Coccidioidomycosis seasonality in California: a longitudinal surveillance study of the climate determinants and spatiotemporal variability of seasonal dynamics, 2000-2021.

Background: Coccidioidomycosis, an emerging fungal disease in the western USA, exhibits seasonal patterns that are poorly understood, including periods of strong cyclicity, aseasonal intervals, and variation in seasonal timing that have been minimally characterized, and unexplained as to their causal factors. Coccidioidomycosis incidence has increased markedly in recent years, and our limited understanding of intra- and inter-annual seasonality has hindered the identification of important drivers of disease transmission, including climate conditions. In this study, we aim to characterize coccidioidomycosis seasonality in endemic regions of California and to estimate the relationship between drought conditions and coccidioidomycosis seasonal periodicity and timing. Methods: We analysed data on all reported incident cases of coccidioidomycosis in California from 2000 to 2021 to characterize seasonal patterns in incidence, and conducted wavelet analyses to assess the dominant periodicity, power, and timing of incidence for 17 counties with consistently high incidence rates. We assessed associations between seasonality parameters and measures of drought in California using a distributed lag nonlinear modelling framework. Findings: All counties exhibited annual cyclicity in incidence (i.e., a dominant wavelet periodicity of 12 months), but there was considerable heterogeneity in seasonal strength and timing across regions and years. On average, 12-month periodicity was most pronounced in the Southern San Joaquin Valley and Central Coast. Further, the annual seasonal cycles in the Southern San Joaquin Valley and the Southern Inland regions occurred earlier than those in coastal and northern counties, yet the timing of annual cycles became more aligned among counties by the end of the study period. Drought conditions were associated with a strong attenuation of the annual seasonal cycle, and seasonal peaks became more pronounced in the 1-2 years after a drought ended. Interpretation: We conclude that drought conditions do not increase the risk of coccidioidomycosis onset uniformly across the year, but instead promote increased risk concentrated within a specific calendar period (September to December). The findings have important implications for public health preparedness, and for how future shifts in seasonal climate patterns and extreme events may impact spatial and temporal coccidioidomycosis risk. Funding: National Institutes of Health.

Scientists' call to action: Microbes, planetary health, and the Sustainable Development Goals.

Microorganisms, including bacteria, archaea, viruses, fungi, and protists, are essential to life on Earth and the functioning of the biosphere. Here, we discuss the key roles of microorganisms in achieving the United Nations Sustainable Development Goals (SDGs), highlighting recent and emerging advances in microbial research and technology that can facilitate our transition toward a sustainable future. Given the central role of microorganisms in the biochemical processing of elements, synthesizing new materials, supporting human health, and facilitating life in managed and natural landscapes, microbial research and technologies are directly or indirectly relevant for achieving each of the SDGs. More importantly, the ubiquitous and global role of microbes means that they present new opportunities for synergistically accelerating progress toward multiple sustainability goals. By effectively managing microbial health, we can achieve solutions that address multiple sustainability targets ranging from climate and human health to food and energy production. Emerging international policy frameworks should reflect the vital importance of microorganisms in achieving a sustainable future.

Recent and forecasted increases in coccidioidomycosis incidence in California linked to hydroclimatic swings.

