Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes.

BACKGROUND: Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes. METHODS: We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons. RESULTS: During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group. CONCLUSIONS: In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes.

BACKGROUND: The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain. METHODS: In this trial involving participants with type 2 diabetes of less than 10 years' duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%. RESULTS: A total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups. CONCLUSIONS: All four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Widespread monoclonal IgE antibody convergence to an immunodominant, proanaphylactic Ara h 2 epitope in peanut allergy.

BACKGROUND: Despite their central role in peanut allergy, human monoclonal IgE antibodies have eluded characterization. OBJECTIVE: We sought to define the sequences, affinities, clonality, and functional properties of human monoclonal IgE antibodies in peanut allergy. METHODS: We applied our single-cell RNA sequencing-based SEQ SIFTER discovery platform to samples from allergic individuals who varied by age, sex, ethnicity, and geographic location in order to understand commonalities in the human IgE response to peanut allergens. Select antibodies were then recombinantly expressed and characterized for their allergen and epitope specificity, affinity, and functional properties. RESULTS: We found striking convergent evolution of IgE monoclonal antibodies (mAbs) from several clonal families comprising both memory B cells and plasmablasts. These antibodies bound with subnanomolar affinity to the immunodominant peanut allergen Ara h 2, specifically a linear, repetitive motif. Further characterization of these mAbs revealed their ability to single-handedly cause affinity-dependent degranulation of human mast cells and systemic anaphylaxis on peanut allergen challenge in humanized mice. Finally, we demonstrated that these mAbs, reengineered as IgGs, inhibit significant, but variable, amounts of Ara h 2- and peanut-mediated degranulation of mast cells sensitized with allergic plasma. CONCLUSIONS: Convergent evolution of IgE mAbs in peanut allergy is a common phenomenon that can reveal immunodominant epitopes on major allergenic proteins. Understanding the functional properties of these molecules is key to developing therapeutics, such as competitive IgG inhibitors, that are able to stoichiometrically outcompete endogenous IgE for allergen and thereby prevent allergic cascade in cases of accidental allergen exposure.

Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001.

BACKGROUND: Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions. OBJECTIVE: Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies. METHODS: We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs. RESULTS: We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model. CONCLUSIONS: We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.

Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.

BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).

Temperate woody species across the angiosperm phylogeny acquire tolerance to water deficit stress during the growing season.

Understanding the capacity of temperate trees to acclimate to limited soil water has become essential in the face of increasing drought risk due to climate change. We documented seasonal - or phenological - patterns in acclimation to water deficit stress in stems and leaves of tree species spanning the angiosperm phylogeny. Over 3 yr of field observations carried out in two US arboreta, we measured stem vulnerability to embolism (36 individuals of 7 Species) and turgor loss point (119 individuals of 27 species) over the growing season. We also conducted a growth chamber experiment on 20 individuals of one species to assess the mechanistic relationship between soil water restriction and acclimation. In three-quarters of species measured, plants became less vulnerable to embolism and/or loss of turgor over the growing season. We were able to stimulate this acclimatory effect by withholding water in the growth chamber experiment. Temperate angiosperms are capable of acclimation to soil water deficit stress, showing maximum vulnerability to soil water deficits following budbreak and becoming more resilient to damage over the course of the growing season or in response to simulated drought. The species-specific tempo and extent of this acclimatory potential constitutes preadaptive climate change resilience.

Outcomes of kidney, liver, and simultaneous liver and kidney transplants from hepatitis c infected donors to hepatitis c naïve recipients: A large single center experience.

