Rapid characterization of spike variants via mammalian cell surface display.

The SARS-CoV-2 spike protein is a critical component of vaccines and a target for neutralizing monoclonal antibodies (nAbs). Spike is also undergoing immunogenic selection with variants that increase infectivity and partially escape convalescent plasma. Here, we describe Spike Display, a high-throughput platform to rapidly characterize glycosylated spike ectodomains across multiple coronavirus-family proteins. We assayed ∼200 variant SARS-CoV-2 spikes for their expression, ACE2 binding, and recognition by 13 nAbs. An alanine scan of all five N-terminal domain (NTD) loops highlights a public epitope in the N1, N3, and N5 loops recognized by most NTD-binding nAbs. NTD mutations in variants of concern B.1.1.7 (alpha), B.1.351 (beta), B.1.1.28 (gamma), B.1.427/B.1.429 (epsilon), and B.1.617.2 (delta) impact spike expression and escape most NTD-targeting nAbs. Finally, B.1.351 and B.1.1.28 completely escape a potent ACE2 mimic. We anticipate that Spike Display will accelerate antigen design, deep scanning mutagenesis, and antibody epitope mapping for SARS-CoV-2 and other emerging viral threats.

Engineering a human P2X2 receptor with altered ligand selectivity in yeast.

P2X receptors are a family of ligand gated ion channels found in a range of eukaryotic species including humans but are not naturally present in the yeast Saccharomyces cerevisiae. We demonstrate the first recombinant expression and functional gating of the P2X2 receptor in baker's yeast. We leverage the yeast host for facile genetic screens of mutant P2X2 by performing site saturation mutagenesis at residues of interest, including SNPs implicated in deafness and at residues involved in native binding. Deep mutational analysis and rounds of genetic engineering yield mutant P2X2 F303Y A304W, which has altered ligand selectivity toward the ATP analog AMP-PNP. The F303Y A304W variant shows over 100-fold increased intracellular calcium amplitudes with AMP-PNP compared to the WT receptor and has a much lower desensitization rate. Since AMP-PNP does not naturally activate P2X receptors, the F303Y A304W P2X2 may be a starting point for downstream applications in chemogenetic cellular control. Interestingly, the A304W mutation selectively destabilizes the desensitized state, which may provide a mechanistic basis for receptor opening with suboptimal agonists. The yeast system represents an inexpensive, scalable platform for ion channel characterization and engineering by circumventing the more expensive and time-consuming methodologies involving mammalian hosts.

Cognitive-behavioral therapy for avoidant/restrictive food intake disorder: A proof-of-concept for mechanisms of change and target engagement.

BACKGROUND: Cognitive-behavioral therapy for avoidant/restrictive food intake disorder (ARFID; CBT-AR) theoretically targets three prototypic motivations (sensory sensitivity, lack of interest/low appetite, fear of aversive consequences), aligned with three modularized interventions. As an exploratory investigation, we: (1) evaluated change in candidate mechanisms in relationship to change in ARFID severity, and (2) tested if assignment (vs. not) to a module resulted in larger improvements in the corresponding mechanism. METHOD: Males and females (N = 42; 10-55 years) participated in an open trial of CBT-AR. RESULTS: Decreases in scaled scores for each candidate mechanism had medium to large correlations with decreases in ARFID severity-sensory sensitivity: -0.7 decrease (r = .42, p = .01); lack of interest/low appetite: -0.3 decrease (r = .60, p < .0001); and fear of aversive consequences: -1.1 decrease (r = .33, p = .05). Linear mixed models revealed significant weekly improvements for each candidate mechanism across the full sample (ps < .0001). There were significant interactions for the sensory and fear of aversive consequences modules-for each, participants who received the corresponding module had significantly larger decreases in the candidate mechanism than those who did not receive the module. DISCUSSION: Sensory sensitivity and fear of aversive consequences improved more if the CBT-AR module was received, but lack of interest/low appetite may improve regardless of receipt of the corresponding module. Future research is needed to test target engagement in CBT-AR with adaptive treatment designs, and to identify valid and sensitive measures of candidate mechanisms. PUBLIC SIGNIFICANCE: The mechanisms through which components of CBT-AR work have yet to be elucidated. We conducted an exploratory investigation to test if assignment (vs. not) to a CBT-AR module resulted in larger improvements in the corresponding prototypic ARFID motivation that the module intended to target. Measures of the sensory sensitivity and the fear of aversive consequences motivations improved more in those who received the corresponding treatment module, whereas the lack of interest/low appetite measure improved regardless of if the corresponding module was received.