Coccidioidomycosis, or Valley fever, is an infectious disease caused by inhalation of Coccidioides spp., fungi found primarily in soils of the southwestern United States. Prior work showed that coccidioidomycosis cases in California sharply increase by nearly 2-fold following wet winters that occur one- and two-years following drought. Statewide drought between 2020-2022 followed by heavy precipitation during the 2022-2023 winter raised concerns over potential increases in coccidioidomycosis cases in the fall of 2023, prompting California Department of Public Health (CDPH) to issue public health alerts. As anticipated, California saw a near record number of cases in 2023, with 9,054 provisional cases reported. During the 2023-2024 California wet season, precipitation was 115% the long-term average, furthering concerns about continued high coccidioidomycosis risk. We developed an ensemble model to forecast coccidioidomycosis cases in California in 2024-2025. Using this model, we predicted a total of 11,846 cases (90% PI: 10,056-14,094) in California between April 1, 2023, and March 31, 2024, encompassing the preliminary state report of 10,593. Our model forecasted 12,244 cases statewide between April 1, 2024, and March 31, 2025 - a 62% increase over the cases reported during the same period two years prior, and on par with the high incidence seen in 2023. The Southern San Joaquin Valley (5,398 cases, 90% PI: 4,556-6,442), Southern Coast (3,322, 90% PI: 2,694-3,961), and Central Coast (1,207 cases, 90% PI: 867-1,585) regions are expected to see the largest number of infections. Our model forecasts that disease incidence will exhibit pronounced seasonality, particularly in endemic regions, with cases rising in June and peaking in November at 1,411 (90% PI: 815-2,172) cases statewide - 98% higher than the peak two years prior (714) and nearly as high as the peak in 2023 (1,462). Near-term forecasts have the potential to inform public health messaging to enhance provider and patient awareness, encourage risk reduction practices, and improve recognition and management of coccidioidomycosis.

Design of parallel 𝛽-sheet nanofibrils using Monte Carlo search, coarse-grained simulations, and experimental testing.

Peptide self-assembly into amyloid fibrils provides numerous applications in drug delivery and biomedical engineering applications. We augment our previously-established computational screening technique along with experimental biophysical characterization to discover 7-mer peptides that self-assemble into "parallel ß-sheets", that is, ß-sheets with N-terminus-to-C-terminus 𝛽-strand vectors oriented in parallel. To accomplish the desired ß-strand organization, we applied the PepAD amino acid sequence design software to the Class-1 cross-ß spine defined by Sawaya et al. This molecular configuration includes two layers of parallel ß-sheets stacked such that N-terminus-to-C-terminus vectors are oriented antiparallel for molecules on adjacent ß-sheets. The first cohort of PepAD identified peptides were examined for their fibrillation behavior in DMD/PRIME20 simulations, and the top performing sequence was selected as a prototype for a subsequent round of sequence refinement. The two rounds of design resulted in a library of eight 7-mer peptides. In DMD/PRIME20 simulations, five of these peptides spontaneously formed fibril-like structures with a predominantly parallel 𝛽-sheet arrangement, two formed fibril-like structure with <50% in parallel 𝛽-sheet arrangement and one remained a random coil. Among the eight candidate peptides produced by PepAD and DMD/PRIME20, five were synthesized and purified. All five assembled into amyloid fibrils composed of parallel ß-sheets based on Fourier transform infrared spectroscopy, circular dichroism, electron microscopy, and thioflavin-T fluorescence spectroscopy measurements.

Deep-water first occurrences of Ediacara biota prior to the Shuram carbon isotope excursion in the Wernecke Mountains, Yukon, Canada.

