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BACKGROUND: Approximately 5% of people infected with Mycobacterium tuberculosis progress to tuberculosis (TB) disease without preventive therapy. There is a need for a prognostic test to identify those at highest risk of incident TB, so that therapy can be targeted. We evaluated host blood transcriptomic signatures for progression to TB disease. METHODS: Close contacts (≥4 hours exposure per week) of adult patients with culture-confirmed pulmonary TB were enrolled in Brazil. Investigation for incident, microbiologically-confirmed or clinically-diagnosed pulmonary or extra-pulmonary TB disease through 24 months of follow-up was symptom-triggered. Twenty previously validated blood TB transcriptomic signatures were measured at baseline by real-time quantitative PCR. Prognostic performance for incident TB was tested using receiver operating characteristic curve (ROC) analysis at 6, 9, 12, and 24 months of follow-up. RESULTS: Between June 2015 and June 2019, 1,854 close contacts were enrolled; Twenty-five progressed to incident TB, of whom 13 had microbiologically-confirmed disease. Baseline transcriptomic signature scores were measured in 1,789 close contacts. Prognostic performance for all signatures was best within 6 months of diagnosis. Seven signatures (Gliddon4, Suliman4, Roe3, Roe1, Penn-Nicholson6, Francisco2, and Rajan5) met the minimum World Health Organization target product profile (TPP) for a prognostic test through 6 months; three (Gliddon4, Rajan5, and Duffy9) through 9 months. None met the TPP threshold through 12 or more months of follow-up. CONCLUSIONS: Blood transcriptomic signatures may be useful for predicting TB risk within 9 months of measurement among TB-exposed contacts, to target preventive therapy administration.

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Diabetes mellitus (DM) is associated with increased fracture risk in White adults. However, the impact of DM on fractures in Black adults is unknown. This systematic review and meta-analysis investigated the association between DM and fractures in adults of African ancestry. MEDLINE, Scopus, CINAHL and Embase databases were searched from their inception up to November 2023 for all studies in the English language investigating the epidemiology of fractures (prevalence, incidence, or risk) in Black men and women (age ≥ 18 years) with type 1 or type 2 DM. Effect sizes for prevalence of previous fractures (%) and incident fracture risk (hazard ratio [HR]) were calculated using a random-effects model on Stata (version 18.0). There were 13 eligible studies, of which 12 were conducted in Black adults from the United States, while one was conducted in adults of West African ancestry from Trinidad and Tobago. We found no fracture data in Black adults with DM living in Africa. Five studies were included in a meta-analysis of incident fracture risk, reporting data from 2926 Black and 6531 White adults with DM. There was increased risk of fractures in Black adults with DM compared to non-DM (HR = 1.65; 95 % confidence interval [CI]: 1.14, 2.39). The risk of fractures was also higher in White adults with DM compared to non-DM (HR = 1.31; 95 % CI: 1.06, 1.61) among these studies. Five studies were included in a meta-analysis of fracture prevalence, of which three also reported fracture prevalence in White adults. There were 175 previous fractures among 993 Black adults with DM and 384 previous fractures among 1467 White adults with DM, with a pooled prevalence of 17.5 % (95 % CI: 15.4, 19.6) and 25.8 % (95 % CI: 4.8, 46.8), respectively. Our results indicate a high burden of fractures in Black adults with DM.

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An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a role during the initial stages after T. cruzi infection, restraining the magnitude of CD8+ T cell responses and parasite control. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation, exhaustion and functional markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell immunity. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, preventing increased parasite replication in T. cruzi infected mice adoptively transferred with Treg cells. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.

