A data-driven semi-parametric model of SARS-CoV-2 transmission in the United States.

To support decision-making and policy for managing epidemics of emerging pathogens, we present a model for inference and scenario analysis of SARS-CoV-2 transmission in the USA. The stochastic SEIR-type model includes compartments for latent, asymptomatic, detected and undetected symptomatic individuals, and hospitalized cases, and features realistic interval distributions for presymptomatic and symptomatic periods, time varying rates of case detection, diagnosis, and mortality. The model accounts for the effects on transmission of human mobility using anonymized mobility data collected from cellular devices, and of difficult to quantify environmental and behavioral factors using a latent process. The baseline transmission rate is the product of a human mobility metric obtained from data and this fitted latent process. We fit the model to incident case and death reports for each state in the USA and Washington D.C., using likelihood Maximization by Iterated particle Filtering (MIF). Observations (daily case and death reports) are modeled as arising from a negative binomial reporting process. We estimate time-varying transmission rate, parameters of a sigmoidal time-varying fraction of hospitalized cases that result in death, extra-demographic process noise, two dispersion parameters of the observation process, and the initial sizes of the latent, asymptomatic, and symptomatic classes. In a retrospective analysis covering March-December 2020, we show how mobility and transmission strength became decoupled across two distinct phases of the pandemic. The decoupling demonstrates the need for flexible, semi-parametric approaches for modeling infectious disease dynamics in real-time.

Disasters collide at the intersection of extreme weather and infectious diseases.

Natural disasters interact to affect the resilience and prosperity of communities and disproportionately affect low income families and communities of colour. However, due to lack of a common theoretical framework, these are rarely quantified. Observing severe weather events (e.g. hurricanes and tornadoes) and epidemics (e.g. COVID-19) unfolding in southeastern US communities led us to conjecture that interactions among catastrophic disturbances might be much more considerable than previously recognized. For instance, hurricane evacuations increase human aggregation, a factor that affects the transmission of acute infections like SARS-CoV-2. Similarly, weather damage to health infrastructure can reduce a community's ability to provide services to people who are ill. As globalization and human population and movement continue to increase and weather events are becoming more intense, such complex interactions are expected to magnify and significantly impact environmental and human health.

Left Knee Open Rectus Femoris Repair With Achilles Allograft Augmentation: A Case Report.

CASE: We present a case of a 48-year-old man with a subacute tear of his left rectus femoris, repaired using Achilles tendon allograft. After fixation distally to the patella using suture anchors and a Krackow suture technique, the allograft was fixed proximally to the remnant rectus femoris tendon with multiple sutures in a variety of stitch configurations. The patient recovered excellently, regaining near-normal flexion and an intact straight leg raise without an extensor lag. CONCLUSION: The literature regarding repair of subacute and chronic rectus femoris ruptures is limited. We provide an additional option for operative repair of subacute and chronic ruptures using Achilles tendon allograft.

Nervus Intermedius Outcomes After Vestibular Schwannoma Surgery and Radiosurgery: A Single-Institution Experience.

OBJECTIVE: Nervus intermedius (NI) dysfunction after the management of vestibular schwannoma (VS) is underreported and is experienced by patients undergoing stereotactic radiosurgery and surgical resection. The aim of this study was to present NI outcomes in a series of patients who underwent all treatment modalities for VS and to review the existing literature. METHODS: We performed a retrospective review of all patients with VS who were treated at our institution between January 1, 2008, and December 31, 2018. Demographic data, tumor size, Koos grade, treatment modality, extent of resection, postoperative facial nerve function, and hearing function were collected. NI outcomes were determined from phone interview using a previously published functional questionnaire. RESULTS: Of 222 patients who were reviewed, 98 patients responded to the questionnaire. Patients were stratified into 3 groups: group 1, 54 patients who underwent radiation; group 2, 27 patients who underwent surgical treatment; group 3, 17 patients who underwent both radiation and surgery. Of patients, 28% presented with preoperative NI dysfunction, most commonly dry eye followed by taste dysfunction and lacrimation dysfunction. Following treatment, 79% of patients experienced NI dysfunction, most commonly dry eye. Statistical differences in dry eye and taste dysfunction were observed when comparing the treatment groups. CONCLUSIONS: NI dysfunction is common following treatment for VS and should be included in pretreatment counseling of patients, as it may impact treatment choice and quality of life. Additional studies are warranted to fully characterize NI dysfunction after treatment.

