Outcomes for nighttime bracing in adolescent idiopathic scoliosis based on brace wear adherence.

BACKGROUND: This study determined brace wear adherence for patients treated with nighttime braces and evaluated the effect of brace adherence on curve progression. METHODS: One hundred twenty-two patients with AIS ages 10-16 years, Risser stages 0-2, major curves 20°-40° treated with Providence nighttime braces prescribed to be worn at least 8 h per night were prospectively enrolled and followed until skeletal maturity or surgery. Brace adherence was measured using iButton temperature sensors after 3 months of brace initiation and at brace discharge. RESULTS: Curve types were single thoracolumbar/lumbar (62%, n = 76), double (36%, n = 44), and single thoracic (2%, n = 2). Brace adherence averaged 7.8 ± 2.3 h after 3 months (98% adherence) and 6.7 ± 2.6 h at brace discharge (84% adherence). Curves that progressed ≥ 6° had decreased brace adherence than non-progressive curves after 3 months (7.0 h vs. 8.1 h, p = 0.010) and at brace discharge (5.9 h vs. 7.1 h, p = 0.017). Multivariate logistic regression analysis showed that increased hours of brace wear [odds ratio (OR) 1.23, 95% confidence interval (CI) 1.06-1.46], single curves (OR 3.11, 95% CI 1.35-7.53), and curves < 25° (OR 2.61, 95% CI 1.12-6.44) were associated with non-progression at brace discharge. CONCLUSIONS: Patients treated with nighttime bracing have a high rate of brace adherence. Lack of curve progression is associated with increased brace wear. Nighttime bracing is effective at limiting curve progression in AIS single thoracolumbar/lumbar and double curves. LEVEL OF EVIDENCE: Prognostic Level 2.

Repeat surgical interventions following "definitive" instrumentation and fusion for idiopathic scoliosis: a 30-year update.

PURPOSE: Although spinal fusion (SF) is considered "definitive" treatment in juvenile/adolescent idiopathic scoliosis (JIS/AIS), complications requiring reoperation continue to occur. The purpose of this study was to characterize the evolving rates of reoperation following SF in JIS/AIS. METHODS: Single-center retrospective review of patients who underwent SF for JIS/AIS as their index surgical treatment between 2013 and 2019. Patient data were collected to identify complications requiring reoperation and factors associated with reoperation. Complication rates from 2013 to 2019 were compared to patients from 1988 to 2012 at the same institution. RESULTS: This study analyzed 934 patients (81.7% female, mean age at surgery 14.5 ± 2.1). Thirty-eight patients (4.1%) required a total of 47 reoperations, a > 50% decrease in overall complication rate from the 2008-2012 population (4.1% vs 9.6%, respectively, p < 0.001). The decrease stemmed mainly from decreases in rates of infection (1.1% vs 4.1%, p < 0.001) and symptomatic implants (0.4% vs 2.1%, p = 0.004). There were, however, non-significant increases in implant failures (0.6% vs 0.2%, p = 0.4367) and pseudoarthrosis (1.0% vs 0.4%, p = 0.5202). Both of these complications were associated with patients with a higher mean weight (implant failure: 70.4 kg ± 21.1 vs 56.1 kg ± 14.9, p = 0.002; pseudoarthrosis: 85.8 kg ± 27.9 vs 55.9 ± 14.5, p = 0.001). CONCLUSIONS: Reoperation following SF for JIS/AIS has decreased over the past 7 years when compared to 25 years of historical controls. The changing landscape of reoperation demands further research into the risk factors for those reoperations that have become more common.

Fate of acetabular dysplasia after closed and open reduction of hips in children with developmental hip dislocation.