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BACKGROUND: The introduction of Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Randomised and non-randomised studies in multiple countries have shown significant reductions in dengue incidence following field releases of wMel-infected Ae. aegypti. We report the public health outcomes from phased, large-scale releases of wMel-Ae. aegypti mosquitoes throughout three contiguous cities in the Aburrá Valley, Colombia. METHODOLOGY/PRINCIPAL FINDINGS: Following pilot releases in 2015-2016, staged city-wide wMel-Ae. aegypti deployments were undertaken in the cities of Bello, Medellín and Itagüí (3.3 million people) between October 2016 and April 2022. The impact of the Wolbachia intervention on dengue incidence was evaluated in two parallel studies. A quasi-experimental study using interrupted time series analysis showed notified dengue case incidence was reduced by 95% in Bello and Medellín and 97% in Itagüí, following establishment of wMel at ≥60% prevalence, compared to the pre-intervention period and after adjusting for seasonal trends. A concurrent clinic-based case-control study with a test-negative design was unable to attain the target sample size of 63 enrolled virologically-confirmed dengue (VCD) cases between May 2019 and December 2021, consistent with low dengue incidence throughout the Aburrá Valley following wMel deployments. Nevertheless, VCD incidence was 45% lower (OR 0.55 [95% CI 0.25, 1.17]) and combined VCD/presumptive dengue incidence was 47% lower (OR 0.53 [95% CI 0.30, 0.93]) among participants resident in wMel-treated versus untreated neighbourhoods. CONCLUSIONS/SIGNIFICANCE: Stable introduction of wMel into local Ae. aegypti populations was associated with a significant and sustained reduction in dengue incidence across three Colombian cities. These results from the largest contiguous Wolbachia releases to-date demonstrate the real-world effectiveness of the method across large urban populations and, alongside previously published results, support the reproducibility of this effectiveness across different ecological settings. TRIAL REGISTRATION: NCT03631719.

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BACKGROUND: The wMel strain of Wolbachia has been successfully introduced into Aedes aegypti mosquitoes and has been shown to reduce the transmission of dengue and other Aedes-borne viruses. Here we report the entomological results from phased, large-scale releases of Wolbachia infected Ae. aegypti mosquitoes throughout three contiguous cities located in the Aburrá Valley, Colombia. METHODOLOGY/PRINCIPAL FINDINGS: Local wMel Wolbachia-infected Ae. aegypti mosquitoes were generated and then released in an initial release pilot area in 2015-2016, which resulted in the establishment of Wolbachia in the local mosquito populations. Subsequent large-scale releases, mainly involving vehicle-based releases of adult mosquitoes along publicly accessible roads and streets, were undertaken across 29 comunas throughout Bello, Medellín and Itagüí Colombia between 2017-2022. In 9 comunas these were supplemented by egg releases that were undertaken by staff or community members. By the most recent monitoring, Wolbachia was found to be stable and established at consistent levels in local mosquito populations (>60% prevalence) in the majority (67%) of areas. CONCLUSION: These results, from the largest contiguous releases of wMel Wolbachia mosquitoes to date, highlight the operational feasibility of implementing the method in large urban settings. Based on results from previous studies, we expect that Wolbachia establishment will be sustained long term. Ongoing monitoring will confirm Wolbachia persistence in local mosquito populations and track its establishment in the remaining areas.

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Collagen architecture determines the biomechanical environment in the eye, and thus characterizing collagen fiber organization and biomechanics is essential to fully understand eye physiology and pathology. We recently introduced instant polarized light microscopy (IPOL) that encodes optically information about fiber orientation and retardance through a color snapshot. Although IPOL allows imaging collagen at the full acquisition speed of the camera, with excellent spatial and angular resolutions, a limitation is that the orientation-encoding color is cyclic every 90 degrees (π/2 radians). In consequence, two orthogonal fibers have the same color and therefore the same orientation when quantified by color-angle mapping. In this study, we demonstrate IPOLπ, a new variation of IPOL, in which the orientation-encoding color is cyclic every 180 degrees (π radians). Herein we present the fundamentals of IPOLπ, including a framework based on a Mueller-matrix formalism to characterize how fiber orientation and retardance determine the color. The improved quantitative capability of IPOLπ enables further study of essential biomechanical properties of collagen in ocular tissues, such as fiber anisotropy and crimp. We present a series of experimental calibrations and quantitative procedures to visualize and quantify ocular collagen orientation and microstructure in the optic nerve head, a region in the back of the eye. There are four important strengths of IPOLπ compared to IPOL. First, IPOLπ can distinguish the orientations of orthogonal collagen fibers via colors, whereas IPOL cannot. Second, IPOLπ requires a lower exposure time than IPOL, thus allowing faster imaging speed. Third, IPOLπ allows visualizing non-birefringent tissues and backgrounds from tissue absorption, whereas both appear dark in IPOL images. Fourth, IPOLπ is cheaper and less sensitive to imperfectly collimated light than IPOL. Altogether, the high spatial, angular, and temporal resolutions of IPOLπ enable a deeper insight into ocular biomechanics and eye physiology and pathology.