A Humanized CB1R Yeast Biosensor Enables Facile Screening of Cannabinoid Compounds.

Yeast expression of human G-protein-coupled receptors (GPCRs) can be used as a biosensor platform for the detection of pharmaceuticals. Cannabinoid receptor type 1 (CB1R) is of particular interest, given the cornucopia of natural and synthetic cannabinoids being explored as therapeutics. We show for the first time that engineering the N-terminus of CB1R allows for efficient signal transduction in yeast, and that engineering the sterol composition of the yeast membrane modulates its performance. Using an engineered cannabinoid biosensor, we demonstrate that large libraries of synthetic cannabinoids and terpenes can be quickly screened to elucidate known and novel structure-activity relationships. The biosensor strains offer a ready platform for evaluating the activity of new synthetic cannabinoids, monitoring drugs of abuse, and developing therapeutic molecules.

Changes in Body Composition and Athletic Performance in National Collegiate Athletic Association Division I Female Field Hockey Athletes Throughout a Competitive Season.

ABSTRACT: Summer, LC, Cheng, R, Moran, JT, Lee, M, Belanger, AJ, TaylorIV, WL, and Gardner, EC. Changes in body composition and athletic performance in National Collegiate Athletic Association Division I female field hockey athletes throughout a competitive season. J Strength Cond Res 38(1): 146-152, 2024-The purposes of this study were (a) to analyze the changes in total and regional body composition measurements in a National Collegiate Athletic Association (NCAA) Division I female field hockey team throughout a 17-game competitive season using dual X-ray absorptiometry (DXA); (b) to examine improvements, if any, in athletic performance measures after a season; and (c) to report on the relationship between these body composition changes and changes in athletic performance. Preseason and postseason dual-energy DXA and performance data from the 2019-2020 season were retrospectively identified for 20 field players (forwards, midfielders, and defenders). Body composition data included total and regional fat mass, lean mass, and body fat percentage, whereas athletic performance measures included the vertical jump, 10-yard dash, and pro-agility (5-10-5) shuttle run. All variables were quantitative and analyzed using paired t -tests or its nonparametric equivalent and an alpha level of p < 0.05 was used to determine significance. After a competitive season, athletes had significant decreases in fat mass and increases in lean mass in their arms, legs, trunks, gynoids, and total body measurements. Android fat mass and body fat percentage also decreased. Athletes performed significantly better on the pro-agility shuttle run at the end of the season, but no significant differences were observed in other performance metrics. Moderate correlations were observed between changes in body composition (total fat mass and total lean mass) and changes in athletic performance. Our study provides a novel, longitudinal assessment of body composition and athletic performance for elite female field hockey athletes that will help trainers and coaches better understand how these variables change throughout a season and allow them to better prepare their players for competitive success.

Discriminative Ability of Lower limb Strength and Power Measures in Lacrosse Athletes.

The objective of this investigation was to compare isokinetic strength, countermovement jump and drop jump variables between high-contributors and low-contributors within NCAA Division I Men's and Women's lacrosse athletes. Men's (N=36) and Women's (N=30) NCAA Division I lacrosse athletes completed strength testing of the quadriceps and hamstring across three speeds (60°·s-1, 180°·s-1, 300°·s-1), countermovement and drop jumps. To determine the discriminative ability of select lower-limb strength and power characteristics participants were categorized as high-contributors (Males N=18, age=20.3±0.4 yrs, height=183.9±5.5 cm, mass=90.8±5.8 kg; Females N=15, age=20.8±0.8 yrs, height=169.3±6.7 cm, mass=64.1±7.2 kg) or low-contributors (Males N=18, age=19.5±0.2 yrs, height=184.1±5.6 cm; mass=87.9±8.1 kg; Females N=15, age=19.7±0.2 yrs, height=169.8±7.0 cm, mass=62.9±7.7 kg ) based upon the number of games the participants competed in during the regular season. Within the male cohort, moderate significant (p<0.05) differences were observed between high-contributors and low-contributors in isokinetic hamstring strength of the left leg at 300°·s-1 (d=0.69) and peak power in countermovement jump (d=0.68). Within the women's cohort a large (d=0.87) significant difference (p<0.05) in isokinetic strength of the left hamstring was observed between high-contributors and low-contributors at 60°·s-1. Hamstring strength and lower-limb power are important strength measures for lacrosse performance and should be prioritized in training prescription for lacrosse athletes.