Acetabular underdevelopment (acetabular dysplasia) is a common finding in children with hip dislocation, and residual acetabular dysplasia can remain after hip reduction. Residual dysplasia leads to unsatisfactory long-term outcomes and osteoarthritis. Dynamics of acetabular dysplasia [measured as Acetabular Index (AI)] in a pediatric cohort that underwent open (OR) or closed reduction are reported. Retrospective data from six tertiary pediatric orthopedic centers were gathered. Hips were classified as having 'Critical', 'Monitoring', or 'Normal' acetabular dysplasia based on age-adjusted normative AI measurements. From 193 hips, 108 (56%) underwent open reduction. Children younger than 24 months had a strong AI decline but children > 24 months did not. Among 78 hips with critical dysplasia at time of OR, 36 (46.2%) remained critical and 19 (24.4%) underwent an acetabular osteotomy (AO) during follow-up. CR hips had a similar AI decline in patients younger and older than 12 months. Among 51 hips with critical dysplasia at the time of CR, 13 (25.5%) remained critical and 21 (41.2%) underwent AO during follow-up. Acetabular dysplasia improves with AI decreasing in children who undergo OR and CR under the age of 2 years with slower acetabular remodeling afterwards. Around 2/3 of patients with AI in the critical range at CR or OR either underwent AO or had significant acetabular dysplasia at final follow-up. Our data supports considering simultaneous AO at the time of OR for hips with AI in the critical range or children who undergo hip open reduction after 24 months of age. Level of Evidence: Level III.

Severity of hip dysplasia as the major factor affecting outcome of closed reduction in children with hip dysplasia.

The objective of this study was to analyze a multicenter cohort of children with developmental dysplasia of the hip (DDH) who underwent treatment with closed reduction. We sought to report the effects that severity of hip dysplasia and age have on the development of femoral head avascular necrosis (AVN) and the need for additional procedures. All patients with DDH and minimum 2 years of follow-up who underwent closed reduction were identified. The following variables were recorded: sex, laterality of hip involvement, age, acetabular index (AI), and International Hip Dysplasia Institute (IHDI) grade. The effects of patient age and pre-procedure IHDI grade on the rate of AVN and need for additional procedures after the closed reduction were analyzed using an alpha of 0.05. Seventy-eight total hips were included in the final analysis. The average patient age was 12 months. AVN of the femoral head was reported in 24 hips (30.8%) and 32 hips (41.0%) required additional surgery. Higher pre-op IHDI grade was associated with higher risk of developing Bucholz-Ogden grades II-IV AVN of the femoral head (P = 0.025) and requiring additional surgery (P= 0.033) regardless of patient age. There were no statistically significant differences for the effect of age on the measured outcomes (P > 0.05). These findings suggest that severity of dislocation (IHDI grade) is a significant risk factor for the development of AVN and need for additional procedure.

Do Children With Medicaid Insurance Have Increased Revision Rates 5 Years After Posterior Spinal Fusions?

BACKGROUND: Socioeconomic disparities in musculoskeletal care are increasingly recognized, however, no studies to date have investigated the role of the insurance carrier on outcomes after posterior spinal fusion (PSF) with segmental spinal instrumentation for adolescent idiopathic scoliosis (AIS). METHODS: A US insurance dataset was queried using the PearlDiver Mariner software for all patients aged 10 to 18 undergoing PSF for a primary diagnosis of AIS between 2010 and 2020. Age, sex, geographic region, number of levels fused, and baseline medical comorbidities were queried. Complications occurring within 90 days of the index surgery were queried using the International Classification of Diseases, Ninth Revision (ICD-9) and International Classification of Diseases, 10th Revision (ICD-10) codes. Revision surgery was also queried up to 5 years after the index PSF. Categorical variables were compared using the Fisher χ 2 tests and continuous variables were compared using independent t tests. All-cause revision within 5 years was compared using the Kaplan-Meier analysis and a log-rank test. Significance was set at P -value <0.05. RESULTS: A total of 10,794 patients were identified with 9006 (83.4%) patients with private insurance and 1788 (16.6%) patients insured by Medicaid. The mean follow-up in the database was 5.36±3 years for patients with private insurance and 4.78±2.9 years for patients with Medicaid insurance ( P <0.001). Children with AIS and Medicaid insurance had a significantly higher prevalence of asthma, hypertension, and obesity. A larger percentage of children with Medicaid insurance (41.3%) underwent a ≥13-level PSF compared with privately insured children (34.5%) ( P <0.001). Medicaid patients did not experience higher odds of postoperative complications; in addition, revision surgeries occurred in 1.1% and 1.8% of patients with private insurance and Medicaid insurance, respectively at 5 years postoperatively ( P =0.223). CONCLUSION: Despite worse baseline comorbidities and longer fusion constructs, AIS patients insured with Medicaid did not have higher rates of complications or revisions at 5-year follow-up versus privately insured patients. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

An Analysis of Scoliosis in Autism Spectrum Disorder.

