Clinical immunogenicity outcomes from GENEr8-1, a phase 3 study of valoctocogene roxaparvovec, an AAV5-vectored gene therapy for hemophilia A.

Gene transfer therapies utilizing adeno-associated virus (AAV) vectors involve a complex drug design with multiple components that may impact immunogenicity. Valoctocogene roxaparvovec is an AAV serotype 5 (AAV5)-vectored gene therapy for treatment of hemophilia A that encodes a B-domain-deleted human factor VIII (FVIII) protein controlled by a hepatocyte-selective promoter. Following previous results from the first-in-human phase 1/2 clinical trial, we assessed AAV5 capsid- and transgene-derived FVIII-specific immune responses with 2 years of follow-up data from GENEr8-1, a phase 3, single-arm, open-label study in 134 adult men with severe hemophilia A. No FVIII inhibitors were detected following administration of valoctocogene roxaparvovec. Immune responses were predominantly directed toward the AAV5 capsid, with all participants developing durable anti-AAV5 antibodies. Cellular immune responses specific for the AAV5 capsid were detected in most participants by interferon-ᵧ enzyme-linked immunosorbent spot assay 2 weeks following dose administration and declined or reverted to negative over the first 52 weeks. These responses were weakly correlated with alanine aminotransferase elevations and showed no association with changes in FVIII activity. FVIII-specific cellular immune responses were less frequent and more sporadic compared with those specific for AAV5 and showed no association with safety or efficacy parameters.

Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model.

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen. METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen. RESULTS: A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population. CONCLUSIONS: The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers. CLINICAL TRIAL REGISTRATION: NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.

Early results of combined total ankle total talus replacement in the revision setting.

BACKGROUND: Revision of failed total ankle replacement (TAR) is challenging and associated with increased morbidity. Given the increased popularity of TAR in treating end-stage ankle arthritis (ESAA), viable revision options are needed. The objective of this case series is to present a minimum 2-year clinical and radiographic outcomes of patient-specific custom 3D-printed total ankle total talus (TATR) prostheses in this unique subset of patients. METHODS: 19 participants with ESAA and failed primary TAR who underwent TATR by a single surgeon at our institution from 2019 to 2021 were retrospectively identified. All participants were indicated for revision of primary STAR implant (Stryker, Kalamazoo, MI) and underwent replacement with 3D-printed titanium implants based on preoperative CT analysis (Additive Orthopaedics, Little Silver, NJ). Custom components included a mobile-bearing total talus and stemmed tibial system, performed through an anterior approach. Pre- and postoperative patient-reported outcomes were assessed using the Patient Reported Outcomes Measurement Information System (PROMIS). Pre- and postoperative implant alignment was assessed using medial distal tibial angle (MDTA) and tibiotalar angle (TTA) on anteroposterior, and sagittal tibial angle (STA) on lateral weight-bearing plain films. RESULTS: The average patient age was 60.6 (range, 39-77) years, with an average follow-up of 37.9 (range, 25.3-57.5) months. There was statistically significant improvement in all PROMIS domains. Short-term survivorship was 100%, with two participants (11.0%) requiring reoperation for postoperative complications: one underwent open reduction internal fixation of the tibia for a periprosthetic fracture, and another underwent medial gutter debridement and tarsal tunnel release for recurrent pain. There were no significant differences in pre- versus postoperative radiographic alignment measured by MDTA (89.9 vs 86.4), TTA (89.7 vs 88.1), or STA (85.2 vs 85.3). CONCLUSION: Custom 3D-printed TATR is a promising option for revision TAR. There was significant short-term improvement in pain and physical function, with excellent short-term survivorship and an acceptable postoperative complication rate.

Randomized self-controlled study comparing open-face vs. closed immobilization masks in fractionated cranial radiotherapy.