BACKGROUND: With the introduction of direct-acting antiviral therapies (DAAs), the non-use rate of hepatitis C virus (HCV)-positive donor organs (D+) has decreased significantly. We present the donor, recipient, and transplant allograft characteristics, along with recipient outcomes, in one of the largest cohorts of HCV-D+ transplants into HCV-naïve recipients (R-). METHODS: Charts of HCV D+/R- kidney (KT), liver (LT), and simultaneous liver-kidney (SLKT) transplant recipients between January 2019 and July 2022 were reviewed. Primary outcomes of interest included waitlist times and 1-year graft failure. Secondary outcomes included hospital and intensive care unit length of stay, post-transplant complications, effectiveness of DAA therapy, and characteristics of patients who relapsed from initial DAA therapy. RESULTS: Fifty-five HCV D+/R- transplants at our center [42 KT (26 nucleic acid testing positive [NAT+], 16 NAT-), 12 LT (eight NAT+, four NAT-), and one SLKT (NAT+)] had a median waitlist time of 69 days for KT, 87 days for LT, and 15 days for SLKT. There were no graft failures at 1 year. All viremic recipients were treated with a 12-week course of DAAs, of which 100% achieved end of treatment response (EOTR)-85.7% (n = 30) achieved sustained virologic response (SVR) and 14.3% relapsed (n = 5; four KT, one LT). All relapsed recipients were retreated and achieved SVR. The most common post-transplantation complications include BK virus infection (n = 9) for KT and non-allograft infections (n = 4) for LT. CONCLUSIONS: Our study has demonstrated no graft failures or recipient deaths at 1 year, and despite a 14.3% relapse rate, we achieved 100% SVR. Complications rates of D+/R- appeared comparable to national D-/R- complication rates. Further studies comparing D+/R- to D-/R- outcomes are needed.

Blood on the drapes: A multispecialty comparison of blood spill estimates.

INTRODUCTION: Estimated blood loss (EBL) is an important part of the perioperative process. This project aims to determine the accuracy of perioperative team members to estimate blood volume on drapes and the operating room floor. METHODS: Aliquots of unused human blood were used to create surgical scenarios, and standardized pictures and videos were taken. Physicians, residents, nurses, medical students, and surgical technicians were surveyed and asked to estimate the blood volume for each series. Accuracy and consistency of responses was analyzed. RESULTS: One hundred and forty five responses were recorded: 57 attending physicians, 36 residents, 27 registered nurses, 17 medical students, and seven circulating surgical techs. Median percent error (PE) for all cases was 211.11%, demonstrating a global overestimation of blood volume. PE for the 150 mL images was statistically significantly lower than that of the 50 and 100 mL images. Circulating Surgical Technicians were the most accurate group, with a median PE of 125%, followed closely by Medical Students (PE = 158.33%). The most accurate specialty was Orthopedics (PE = 168.06%). The least accurate groups were Attending Physicians (PE = 286.11%) and General surgery (GSGY) (PE = 327.78%). The most accurate orthopedic surgery and GSGY subspecialties were Hand (PE = 237.64%) and Vascular (PE = 108.33%), respectively. Statistical analyses showed no significant differences by clinical role, surgical specialty, or subspecialty. CONCLUSION: This study demonstrates a global overestimation of blood volume when using the visual method, with improved accuracy at higher volumes. Our findings highlight the limitations of visual estimation methods for EBL.

Effects of testosterone on urogenital tract morphology and androgen receptor expression in immature Eastern Fence lizards (Sceloporus undulatus).

In non-avian reptiles, the onset of sexual dimorphism of the major structures of the urogenital tract varies temporally relative to gonadal differentiation, more so than in other amniote lineages. In the current study, we used tonic-release implants to investigate the effects of exogenous testosterone (T) on postnatal development of the urogenital tract in juvenile Eastern Fence Lizards (Sceloporus undulatus) to better understand the mechanisms underlying the ontogeny of sexual differentiation in reptiles. We examined gonads, mesonephric kidneys and ducts (male reproductive tract primordia), paramesonephric ducts (oviduct primordia), sexual segments of the kidneys (SSKs), and hemiphalluses to determine which structures were sexually dimorphic independent of T treatment and which structures exhibited sexually dimorphic responses to T. To better understand tissue-level responsiveness to T treatment, we also characterized androgen receptor (AR) expression by immunohistochemistry. At approximately 4 months after hatching in control animals, gonads were well differentiated but quiescent; paramesonephric ducts had fully degenerated in males; mesonephric kidneys, mesonephric ducts, and SSKs remained sexually undifferentiated; and hemiphalluses could not be everted in either sex. Exogenous T caused enlargement, regionalization, and secretory activity of the mesonephric ducts and SSKs in both sexes; enlargement and regionalization of the oviducts in females; and enlargement of male hemipenes. The most responsive tissues exhibited moderate but diffuse staining for AR in control lizards and intense nuclear staining in T-treated lizards, suggestive of autoregulation of AR. The similarity between sexes in the responsiveness of the mesonephric ducts and SSK to T indicates an absence of sexually dimorphic organizational effects in these structures prior to treatment, which was initiated approximately 2 months after hatching. In contrast, the sex-specific responses in oviducts and hemipenes indicate that significant organization and/or differentiation had taken place prior to treatment.