Ediacara-type macrofossils appear as early as ~575 Ma in deep-water facies of the Drook Formation of the Avalon Peninsula, Newfoundland, and the Nadaleen Formation of Yukon and Northwest Territories, Canada. Our ability to assess whether a deep-water origination of the Ediacara biota is a genuine reflection of evolutionary succession, an artifact of an incomplete stratigraphic record, or a bathymetrically controlled biotope is limited by a lack of geochronological constraints and detailed shelf-to-slope transects of Ediacaran continental margins. The Ediacaran Rackla Group of the Wernecke Mountains, NW Canada, represents an ideal shelf-to-slope depositional system to understand the spatiotemporal and environmental context of Ediacara-type organisms' stratigraphic occurrence. New sedimentological and paleontological data presented herein from the Wernecke Mountains establish a stratigraphic framework relating shelfal strata in the Goz/Corn Creek area to lower slope deposits in the Nadaleen River area. We report new discoveries of numerous Aspidella hold-fast discs, indicative of frondose Ediacara organisms, from deep-water slope deposits of the Nadaleen Formation stratigraphically below the Shuram carbon isotope excursion (CIE) in the Nadaleen River area. Such fossils are notably absent in coeval shallow-water strata in the Goz/Corn Creek region despite appropriate facies for potential preservation. The presence of pre-Shuram CIE Ediacara-type fossils occurring only in deep-water facies within a basin that has equivalent well-preserved shallow-water facies provides the first stratigraphic paleobiological support for a deep-water origination of the Ediacara biota. In contrast, new occurrences of Ediacara-type fossils (including juvenile fronds, Beltanelliformis, Aspidella, annulated tubes, and multiple ichnotaxa) are found above the Shuram CIE in both deep- and shallow-water deposits of the Blueflower Formation. Given existing age constraints on the Shuram CIE, it appears that Ediacaran organisms may have originated in the deeper ocean and lived there for up to ~15 million years before migrating into shelfal environments in the terminal Ediacaran. This indicates unique ecophysiological constraints likely shaped the initial habitat preference and later environmental expansion of the Ediacara biota.

Comment on Grabala et al. Radiological Outcomes of Magnetically Controlled Growing Rods for the Treatment of Children with Various Etiologies of Early-Onset Scoliosis-A Multicenter Study. J. Clin. Med. 2024, 13, 1529.

We read with great interest the study titled "Radiological Outcomes of Magnetically Controlled Growing Rods for the Treatment of Children with Various Etiologies of Early-Onset Scoliosis-A Multicenter Study" by Grabala and colleagues [...].

COVID-19 Vaccination and Incidence of Pediatric SARS-CoV-2 Infection and Hospitalization.

Importance: A SARS-CoV-2 vaccine was approved for adolescents aged 12 to 15 years on May 10, 2021, with approval for younger age groups following thereafter. The population level impact of the pediatric COVID-19 vaccination program has not yet been established. Objective: To identify whether California's pediatric COVID-19 immunization program was associated with changes in pediatric COVID-19 incidence and hospitalizations. Design, Setting, and Participants: A case series on COVID-19 vaccination including children aged 6 months to 15 years was conducted in California. Data were obtained on COVID-19 cases in California between April 1, 2020, and February 27, 2023. Exposure: Postvaccination evaluation periods spanned 141 days (June 10 to October 29, 2021) for adolescents aged 12 to 15 years, 199 days (November 29, 2021, to June 17, 2022) for children aged 5 to 11 years, and 225 days (July 17, 2022, to February 27, 2023) for those aged 6 to 59 months. During these periods, statewide vaccine coverage reached 53.5% among adolescents aged 12 to 15 years, 34.8% among children aged 5 to 11 years, and 7.9% among those aged 6 to 59 months. Main Outcomes and Measures: Age-stepped implementation of COVID-19 vaccination was used to compare observed county-level incidence and hospitalization rates during periods when each age group became vaccine eligible to counterfactual rates predicted from observations among other age groups. COVID-19 case and hospitalization data were obtained from the California reportable disease surveillance system. Results: Between April 1, 2020, and February 27, 2023, a total of 3 913 063 pediatric COVID-19 cases and 12 740 hospitalizations were reported in California. Reductions of 146 210 cases (95% prediction interval [PI], 136 056-158 948) were estimated among adolescents aged 12 to 15 years, corresponding to a 37.1% (35.5%-39.1%) reduction from counterfactual predictions. Reductions of 230 134 (200 170-265 149) cases were estimated among children aged 5 to 11 years, corresponding to a 23.7% (20.6%-27.3%) reduction from counterfactual predictions. No evidence of reductions in COVID-19 cases statewide were found among children aged 6 to 59 months (estimated averted cases, -259; 95% PI, -1938 to 1019), although low transmission during the evaluation period may have limited the ability to do so. An estimated 168 hospitalizations (95% PI, 42-324) were averted among children aged 6 to 59 months, corresponding to a 24.4% (95% PI, 6.1%-47.1%) reduction. In meta-analyses, county-level vaccination coverage was associated with averted cases for all age groups. Despite low vaccination coverage, pediatric COVID-19 immunization in California averted 376 085 (95% PI, 348 355-417 328) reported cases and 273 (95% PI, 77-605) hospitalizations among children aged 6 months to 15 years over approximately 4 to 7 months following vaccination availability. Conclusions and Relevance: The findings of this case series analysis of 3 913 063 cases suggest reduced pediatric SARS-CoV-2 transmission following immunization. These results support the use of COVID-19 vaccines to reduce COVID-19 incidence and hospitalization in pediatric populations.

CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression.

Metastatic prostate cancer (PCa) poses a significant therapeutic challenge with high mortality rates. Utilizing CRISPR-Cas9 in vivo, we target five potential tumor suppressor genes (Pten, Trp53, Rb1, Stk11, and RnaseL) in the mouse prostate, reaching humane endpoint after eight weeks without metastasis. By further depleting three epigenetic factors (Kmt2c, Kmt2d, and Zbtb16), lung metastases are present in all mice. While whole genome sequencing reveals few mutations in coding sequence, RNA sequencing shows significant dysregulation, especially in a conserved genomic region at chr5qE1 regulated by KMT2C. Depleting Odam and Cabs1 in this region prevents metastasis. Notably, the gene expression signatures, resulting from our study, predict progression-free and overall survival and distinguish primary and metastatic human prostate cancer. This study emphasizes positive genetic interactions between classical tumor suppressor genes and epigenetic modulators in metastatic PCa progression, offering insights into potential treatments.

Structural Consequences of Introducing Bioactive Domains to Designer ß-Sheet Peptide Self-Assemblies.

We applied solid- and solution-state nuclear magnetic resonance spectroscopy to examine the structure of multidomain peptides composed of self-assembling ß-sheet domains linked to bioactive domains. Bioactive domains can be selected to stimulate specific biological responses (e.g., via receptor binding), while the ß-sheets provide the desirable nanoscale properties. Although previous work has established the efficacy of multidomain peptides, molecular-level characterization is lacking. The bioactive domains are intended to remain solvent-accessible without being incorporated into the ß-sheet structure. We tested for three possible anticipated molecular-level consequences of introducing bioactive domains to ß-sheet-forming peptides: (1) the bioactive domain has no effect on the self-assembling peptide structure; (2) the bioactive domain is incorporated into the ß-sheet nanofiber; and (3) the bioactive domain interferes with self-assembly such that nanofibers are not formed. The peptides involved in this study incorporated self-assembling domains based on the (SL)6 motif and bioactive domains including a VEGF-A mimic (QK), an IGF-mimic (IGF-1c), and a de novo SARS-CoV-2 binding peptide (SBP3). We observed all three of the anticipated outcomes from our examination of peptides, illustrating the unintended structural effects that could adversely affect the desired biofunctionality and biomaterial properties of the resulting peptide hydrogel. This work is the first attempt to evaluate the structural effects of incorporating bioactive domains into a set of peptides unified by a similar self-assembling peptide domain. These structural insights reveal unmet challenges in the design of highly tunable bioactive self-assembling peptide hydrogels.

Implementation of a health system intervention to reduce time from presentation to surgical intervention for pediatric testicular torsion.

