics for monitoring continuous digital biomarkers to increase the positivity rate of COVID-19 diagnostic testing. We found that resting heart rate features distinguished between COVID-19 positive and negative cases earlier in the course of the infection than steps features, as early as ten and five days prior to the diagnostic test, respectively. We also found that including steps features increased the area under the receiver operating characteristic curve (AUC-ROC) by 7-11% when compared with RHR features alone, while including RHR features improved the AUC of the ITA model's precision-recall curve (AUC-PR) by 38-50% when compared with steps features alone. The best AUC-ROC (0.73 ± 0.14 and 0.77 on the cross-validated training set and independent test set, respectively) and AUC-PR (0.55 ± 0.21 and 0.24) were achieved by using data from a single device type (Fitbit) with high-resolution (minute-level) data. Finally, we show that ITA generates up to a 6.5-fold increase in the positivity rate in the cross-validated training set and up to a 3-fold increase in the positivity rate in the independent test set, including both symptomatic and asymptomatic (up to 27%) individuals. Our findings suggest that, if deployed on a large scale and without needing self-reported symptoms, the ITA method could improve allocation of diagnostic testing resources and reduce the burden of test shortages.

A capped Tudor domain within a core subunit of the Sin3L/Rpd3L histone deacetylase complex binds to nucleic acid G-quadruplexes.

Chromatin-modifying complexes containing histone deacetylase (HDAC) activities play critical roles in the regulation of gene transcription in eukaryotes. These complexes are thought to lack intrinsic DNA-binding activity, but according to a well-established paradigm, they are recruited via protein-protein interactions by gene-specific transcription factors and posttranslational histone modifications to their sites of action on the genome. The mammalian Sin3L/Rpd3L complex, comprising more than a dozen different polypeptides, is an ancient HDAC complex found in diverse eukaryotes. The subunits of this complex harbor conserved domains and motifs of unknown structure and function. Here, we show that Sds3, a constitutively-associated subunit critical for the proper functioning of the Sin3L/Rpd3L complex, harbors a type of Tudor domain that we designate the capped Tudor domain. Unlike canonical Tudor domains that bind modified histones, the Sds3 capped Tudor domain binds to nucleic acids that can form higher-order structures such as G-quadruplexes and shares similarities with the knotted Tudor domain of the Esa1 histone acetyltransferase that was previously shown to bind single-stranded RNA. Our findings expand the range of macromolecules capable of recruiting the Sin3L/Rpd3L complex and draw attention to potentially new biological roles for this HDAC complex.

C1-C2 Wiring With Timed Self-Obsolescence for Complex C2 Body Fracture.

BACKGROUND AND IMPORTANCE: Fractures of C2 are typically managed nonoperatively with good rates of healing. Management decisions are complicated, however, when there are additional fractures in the axis possibly leading to increased instability. Additionally, the techniques used for treating these unstable axis fractures can have either significant complications or permanent loss of range of motion. Here, we present a novel technique for the reduction and stabilization of complex C2 body fracture. CLINICAL PRESENTATION: A 34-yr-old woman with a complex C2 body fracture, which included a right pars and left lateral mass fracture, presented after a water slide accident. It was felt that this fracture was both unstable and would not heal in an anatomically acceptable way so an open surgical reduction was needed. After consideration of more traditional fusion and osteosynthesis techniques, we chose to perform a C1-C2 internal stabilization with C1 sublaminar and C2 spinous process wiring. The patient was then instructed to wear a Miami J collar for 3 mo. CONCLUSION: The outcome was favorable with good approximation and healing with preserved range of motion.

KDM5A and PHF2 positively control expression of pro-metastatic genes repressed by EWS/Fli1, and promote growth and metastatic properties in Ewing sarcoma.