MrgprC11+ sensory neurons mediate glabrous skin itch.

Itch arising from glabrous skin (palms and soles) has attracted limited attention within the field due to the lack of methodology. This is despite glabrous itch arising from many medical conditions such as plantar and palmar psoriasis, dyshidrosis, and cholestasis. Therefore, we developed a mouse glabrous skin behavioral assay to investigate the contribution of three previously identified pruriceptive neurons in glabrous skin itch. Our results show that MrgprA3+ and MrgprD+ neurons, although key mediators for hairy skin itch, do not play important roles in glabrous skin itch, demonstrating a mechanistic difference in itch sensation between hairy and glabrous skin. We found that MrgprC11+ neurons are the major mediators for glabrous skin itch. Activation of MrgprC11+ neurons induced glabrous skin itch, while ablation of MrgprC11+ neurons reduced both acute and chronic glabrous skin itch. Our study provides insights into the mechanisms of itch and opens up new avenues for future glabrous skin itch research.

Most Publications Regarding Platelet-Rich Plasma Use in the Knee Are From Asia, Investigate Injection for Osteoarthritis, and Show Outcome Improvement: A Scoping Review.

PURPOSE: To evaluate and synthesize the available literature related to platelet-rich plasma (PRP) treatment of knee pathologies and to provide recommendations to inform future research in the field. METHODS: PubMed, CINAHL, and Scopus databases were queried on October 6, 2023. All identified citations were collated and uploaded into Covidence for screening and data extraction. Studies were included if they were human studies published in English with adult cohorts that received PRP as a procedural injection or surgical augmentation for knee pathologies with patient-reported outcome measures (PROMs) and level of evidence Levels I-IV. RESULTS: Our search yielded 2,615 studies, of which 155 studies from 2006 to 2023 met the inclusion criteria. Median follow-up was 9 months (±11.2 months). Most studies (75.5%) characterized the leukocyte content of PRP, although most studies (86%) did not use a comprehensive classification scheme. In addition, most studies were from Asia (50%) and Europe (32%) and were from a single center (96%). In terms of treatment, 74% of studies examined PRP as a procedural injection, whereas 26% examined PRP as an augmentation. Most studies (68%) examined treatment of knee osteoarthritis. Many studies (83%) documented significant improvements in PROMs, including 93% of Level III/IV evidence studies and 72% of Level I/II evidence studies, although most studies (70%) failed to include minimal clinically important difference values. The visual analog scale was the most-used PROM (58% of studies), whereas the Short Form Health Survey 36-item was the least-used PROM (5% of studies). CONCLUSIONS: Most published investigations of knee PRP are performed in Asia, investigate procedural injection for osteoarthritis, and show significant outcome improvements. In addition, this review highlights the need for better classification of PRP formulations. LEVEL OF EVIDENCE: Level IV, scoping Review of level I-IV studies.

Distinct risk profiles for short-term surgical complications and venous thromboembolism exist among extensor mechanism repair procedures.

PURPOSE: Extensor mechanism injuries, which comprise patella fractures, patella tendon tears and quadriceps tendon tears, are severely debilitating injuries and a common cause of traumatic knee pathology that requires surgical intervention. Risk factors for short-term surgical complications and venous thromboembolism (VTE) in this population have not been well characterised. The aim of this study was to identify perioperative risk factors associated with these short-term complications. METHODS: The National Surgical Quality Improvement Program database was used to identify patients who underwent an isolated, primary extensor mechanism repair from 2015 to 2020. Patients were stratified by injury type. Demographic data were collected and compared. A multivariate logistic regression was used to control for demographic and comorbid factors while assessing risk factors for developing short-term complications. RESULTS: A total of 8355 patients were identified for inclusion in this study. Overall, 3% of patients sustained short-term surgical complications and 1% were diagnosed with VTE within 30 days of surgery. Patella fracture fixation had a nearly twofold higher risk for surgical complications compared to quadriceps tendon repair (p = 0.004). Patella tendon repair had a twofold higher risk for VTE (p = 0.045), specifically deep vein thrombosis (p = 0.020), compared to patella fracture fixation. Increasing age, smoking and American Society of Anesthesiologists Classifications 3 and 4 were also found to be risk factors for surgical complications (p = 0.012, p = 0.004, p = 0.011 and p = 0.032, respectively). CONCLUSION: This study used a nationally representative, widely validated, peer-reviewed database to provide valuable insights into risk factors for short-term postoperative complications associated with extensor mechanism repair procedures, revealing notable differences in risk profiles among distinct surgical procedures. The results of this study will inform surgeons and patients in enhancing risk assessment, guiding procedure-specific decision-making, optimising preoperative care, improving postoperative monitoring and contributing to future research of extensor mechanism injuries. LEVEL OF EVIDENCE: Level III.