Building Community Partnership to Sustain the Minnesota Student Parent Support Initiative.

PURPOSE: Considerable attention has been given to the sustainability of adolescent health programs as federal funds have become limited. This article describes important steps and lessons learned in seeking buy-in from stakeholders to promote sustainability and secure non-federal funds to maintain the Minnesota Student Parent Support Initiative (MSPSI) after federal funding ended. DESCRIPTION: MSPSI was established in 2010 to address the academic and health needs of expectant and parenting postsecondary students. MSPSI provided coordinated case management and referrals to health, education, and social services for expectant and parenting adolescents, as well as for their children, through Student Parent Centers (SPCs). Six important actions sustained the SPCs after the Office of Population Affairs (OPA) grant funds ended in November 2017: (1) preparing and planning for sustainability, (2) creating and engaging a sustainability committee, (3) assessing sustainability needs and creating a sustainability plan, (4) creating a data system to collect relevant data, (5) building capacity to support communication with decision makers, and (6) sharing data and success stories. ASSESSMENT: The implementation of the sustainability plan resulted in ongoing communications and data sharing with key partners that helped secure additional funds for continuing the program after OPA funding ended. CONCLUSION: Implementing the MSPSI sustainability plan developed from OPA's sustainability framework was effective in sustaining the SPCs after federal funding ended. The sustainability planning, the ability to secure funds, the attempt at passing legislation, and the lessons shared in this article provide valuable guidance to organizations seeking strategies to sustain adolescent health programs.

Injury patterns and risk factors for orthopaedic trauma from snowboarding and skiing: a national perspective.

PURPOSE: Alpine skiing and snowboarding are both popular winter sports that can be associated with significant orthopaedic injuries. However, there is a lack of nationally representative injury data for the two sports. METHODS: The National Trauma Data Bank was queried for patients presenting to emergency departments due to injuries sustained from skiing and snowboarding during 2011 and 2012. Patient demographics, comorbidities, and injury patterns were tabulated and compared between skiing and snowboarding. Risk factors for increased injury severity score and lack of helmet use were identified using multivariate logistic regression. RESULTS: Of the 6055 patients identified, 55.2 % were skiers. Sixty-one percent had fractures. Lower extremity fractures were the most common injury and occurred more often in skiers (p < 0.001). Upper extremity fractures were more common in snowboarders, particularly distal radius fractures (p < 0.001). On multivariate analysis, increased injury severity was independently associated with age 18-29, 60-69, 70+, male sex, a positive blood test for alcohol, a positive blood test for an illegal substance, and wearing a helmet. Lack of helmet use was associated with age 18-29, 30-39, smoking, a positive drug test for an illegal substance, and snowboarding. CONCLUSIONS: Young adults, the elderly, and those using substances were shown to be at greater risk of increased injury severity and lack of helmet use. The results of this study can be used clinically to guide the initial assessment of these individuals following injury, as well as for targeting preventive measures and education. LEVEL OF EVIDENCE: Prognostic Level III.

The epidemiology of back/neck/spine injuries in National Collegiate Athletic Association men's and women's ice hockey, 2009/2010 to 2014/2015.