Prediction of Long Bone Fractures in Multiple Myeloma Patients in an Advanced Imaging World.

BACKGROUND: Multiple myeloma (MM) affects the long bones in 25% of patients. The advent of positron-emission tomography/computed tomography (PET/CT) scanners offers the possibility of both metabolic and radiographic information and may help determine fracture risk. To the best of our knowledge, no published study correlates these two factors with long bone fractures. OBJECTIVES: To evaluate the impact of PET/CT on fracture risk assessment in multiple myeloma patients. METHODS: We identified all bone marrow biopsy proven multiple myeloma patients from 1 January 2010 to 31 January 2015 at a single institution. We prospectively followed patients with long bone lesions using PET/CT scan images. RESULTS: We identified 119 patients (59 males/60 females) with 256 long bone lesions. Mean age at diagnosis was 58 years. The majority of lesions were in the femur (n=150, 59%) and humerus (n=84, 33%); 13 lesions in 10 patients (8%) required surgery for impending (n=4) or actual fracture (n=9). Higher median SUVmax was measured for those with cortical involvement (8.05, range 0-50.8) vs. no involvement (5.0, range 2.1-18.1). SUVmax was found to be a predictor of cortical involvement (odds ratio = 1.17, P = 0.026). No significant correlation was found between SUVmax and pain or fracture (P = 0.43). CONCLUSIONS: Improved medical treatment resulted improvement in 8% of patients with an actual or impending fracture. The orthopedic surgeons commonly use the Mirels classification for long bone fracture prediction. Adding PET/CT imaging to study in myeloma long bone lesions did not predict fracture risk directly but suggested it indirectly by cortical erosion.

Pain Scores and Activity Tolerance in the Early Postoperative Period After Hip Arthroscopy.

BACKGROUND: Despite the rapid growth in the use of hip arthroscopy, standardized data on postoperative pain scores and activity level are lacking. PURPOSE: To quantify narcotic consumption and use of the stationary bicycle in the early postoperative period after hip arthroscopy. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: In this prospective case series, patients undergoing a primary hip arthroscopy procedure by a single surgeon were asked to fill out a daily survey for 9 days postoperatively. Patients were asked to report their pain level each day on a visual analog scale from 1 to 10, along with the amount of narcotic pain pills they used during those postoperative days (PODs). Narcotic usage was converted to a morphine-equivalent dosage (MED) for each patient. Patients were also instructed to cycle daily starting on the night of surgery for a minimum of 3 minutes twice per day and were asked to rate their pain as a percentage of their preoperative pain level and the number of minutes spent cycling on a stationary bicycle per day. RESULTS: A total of 212 patients were enrolled in this study. Pain levels (POD1, 5.5; POD4, 3.8; POD9, 2.9; P < .0001) and the percentage of preoperative pain (POD1, 51.6%; POD4, 31.8%; POD9, 29.5%; P < .01) significantly decreased over the study period. The amount of narcotics used per day (reported in MED) also significantly decreased (POD1, 27.3; POD4, 22.3; POD9, 8.5; P < .0001). By POD4, 41% of patients had discontinued all narcotics, and by POD9, 65% of patients were completely off narcotic medication. Patients were able to significantly increase the number of minutes spent cycling each day (POD1, 7.6 minutes; POD4, 13.8 minutes; POD9, 19.0 minutes; P < .0001). Patients who received a preoperative narcotic prescription for the affected hip were significantly more likely to require an additional postoperative narcotic prescription (P < .001). CONCLUSION: Patients can expect a rapid decrease in narcotic consumption along with a high degree of activity tolerance in the early postoperative period after hip arthroscopy.

The statistics of epidemic transitions.

Emerging and re-emerging pathogens exhibit very complex dynamics, are hard to model and difficult to predict. Their dynamics might appear intractable. However, new statistical approaches-rooted in dynamical systems and the theory of stochastic processes-have yielded insight into the dynamics of emerging and re-emerging pathogens. We argue that these approaches may lead to new methods for predicting epidemics. This perspective views pathogen emergence and re-emergence as a "critical transition," and uses the concept of noisy dynamic bifurcation to understand the relationship between the system observables and the distance to this transition. Because the system dynamics exhibit characteristic fluctuations in response to perturbations for a system in the vicinity of a critical point, we propose this information may be harnessed to develop early warning signals. Specifically, the motion of perturbations slows as the system approaches the transition.