BACKGROUND: Children with autism/Asperger are grouped into the diagnosis of autism spectrum disorder (ASD). It remains uncertain whether children with ASD and scoliosis have radiographic and clinical outcomes similar to idiopathic scoliosis (IS) patients. METHODS: A single-center, retrospective review of a prospective scoliosis registry evaluated patients who had a posterior spinal fusion±Anterior Spinal Fusion and an underlying diagnosis of ASD between 1990 and 2021. A 2:1 match with AIS patients by age and sex was compared using demographic, radiographic, intraoperative, and SRS-22/30 variables. RESULTS: Thirty patients with ASD (63% male, mean age at surgery 14.6±2.5 y) met inclusion criteria, with a follow-up of 2.46±1.00 years. Despite no differences in curve magnitude preoperatively, patients with ASD had a higher percent correction at 2-year follow-up (66% vs. 57%, P =0.01) and improved mean curve magnitude (20±10 degrees) at 2-year follow-up compared with IS patients (27±11 degrees, P <0.01). ASD patients had less lumbar lordosis preoperatively (40±12 vs. 53±14, P <0.01), but there were no significant differences in sagittal parameters at 2-year follow-up. There were no significant differences in the rate of complications at 2-year follow-up between ASD and AIS cohorts. CONCLUSIONS: Although patients with ASD exhibited decreased lordosis compared with IS patients preoperatively, their radiographic outcomes at 2-year follow-up were the same. In addition, ASD patients maintained greater curve correction than IS patients at 2 years follow-up. LEVEL OF EVIDENCE: Prognostic retrospective study.

Early brace treatment for idiopathic scoliosis may change the paradigm to improve curves.

PURPOSE: This study evaluated whether early brace treatment of curves < 25° decreased the prevalence of curve progression and surgery. METHODS: In a retrospective review, patients with idiopathic scoliosis Risser stages 0 to 2 braced at < 25° were followed until brace discontinuation, skeletal maturity, or surgery. Patients with predominantly primary thoracolumbar/lumbar curves were prescribed nighttime braces (NTB) and thoracic curves were prescribed fulltime braces (FTB). Comparisons were made for TLSO type (NTB vs. FTB) and triradiate cartilage (TRC) status (open vs. closed) at brace prescription. RESULTS: 283 patients were included, 81% who were Risser stage 0 with curves averaging 21.8° ± 2.1° at brace prescription. The average curve change was 2.4° ± 11.2°. Curves improved ≥ 6° in 23% of patients. Patients who were not skeletally mature at brace discontinuation (n = 39) had lower Cobb angles (16.7° vs. 23.9°, p < 0.001), better curve improvement (- 4.7° vs. 2.1°, p < 0.001), and were braced for a shorter period of time (1.8 years vs. 2.3 years, p = 0.011) than those who were skeletally mature at brace discontinuation (n = 239). Only 7% of patients in NTB and 8% of patients in FTB with open TRC required surgery. The numbers needed to treat to prevent surgery in patients in FTB with open TRC was calculated to be 4. CONCLUSION: Early brace treatment (Cobb < 25° and open TRC) may not only reduce curve progression and the need for surgical treatment but may also result in curve improvement, thus challenging the paradigm that the goal of bracing is merely to stop curve progression. LEVEL OF EVIDENCE: 3-retrospective cohort study.

Outcomes of Open Reduction in Children With Developmental Hip Dislocation: A Multicenter Experience Over a Decade.