PURPOSE: To compare patient discomfort and immobilisation performance of open-face and closed immobilization masks in cranial radiotherapy. MATERIAL AND METHODS: This was a single-center randomized self-controlled clinical trial. At CT simulation, an open-face and closed mask was made for each patient and treatment plans with identical dose prescription were generated for each mask. Patients were randomised to start treatment with an open-face or closed mask. Masks were switched halfway through the treatment course; every patient was their own control. Patients self-reported discomfort, anxiety and pain using the visual analogue scale (VAS). Inter- and intrafraction set-up variability was measured with planar kV imaging and a surface guided radiotherapy (SGRT) system for the open-face masks. RESULTS: 30 patients with primary or metastatic brain tumors were randomized - 29 completed radiotherapy to a median total dose of 54 Gy (range 30-60 Gy). Mean discomfort VAS score was significantly lower with open-face masks (0.5, standard deviation 1.0) vs. closed masks (3.3, standard deviation 2.9), P < 0.0001. Anxiety and pain VAS scores were significantly lower with open-face masks (P < 0.0001). Closed masks caused more discomfort in infraorbital (P < 0.001) and maxillary (P = 0.02) areas. Two patients and 27 patients preferred closed or open-face masks, respectively. Interfraction longitudinal shifts and roll and yaw rotations were significantly smaller and lateral shifts were significantly larger with closed masks in combination with the laser system (P < 0.05) compared to open masks in combination with a SGRT system. Intrafraction variability did not differ between the masks. CONCLUSIONS: Open-face masks are associated with decreased patient discomfort without compromising patient positioning and immobilisation accuracy.

Recognition of nonself is necessary to activate Drosophila's immune response against an insect parasite.

BACKGROUND: Innate immune responses can be activated by pathogen-associated molecular patterns (PAMPs), danger signals released by damaged tissues, or the absence of self-molecules that inhibit immunity. As PAMPs are typically conserved across broad groups of pathogens but absent from the host, it is unclear whether they allow hosts to recognize parasites that are phylogenetically similar to themselves, such as parasitoid wasps infecting insects. RESULTS: Parasitoids must penetrate the cuticle of Drosophila larvae to inject their eggs. In line with previous results, we found that the danger signal of wounding triggers the differentiation of specialized immune cells called lamellocytes. However, using oil droplets to mimic infection by a parasitoid wasp egg, we found that this does not activate the melanization response. This aspect of the immune response also requires exposure to parasite molecules. The unidentified factor enhances the transcriptional response in hemocytes and induces a specific response in the fat body. CONCLUSIONS: We conclude that a combination of danger signals and the recognition of nonself molecules is required to activate Drosophila's immune response against parasitic insects.

East Asian summer monsoon delivers large abundances of very-short-lived organic chlorine substances to the lower stratosphere.

Deep convection in the Asian summer monsoon is a significant transport process for lifting pollutants from the planetary boundary layer to the tropopause level. This process enables efficient injection into the stratosphere of reactive species such as chlorinated very-short-lived substances (Cl-VSLSs) that deplete ozone. Past studies of convective transport associated with the Asian summer monsoon have focused mostly on the south Asian summer monsoon. Airborne observations reported in this work identify the East Asian summer monsoon convection as an effective transport pathway that carried record-breaking levels of ozone-depleting Cl-VSLSs (mean organic chlorine from these VSLSs ~500 ppt) to the base of the stratosphere. These unique observations show total organic chlorine from VSLSs in the lower stratosphere over the Asian monsoon tropopause to be more than twice that previously reported over the tropical tropopause. Considering the recently observed increase in Cl-VSLS emissions and the ongoing strengthening of the East Asian summer monsoon under global warming, our results highlight that a reevaluation of the contribution of Cl-VSLS injection via the Asian monsoon to the total stratospheric chlorine budget is warranted.

Distinct T cell polyfunctional profile in SARS-CoV-2 seronegative children associated with endemic human coronavirus cross-reactivity.

SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on SARS-CoV-2 antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were detectable in 83% of seropositive and 60% of seronegative children. Although the magnitude of the CD4+ T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4+ T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children.

Normal Values for Distal Tibiofibular Syndesmotic Space With and Without Subject-Driven External Rotation Stress.