Ewing sarcoma is an aggressive malignant neoplasm with high propensity for metastasis and poor clinical outcomes. The EWS/Fli1 oncofusion is the disease driver in > 90% of cases, but presents a difficult therapeutic target. Moreover, EWS/Fli1 plays a complex role in disease progression, with inhibitory effects on critical steps of metastasis. Like many other pediatric cancers, Ewing sarcoma is a disease marked by epigenetic dysregulation. Epigenetic mechanisms present alternative targeting opportunities, but their contributions to Ewing sarcoma metastasis and disease progression remain poorly understood. Here, we show that the epigenetic regulators KDM5A and PHF2 promote growth and metastatic properties in Ewing sarcoma, and, strikingly, activate expression many pro-metastatic genes repressed by EWS/Fli1. These genes include L1CAM, which is associated with adverse outcomes in Ewing sarcoma, and promotes migratory and invasive properties. KDM5A and PHF2 retain their growth promoting effects in more metastatically potent EWS/Fli1low cells, and PHF2 promotes both invasion and L1CAM expression in this cell population. Furthermore, KDM5A and PHF2 each contribute to the increased metastatic potency of EWS/Fli1low cells in vivo. Together, these studies identify KDM5A and PHF2 as novel disease-promoting factors, and potential new targets, in Ewing sarcoma, including the more metastatically potent EWS/Fli1low cell population.

KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1-driven and independent disease-promoting gene expression in fusion-positive Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young adults. RMS exists as two major disease subtypes, oncofusion-negative RMS (FN-RMS) and oncofusion-positive RMS (FP-RMS). FP-RMS is characterized by recurrent PAX3/7-FOXO1 driver oncofusions and is a biologically and clinically aggressive disease. Recent studies have revealed FP-RMS to have a strong epigenetic basis. Epigenetic mechanisms represent potential new therapeutic vulnerabilities in FP-RMS, but their complex details remain to be defined. We previously identified a new disease-promoting epigenetic axis in RMS, involving the chromatin factor KDM3A and the Ets1 transcription factor. In the present study, we define the KDM3A and Ets1 FP-RMS transcriptomes and show that these interface with the recently characterized PAX3/FOXO1-driven gene expression program. KDM3A and Ets1 positively control numerous known and candidate novel PAX3/FOXO1-induced RMS-promoting genes, including subsets under control of PAX3/FOXO1-associated superenhancers (SE), such as MEST. Interestingly, KDM3A and Ets1 also positively control a number of known and candidate novel FP-RMS-promoting, but not PAX3/FOXO1-dependent, genes. Epistatically, Ets1 is downstream of, and exerts disease-promoting effects similar to, both KDM3A and PAX3/FOXO1. MEST also manifests disease-promoting properties in FP-RMS, and KDM3A and Ets1 each impacts activation of the PAX3/FOXO1-associated MEST SE. Taken together, our studies show that the KDM3A/Ets1 epigenetic axis plays an important role in disease promotion in FP-RMS, and provide insight into potential new ways to target aggressive phenotypes in this disease.

Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview.

INTRODUCTION: Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable, providing additional incentive for understanding of their contribution to cancer and other types of neoplasia. Areas covered: The Jumonji-domain histone demethylase (JHDM) family exemplifies many of the above traits. This review summarizes the current state of knowledge of the functions and pharmacologic targeting of JHDMs in cancer and other neoplastic processes, with an emphasis on diseases affecting the pediatric population. Expert opinion: To date, the JHDM family has largely been studied in the context of normal development and adult cancers. In contrast, comparatively few studies have addressed JHDM biology in cancer and other neoplastic diseases of childhood, especially solid (non-hematopoietic) neoplasms. Encouragingly, the few available examples support important roles for JHDMs in pediatric neoplasia, as well as potential roles for JHDM pharmacologic inhibition in disease management. Further investigations of JHDMs in cancer and other types of neoplasia of childhood can be expected to both enlighten disease biology and inform new approaches to improve disease outcomes.

Bone Graft Substitutes in Single- or Double-Level Anterior Cervical Discectomy and Fusion: A Systematic Review.