BACKGROUND: Open reduction of the hip is commonly performed in children with severe developmental dysplasia of the hip, or in cases that are refractory to nonoperative forms of treatment. The open reduction has been associated with numerous complications including avascular necrosis (AVN) of the femoral head, the need for reoperation, and residual radiographic dysplasia. This study seeks to determine the effects of preoperative severity of dysplasia, associated procedures (femoral and acetabular osteotomies), age on AVN, and the need for reoperation. METHODS: Children with developmental dysplasia of the hip and a minimum of 2 years of follow-up who underwent open reduction were identified. The following data points were recorded: sex, laterality of hip involvement, simultaneous procedures, surgical approach used, age, acetabular index, and International Hip Dysplasia Institute grade. We analyzed the effects of preoperative International Hip Dysplasia Institute, age, surgical approach (anterior/medial), bilateral reduction, and simultaneous femoral shortening or pelvic osteotomy on the outcomes of AVN and reoperation. RESULTS: One hundred eighty-five hips in 149 patients were included in this study with an average follow-up of 4 years (range: 2 to 5 y). The average age at index surgery was 23 months (range: 1 to 121 mo). Overall, 60 hips (32.4%) required secondary surgical procedures at an average age of 58.5 months. High-grade AVN was noted in 24 hips (13.0%) and was found to be associated with the severity of the hip dislocation ( P = 0.02). A higher rate of reoperation was found in children over 18 months at the time of open reduction who did not receive an acetabular osteotomy ( P = 0.012). CONCLUSION: Approximately 1/3 of patients require another operative intervention within the first 4 years after open reduction of the hip. We found the severity of hip dislocation to be associated with a higher risk of AVN development. These findings support performing an acetabular osteotomy in children over 18 months of age at the time of open reduction to decrease the likelihood of requiring future reoperation during the first 4 years after the index procedure. LEVEL OF EVIDENCE: Level III.

Upper extremity neuromonitoring changes are more common than lower extremity during spinal fusion for Scheuermann's kyphosis.

INTRODUCTION: The purpose of this study is to determine the incidence of intraoperative neuromonitoring (IONM) changes and postoperative neurologic deficit in patients with Scheuermann's Kyphosis (SK) undergoing posterior spinal fusion (PSF). METHODS: Single-center, retrospective chart review of the clinical, surgical and IONM data (somatosensory evoked potential (SSEP) and neurogenic motor evoked potential (NMEP) or transcranial motor evoked potential (TcMEP)) from patients with SK undergoing PSF at our center from 1993 to 2021. RESULTS: One hundred and four SK patients (mean 16.4 ± 1.9 years) underwent PSF with correction of kyphosis from mean 79.4 ± 10.8° to 35.4 ± 13.9°. MEP data were obtained using either NMEP in 34.6% of patients) or TcMEP in 65.4% of patients. Only 3.8% of cases had lower extremity (LE) IONM changes during surgery, with no postoperative neurologic deficits in those patients. IONM changes occurred more frequently in the upper extremities (UE) with 14 (13.4%) patients having changes in UE SSEPs. Patients with UE IONM changes had significantly longer surgical times (p = 0.0096) and higher number of levels fused (p = 0.003) compared to patients without changes. Their weight, but not BMI, was also significantly higher (p = 0.036). These UE IONM changes resolved with arm repositioning in all but one patient who had a postoperative UE neurapraxia that resolved by 6 weeks. There was 1 postoperative transient femoral nerve palsy without IONM changes thought to be due to patient positioning. CONCLUSION: The incidence of critical LE IONM changes during PSF for SK is 3.4%, which is similar to that reported in AIS. UE IONM changes are significantly more common at 13.4%, revealing that these patients are vulnerable to malpositioning of the arms during surgery.

Dampened psychobiological responses to stress and substance use in adolescence.