Altered Tissue Composition, Microarchitecture, and Mechanical Performance in Cancellous Bone From Men With Type 2 Diabetes Mellitus.

People with type 2 diabetes mellitus (T2DM) have normal-to-high BMDs, but, counterintuitively, have greater fracture risks than people without T2DM, even after accounting for potential confounders like BMI and falls. Therefore, T2DM may alter aspects of bone quality, including material properties or microarchitecture, that increase fragility independently of bone mass. Our objective was to elucidate the factors that influence fragility in T2DM by comparing the material properties, microarchitecture, and mechanical performance of cancellous bone in a clinical population of men with and without T2DM. Cancellous specimens from the femoral neck were collected during total hip arthroplasty (T2DM: n = 31, age = 65 ± 8 years, HbA1c = 7.1 ± 0.9%; non-DM: n = 34, age = 62 ± 9 years, HbA1c = 5.5 ± 0.4%). The T2DM specimens had greater concentrations of the advanced glycation endproduct pentosidine (+ 36%, P < 0.05) and sugars bound to the collagen matrix (+ 42%, P < 0.05) than the non-DM specimens. The T2DM specimens trended toward a greater bone volume fraction (BV/TV) (+ 24%, NS, P = 0.13) and had greater mineral content (+ 7%, P < 0.05) than the non-DM specimens. Regression modeling of the mechanical outcomes revealed competing effects of T2DM on bone mechanical behavior. The trend of higher BV/TV values and the greater mineral content observed in the T2DM specimens increased strength, whereas the greater values of pentosidine in the T2DM group decreased postyield strain and toughness. The long-term medical management and presence of osteoarthritis in these patients may influence these outcomes. Nevertheless, our data indicate a beneficial effect of T2DM on cancellous microarchitecture, but a deleterious effect of T2DM on the collagen matrix. These data suggest that high concentrations of advanced glycation endproducts can increase fragility by reducing the ability of bone to absorb energy before failure, especially for the subset of T2DM patients with low BV/TV. © 2019 American Society for Bone and Mineral Research.

Anticipating epidemic transitions with imperfect data.

Epidemic transitions are an important feature of infectious disease systems. As the transmissibility of a pathogen increases, the dynamics of disease spread shifts from limited stuttering chains of transmission to potentially large scale outbreaks. One proposed method to anticipate this transition are early-warning signals (EWS), summary statistics which undergo characteristic changes as the transition is approached. Although theoretically predicted, their mathematical basis does not take into account the nature of epidemiological data, which are typically aggregated into periodic case reports and subject to reporting error. The viability of EWS for epidemic transitions therefore remains uncertain. Here we demonstrate that most EWS can predict emergence even when calculated from imperfect data. We quantify performance using the area under the curve (AUC) statistic, a measure of how well an EWS distinguishes between numerical simulations of an emerging disease and one which is stationary. Values of the AUC statistic are compared across a range of different reporting scenarios. We find that different EWS respond to imperfect data differently. The mean, variance and first differenced variance all perform well unless reporting error is highly overdispersed. The autocorrelation, autocovariance and decay time perform well provided that the aggregation period of the data is larger than the serial interval and reporting error is not highly overdispersed. The coefficient of variation, skewness and kurtosis are found to be unreliable indicators of emergence. Overall, we find that seven of ten EWS considered perform well for most realistic reporting scenarios. We conclude that imperfect epidemiological data is not a barrier to using EWS for many potentially emerging diseases.

A review of sarcopenia: Enhancing awareness of an increasingly prevalent disease.