BACKGROUND: The diagnosis and treatment of distal tibiofibular syndesmosis (DTFS) injury can be challenging, especially in cases of subtle instability that may be masked on 2-dimensional conventional radiographs. Weightbearing computed tomography (WBCT) has recently emerged as a useful diagnostic tool allowing direct assessment of distal tibiofibular area widening. The purpose of the current study was to examine and report normal threshold values for DTFS area measurements in a cohort of healthy volunteers, assessing the ankles in natural weightbearing position and under subject-driven external rotation stress. METHODS: In this prospective study, we enrolled 25 healthy volunteers without a history of DTFS injury or high ankle sprain, previous foot and ankle surgery, or current ankle pain. Subjects with any prior ankle injuries were excluded. Study participants underwent bilateral standing nonstress and external rotation stress WBCT scans. The DTFS area (mm2) was semiautomatically quantified on axial-plane WBCT images 1 cm proximal to the apex of the talar dome using validated software. Syndesmosis area values were compared between "unstressed" and "stressed" ankles, as well as left and right ankles. Statistical analysis was performed using independent t tests/Wilcoxon analysis with statistical significance defined as P <.05. RESULTS: The study cohort consisted of 50 ankles in 25 patients (12 males, 48%) with a mean age of 28.7 ± 9.3 years. In the unstressed ankle, the mean pooled DTFS area was determined to be 103.8 + 20.8 mm2. The mean syndesmosis area of unstressed left ankles (104.2 + 19.5 mm2) was similar to unstressed right ankles (109.2 + 17.2 mm2) in the cohort (P = .117). With external rotation stress, the DTFS area of left ankles (mean difference -0.304 mm2, CI -12.1 to 11.5; P = .082), right ankles (mean difference -5.5 mm2, CI 16.7-5.7; P = .132), and all ankles (mean difference -2.9 mm2, CI -10.8 to 5.1; P = .324) remained similar. CONCLUSION: This study presents normal values and range for DTFS area calculation. In uninjured ankles with expected intact ligaments, subject-driven external rotation stress did not result in significant widening of the DTFS space as imaged on with WBCT. LEVEL OF EVIDENCE: Level II, cross-sectional study.

Comparing the immune abnormalities in MIS-C to healthy children and those with inflammatory disease reveals distinct inflammatory cytokine production and a monofunctional T cell response.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, hyperinflammatory disease that occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying immune pathology of MIS-C is incompletely understood, with limited data comparing MIS-C to clinically similar paediatric febrile diseases at presentation. SARS-CoV-2-specific T cell responses have not been compared in these groups to assess whether there is a T cell profile unique to MIS-C. In this study, we measured inflammatory cytokine concentration and SARS-CoV-2-specific humoral immunity and T cell responses in children with fever and suspected MIS-C at presentation (n = 83) where MIS-C was ultimately confirmed (n = 58) or another diagnosis was made (n = 25) and healthy children (n = 91). Children with confirmed MIS-C exhibited distinctly elevated serum IL-10, IL-6, and CRP at presentation. No differences were detected in SARS-CoV-2 spike IgG serum concentration, neutralisation capacity, antibody dependant cellular phagocytosis, antibody dependant cellular cytotoxicity or SARS-CoV-2-specific T cell frequency between the groups. Healthy SARS-CoV-2 seropositive children had a higher proportion of polyfunctional SARS-CoV-2-specific CD4+ T cells compared to children with MIS-C and those with other inflammatory or infectious diagnoses, who both presented a largely monofunctional SARS-CoV-2-specific CD4+ T cell profile. Treatment with steroids and/or intravenous immunoglobulins resulted in rapid reduction of inflammatory cytokines but did not affect the SARS-CoV-2-specific IgG or CD4+ T cell responses in MIS-C. In these data, MIS-C had a unique cytokine profile but not a unique SARS-CoV-2 specific humoral or T cell cytokine response.

Vosoritide therapy in children with achondroplasia aged 3-59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years. METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 µg/kg for infants aged 0-23 months; 15·0 µg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697. FINDINGS: Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53). INTERPRETATION: Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline. FUNDING: BioMarin Pharmaceutical.

Congenital Vertical Talus: An Updated Review.

Congenital vertical talus (CVT) is the presence of rigid flatfoot deformity characterized by hindfoot valgus and equinus. This foot deformity is associated with midfoot dorsiflexion and forefoot abduction due to a fixed dorsal dislocation of the navicular relative to the head of the talus. It is often underdiagnosed in children due to its similarity to other disorders of the foot. Misdiagnosis of CVT and subsequent failure to address it leads to significant disability and pain. While past surgical management consisted of soft tissue releases that produced varying efficacy, current management of CVT consists of serial casting and minimally invasive procedures that have yielded excellent long-term outcomes. This review provides insight into the diagnosis and treatment of CVT with the intention of highlighting the importance of promptness of intervention to prevent further disability.

Natural selection has driven the recurrent loss of an immunity gene that protects Drosophila against a major natural parasite.