This study describes the epidemiology of back/neck/spine injuries in National Collegiate Athletic Association (NCAA) men's and women's ice hockey. Data from 66 NCAA men's and 29 women's ice hockey programmes (total of 147 and 67 team-seasons, respectively) were analysed from the NCAA Injury Surveillance Program during the 2009/2010-2014/2015 academic years. In the study period, 226 and 97 back/neck/spine injuries were reported in men and women, respectively, for injury rates of 0.56 and 0.65/1000 athlete exposures. Injury rates were higher in competitions than practices in men (injury rate ratio [IRR] = 4.22; 95% confidence interval [CI]: 3.24-5.49) and women (IRR = 2.49; 95% CI: 1.67-3.70). Most injuries occurred in the lower back/lumbar spine (men: 52.2%; women: 48.5%). There were notably low rates of fractures and severe spinal injuries for both sexes. This study enhances our understanding of the incidence, mechanisms and factors influencing these injuries and can ultimately lead to more effective injury prevention.

NK cell maturation and function in C57BL/6 mice are altered by caloric restriction.

NK cells are a heterogenous population of innate lymphocytes with diverse functional attributes critical for early protection from viral infections. We have previously reported a decrease in influenza-induced NK cell cytotoxicity in 6-mo-old C57BL/6 calorically restricted (CR) mice. In the current study, we extend our findings on the influence of CR on NK cell phenotype and function in the absence of infection. We demonstrate that reduced mature NK cell subsets result in increased frequencies of CD127(+) NK cells in CR mice, skewing the function of the total NK cell pool. NK cells from CR mice produced TNF-α and GM-CSF at a higher level, whereas IFN-γ production was impaired following IL-2 plus IL-12 or anti-NK1.1 stimulation. NK cells from CR mice were highly responsive to stimulation with YAC-1 cells such that CD27(-)CD11b(+) NK cells from CR mice produced granzyme B and degranulated at a higher frequency than CD27(-)CD11b(+) NK cells from ad libitum fed mice. CR has been shown to be a potent dietary intervention, yet the mechanisms by which the CR increases life span have yet to be fully understood. To our knowledge, these findings are the first in-depth analysis of the effects of caloric intake on NK cell phenotype and function and provide important implications regarding potential ways in which CR alters NK cell function prior to infection or cancer.

Telerehabilitation to Address the Rehabilitation Gap in Anterior Cruciate Ligament Care: Survey of Physical Therapists/Care Providers.

Background: While the importance of structured rehabilitation following anterior cruciate ligament reconstruction (ACLR), particularly in the return-to-sport phase, is known, for most patients, supervised physical therapy is often completed before this time point. The recent emergence of telerehabilitation and other digital health interventions has the potential to address this "rehabilitation gap." Methods: The study was conducted as a cross-section, online survey collecting qualitative and quantitative data from open and closed questions. Inclusion criteria included local qualified physical therapists or other professionals working with ACLR patients. Results: Eighty-three percent of respondents experienced a "rehabilitation gap" with their ACLR patients. Few reported currently utilizing apps or websites (9.74%). The majority (41/58) reported experience with telerehabilitation, and 84% felt that there was a role for digital rehabilitation strategies to address the "rehabilitation gap." The vast majority (94.74%) of participants felt that standard commercial insurance did not permit sufficient rehabilitation. Discussion: While the majority of our respondents acknowledged the existence of a "rehabilitation gap," as well as familiarity with and confidence in telerehabilitation, few were using this technique at the time of our survey. This suggests an opportunity for development in this space.

Describing the women of orthopaedic surgery.

Aims: The purpose of this survey study was to examine the demographic and lifestyle factors of women currently in orthopaedic surgery. Methods: An electronic survey was conducted of practising female orthopaedic surgeons based in the USA through both the Ruth Jackson Society and the online Facebook group "Women of Orthopaedics". Results: The majority of surveyed female orthopaedic surgeons reported being married (76.4%; 285/373) and having children (67.6%; 252/373). In all, 66.5% (247/373) were collegiate athletes; 82.0% (306/373) reported having no female orthopaedic surgeon mentors in undergraduate and medical school. Their mean height is 65.8 inches and average weight is 147.3 lbs. Conclusion: The majority of female orthopaedic surgeons did not have female mentorship during their training. Additionally, biometrically, their build is similar to that of the average American woman.