Substance use increases throughout adolescence, and earlier substance use may increase risk for poorer health. However, limited research has examined whether stress responses relate to adolescent substance use, especially among adolescents from ethnic minority and high-adversity backgrounds. The present study assessed whether blunted emotional and cortisol responses to stress at age 14 related to substance use by ages 14 and 16, and whether associations varied by poverty status and sex. A sample of 277 Mexican-origin youth (53.19% female; 68.35% below the poverty line) completed a social-evaluative stress task, which was culturally adapted for this population, and provided saliva samples and rated their anger, sadness, and happiness throughout the task. They also reported whether they had ever used alcohol, marijuana, cigarettes, and vaping of nicotine at age 14 and again at age 16. Multilevel models suggested that blunted cortisol reactivity to stress was associated with alcohol use by age 14 and vaping nicotine by age 16 among youth above the poverty line. Also, blunted sadness and happiness reactivity to stress was associated with use of marijuana and alcohol among female adolescents. Blunted stress responses may be a risk factor for substance use among youth above the poverty line and female adolescents.

Estrogen receptor beta activity contributes to both tumor necrosis factor alpha expression in the hypothalamic paraventricular nucleus and the resistance to hypertension following angiotensin II in female mice.

Sex differences in the sensitivity to hypertension and inflammatory processes are well characterized but insufficiently understood. In male mice, tumor necrosis factor alpha (TNFα) in the hypothalamic paraventricular nucleus (PVN) contributes to hypertension following slow-pressor angiotensin II (AngII) infusion. However, the role of PVN TNFα in the response to AngII in female mice is unknown. Using a combination of in situ hybridization, high-resolution electron microscopic immunohistochemistry, spatial-temporal gene silencing, and dihydroethidium microfluorography we investigated the influence of AngII on both blood pressure and PVN TNFα signaling in female mice. We found that chronic (14-day) infusion of AngII in female mice did not impact blood pressure, TNFα levels, the expression of the TNFα type 1 receptor (TNFR1), or the subcellular distribution of TNFR1 in the PVN. However, it was shown that blockade of estrogen receptor ß (ERß), a major hypothalamic estrogen receptor, was accompanied by both elevated PVN TNFα and hypertension following AngII. Further, AngII hypertension following ERß blockade was attenuated by inhibiting PVN TNFα signaling by local TNFR1 silencing. It was also shown that ERß blockade in isolated PVN-spinal cord projection neurons (i.e. sympathoexcitatory) heightened TNFα-induced production of NADPH oxidase (NOX2)-mediated reactive oxygen species, molecules that may play a key role in mediating the effect of TNFα in hypertension. These results indicate that ERß contributes to the reduced sensitivity of female mice to hypothalamic inflammatory cytokine signaling and hypertension in response to AngII.

Prioritizing Elective Surgical Cases During a Pandemic or Global Crisis: The Elective-Pediatric Orthopedic Surgical Timing (E-POST) Score.

BACKGROUND: As the first wave of the COVID-19 pandemic stabilized and resources became more readily available, elective surgery was reinitiated and hospitals realized that there was little guidance on how to prioritize elective cases. METHODS: A prioritization tool was formulated based on clinically relevant elements and previous literature. Nine pediatric orthopaedic surgeons from North American institutions evaluated 25 clinical scenarios on 2 occasions separated in time. Intra-rater and inter-rater reliability were calculated [intraclass correlation coefficient (ICC)]. Surgeons also ranked the importance of each element and how confident they were with scoring each factor. RESULTS: Intra-rater ICC for total score showed good to excellent consistency; highest at 0.961 for length of stay (LOS) and lowest at 0.705 for acuity. Inter-rater ICC showed good to excellent agreement for American Society of Anesthesiologists score, LOS, duration of surgery, and transfusion risk and moderate agreement for surgical acuity and personal protective equipment (PPE) use. Transfusion risk and duration of surgery were deemed least important, and surgeons were least confident in scoring PPE and transfusion risk. Based on findings, the novel Elective-Pediatric Orthopedic Surgical Timing (E-POST) score for prioritizing elective cases was developed, consisting of 5 factors: surgical acuity, global health status, LOS, duration of surgery, and PPE requirement. CONCLUSIONS: The E-POST numeric total score or subscore may help objectively prioritize elective cases during a global crisis. LEVEL OF EVIDENCE: Level V.

Angiotensin II Infusion Results in Both Hypertension and Increased AMPA GluA1 Signaling in Hypothalamic Paraventricular Nucleus of Male but not Female Mice.