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Collagen architecture determines the biomechanical environment in the eye, and thus characterizing collagen fiber organization and biomechanics is essential to fully understand eye physiology and pathology. We recently introduced instant polarized light microscopy (IPOL) that encodes optically information about fiber orientation and retardance through a color snapshot. Although IPOL allows imaging collagen at the full acquisition speed of the camera, with excellent spatial and angular resolutions, a limitation is that the orientation-encoding color is cyclic every 90 degrees (π/2 radians). In consequence, two orthogonal fibers have the same color and therefore the same orientation when quantified by color-angle mapping. In this study, we demonstrate IPOLπ, a new variation of IPOL, in which the orientation-encoding color is cyclic every 180 degrees (π radians). Herein we present the fundamentals of IPOLπ, including a framework based on a Mueller-matrix formalism to characterize how fiber orientation and retardance determine the color. The improved quantitative capability of IPOLπ enables further study of essential biomechanical properties of collagen in ocular tissues, such as fiber anisotropy and crimp. We present a series of experimental calibrations and quantitative procedures to visualize and quantify ocular collagen orientation and microstructure in the optic nerve head, a region in the back of the eye. There are four important strengths of IPOLπ compared to IPOL. First, IPOLπ can distinguish the orientations of orthogonal collagen fibers via colors, whereas IPOL cannot. Second, IPOLπ requires a lower exposure time than IPOL, thus allowing faster imaging speed. Third, IPOLπ allows visualizing non-birefringent tissues and backgrounds from tissue absorption, whereas both appear dark in IPOL images. Fourth, IPOLπ is cheaper and less sensitive to imperfectly collimated light than IPOL. Altogether, the high spatial, angular, and temporal resolutions of IPOLπ enable a deeper insight into ocular biomechanics and eye physiology and pathology.

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Hemophilia A is an inherited bleeding disorder caused by defective or deficient coagulation factor VIII (FVIII) activity. Until recently, the only treatment for prevention of bleeding involved IV administration of FVIII. Gene therapy with adeno-associated vectors (AAVs) has shown some efficacy in patients with hemophilia A. However, limitations persist due to AAV-induced cellular stress, immunogenicity, and reduced durability of gene expression. Herein, we examined the efficacy of liver-directed gene transfer in FVIII knock-out mice by AAV8-GFP. Surprisingly, compared with control mice, FVIII knockout (F8TKO) mice showed significant delay in AAV8-GFP transfer in the liver. We found that the delay in liver-directed gene transfer in F8TKO mice was associated with absence of liver sinusoidal endothelial cell (LSEC) fenestration, which led to aberrant expression of several sinusoidal endothelial proteins, causing increased capillarization and decreased permeability of LSECs. This is the first study to link impaired liver-directed gene transfer to liver-endothelium maladaptive structural changes associated with FVIII deficiency in mice.

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BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) has mandated all hospitals to publish the charges of 300 common procedures to provide price transparency. The aims of our study are to evaluate 50 top orthopedic hospitals to determine compliance with this mandate and to assess the ease of finding cost information for arthroplasty procedures. METHODS: The websites of the top 50 US News and World Report (USNWR) orthopedic hospitals were searched to find publicly accessible procedural charges. Data included the number of clicks to locate pricing documents, number of files provided, and number of data rows pertaining to arthroplasty. Charge data was queried based on Diagnosis related group (DRG) codes (469, 470), Current Procedural Technology (CPT) codes (27130, 27477), and keyword searches ("arthroplasty", "total hip", and "total knee"). RESULTS: Forty-four (88%) of the top 50 USNWR Orthopedic institutions had publicly accessible files containing cost information. Thirty three of the 44 institutions provided results with DRG search while less than 10 institutions used CPT and keyword searches. There was an average of 226,190 (range 304-1,121,876) rows of data per file. Average charges varied depending on the use of DRG, CPT or keyword searches ($6,663-$117,072). CONCLUSION: The majority of compliant hospitals published large data files requiring the use of DRG codes to find cost information with extreme variation in resultant charges provided. These findings underscore the lack of direct patient benefit afforded by the current mandate, as pricing determinations require expert knowledge in medical coding and have a high variability in the reported charges.