STUDY DESIGN: Systematic review OBJECTIVE.: To undertake a systematic review of published literature to evaluate efficacy of bone graft substitutes on radiographic and clinical outcomes in single- or double-level anterior cervical discectomy and fusion (ACDF) for degenerative disease. SUMMARY OF BACKGROUND DATA: ACDF is one of the most common spinal surgeries completed in the United States. Today bone graft substitutes including ceramic-based synthetic bone grafts, allografts, bone morphogenetic proteins (BMPs), mesenchymal stem cells, and bone marrow aspirate are widely used to enhance fusions; even though the efficacy of these substitutes is poorly defined. Critical evaluation of these products is necessary to optimize radiographic and clinical outcomes for ACDF in degenerative disease. METHODS: A systematic literature review of 22 published articles was conducted. All articles reported results on patients who underwent a single- or double-level ACDF performed using a bone graft substitute and reported results on radiographic fusion rates at least 6 months after surgery. RESULTS: All studies using BMP showed 100% fusion rate despite length of the study or whether additional bone graft substitutes were used. Use of only ceramic-based synthetics had the lowest fusion rate, 80.5%. Use of only mesenchymal stem cells resulted in an average fusion rate of 87.7%. When used alone, allograft resulted in an average fusion rate of 87.3%. This was significantly influenced by one outlier, Kim et al, which when removed, increased the fusion rate to 93.5%. Clinical outcomes were improved postoperatively irrespective of the graft used, although dysphagia was significantly greater in studies using BMP (P < 0.001). CONCLUSION: Allograft alone has the lowest cost with similar fusion rates and clinical outcomes compared to other bone graft substitutes. Physicians should consider this when choosing to use bone graft substitutes for routine ACDFs. LEVEL OF EVIDENCE: 4.

Accuracy of intraoperative computed tomography image-guided surgery in placing pedicle and pelvic screws for primary versus revision spine surgery.

OBJECT: Revision spine surgery, which is challenging due to disrupted anatomy, poor fluoroscopic imaging, and altered tactile feedback, may benefit from CT image-guided surgery (CT-IGS). This study evaluates accuracy of CT-IGS-navigated screws in primary versus revision spine surgery. METHODS: Pedicle and pelvic screws placed with the O-arm in 28 primary (313 screws) and 33 revision (429 screws) cases in which institutional postoperative CT scans were available were retrospectively reviewed for placement accuracy. Screw accuracy was categorized as 1) good (< 1-mm pedicle breach in any direction or "in-out-in" thoracic screws through the lateral thoracic pedicle wall and in the costovertebral joint); 2) fair (1- to 3-mm breach); or 3) poor (> 3-mm breach). RESULTS: Use of CT-IGS resulted in high rates of good or fair screws for both primary (98.7%) and revision (98.6%) cases. Rates of good or fair screws were comparable for the following regions: C7-T3 at 100% (good or fair) in primary versus 100% (good or fair) in revision; T4-9 at 96.8% versus 100%; T10-L2 at 98.2% versus 99.3%; L3-5 at 100% versus 99.2%; and pelvis at 98.7% versus 98.6%, respectively. On the other hand, revision sacral screws had statistically significantly lower rates of good placement compared with primary (100% primary vs 80.6% revision, p = 0.027). Of these revision sacral screws, 11.1% had poor placement, with bicortical screws extending > 3 mm beyond the anterior cortex. Revision pelvic screws demonstrated the highest rate of fair placement (28%), with the mode of medial breach in all cases directed into the sacral-iliac joint. CONCLUSIONS: In the cervical, thoracic, and lumbar spine, CT-IGS demonstrated comparable accuracy rates for both primary and revision spine surgery. Use of 3D imaging of the bony pedicle anatomy appears to be sufficient for the spine surgeon to overcome the difficulties associated with instrumentation in revision cases. Although the bony structures of sacral pedicles and pelvis are relatively larger, the complexity of local anatomy was not overcome with CT-IGS, and an increased trend toward inaccurate screw placement was demonstrated.

Instrumenting the small thoracic pedicle: the role of intraoperative computed tomography image-guided surgery.