The hypothalamic paraventricular nucleus (PVN) plays a key role in hypertension, however the signaling pathways that contribute to the adaptability of the PVN during hypertension are uncertain. We present evidence that signaling at the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor contributes to increased blood pressure in a model of neurogenic hypertension induced by 14-day slow-pressor angiotensin II (AngII) infusion in male mice. It was found that AngII hypertension was associated with an increase in plasma membrane affiliation of GluA1, but decreased GluA2, in dendritic profiles of PVN neurons expressing the TNFα type 1 receptor, a modulator of AMPA receptor trafficking. The increased plasma membrane GluA1 was paralleled by heightened AMPA currents in PVN-spinal cord projection neurons from AngII-infused male mice. Significantly, elevated AMPA currents in AngII-treated mice were blocked by 1-Naphthyl acetyl spermine trihydrochloride, pointing to the involvement of GluA2-lacking GluA1 receptors in the heightened AMPA signaling in PVN neurons. A further functional role for GluA1 in the PVN was demonstrated by the attenuated hypertensive response following silencing of GluA1 in the PVN of AngII-infused male mice. In female mice, AngII-infusion did not impact blood pressure or plasma membrane localization of GluA1 . Post-translational modifications that increase the plasma membrane localization of AMPA GluA1 and heighten the rapid excitatory signaling actions of glutamate in PVN neurons may serve as a molecular substrate underlying sex differences in hypertension.

Acute Delta 9-tetrahydrocannabinol administration differentially alters the hippocampal opioid system in adult female and male rats.

Our prior studies demonstrated that the rat hippocampal opioid system can undergo sex-specific adaptations to external stimuli that can influence opioid-associated learning processes. This opioid system extensively overlaps with the cannabinoid system. Moreover, acute administration of Δ9 Tetrahydrocannabinoid (THC), the primary psychoactive constituent of cannabis, can alter cognitive behaviors that involve the hippocampus. Here, we use light and electron microscopic immunocytochemical methods to examine the effects of acute THC (5 mg/kg, i.p., 1 h) on mossy fiber Leu-Enkephalin (LEnk) levels and the distribution and phosphorylation levels of delta and mu opioid receptors (DORs and MORs, respectively) in CA3 pyramidal cells and parvalbumin dentate hilar interneurons of adult female and male Sprague-Dawley rats. In females with elevated estrogen states (proestrus/estrus stage), acute THC altered the opioid system so that it resembled that seen in vehicle-injected females with low estrogen states (diestrus) and males: (1) mossy fiber LEnk levels in CA2/3a decreased; (2) phosphorylated-DOR levels in CA2/3a pyramidal cells increased; and (3) phosphorylated-MOR levels increased in most CA3b laminae. In males, acute THC resulted in the internalization of MORs in parvalbumin-containing interneuron dendrites which would decrease disinhibition of granule cells. In both sexes, acute THC redistributed DORs to the near plasma membrane of CA3 pyramidal cell dendrites, however, the dendritic region varied with sex. Additionally, acute THC also resulted in a sex-specific redistribution of DORs within CA3 pyramidal cell dendrites which could differentially promote synaptic plasticity and/or opioid-associated learning processes in both females and males.

Estrogen Receptor ß Contributes to Both Hypertension and Hypothalamic Plasticity in a Mouse Model of Peri-Menopause.

Hypertension susceptibility in women increases at the transition to menopause, termed perimenopause, a state characterized by erratic estrogen fluctuation and extended hormone cycles. Elucidating the role of estrogen signaling in the emergence of hypertension during perimenopause has been hindered by animal models that are confounded by abrupt estrogen cessation or effects of aging. In the present study, accelerated ovarian failure (AOF) in estrogen receptor ß (ERß) reporter mice was induced by 4-vinylcyclohexene diepoxide in young mice to model early-stage ovarian failure (peri-AOF) characteristic of peri-menopause. It was found that administering ERß agonists suppressed elevated blood pressure in a model of neurogenic hypertension induced by angiotensin II (AngII) in peri-AOF, but not in age-matched male mice. It was also found that ERß agonist administration in peri-AOF females, but not males, suppressed the heightened NMDAR signaling and reactive oxygen production in ERß neurons in the hypothalamic paraventricular nucleus (PVN), a critical neural regulator of blood pressure. It was further shown that deleting ERß in the PVN of gonadally intact females produced a phenotype marked by a sensitivity to AngII hypertension. These results suggest that ERß signaling in the PVN plays an important role in blood pressure regulation in female mice and contributes to hypertension susceptibility in females at an early stage of ovarian failure comparable to human perimenopause.