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BACKGROUND: The clinical examination for laxity has been considered a mainstay in evaluation of the painful knee arthroplasty, especially for the diagnosis of instability. More than 10 mm of anterior-posterior (AP) translation in flexion has been described as important in the diagnosis of flexion instability. The inter-observer reliability of varus/valgus and AP laxity testing has not been tested. METHODS: Ten subjects with prior to total knee arthroplasty (TKA) were examined by 4 fellowship-trained orthopedic knee arthroplasty surgeons. Each surgeon evaluated each subject in random order and was blinded to the results of the other surgeons. Each surgeon performed an anterior drawer test at 30 and 90 degrees of flexion and graded the instability as 0-5 mm, 5-10 mm or >10 mm. Varus-valgus testing was also graded. Motion capture was used during the examination to determine the joint position and estimate joint reaction force during the examination. RESULTS: Inter-rater reliability (IRR) was poor at 30 and 90 degrees for both the subjective rater score and the measured AP laxity in flexion (k = 018-0.22). Varus-valgus testing similarly had poor reliability. Force applied by the rater also had poor IRR. CONCLUSION: Clinical testing of knee laxity after TKA has poor reliability between surgeons using motion analysis. It is unclear if this is from differences in examiner technique or from differences in pain or quadriceps function of the subjects. Instability after TKA should not be diagnosed strictly by clinical testing and should involve a complete clinical assessment of the patient.

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BACKGROUND: Preoperative opioid use strongly correlates with greater postoperative opioid use and complications following total joint arthroplasty (TJA). However, there is a lack of information regarding the effect of opioid consumption during the hospital stay and within the operating room on postoperative opioid use. METHODS: We retrospectively reviewed 369 consecutive patients undergoing primary TJA at an academic center over a 9-month period. Ninety-day preoperative and postoperative opioid prescriptions were obtained from the state's drug monitoring database. In-hospital opioid consumption data was obtained from the preoperative unit, operating room, postanesthesia care unit (PACU), and hospital floor. Multivariate analysis was utilized to compare patients' total in-hospital opioid consumption with their preoperative and postoperative use, along with opioid use throughout the hospitalization. RESULTS: Total in-hospital opioid consumption was independently associated with postoperative opioid use (rs = 0.17, P = .0010). Opioids consumed on the hospital floor correlated with opioid use in the preoperative unit (rs = 0.11, P = .0338) and PACU (rs = 0.15, P = .0032). Increased preoperative opioid consumption was the greatest risk factor for excessive postoperative use (rs = 0.44, P < .0001). A greater proportion of patients <65 years of age were high posthospital opioid consumers (P = .0146) and significantly more TKA patients were in the higher use groups (P = .0006). CONCLUSION: In-hospital opioid use is independently associated with preoperative and postoperative consumption. Preoperative opioid use remains the greatest risk factor for increased opioid consumption after TJA. Multimodal approaches to decrease reliance on opioids for pain control during hospitalization may offer hope to further decrease postoperative usage. LEVEL OF EVIDENCE: III.

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BACKGROUND: Blood flow restriction (BFR) therapy has been proposed to help patients build strength with fewer repetitions than standard physical therapy (PT). We sought to determine if BFR would improve quadriceps and hamstring strength in patients with instability and perceived weakness >1 year after primary total knee arthroplasty (TKA). METHODS: We retrospectively reviewed 48 patients with painful TKAs and flexion instability as well as quadriceps and hamstring weakness who performed a 6-week PT program and received isokinetic strength measurements (ISMs). Thirty-six patients completed a standard PT program (non-BFR) and 12 patients completed a BFR regimen. ISMs were taken before and after PT to quantify quadriceps and hamstring power, torque, and work compared to the contralateral leg. Statistical analysis was conducted on pre-PT and post-PT ISMs and decisions for revision surgery. RESULTS: There were no differences in ISMs after PT between the BFR and non-BFR groups. The non-BFR group showed statistically significant strength improvements in flexion but not extension (+28.7%-32.8%, P = .0145-.255). Although no significant difference was found in the BFR group, they saw improvements in all extension strength metrics (19.4%-23.4%, P = .3315-.3901) and flexion (25.7%-29.9%, P = .1994-.2392). No difference was observed between the groups in the rates of subsequent revision TKA (8.3% vs 16.7%, P = .3362). CONCLUSION: BFR did not improve quadriceps and hamstring strength compared to PT alone in patients with instability and weakness after TKA. Over 80% of total patients chose to avoid revision TKA after completion of focused PT with or without BFR.