PURPOSE: Testicular salvage rates for torsion are time-dependent1. Door to detorsion time has been identified as an independent testicular survival factor2. We describe an initiative to reduce door to incision (DTI) time for pediatric testicular torsion. MATERIALS AND METHODS: An institutional multidisciplinary quality improvement initiative with a primary outcome of reducing DTI time for pediatric testicular torsion was developed with multidisciplinary stakeholders. Several process and balancing measures were used as secondary outcomes to help interpret and verify the observed change in DTI time. Interventions were implemented in cycles. Initial interventions standardized assessment of suspected torsion by Emergency Medicine utilizing a validated scoring system. A threshold Testicular Workup for Ischemia and Suspected Torsion (TWIST) score led to parallel notification of essential services for rapid assessment and case prioritization3. Subsequently, bedside ultrasound in the Emergency Department was implemented. Progress was tracked in a live dashboard and analyzed with X-mR process control charts and Nelson rules. These tools are used in quality improvement and process control to demonstrate the significance of changes as they are being implemented, prior to when traditional hypothesis testing would be able to do so. We aimed to increase the proportion of cases with DTI times under 4 h from 64% to >90% within one year. RESULTS: We observed 22 torsion cases prior to and 62 following initial implementation. The percentage of cases with DTI times under 4 h improved from 64% to 95%. At week 29, a shift identified a significant change on the X chart, with reduction in mean DTI time from 221 to 147 min. At the same time, a shift on the mR chart identified reduction in patient-to-patient variation. Mean time from arrival to Urology evaluation decreased from 140 to 56 min, mean time from arrival to scrotal ultrasound decreased from 70 to 36 min, and mean time from scrotal ultrasound to surgical incision decreased from 128 to 80 min. These improvements highlight the two key successes of our project: application of the TWIST score and bedside ultrasound for rapid assessment of suspected testicular torsions, and parallel processing of the evaluation and management. CONCLUSIONS: Implementation of a protocol for pediatric testicular torsion increased the proportion of cases with DTI time <4 h to 95%, decreased mean DTI time, and decreased variation. Our protocol provides a model to improve timeliness of care in treating pediatric testicular torsion.

Health-related quality of life in early onset scoliosis patients treated with the spring distraction system: what to expect in the first 2 years after surgery.

PURPOSE: The Spring Distraction System (SDS) is a novel "growth-friendly" implant for the treatment of Early-Onset Scoliosis (EOS). This prospective study aims to determine the evolution of the "24-Item Early-Onset Scoliosis Questionnaire" (EOSQ-24) scores during 2-year follow-up after SDS surgery. Secondary aims include investigating the relation between EOSQ-24 scores and EOS etiology, and evaluating the impact of an unplanned return to the operating room (UPROR) on HRQoL. METHODS: All SDS patients with at least 2-year follow-up were included. Caregivers completed the EOSQ-24 pre-operatively, post-operatively, and at 6, 12, and 24 month follow-up. Mean total and -domain scores were graphed over time. Repeated-measures ANOVA analyzed the influence of etiology on EOSQ-24 scores. Multiple regression analyzed associations between UPRORs and EOSQ-24 scores. RESULTS: Forty-nine patients were included. Mean total EOSQ-24 scores decreased from 70 pre-operatively to 66 post-operatively, then gradually increased to 75 (24 months). Most domains exhibited changes over time, with initial declines, but eventually surpassing pre-operative levels after 2-year follow-up. Neuromuscular/Syndromic patients had lower scores, but showed similar improvements over time compared with other etiologies. Multiple regression showed lower Parental Burden domain score (- 14 points) in patients with UPRORs, although no significant reductions were found in total score, or in other domains. CONCLUSION: HRQoL decreases immediately following SDS surgery but quickly recovers and exceeds pre-operative levels at 2-year follow-up in all domains. Neuromuscular/Syndromic patients have lower initial scores, but progress similarly over time. UPRORs do not influence EOSQ-24 scores, except for a negative impact on the Parental Burden domain in the short term. LEVEL OF EVIDENCE: III.

STING activation counters glioblastoma by vascular alteration and immune surveillance.

Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New immunotherapy approaches and a deeper understanding of immune surveillance of GBM are needed to advance treatment options for this devastating disease. In this study, we used two preclinical models of GBM: orthotopically delivering either GBM stem cells or employing CRISPR-mediated tumorigenesis by adeno-associated virus, to establish immunologically proficient and non-inflamed tumors, respectively. After tumor development, the innate immune system was activated through long-term STING activation by a pharmacological agonist, which reduced tumor progression and prolonged survival. Recruitment and activation of cytotoxic T-cells were detected in the tumors, and T-cell specificity towards the cancer cells was observed. Interestingly, prolonged STING activation altered the tumor vasculature, inducing hypoxia and activation of VEGFR, as measured by a kinome array and VEGF expression. Combination treatment with anti-PD1 did not provide a synergistic effect, indicating that STING activation alone is sufficient to activate immune surveillance and hinder tumor development through vascular disruption. These results guide future studies to refine innate immune activation as a treatment approach for GBM, in combination with anti-VEGF to impede tumor progression and induce an immunological response against the tumor.

Association between wildfires and coccidioidomycosis incidence in California, 2000-2018: a synthetic control analysis.

The frequency and severity of wildfires in the Western United States have increased over recent decades, motivating hypotheses that wildfires contribute to the incidence of coccidioidomycosis, an emerging fungal disease in the Western United States with sharp increases in incidence observed since 2000. While coccidioidomycosis outbreaks have occurred among wildland firefighters clearing brush, it remains unknown whether fires are associated with an increased incidence among the general population. Methods: We identified 19 wildfires occurring within California's highly endemic San Joaquin Valley between 2003 and 2015. Using geolocated surveillance records, we applied a synthetic control approach to estimate the effect of each wildfire on the incidence of coccidioidomycosis among residents that lived within a hexagonal buffer of 20 km radii surrounding the fire. Results: We did not detect excess cases due to wildfires in the 12 months (pooled estimated percent change in cases: 2.8%; 95% confidence interval [CI] = -29.0, 85.2), 13-24 months (7.9%; 95% CI = -27.3, 113.9), or 25-36 months (17.4%; 95% CI = -25.1, 157.1) following a wildfire. When examined individually, we detected significant increases in incidence following three of the 19 wildfires, all of which had relatively large adjacent populations, high transmission before the fire, and a burn area exceeding 5,000 acres. Discussion: We find limited evidence that wildfires drive increases in coccidioidomycosis incidence among the general population. Nevertheless, our results raise concerns that large fires in regions with ongoing local transmission of Coccidioides may be associated with increases in incidence, underscoring the need for field studies examining Coccidioides spp. in soils and air pre- and post-wildfires.

A planetary health innovation for disease, food and water challenges in Africa.

Many communities in low- and middle-income countries globally lack sustainable, cost-effective and mutually beneficial solutions for infectious disease, food, water and poverty challenges, despite their inherent interdependence1-7. Here we provide support for the hypothesis that agricultural development and fertilizer use in West Africa increase the burden of the parasitic disease schistosomiasis by fuelling the growth of submerged aquatic vegetation that chokes out water access points and serves as habitat for freshwater snails that transmit Schistosoma parasites to more than 200 million people globally8-10. In a cluster randomized controlled trial (ClinicalTrials.gov: NCT03187366) in which we removed invasive submerged vegetation from water points at 8 of 16 villages (that is, clusters), control sites had 1.46 times higher intestinal Schistosoma infection rates in schoolchildren and lower open water access than removal sites. Vegetation removal did not have any detectable long-term adverse effects on local water quality or freshwater biodiversity. In feeding trials, the removed vegetation was as effective as traditional livestock feed but 41 to 179 times cheaper and converting the vegetation to compost provided private crop production and total (public health plus crop production benefits) benefit-to-cost ratios as high as 4.0 and 8.8, respectively. Thus, the approach yielded an economic incentive-with important public health co-benefits-to maintain cleared waterways and return nutrients captured in aquatic plants back to agriculture with promise of breaking poverty-disease traps. To facilitate targeting and scaling of the intervention, we lay the foundation for using remote sensing technology to detect snail habitats. By offering a rare, profitable, win-win approach to addressing food and water access, poverty alleviation, infectious disease control and environmental sustainability, we hope to inspire the interdisciplinary search for planetary health solutions11 to the many and formidable, co-dependent global grand challenges of the twenty-first century.