DPP4 inhibition mitigates ANG II-mediated kidney immune activation and injury in male mice.

Recent evidence suggests that dipeptidyl peptidase-4 (DPP4) inhibition with saxagliptin (Saxa) is renoprotective under comorbid conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS), such as diabetes, obesity, and hypertension, which confer a high cardiovascular risk. Immune system activation is now recognized as a contributor to RAAS-mediated tissue injury, and, importantly, immunomodulatory effects of DPP4 have been reported. Accordingly, we examined the hypothesis that DPP4 inhibition with Saxa attenuates angiotensin II (ANG II)-induced kidney injury and albuminuria via attenuation of immune activation in the kidney. To this end, male mice were infused with either vehicle or ANG II (1,000 ng/kg/min, s.c.) for 3 wk and received either placebo or Saxa (10 mg/kg/day, p.o.) during the final 2 wk. ANG II infusion increased kidney, but not plasma, DPP4 activity in vivo as well as DPP4 activity in cultured proximal tubule cells. The latter was prevented by angiotensin receptor blockade with olmesartan. Further, ANG II induced hypertension and kidney injury characterized by mesangial expansion, mitochondrial damage, reduced brush border megalin expression, and albuminuria. Saxa inhibited DPP4 activity ∼50% in vivo and attenuated ANG II-mediated kidney injury, independent of blood pressure. Further mechanistic experiments revealed mitigation by Saxa of proinflammatory and profibrotic mediators activated by ANG II in the kidney, including CD8+ T cells, resident macrophages (CD11bhiF4/80loLy6C-), and neutrophils. In addition, Saxa improved ANG II suppressed anti-inflammatory regulatory T cell and T helper 2 lymphocyte activity. Taken together, these results demonstrate, for the first time, blood pressure-independent involvement of renal DPP4 activation contributing to RAAS-dependent kidney injury and immune activation.NEW & NOTEWORTHY This work highlights the role of dipeptidyl peptidase-4 (DPP4) in promoting ANG II-mediated kidney inflammation and injury. Specifically, ANG II infusion in mice led to increases in blood pressure and kidney DPP4 activity, which then led to activation of CD8+ T cells, Ly6C- macrophages, and neutrophils and suppression of anti-inflammatory T helper 2 lymphocytes and regulatory T cells. Collectively, this led to kidney injury, characterized by mesangial expansion, mitochondrial damage, and albuminuria, which were mitigated by DPP4 inhibition independent of blood pressure reduction.

Childhood uveitis not associated with juvenile idiopathic arthritis: a national survey of incidence, management and visual outcomes.

AIMS: To estimate the incidence of childhood uveitis not associated with juvenile idiopathic arthritis (JIA) in the United Kingdom. METHODS: Children under 16 years who presented with a new diagnosis of uveitis from November 2014 to October 2015 were identified prospectively through the British and Scottish Ophthalmological Surveillance Unit reporting card system. Incident questionnaires were sent to reporting ophthalmologists at presentation and 12 months. RESULTS: From 1st November 2014 to 31st October 2015, 119 cases were reported. Thirty-nine cases were excluded. The estimated minimum annual incidence of non-JIA uveitis in children younger than 16 years is 0.66 per 100,000 (95% CI 0.52-0.82). Median age at presentation was 10 years. 73% had bilateral uveitis. Median (IQR) BCVA in the worse eye was 0.3 (IQR 0.1-0.66) logMAR. The location of uveitis was: anterior 36%, intermediate 24%, posterior 6.8% and panuveitis 30%. 70% of cases were idiopathic. Most children were started on topical corticosteroids at presentation (86%, n = 51). At presentation, 31% (n = 19) were on started on systemic corticosteroids. At 1 year only 13% (n = 7) remained on corticosteroids, with the majority transitioned to steroid-sparing agents: methotrexate (30.8%, n = 16), mycophenolate (5.8%) and anti-TNF agents 5 (9.6%). At 1 year, 46% had ongoing intraocular inflammation despite treatment. The most common ocular adverse event was raised intraocular pressure (13.5%, n = 7). CONCLUSION: Our study provides the first national population-based data of non-JIA childhood uveitis. Most children remain on treatment at 1 year, but visual acuity improves and none were eligible for sight-impairment registration.