Polymorphisms in immunity genes can have large effects on susceptibility to infection. To understand the origins of this variation, we have investigated the genetic basis of resistance to the parasitoid wasp Leptopilina boulardi in Drosophila melanogaster. We found that increased expression of the gene lectin-24A after infection by parasitic wasps was associated with a faster cellular immune response and greatly increased rates of killing the parasite. lectin-24A encodes a protein that is strongly up-regulated in the fat body after infection and localizes to the surface of the parasite egg. In certain susceptible lines, a deletion upstream of the lectin-24A has largely abolished expression. Other mutations predicted to abolish the function of this gene have arisen recurrently in this gene, with multiple loss-of-expression alleles and premature stop codons segregating in natural populations. The frequency of these alleles varies greatly geographically, and in some southern African populations, natural selection has driven them near to fixation. We conclude that natural selection has favored the repeated loss of an important component of the immune system, suggesting that in some populations, a pleiotropic cost to lectin-24A expression outweighs the benefits of resistance.

Risk Factors Associated With Worse Clinical Outcomes of Ankle Fractures Involving the Posterior Malleolus.

Background: Ankle fractures involving the posterior malleolus (PM) tend to result in inferior clinical outcomes compared to other ankle fractures. However, it is unclear which specific risk factors and fracture characteristics are associated with negative outcomes in these fractures. The aim of this study was to identify risk factors for poor postoperative patient-reported outcomes in patients with fractures involving the PM. Methods: This retrospective cohort study included patients who sustained ankle fractures involving the PM between March 2016 and July 2020 and had preoperative computed tomography (CT) scans. In total, 122 patients were included for analysis. One patient (0.8%) had an isolated PM fracture, 19 (15.6%) had bimalleolar ankle fractures involving the PM, and 102 (83.6%) had trimalleolar fractures. Fracture characteristics including the Lauge-Hansen (LH) and Haraguchi classifications and posterior malleolar fragment size were collected from preoperative CT scans. Patient Reported Outcome Measurement Information System (PROMIS) scores were collected preoperatively and at a minimum of 1 year postoperatively. The association between various demographic and fracture characteristics with postoperative PROMIS scores was assessed. Results: Involvement of more malleoli was associated with worse PROMIS Physical Function (P = .04), Global Physical Health (P = .04), and Global Mental Health (P < .001), and Depression scores (P = .001). Elevated BMI was also associated with worse PROMIS Physical Function (P = .0025), Pain Interference (P = .0013), and Global Physical Health (P = .012) scores. Time to surgery, fragment size, Haraguchi classification, and LH classification were not associated with PROMIS scores. Conclusion: In this cohort, we found that trimalleolar ankle fractures were associated with inferior PROMIS outcomes compared with bimalleolar ankle fractures involving the PM in multiple domains. Level of Evidence: Level III, retrospective cohort study.

Hunting Drosophila viruses from wild populations: A novel isolation approach and characterisation of viruses.

Metagenomic studies have demonstrated that viruses are extremely diverse and abundant in insects, but the difficulty of isolating them means little is known about the biology of these newly discovered viruses. To overcome this challenge in Drosophila, we created a cell line that was more permissive to infection and detected novel viruses by the presence of double-stranded RNA. We demonstrate the utility of these tools by isolating La Jolla virus (LJV) and Newfield virus (NFV) from several wild Drosophila populations. These viruses have different potential host ranges, with distinct abilities to replicate in five Drosophila species. Similarly, in some species they cause high mortality and in others they are comparatively benign. In three species, NFV but not LJV caused large declines in female fecundity. This sterilization effect was associated with differences in tissue tropism, as NFV but not LJV was able to infect Drosophila melanogaster follicular epithelium and induce follicular degeneration in the ovary. We saw a similar effect in the invasive pest of fruit crops Drosophila suzukii, where oral infection with NFV caused reductions in the fecundity, suggesting it has potential as a biocontrol agent. In conclusion, a simple protocol allowed us to isolate new viruses and demonstrate that viruses identified by metagenomics have a large effect on the fitness of the model organism D. melanogaster and related species.

Application of the Mayo Periprosthetic Joint Infection Risk Score for Total Ankle Arthroplasty.