Comment on Burgos et al. Fusionless All-Pedicle Screws for Posterior Deformity Correction in AIS Immature Patients Permit the Restoration of Normal Vertebral Morphology and Removal of the Instrumentation Once Bone Maturity Is Reached. J. Clin. Med. 2023, 12, 2408.

With great interest, we read the recently published paper "Fusionless All-Pedicle Screws for Posterior Deformity Correction in AIS Immature Patients Permit the Restoration of Normal Vertebral Morphology and Removal of the Instrumentation Once Bone Maturity is Reached" by Burgos et al. [...].

Reframing Optimal Control Problems for Infectious Disease Management in Low-Income Countries.

Optimal control theory can be a useful tool to identify the best strategies for the management of infectious diseases. In most of the applications to disease control with ordinary differential equations, the objective functional to be optimized is formulated in monetary terms as the sum of intervention costs and the cost associated with the burden of disease. We present alternate formulations that express epidemiological outcomes via health metrics and reframe the problem to include features such as budget constraints and epidemiological targets. These alternate formulations are illustrated with a compartmental cholera model. The alternate formulations permit us to better explore the sensitivity of the optimal control solutions to changes in available budget or the desired epidemiological target. We also discuss some limitations of comprehensive cost assessment in epidemiology.

Surgical treatment of neuromuscular Early Onset Scoliosis with a bilateral posterior one-way rod compared to the Spring Distraction System: study protocol for a limited-efficacy Randomized Controlled Trial (BiPOWR).

BACKGROUND: Early Onset Scoliosis (EOS) is a progressive spinal deformity in children, and a potentially life-threatening disease. "Growth-friendly" surgical techniques aim to control the deformity, while allowing the spine and trunk to maintain growth. Current "growth-friendly" systems such as the traditional growing rod (TGR) and magnetically controlled growing rod (MCGR) have limitations that reduce their efficacy and cost-effectiveness. Recently, two "growth-friendly" systems have been developed that mitigate many of these limitations, the Spring Distraction System (SDS) and the One Way Self-Expanding Rod (OWSER). The purpose of the multicenter BiPOWR trial is to investigate, describe and compare the 1-year limited-efficacy and -safety of both strategies in the treatment of neuromuscular EOS. METHODS: After informed consent, 28 neuromuscular EOS patients will be randomized to receive either the SDS or the OWSER. Patients and caregivers will be blinded to allocation until after surgery. Primary outcomes will be maintenance of coronal curve correction and the occurrence of serious adverse events. In addition, spinal growth, implant lengthening, and perioperative findings are recorded systematically. At each follow-up moment, the Early Onset Scoliosis Questionnaire (EOSQ-24) will be used to assess health-related quality of life. All outcomes will be compared between groups. DISCUSSION: The BiPOWR trial is the first randomized controlled trial that compares two specific "growth-friendly" implants in a specified EOS population. It will determine the 1-year limited-efficacy and safety of the SDS and OWSER implants. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04021784 (13-06-2019). CCMO registry: NL64018.041.17 (06-05-2019).

Three-dimensional correction of scoliosis by a double spring reduction system as a dynamic internal brace: a pre-clinical study in Göttingen minipigs.