All-soft tissue quadriceps tendon autograft and bone-patellar tendon-bone autograft demonstrate no significant ACL tunnel widening: An MRI comparison.

PURPOSE: This study sought to quantify the tunnel widening associated with quadriceps tendon (QT) autograft after anterior cruciate ligament reconstruction (ACLR) and compare it to bone-patellar tendon-bone (BTB) autografts. METHODS: A retrospective review of each ACLR performed at a single academic institution from 2011 to 2021 were reviewed. Subjects with repeat ipsilateral knee magnetic resonance imaging (MRI) studies performed after ACLR were included. Two reviewers independently measured the maximum diameter of the femoral and tibial tunnels 1 cm from the aperture. Tunnel widening was calculated as the difference between the initial drilled diameter and the measured diameters. RESULTS: Seventy-five patients (38 BTB and 37 QT autografts) were identified including 42 females and 33 males. With respect to graft type (QT vs. BTB), there was no statistically significant difference in median patient age (19.0 (16.0-31.5) years vs. 20.0 (16.8-30.0) years respectively; p = n.s.) or median time to MRI (12.0 [9.0-19.5] months vs. 13.0 [7.0-43.3] months respectively, p = n.s.). Mean tunnel diameter changes or widening was statistically significantly greater for QT autografts than BTB autografts at the tibial tunnel: (0.4 [±0.6] mm] vs. -0.4 [±1.1 mm; p < 0.001). Similarly, the mean tunnel diameter change was also significantly greater at the femoral tunnel for QT compared to BTB. (0.2 [±0.6] mm vs. -0.4 [±0.8] mm; p < 0.001) However, no patients with QT grafts demonstrated tibial or femoral tunnel diameters >12 mm. CONCLUSION: Although QT autografts had a statistically significant greater amount of tunnel widening compared to BTB autografts; the mean tibial and femoral net widening of 0.4 mm and 0.2 mm, respectively, does not meet previously reported clinically significant values. Thus, the tunnel widening presented in this study is unlikely to affect clinical outcomes and should not preclude the use of either graft. LEVEL OF EVIDENCE: Level III (Retrospective comparative study).

Genu Valgum in Pediatric Patients Presenting With Patellofemoral Instability.

BACKGROUND: Lower extremity valgus is a commonly described factor associated with patellofemoral instability (PFI) and, if identified before skeletal maturity, can be treated with guided growth. The prevalence of valgus alignment in the pediatric and adolescent PFI population is largely unknown. PURPOSE: The aim of this study was to report the prevalence of valgus alignment in adolescent patients presenting with PFI; with secondary assessment of high-grade valgus (zone II or III), coronal asymmetry, and associations of these findings with body mass index (BMI). STUDY DESIGN: A retrospective cohort study. METHODS: A total of 279 consecutive patients (349 knees) with a diagnosis of PFI presenting to a single orthopedic pediatric sport medicine surgeon were identified. A retrospective chart review was performed to collect demographic and clinical data, chronologic and bone age, sex, BMI, mechanism of injury, and the presence of osteochondral fracture. Full-length standing hip-to-ankle alignment radiographs were graded for knee alignment mechanical zone utilizing standard linear femoral head center to talar center assessment. In addition, mechanical axis deviation, mechanical lateral distal femoral angle and medial proximal tibial angle (MPTA) were also calculated. RESULTS: Mean patient age was 14.0±2.5 years. There were 162 (58.1%) females and mean BMI was 24.3±6.4. Seventy patients (25.1%) had bilateral PFI. Standing alignment radiographs were available for 81.4% of knees (n=284). Valgus alignment was present in 172 knees with PFI (60.6%). High-grade valgus, defined as zone 2 or greater, was present in 66 knees (23.3%). Overall, 48.9% had asymmetry of coronal alignment (n=139). The mean mechanical lateral distal femoral angle was 85.4±2.8 and the mean MPTA was 88.2±2.6. There was a greater MPTA in female patients (88.8±2.4 vs. 87.5±2.7, P <0.001). A higher BMI (24.87±6.95, P =0.03) was associated with valgus alignment. CONCLUSIONS: There is a high (60%) prevalence of lower extremity valgus in adolescent patients presenting with PFI, with nearly 1 in 4 presenting with high-grade valgus. The treatment team should be aware of this association as it may be an important consideration in the pediatric and adolescent PFI populations. LEVEL OF EVIDENCE: Level III.