Orthopaedic Injury Patterns Related to Ice Skating, Inline Skating, and Roller Skating: A 20-Year Epidemiologic Analysis.

Background: Ice skating, inline skating, and roller skating are popular sports in the United States (US). Although they are similar, injuries incurred may be distinct and may have evolved over time. Purpose: To characterize injuries related to ice skating, inline skating, and roller skating and track injury patterns over a 20-year period. Study Design: Descriptive epidemiology study. Methods: The current study utilized the National Electronic Injury Surveillance System, a database reporting consumer product-related injuries seen at emergency departments in the US. All ice skating, inline skating, and roller skating injuries between 2002 and 2021 were identified, and patient demographics, types of injury, and year of injury were compared between skating types. Results: A total of 1,656,746 skating-related injuries were estimated nationally: 24% (403,791) for ice skating, 24% (400,172) for inline skating, and 52% (852,783) for roller skating. While the incidence of ice-skating- and roller-skating-related injuries decreased by 34.4% (from 22,490 in 2002-2004 to 14,758 in 2019-2021) and 29.6% (from 42,452 in 2002-2004 to 31,980 in 2019-2021), respectively, injuries related to inline skating decreased comparatively more, by 75.8% over the study period (from 48,097 in 2002-2004 to 11,662 in 2019-2021). Injuries occurred predominantly to the head/face/neck for ice skating (n = 139,501; 34.5% of injuries), whereas injuries occurred predominantly in the shoulder/arm/elbow/wrist for inline skating (n = 212,088, 53.0% of injuries) and roller skating (n = 425,216, 49.9% of injuries). Fracture was the most common injury type for all 3 skating types (n = 614,853, 37.1% of injuries), and the majority of fractures occurred in the upper extremity (shoulder/arm/elbow/wrist) for all 3 skating types (n = 59,624, 60.0% [ice skating]; n = 69,197, 41.2% [inline skating], and n = 237,099, 68.2% [roller skating]). Lower extremity (leg/knee/ankle) fractures were more common among ice skating (n = 28,019, 28.2%) and roller skating (n = 82,094, 23.6%) injuries compared with inline skating (n = 21,391, 12.7%). Conclusion: In the current study, we found that fractures were the most common type of injury regardless of skating type but that the location of the injury/fracture varied by skating type.

An Epidemiological Study of Cell Phone-Related Injuries of the Hand and Wrist Reported in United States Emergency Departments From 2011 to 2020.

Purpose: Increasing ownership and use of mobile phones has been recently linked to reports of hand and wrist pain from overuse, as well as more serious injuries related to distracted behaviors, such as falls and texting while driving. We describe the epidemiology of hand and wrist injuries presenting to US emergency departments from 2011 to 2020, which were associated with cell phone use using the Consumer Product Safety Commission's National Electronic Injury Surveillance System. Methods: The National Electronic Injury Surveillance System database was queried for treatment records from 2011 through to 2020 for all cell phone-related injuries of the lower arm, wrist, hand, and fingers. Using parameters provided by the National Electronic Injury Surveillance System database, there were 1,213 unique cases, yielding a total weighted estimate of 50,487 national cases presenting to emergency departments in the United States. Results: Between 2011 and 2020, the weighted estimate of annual cell phone-related injuries ranged from 3,389 to 7,320 cases. Falls were the most common cause of injury, accounting for 29.8% of estimated cases. The most common types of injuries were lacerations (22.3%). The national estimate of cell phone-related injury was the highest in the age range of 11-20 years (26.4%), followed by 21-30 years (22.2%). Women were affected more frequently than men (59.6% vs 40.4%). Conclusions: Upper extremity injuries related to cell phone use represent an increasing burden of disease to the US healthcare system. Raising awareness regarding cell phone-related injuries and in-home fall-prevention strategies, especially among elderly individuals, should be considered as means of decreasing the number of such injuries. Strategies for decreasing the burden of cell phone-related injuries occurring as a result of falls among teenagers and young adults should focus on minimizing distractions while using a cell phone. Limitations of the study include inaccuracies related to probability-weighted case estimation and limitations in reporting injuries. Clinical relevance: Knowledge of the burden of upper extremities injuries associated with this common handheld device can help to both raise awareness of this issue, as well as to potentially inform injury-prevention strategies.