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BACKGROUND: Many patients have unmet social needs that may affect their health care utilization and outcomes. We sought to examine a program to determine the types of social needs facing arthroplasty patients and methods used to address these needs. METHODS: We conducted a pilot, retrospective review of our integrated social needs program for total joint arthroplasty (TJA) patients. A 16-question needs assessment was instituted as part of our perioperative protocol between February 1, 2020, to October 1, 2020. We examined the types of social needs in 250 primary TJA patients and a resolution method. We evaluated associations between social needs and demographics and Area Deprivation Index (ADI). Outcome measures were also evaluated, including readmissions, discharge date, and outcome score changes. RESULTS: Forty-four (17.6%) patients had a social need. Social needs frequency increased in non-White patients (P ≤ .0001), non-English speakers (P = .0304), younger patients (P = .001), nonmarried patients (P = .0006), unemployed patients (P = .0189), and patients with less health literacy (P = .0215). ADI scores were positively associated with social needs at the national (P = .0006) and state levels (P = .0004). Overall, 75.9% of needs centered around utility payments, employment, prescription costs, education, and transportation. In addition, 64% of the identified needs were resolved through outside referrals. Ninety-day readmissions were significantly higher in patients with social needs (P = .0087). DISCUSSION: Overall, 17.6% of patients in our state have social needs before TJA. Factors increasing the risk of social needs include younger age, minority race, single or divorced marital status, unemployment, low health literacy, and higher ADI. The 90-day readmission rate was significantly higher in patients with social needs.

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BACKGROUND: While interest has focused on opioid use after total hip arthroplasty, little research has investigated opioid use in elderly patients after hip fracture. We hypothesize that a substantial number of opioid-naïve elderly patients go on to chronic opioid use after hip fracture surgery. METHODS: We reviewed a consecutive series of 219 patients 65 years and older who underwent surgical fixation between January 1, 2016 and February 28, 2019 for a native hip fracture. Patients were excluded for polytrauma, periprosthetic or pathologic fractures, recent major surgery, or death within 90 days of their hip surgery. The state prescription monitoring database was used to determine opioid use. RESULTS: Overall, 58 patients (26%) were postoperative chronic opioid users. Of the initial 188 opioid-naïve patients, 43 (23%) became chronic users. Of the 31 preoperative opioid users, 15 (48%) continued as chronic users. Chronic postoperative users were more likely to be White (76% vs 91%, P = .04), younger (78 vs 82 years, P = .003), and preoperative opioid users (odds ratio 3.3, P = .007). Arthroplasty vs fixation did not affect the rate of chronic opioid use (P = .22). CONCLUSION: Chronic opioid use is surprisingly common after hip fracture repair in the elderly. Twenty-three percent of opioid-naïve hip fracture patients became chronic users after surgery. Continued vigilance is needed by orthopedic surgeons to limit the amount and duration of postoperative narcotic prescriptions and to monitor for continued use.

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BACKGROUND: Determining the clinical effort associated with preparing for revision total hip and knee arthroplasty is necessary to maintain the appropriate work relative value unit rating. We have investigated the work done by the orthopedic surgical team in the days and weeks prior to revision hip and knee arthroplasty using a count of time by team members in the electronic medical record (EMR). METHODS: EMR audit logs were generated, and preoperative work (POW) was calculated for members of the surgical team for 200 sequential revision cases. Independent samples t-tests were conducted to compare total POW for procedure, age, gender, insurance, and health literacy; significance threshold was set at P = .05. RESULTS: POW was 97.7 minutes (standard deviation [SD] 53.1). Surgeon POW accounted for 10.5 minutes (SD 9.3), nurses for 29.9 minutes (SD 34.2), mid-level providers for 22.1 minutes (SD 17.0), and office technicians for 34.1 minutes (SD 35.2). There was no difference in total POW based on procedure (hip vs knee), age, gender, insurance type, or health literacy. CONCLUSION: Revision arthroplasty requires substantial preoperative preparation from the surgical team. Most of this is by nurses, mid-level providers, and office staff. This does not seem to be different for hip or knee revisions or by age and gender. EMR audit logs capture the bare minimum POW required to prepare a patient for revision arthroplasty.

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The subcellular localization of RAS GTPases defines the operational compartment of the EGFR-ERK1/2 signaling pathway within cells. Hence, we used live-cell imaging to demonstrate that endogenous KRAS and NRAS tagged with mNeonGreen are predominantly localized to the plasma membrane. NRAS was also present in the Golgi apparatus and a tubular, plasma-membrane derived endorecycling compartment, enriched in recycling endosome markers (TERC). In EGF-stimulated cells, there was essentially no colocalization of either mNeonGreen-KRAS or mNeonGreen-NRAS with endosomal EGFR, which, by contrast, remained associated with endogenous Grb2-mNeonGreen, a receptor adaptor upstream of RAS. ERK1/2 activity was diminished by blocking cell surface EGFR with cetuximab, even after most ligand-bound, Grb2-associated EGFRs were internalized. Endogenous mCherry-tagged RAF1, an effector of RAS, was recruited to the plasma membrane, with subsequent accumulation in mNG-NRAS-containing TERCs. We propose that a small pool of surface EGFRs sustain signaling within the RAS-ERK1/2 pathway and that RAS activation persists in TERCs, whereas endosomal EGFR does not significantly contribute to ERK1/2 activity.