Comparison of Gait and Functional Outcomes Between Open and Arthroscopic Treatment of Adolescent and Young Adult Femoroacetabular Impingement.

BACKGROUND: Management of femoroacetabular impingement (FAI) through an arthroscopic or surgical hip dislocation (SHD) approach has been shown to have similar clinical success and patient-reported outcomes. However, there are limited data comparing functional outcomes. The purpose of this study was to compare gait and functional outcomes of adolescent/young adult patients with FAI treated by either an arthroscopic or open SHD approach. METHODS: We identified prospectively enrolled adolescent/young adult patients (≤20 years old) who underwent surgical treatment for FAI through an SHD or arthroscopic approach. Participants were evaluated in a movement science lab preoperatively and postoperatively (minimum 8 months postoperatively) with barefoot walking and a 30-second single-limb balance trial on the affected side. Participants also completed the Harris Hip Score at the same timepoints. Differences from preoperative to postoperative were determined using a paired-samples t test for each surgical technique, and differences between the SHD and arthroscopic groups were determined using an independent samples t test (α=0.05). RESULTS: Fifty-five participants (42F, 16.2±1.4 y) were tested and grouped by surgical intervention. The SHD and arthroscopy groups consisted of 28 and 27 participants, respectively, with no significant difference between the SHD and arthroscopic cohorts in age (16.4±1.2 vs. 15.9±1.5 y, respectively, P =0.218) or sex distribution (78.6% vs. 74.1% females, respectively, P =0.75). Each group demonstrated significant postoperative improvement in Harris Hip Score (SHD: 64.8±16.4 to 81.8±17.8; arthroscopy: 57.0±16.7 to 84.7±19.7; preoperatively to postoperatively, respectively, both P <0.001). During gait, increased maximum hip flexion was observed following surgical intervention for the SHD group (32.3±5.7 vs. 36.1±5.2, P =0.003). No other clinically significant changes were detected in the SHD or arthroscopic groups preoperatively to postoperatively in trunk, pelvis, or hip kinematics in the coronal plane. During the balance task, neither cohort demonstrated markers of clinically significant abductor dysfunction. However, post operatively, the arthroscopy group was able to balance longer than the SHD group (18.8±7.8 vs. 14.2±2.7 s, respectively, P =0.008), although no differences were detected in trunk or pelvis position in the coronal plane during balance. CONCLUSIONS: Both open SHD and arthroscopic treatment of FAI resulted in improved clinical outcomes with no clinically significant abductor dysfunction 1 year post operatively. However, further study is needed to determine whether more dynamic tasks can potentially elicit subtle differences between the groups. LEVELS OF EVIDENCE: Level II-prospective study.

Risk Factors for Suboptimal Outcome of FAI Surgery in the Adolescent Patient.