Bucket-Handle Meniscus Tear Management With Meniscectomy Versus Repair Correlates With Patient, Socioeconomic, and Hospital Factors.

INTRODUCTION: Bucket-handle meniscus tears are common knee injuries that are often treated surgically with meniscectomy or meniscal repair. Although clinical factors may influence the choice of one treatment approach over the other, the influence of patient, socioeconomic, and hospital factors remains poorly characterized. This study aimed to estimate the relative nationwide utilization of these two procedures and delineate a variety of factors that are associated with the selection of one treatment approach over the other. METHODS: Meniscal repair and meniscectomy procedures conducted for isolated bucket-handle meniscus tears in 2016 and 2017 were identified in the Nationwide Ambulatory Surgery Sample database. Cases were weighted using nationally representative discharge weights. Univariate analyses and a multivariable logistic regression model were used to compare patient, socioeconomic, and hospital factors associated with meniscal repair versus meniscectomy. RESULTS: In total, 12,239 cases were identified, which represented 17,236 cases after weighting. Of these, meniscal repair was conducted for 4,138 (24.0%). Based on the logistic regression model, meniscal repair was less likely for older and sicker patients. By contrast, several factors were associated with markedly higher odds of undergoing meniscal repair compared with meniscectomy. These included urban teaching hospitals; geographic location in the midwest, south, and west; and higher median household income. DISCUSSION: Using a large nationally representative cohort, the current data revealed that only 24.0% of surgically treated bucket-handle meniscus tears were treated using repair. Identification of patient, socioeconomic, and hospital factors differentially associated with meniscal repair suggest that other factors may systematically influence surgical decision-making for this patient population. Surgeons should be conscious of these potential healthcare disparities when determining the optimal treatment for their patients. LEVEL OF EVIDENCE: Level III.

Previous Isolated Medial Bucket-Handle Meniscus Repair Significantly Increases Risk of Subsequent Ipsilateral Anterior Cruciate Ligament Reconstruction.

Purpose: (1) To define the incidence of surgically treated isolated bucket-handle meniscus tears (BHMTs); (2) to investigate risk of subsequent ipsilateral anterior cruciate ligament reconstruction (ACLR) in patients who underwent previous isolated bucket handle (BH) meniscus repair; and (3) to investigate the risk of subsequent ACLR for various types of surgically treated meniscal tears. Methods: A retrospective review of a national database was conducted to identify patients, aged 10 to 40 years, who underwent primary isolated BH meniscus surgery from 2015 to 2020. Patients were stratified by operative method. A control group of 500,000 age-matched patients was randomly selected to establish a benchmark rate of ACLR. Kaplan-Meier analysis was performed to compare the timing and incidence of subsequent ipsilateral ACLR after primary isolated BH meniscus surgery to the control group within 2 and 5 years. Results: In total, 1,767 patients with isolated BHMTs treated with surgery were identified and met inclusion criteria. The incidence of isolated BHMTs among all surgically treated (repair or meniscectomy) meniscal injuries was 1.67%. Isolated BH repairs had significantly greater odds of ACLR within 5 years compared to the control group (odds ratio [OR] 6.09; 95% confidence interval [CI] 2.86-12.99; P < .001). Medial BH repairs had the greatest odds of ACLR within 5 years (OR 9.15; 95% CI 4.27-19.57; P < .001). Lateral BH repair was not associated with subsequent ipsilateral ACLR within 5 years (OR 2.63; CI 0.37-18.90; P = .340). Conclusions: Isolated BHMTs comprised 1.67% of all surgically treated meniscal injuries. Patients who underwent prior surgery for isolated BHMT were at increased risk of undergoing subsequent ipsilateral ACLR compared with the general population. Isolated medial BHMTs treated with repair had the highest risk for subsequent ACLR. Level of Evidence: Level III, retrospective cohort study.

SARS-COV-2 Omicron variants conformationally escape a rare quaternary antibody binding mode.