The combination of a neprilysin inhibitor (sacubitril) and angiotensin-II receptor blocker (valsartan) attenuates glomerular and tubular injury in the Zucker Obese rat.

OBJECTIVE: Diabetic nephropathy (DN) is characterized by glomerular and tubulointerstitial injury, proteinuria and remodeling. Here we examined whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses renal injury in a pre-clinical model of early DN more effectively than valsartan monotherapy. METHODS: Sixty-four male Zucker Obese rats (ZO) at 16 weeks of age were distributed into 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val) (68 mg kg-1 day-1; ZOSV); and Group 3: valsartan (val) (31 mg kg-1 day-1; ZOV). Group 4 received hydralazine, an anti-hypertensive drug (30 mg kg-1 day-1, ZOH). Six Zucker Lean (ZL) rats received saline (Group 5) and served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. RESULTS: Mean arterial pressure (MAP) increased in ZOC (+ 28%), but not in ZOSV (- 4.2%), ZOV (- 3.9%) or ZOH (- 3.7%), during the 10 week-study period. ZOC were mildly hyperglycemic, hyperinsulinemic and hypercholesterolemic. ZOC exhibited proteinuria, hyperfiltration, elevated renal resistivity index (RRI), glomerular mesangial expansion and podocyte foot process flattening and effacement, reduced nephrin and podocin expression, tubulointerstitial and periarterial fibrosis, increased NOX2, NOX4 and AT1R expression, glomerular and tubular nitroso-oxidative stress, with associated increases in urinary markers of tubular injury. None of the drugs reduced fasting glucose or HbA1c. Hypercholesterolemia was reduced in ZOSV (- 43%) and ZOV (- 34%) (p < 0.05), but not in ZOH (- 13%) (ZOSV > ZOV > ZOH). Proteinuria was ameliorated in ZOSV (- 47%; p < 0.05) and ZOV (- 30%; p > 0.05), but was exacerbated in ZOH (+ 28%; p > 0.05) (ZOSV > ZOV > ZOH). Compared to ZOC, hyperfiltration was improved in ZOSV (p < 0.05 vs ZOC), but not in ZOV or ZOH. None of the drugs improved RRI. Mesangial expansion was reduced by all 3 treatments (ZOV > ZOSV > ZOH). Importantly, sac/val was more effective in improving podocyte and tubular mitochondrial ultrastructure than val or hydralazine (ZOSV > ZOV > ZOH) and this was associated with increases in nephrin and podocin gene expression in ZOSV (p < 0.05), but not ZOV or ZOH. Periarterial and tubulointerstitial fibrosis and nitroso-oxidative stress were reduced in all 3 treatment groups to a similar extent. Of the eight urinary proximal tubule cell injury markers examined, five were elevated in ZOC (p < 0.05). Clusterin and KIM-1 were reduced in ZOSV (p < 0.05), clusterin alone was reduced in ZOV and no markers were reduced in ZOH (ZOSV > ZOV > ZOH). CONCLUSIONS: Compared to val monotherapy, sac/val was more effective in reducing proteinuria, renal ultrastructure and tubular injury in a clinically relevant animal model of early DN. More importantly, these renoprotective effects were independent of improvements in blood pressure, glycemia and nitroso-oxidative stress. These novel findings warrant future clinical investigations designed to test whether sac/val may offer renoprotection in the setting of DN.

USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia.

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. EXPERIMENTAL DESIGN: To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models. RESULTS: We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo. CONCLUSIONS: These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.