BACKGROUND: Surgical treatment for adolescent patients with femoroacetabular impingement (FAI) is increasing. The purpose of this study was to determine the clinical outcomes of FAI surgery in a multicenter cohort of adolescent patients and to identify predictors of suboptimal outcomes. METHODS: One hundred twenty-six adolescent hips (114 patients < 18 years of age) undergoing surgery for symptomatic FAI were studied from a larger multicenter cohort. The group included 74 (58.7%) female and 52 male hips (41.3%) with a mean age of 16.1 (range 11.3 to 17.8). Clinical outcomes included the modified Harris Hip Score (mHHS), Hip disability and Osteoarthritis Outcome Score (5 domains), and University of California Los Angeles activity score. Failure was defined as revision surgery or clinical failure (inability to reach minimally clinical important differences or patient acceptable symptoms state for the mHHS). Statistical analysis was used to identify factors significantly associated with failure. RESULTS: There was clinically important improvement in all patient-reported outcomes for the overall group, but an 18.3% failure rate. This included a revision rate of 8.7%. Females were significantly more likely than males to be classified as a failure (25.7 vs. 7.7%, P =0.01), in part because of lower preoperative mHHS (59.1 vs. 67.0, P < 0.001). Mild cam deformity (alpha angle <55 degrees) was present in 42.5% of female hips compared with 17.3% male hips. Higher alpha angles were inversely correlated with failure. Alpha angles >63 have a failure rate of 8.3%, between 55 and 63 degrees, 12.0% failure rate, and <55 degrees (mild cam) failure rate of 37.5%. Patients who participated in athletics had a 10.3% failure rate compared with nonathletes at 25.0% ( P =0.03, RR (relative risk) 2.4). CONCLUSIONS: Adolescent patients undergoing surgical treatment for FAI generally demonstrate significant improvement. However, female sex, mild cam deformities, and lack of sports participation are independently associated with higher failure rates. These factors should be considered in surgical decision-making and during patient counseling. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Changes in Fracture Shortening Occur in the First 2 Weeks Following Completely Displaced Adolescent Clavicle Fractures.

BACKGROUND: Shortening of midshaft clavicle fractures has been described as a critical fracture characteristic to guide treatment. The degree to which shortening may change in the initial weeks following injury has not been well studied. The purpose of this study was to evaluate the change in shortening of adolescent clavicle fractures in the first 2 weeks following injury. METHODS: This was a multicenter study of prospectively collected data, which was acquired as a part of a cohort study of adolescent clavicle fractures. A consecutive series of patients 10 to 18 years of age with completely displaced diaphyseal clavicle fractures with baseline radiographs 0 to 6 days from the date of injury, as well as 7 to 21 days from the date of injury, were included. Measurements of end-to-end (EES) and cortex-to-corresponding-cortex (CCS) shortening were performed. RESULTS: A total of 142 patients were included. Baseline radiographs were obtained at a mean of 1.0 day following injury with mean EES of 22.3 mm, and 69% of patients demonstrating > 20 mm of shortening. Follow-up radiographs obtained at a mean of 13.8 days postinjury demonstrated a mean absolute change in EES of 5.4 mm. Forty-one percentage of patients had >5 mm of change in EES. When analyzing changes in shortening relative to the specific threshold of 20 mm, 18 patients (41%) with <20 mm EES increased to ≥20 mm EES, and 19 patients (19%) with ≥20 mm EES decreased to <20 mm EES at 2-week follow-up. CONCLUSIONS: Clinically significant changes in fracture shortening occurred in 41% of adolescents with completely displaced clavicle fractures in the first 2 weeks after injury. In 26% of patients, this resulted in a change from above or below the commonly used shortening threshold of 20 mm, potentially altering the treatment plan by many providers. There is no evidence to suggest that adolescent clavicle fracture shortening affects outcomes, and as such, the authors do not advocate for the use of this parameter to guide treatment. However, among physicians who continue to use this parameter to guide treatment, this study supports that repeat radiographic assessment 2 weeks postinjury may be a better measure of the true shortening of this common adolescent injury. LEVEL OF EVIDENCE: Level IV-case series.

Isothiourea-Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols.

The development of methods for the selective acylative kinetic resolution (KR) of tertiary alcohols is a recognised synthetic challenge with relatively few successful substrate classes reported to date. In this manuscript, a highly enantioselective isothiourea-catalysed acylative KR of tertiary pyrazolone alcohols is reported. The scope and limitations of this methodology have been developed, with high selectivity observed across a broad range of substrate derivatives incorporating varying substitution at N(2)-, C(4)- and C(5)-, as well as bicyclic constraints within the pyrazolone scaffold (30 examples, selectivity factors (s) typically >100) at generally low catalyst loadings (1 mol%). The application of this KR method to tertiary alcohols derived from a natural product (geraniol), alongside pharmaceutically relevant drug compounds (indomethacin, gemfibrozil and probenecid), with high efficiency (s > 100) is also described. The KR process is readily amenable to scale up, with effective resolution on a 50 g (0.22 mol) scale demonstrated. The key structural motif leading to excellent selectivity in this KR process has been probed through computation, with an NC=O•••isothiouronium interaction observed within the favoured transition state. Similarly, the effect of C(5)-aryl substitution that leads to reduced experimental selectivity is probed, with a competitive π-isothiouronium interaction identified as leading to reduced selectivity.