The ongoing evolution of SARS-CoV-2 into more easily transmissible and infectious variants has provided unprecedented insight into mutations enabling immune escape. Understanding how these mutations affect the dynamics of antibody-antigen interactions is crucial to the development of broadly protective antibodies and vaccines. Here we report the characterization of a potent neutralizing antibody (N3-1) identified from a COVID-19 patient during the first disease wave. Cryogenic electron microscopy revealed a quaternary binding mode that enables direct interactions with all three receptor-binding domains of the spike protein trimer, resulting in extraordinary avidity and potent neutralization of all major variants of concern until the emergence of Omicron. Structure-based rational design of N3-1 mutants improved binding to all Omicron variants but only partially restored neutralization of the conformationally distinct Omicron BA.1. This study provides new insights into immune evasion through changes in spike protein dynamics and highlights considerations for future conformationally biased multivalent vaccine designs.

Energy intake and response to infection with influenza.

Influenza is a worldwide public health concern, particularly with emerging new strains of influenza to which vaccines are ineffective, limited, or unavailable. In addition, the relationship between adequate nutrition and immune function has been repeatedly demonstrated. Mouse models provide strong evidence that energy extremes, including energy restriction (ER) and diet-induced obesity (DIO), have deleterious effects on the immune response to influenza infection. Both ER and DIO mice demonstrate increased susceptibility and mortality to influenza infection. The effects of ER are more pronounced during innate responses to influenza infection, whereas the effects of DIO are evidenced during innate and adaptive responses to both primary and secondary infection. There are striking similarities between ER and DIO during influenza infection, including impaired natural killer cell function and altered inflammation. Future studies must develop effective nutritional paradigms to offset the effects of these energy extremes on the immune response to an acute infection.

Supplementation with galacto-oligosaccharides increases the percentage of NK cells and reduces colitis severity in Smad3-deficient mice.

The gut microbiota plays an essential role in intestinal immunity. Prebiotics, including galacto-oligosaccharides (GOS), are fermentable fibers that beneficially affect the host by stimulating the growth of specific microbial populations. We investigated the effect of GOS on colitis development and on immune variables in Smad3-deficient mice treated with the pathogen Helicobacter hepaticus. Mice were supplemented daily with 5000 mg GOS/kg body weight 2 wk prior to infection and 4 wk postinfection, a time period during which colitis severity peaks in this model. Mice (n = 4-8/treatment at each time) were killed preinfection (0 d) and at 3, 7, and 28 d postinfection to evaluate immune variables in the spleen and in mesenteric lymph nodes (MsLN) by flow cytometry. Colon and cecum samples were collected for histopathologic analysis. Fecal pellets (n = 8-9/treatment) were collected prior to infection to measure relative changes in Bifidobacterium ssp. and Lactobacillum ssp. by real-time PCR. GOS significantly reduced colitis severity in response to H. hepaticus (P < 0.0001). This was associated with a significant increase in the percentage of NK cells in the spleen (P < 0.001) and in MsLN (P < 0.001) at 3 d postinfection and a 1.5-fold increase in fecal Bifidobacterium ssp. (P = 0.003). GOS stimulated NK expression of CCR9, a chemokine receptor involved in lymphocyte trafficking to the gut preinfection (0 d) in the blood (P = 0.02), spleen (P = 0.033), and MsLN (P = 0.017). In addition, GOS stimulated colonic IL-15 production 3 d postinfection (P < 0.001). These data suggest that GOS reduces colitis by modulating the function and trafficking of NK cells and may provide a novel therapeutic strategy for individuals with inflammatory bowel disease.

Coronal Malalignment-When and How to Perform a Tibial Tubercle Osteotomy.

Coronal malalignment of the patellofemoral joint may contribute to both instability as well as pain and joint overload. The use of distal realignment procedures has evolved to include uniplanar and multiplanar osteotomies, which allows patient-specific treatment. With a careful understanding of the complex pathoanatomy, including osseous, soft tissue, and dynamic muscular factors, an appropriately designed tibial tubercle osteotomy (TTO) is an invaluable tool for the orthopedic surgeon to improve joint biomechanics and off-load articular injuries. Current techniques have improved TTO surgery to limit complications and produce reliably good results.