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BACKGROUND: Patients who have total knee arthroplasty (TKA) likely suffer from decreased postural stability because of postoperative changes in musculoskeletal structure and loss of proprioception. The purpose of this experimental biomechanical study was to determine if patients who have TKA improve their dynamic postural control during walking after TKA as compared with before TKA. The secondary purpose was to assess changes in postural control between post-TKA patients and healthy controls. METHODS: Twenty-three patients who had primary knee osteoarthritis scheduled to undergo unilateral or bilateral TKA were prospectively enrolled. Each patient was tested at 3 months, 6 months, and 12 months after TKA. Ten healthy controls matched for age, sex, and body mass index were selected from a database of previous healthy volunteers without knee osteoarthritis. Ten Vicon cameras and four AMTI force platforms were used to collect the marker and center of pressure (COP) data while participants performed gait. RESULTS: Initial improvement in the double stance ratio was found by 6 months after TKA compared with before TKA. Patients showed improved postural control as evidenced by a faster mediolateral COP velocity and decreased double stance ratio at 12-month post-TKA compared with pre-TKA (P < .05). However, patients who underwent TKA exhibited limited ability to maintain consistent COP movement during walking with increased variability in COP parameters as compared with controls (P < .05). CONCLUSION: Patients exhibited improvement in dynamic postural control after TKA with time, but had higher variability in COP parameters during gait than controls. It is possible that therapy aimed to improve proprioceptive balance after TKA may improve dynamic postural control.

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OBJECTIVE: To determine the outcomes of chronic hepatitis B virus (HBV) infection in a large, prospectively studied cohort of children in the US and Canada. STUDY DESIGN: This was a prospective, observational study of children with chronic HBV enrolled in 7 clinical centers and evaluated at baseline, weeks 24 and 48, and annually thereafter, with analysis of demographic, clinical, physical examination, and blood test data. RESULTS: Among 362 children followed for a median of 4.2 years, elevated alanine aminotransferase (ALT) levels (>1 upper limit of normal) were present in 72% at last evaluation, including in 60% of children with loss of hepatitis B e antigen during follow-up and 70% of those who were hepatitis B e antigen negative at baseline. Significant ALT flares (male patients ≥400 U/L, female patients ≥350 U/L) occurred in 13 children. Of 129 children who fulfilled the American Association for the Study of Liver Diseases treatment criteria during follow-up, anti-HBV treatment was initiated in only 25. One child died (unrelated to liver disease), 1 developed cirrhosis, but no episodes of cirrhotic decompensation or hepatocellular carcinoma were observed. Decline in platelet count was inversely associated with ALT elevations. CONCLUSIONS: In a cohort of children with chronic HBV infection in the US and Canada, many children remained at risk of progressive liver disease due to active hepatitis, but major clinical outcomes such as cirrhosis, cancer, and death were rare. Many children who met criteria for treatment remained untreated.

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Ligand binding triggers clathrin-mediated and, at high ligand concentrations, clathrin-independent endocytosis of EGFR. Clathrin-mediated endocytosis (CME) of EGFR is also induced by stimuli activating p38 MAPK. Mechanisms of both ligand- and p38-induced endocytosis are not fully understood, and how these pathways intermingle when concurrently activated remains unknown. Here we dissect the mechanisms of p38-induced endocytosis using a pH-sensitive model of endogenous EGFR, which is extracellularly tagged with a fluorogen-activating protein, and propose a unifying model of the crosstalk between multiple EGFR endocytosis pathways. We found that a new locus of p38-dependent phosphorylation in EGFR is essential for the receptor dileucine motif interaction with the σ2 subunit of clathrin adaptor AP2 and concomitant receptor internalization. p38-dependent endocytosis of EGFR induced by cytokines was additive to CME induced by picomolar EGF concentrations but constrained to internalizing ligand-free EGFRs due to Grb2 recruitment by ligand-activated EGFRs. Nanomolar EGF concentrations rerouted EGFR from CME to clathrin-independent endocytosis, primarily by diminishing p38-dependent endocytosis.

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