BACKGROUND CONTEXT: Adolescent idiopathic scoliosis (AIS) is a major skeletal deformity that is characterized by a combination of apical rotation, lateral bending and apical lordosis. To provide full 3D correction, all these deformations should be addressed. We developed the Double Spring Reduction (DSR) system, a (growth-friendly) concept that continuously corrects the deformity through two different elements: A posterior convex Torsional Spring Implant (TSI) that provides a derotational torque at the apex, and a concave Spring Distraction System (SDS), which provides posterior, concave distraction to restore thoracic kyphosis. PURPOSE: To determine whether the DSR components are able to correct an induced idiopathic-like scoliosis and to compare correction realized by the TSI alone to correction enforced by the complete DSR implant. STUDY DESIGN/SETTING: Preclinical randomized animal cohort study. PATIENT SAMPLE: Twelve growing Göttingen minipigs. OUTCOME MEASURES: Coronal Cobb angle, T10-L3 lordosis/kyphosis, apical axial rotation, relative anterior lengthening. METHODS: All mini-pigs received the TSI with a contralateral tether to induce an idiopathic-like scoliosis with apical rotation (mean Cobb: 20.4°; mean axial apical rotation: 13.1°, mean lordosis: 4.9°). After induction, the animals were divided into two groups: One group (N=6) was corrected by TSI only (TSI only-group), another group (N=6) was corrected by a combination of TSI and SDS (DSR-group). 3D spinal morphology on CT was compared between groups over time. After 2 months of correction, animals were euthanized. RESULTS: Both intervention groups showed excellent apical derotation (TSI only-group: 15.0° to 5.4°; DSR-group: 11.2° to 3.5°). The TSI only-group showed coronal Cobb improvement from 22.5° to 6.0°, while the DSR-group overcorrected the 18.3° Cobb to -9.2°. Lordosis was converted to kyphosis in both groups (TSI only-group: -4.6° to 4.3°; DSR-group: -5.2° to 25.0°) which was significantly larger in the DSR-group (p<.001). CONCLUSIONS: The TSI alone realized strong apical derotation and moderate correction in the coronal and sagittal plane. The addition of distraction on the posterior concavity resulted in more coronal correction and reversal of induced lordosis into physiological kyphosis. CLINICAL SIGNIFICANCE: This study shows that dynamic spring forces could be a viable method to guide the spine towards healthy alignment, without fusing it or inhibiting its growth.

Cognition and Diabetes: Examining Sex Differences Using a Longitudinal Sample of Older Adults.

Objectives: This study aims to investigate sex-based differences in the diabetes status and cognition relationship using a representative sample of older Americans. Methods: Using a sample of 19,190 females and 15,580 males from the Health and Retirement Study, we conduct mixed-effects linear regression analyses to examine sex differences in the association between diabetes and cognition over a 20-year follow-up period among older adults in the United States. Main Findings: Females experience slightly steeper declines in cognition that are further exacerbated by diabetes. At age 65, females without diabetes have significantly higher cognition than males; this gap is eliminated by age 85. Among diabetics, there is no initial sex disparity, but females' cognition becomes significantly lower than males' over the following 20 years. Principal Conclusions: Relative to males, females are particularly susceptible to diabetes-related declines in cognition with increasing age.

A hierarchical model for analyzing multisite individual-level disease surveillance data from multiple systems.

Passive surveillance systems are widely used to monitor diseases occurrence over wide spatial areas due to their cost-effectiveness and integration into broadly distributed healthcare systems. However, such systems are generally associated with imperfect ascertainment of disease cases and with heterogeneous capture probabilities arising from factors such as differential access to care. Augmenting passive surveillance systems with other surveillance efforts provides a way to estimate the true number of incident cases. We develop a hierarchical modeling framework for analyzing data from multiple surveillance systems that allows for individual-level covariate-dependent heterogeneous capture probabilities, and borrows information across surveillance sites to improve estimation of the true number of incident cases. Inference is carried out via a two-stage Bayesian procedure. Simulation studies illustrated superior performance of the proposed approach with respect to bias, root mean square error, and coverage compared to a model that does not borrow information across sites. We applied the proposed model to data from three surveillance systems reporting pulmonary tuberculosis (PTB) cases in a major center of ongoing transmission in China. The analysis yielded bias-corrected estimates of PTB cases from the passive system and led to the identification of risk factors associated with PTB rates, as well as factors influencing the operating characteristics of the implemented surveillance systems.