Reducing inequities in maternal and child health in rural Guatemala through the CBIO+ Approach of Curamericas: 10. Summary, cost effectiveness, and policy implications.

BACKGROUND: This is the final of 10 papers that describe the implementation of the Expanded Census-Based, Impact-Oriented Approach (CBIO+) by Curamericas/Guatemala in the Cuchumatanes mountains of the Department of Huehuetenango and its effectiveness in improving the health and well-being of women and children in a population of 98,000 in three municipalities. The CBIO+ Approach consists of three components: the CBIO (Census-Based, Impact-Oriented) Approach, the Care Group Approach, and the Community Birthing Center Approach. METHODS: Each of the preceding papers was summarized. An assessment was made regarding the degree to which the initial implementation research hypotheses were confirmed. The total field cost per capita for operation of the Project was calculated. An assessment of the cost-effectiveness of the Project was made based on the estimated impact of the Project, the number of lives saved, and the number of disability-adjusted life years averted. RESULTS: The Project attained a number of notable achievements in terms of expanding the coverage of key maternal and child health interventions, improving the nutritional status of children, reducing the mortality of children and mothers, providing quality care for mothers at the Community Birthing Centers (Casas Maternas Rurales) that integrate traditional midwives (comadronas) into the care of women during childbirth at the birthing centers, as well as empowering women and building social capital in the communities. CBIO+ is an effective and affordable approach that is particularly notable for its capacity to engage communities in the process of improving the health of mothers and children. Overall, there is strong and consistent evidence in support of the research hypotheses. The findings did produce evidence of declines in under-5 and maternal mortality, but they were not as robust as had been hoped. CONCLUSION: CBIO+ is an approach that has been effective in engaging communities in the process of improving the health of their mothers and children and in reducing health inequities in this marginalized, difficult-to-reach population of Indigenous Maya people. The CBIO+ Approach is cost-effective and merits further development and broader application in Guatemala and beyond.

Reducing inequities in maternal and child health in rural Guatemala through the CBIO+ Approach of Curamericas: 8. Impact on women's empowerment.

BACKGROUND: Indigenous Maya women in the rural highlands of Guatemala have traditionally faced constraints to decision-making and participation in community affairs. Anecdotal experiences from previous Curamericas Global projects in Guatemala and Liberia have suggested that interventions using the CBIO+ Approach (which consists of implementing together the Census-Based, Impact-Oriented Approach, the Care Group Approach, and Community Birthing Centers), can be empowering and can facilitate improvements in maternal and child health. This paper, the eighth in a series of 10 papers examining the effectiveness of CBIO+ in improving the health and well-being of mothers and children in an isolated mountainous rural area of the Department of Huehuetenango, explores changes in women's empowerment among mothers of young children associated with the Curamericas/Guatemala Maternal and Child Health Project, 2011-2015. METHODS: Knowledge, practice, and coverage (KPC) surveys and focus group discussions (FGDs) were used to explore six indicators of women's empowerment focusing on participation in health-related decision-making and participation in community meetings. KPC surveys were conducted at baseline (January 2012) and endline (June 2015) using standard stratified cluster sampling. Seventeen FGDs (9 with women, 3 with men, 2 with mothers-in-law, and 3 with health committees), approximately 120 people in all, were conducted to obtain opinions about changes in empowerment and to identify and assess qualitative factors that facilitate and/or impede women's empowerment. RESULTS: The KPC surveys revealed statistically significant increases in women's active participation in community meetings. Women also reported statistically significant increases in rates of participation in health-related decision-making. Further, the findings show a dose-response effect for two of the six empowerment indicators. The qualitative findings from FGDs show that the Project accelerated progress in increasing women's empowerment though women still face major barriers in accessing needed health care services for themselves and their children. CONCLUSION: The Project achieved some notable improvements in women's decision-making autonomy and participation in community activities. These improvements often translated into making decisions to practice recommended health behaviors. Traditional cultural norms and the barriers to accessing needed health services are not easily overcome, even when empowerment strategies are effective.