Sarcopenia is defined as an age associated decline in skeletal muscle mass. The pathophysiology of sarcopenia is multifactorial, with decreased caloric intake, muscle fiber denervation, intracellular oxidative stress, hormonal decline, and enhanced myostatin signaling all thought to contribute. Prevalence rates are as high as 29% and 33% in elderly community dwelling and long-term care populations, respectively, with advanced age, low body mass index, and low physical activity as significant risk factors. Sarcopenia shares many characteristics with other disease states typically associated with risk of fall and fracture, including osteoporosis, frailty, and obesity. There is no current universally accepted definition of sarcopenia. Diagnosing sarcopenia with contemporary operational definitions requires assessments of muscle mass, muscle strength, and physical performance. Screening is recommended for both elderly patients and those with conditions that noticeably reduce physical function. Sarcopenia is highly prevalent in orthopedic patient populations and correlates with higher hospital costs and rates of falling, fracture, and mortality. As no muscle building agents are currently approved in the United States, resistance training and nutritional supplementation are the primary methods for treating sarcopenia. Trials with various agents, including selective androgen receptor modulators and myostatin inhibitors, show promise as future treatment options. Increased awareness of sarcopenia is of great importance to begin reaching consensus on diagnosis and to contribute to finding a cure for this condition.

Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance.

Bisphosphonates are the most widely prescribed pharmacologic treatment for osteoporosis and reduce fracture risk in postmenopausal women by up to 50%. However, in the past decade these drugs have been associated with atypical femoral fractures (AFFs), rare fractures with a transverse, brittle morphology. The unusual fracture morphology suggests that bisphosphonate treatment may impair toughening mechanisms in cortical bone. The objective of this study was to compare the compositional and mechanical properties of bone biopsies from bisphosphonate-treated patients with AFFs to those from patients with typical osteoporotic fractures with and without bisphosphonate treatment. Biopsies of proximal femoral cortical bone adjacent to the fracture site were obtained from postmenopausal women during fracture repair surgery (fracture groups, n = 33) or total hip arthroplasty (nonfracture groups, n = 17). Patients were allocated to five groups based on fracture morphology and history of bisphosphonate treatment [+BIS Atypical: n = 12, BIS duration: 8.2 (3.0) y; +BIS Typical: n = 10, 7.7 (5.0) y; +BIS Nonfx: n = 5, 6.4 (3.5) y; -BIS Typical: n = 11; -BIS Nonfx: n = 12]. Vibrational spectroscopy and nanoindentation showed that tissue from bisphosphonate-treated women with atypical fractures was harder and more mineralized than that from bisphosphonate-treated women with typical osteoporotic fractures. In addition, fracture mechanics measurements showed that tissue from patients treated with bisphosphonates had deficits in fracture toughness, with lower crack-initiation toughness and less crack deflection at osteonal boundaries than that of bisphosphonate-naïve patients. Together, these results suggest a deficit in intrinsic and extrinsic toughening mechanisms, which contribute to AFFs in patients treated with long-term bisphosphonates.

Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease.

Mitochondrial respiratory chain (RC) disease therapies directed at intra-mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array of human diseases whose pathogenesis involves RC dysfunction.

Multifunctional ultrasmall nanoplatforms for vascular-targeted interstitial photodynamic therapy of brain tumors guided by real-time MRI.

Photodynamic therapy (PDT) for brain tumors appears to be complementary to conventional treatments. A number of studies show the major role of the vascular effect in the tumor eradication by PDT. For interstitial PDT (iPDT) of brain tumors guided by real-time imaging, multifunctional nanoparticles consisting of a surface-localized tumor vasculature targeting neuropilin-1 (NRP-1) peptide and encapsulated photosensitizer and magnetic resonance imaging (MRI) contrast agents, have been designed. Nanoplatforms confer photosensitivity to cells and demonstrate a molecular affinity to NRP-1. Intravenous injection into rats bearing intracranial glioma exhibited a dynamic contrast-enhanced MRI for angiogenic endothelial cells lining the neovessels mainly located in the peripheral tumor. By using MRI completed by NRP-1 protein expression of the tumor and brain adjacent to tumor tissues, we checked the selectivity of the nanoparticles. This study represents the first in vivo proof of concept of closed-head iPDT guided by real-time MRI using targeted ultrasmall nanoplatforms. From the clinical editor: The authors constructed tumor vascular peptide targeting multifunctional silica-based nanoparticles, with encapsulated gadolinium oxide as MRI contrast agent and chlorin as a photosensitizer, as a proof of concept novel treatment for glioblastoma in an animal model.