OBJECT: Traditionally, instrumentation of thoracic pedicles has been more difficult because of their relatively smaller size. Thoracic pedicles are at risk for violation during surgical instrumentation, as is commonly seen in patients with scoliosis and in women. The laterally based "in-out-in" approach, which technically results in a lateral breach, is sometimes used in small pedicles to decrease the comparative risk of a medial breach with neurological involvement. In this study the authors evaluated the role of CT image-guided surgery in navigating screws in small thoracic pedicles. METHODS: Thoracic (T1-12) pedicle screw placements using the O-arm imaging system (Medtronic Inc.) were evaluated for accuracy with preoperative and postoperative CT. "Small" pedicles were defined as those ≤ 3 mm in the narrowest diameter orthogonal to the long axis of the pedicle on a trajectory entering the vertebral body on preinstrumentation CT. A subset of "very small" pedicles (≤ 2 mm in the narrowest diameter, 13 pedicles) was also analyzed. Screw accuracy was categorized as good (< 1 mm of pedicle breach in any direction or in-out-in screws), fair (1-3 mm of breach), or poor (> 3 mm of breach). RESULTS: Twenty-one consecutive patients (age range 32-71 years) had large (45 screws) and small (52 screws) thoracic pedicles. The median pedicle diameter was 2.5 mm (range 0.9-3 mm) for small and 3.9 mm (3.1-6.7 mm) for large pedicles. Computed tomography-guided surgical navigation led to accurate screw placement in both small (good 100%, fair 0%, poor 0%) and large (good 96.6%, fair 0%, poor 3.4%) pedicles. Good screw placement in very small or small pedicles occurred with an in-out-in trajectory more often than in large pedicles (large 6.8% vs small 36.5%, p < 0.0005; vs very small 69.2%, p < 0.0001). There were no medial breaches even though 75 of the 97 screws were placed in postmenopausal women, traditionally at higher risk for osteoporosis. CONCLUSIONS: Computed tomography-guided surgical navigation allows for safe, effective, and accurate instrumentation of small (≤ 3 mm) to very small (≤ 2 mm) thoracic pedicles.

Long-term results of anterior versus posterior operations for herniated cervical discs: analysis of 6,000 patients.

OBJECTIVE: To analyze the long-term outcomes of anterior versus posterior approaches for cervical disc herniation. METHODS: The records of 6,000 patients who had operations for cervical disc herniation (radiating arm pain and/or motor symptoms involving the upper extremity) and who had been followed for at least 2 years (mean: 7.1 years) were culled from the world literature and included in this analysis. The outcome (good/excellent, according to the patient) of anterior versus posterior surgery was compared. RESULTS: Of the 6,000 patients, 2,888 (48.1%) had anterior operations (anterior cervical discectomies, with or without fusion) and 3,112 (51.9%) patients were operated on posteriorly (laminoforaminotomies/'keyhole' facetectomies). Although initially equal, in long-term follow-up, patients who had anterior operations had 80% good/excellent results, whereas patients with the posterior approach had 94% good/excellent results. The difference was significant (p < 0.05). CONCLUSION: The better long-term results with the posterior operation might be due to the more complete opening of the foramen for neural decompression at the time of the operation and thereafter.

Intrathecal baclofen in the treatment of adult spasticity.

Medical management of adult spasticity, a condition of increased muscle tone and deep tendon reflexes, is often challenging and complex. Oral medications such as baclofen often have unacceptable supraspinal side effects at effective doses. Intrathecal baclofen delivered by an implanted catheter and pump system provides good relief of spasticity while overcoming these limitations. In this paper the authors survey the use of oral and intrathecal baclofen therapy, detail the surgical process, and explain the risks and benefits of the procedure.

Surgical management of high-grade gliomas.

High-grade gliomas, in particular anaplastic astrocytoma and glioblastoma multiforme, represent two of the most devastating forms of brain cancer. In spite of the poor prognosis, new treatments and emerging therapies are making an impact on this disease. This review discusses the role of the surgical management of high-grade gliomas and provides an overview of the currently available therapies which depend on surgical intervention. At the same time, cutting-edge clinical trials for patients with malignant brain tumors are reviewed to provide further insights into potential future therapies.