BACKGROUND: Assessing patient's risk of infection is fundamental for prevention of periprosthetic joint infection (PJI) after total ankle arthroplasty (TAA). The Mayo Prosthetic Joint Infection Risk Score (Mayo Score) is based on data from total hip and knee arthroplasty and has not been validated for application for TAA. METHODS: A total of 405 consecutive TAA cases were followed for 6 months for PJI. Individual patients' Mayo Scores were calculated and analyzed with logistic regression and receiver operating characteristic (ROC) for predictability for PJI. A critical cut-off Mayo Score for patients at high risk of PJI was determined by best Youden index. Among the Mayo Score-defined high-risk patients, the contribution of different risk factors were compared between the PJI and non-PJI patients. RESULTS: There were 10 cases of PJI (2.5%) among the 405 cases within 6 months after TAA. Of the 405 patients, the Mayo Scores ranged between -4 and 13 (median 2; interquartile range 0-5). The average Mayo Score was 2.5 ± 3.4 in the non-PJI patients and 7.7 ± 3.1 in the PJI patients (P < .001). Logistic regression showed that the probability of PJI increased with higher Mayo Scores (odds ratio 1.48, 95% CI 1.23-1.78). All but 1 PJI patients had a Mayo Score >5. The sensitivity and specificity were 90.0% and 84.3%, respectively, when a Mayo Score >5 was used as a criterion for high risk of PJI. CONCLUSION: This study demonstrated that the Mayo Score could similarly predict PJI risk after TAA as in total hip and knee arthroplasty. Data analysis suggests that a Mayo Score >5 could be a criterion for identifying high-risk patients for PJI, although further validation with a large number of PJI cases is necessary. LEVEL OF EVIDENCE: Level II, developing diagnositic criteria with consecutive cases.

Determinants of healing and readiness for prosthetic fitting after transtibial amputation: Integrative literature review.

BACKGROUND: Healing after an amputation is a critical step in the recovery process. Delayed wound healing can lead to deconditioning and flexion contractures which reduce a patient's ability to use a prosthesis, ambulate independently, and return to community participation. The purpose of this integrative literature review was to determine the evidence-based physiological factors, comorbidities, postoperative management, and outcome measures associated with healing after transtibial amputation and address how these factors clinically guide readiness for prosthetic intervention. METHODS: Authors completed Google Scholar searches to identify the most effective search terms to locate salient publications. Authors also completed literature searches of Ovid MEDLINE and Epub Ahead of Print, In-Process, and Other Nonindexed Citations and Daily <1946 to August 6, 2020>; Embase Classic + Embase <1947 to August 6, 2020>; and CINAHL Complete <1946 to August 6, 2020> databases using the following search terms: "transtibial," "trans-tibial," "below knee," "BKA," "amputation," amputation stump," "amputee," "wound healing," and "heal/s/ed/ing." The authors decided to include all levels of evidence to capture the maximum number of articles related to the determinants of healing and readiness for prosthetic fitting after transtibial amputation. RESULTS: The searches identified 2067 potential articles for review, and after removing articles not relevant to the topic, authors completed full-text assessment on 20 articles. These included review and synthesis on three randomized controlled trials and 12 cohort studies. CONCLUSION: Preamputation assessment is most critical in patients who present with a longer list of comorbidities and suboptimal physiologic factors known to predict wound complications. Clinical judgment is most subjective when determining the degree of healing over time. Readiness for prosthetic treatment need not wait for complete healing of the residuum. Future research is needed to assess transcutaneous oxygen profusion along with other noninvasive measures of blood flow and perfusion as a more objective way to track progression of healing over time. This objective methodology would quantify healing, reduce subjectivity, and promote research to compare different enhanced recovery after surgery protocols for their impact on healing after amputation.

Composite Free Tissue Transfer for Reconstruction of Lower Extremity Tendon Injuries: A Systematic Review.

BACKGROUND: Tendon rupture with extensive soft tissue loss has few reconstructive options. Composite free tissue transfers including skin and tendon offer an attractive reconstructive approach. Unfortunately, most studies discussing them come from sparse case reports. We systematically assess evidence supporting composite flap use in single-stage reconstruction of lower extremity tendon and soft tissue defects. METHODS: A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. OvidMEDLINEqueried for records pertaining to the study question using Medical Subject Heading (MeSH) terms such as "lower extremity," "tendon," and "composite flap." No limitations were placed on the year of publication, country of origin, or study size. Study characteristics and patient demographics were collected. Primary outcomes included:(1) defect location, composite flap characteristics;(2) return to ambulation;(3) joint range of motion;(4) patient satisfaction, and (5) complications. RESULTS: In total, 29 articles examining 173 patients with lower extremity tendon defects and soft tissue loss were identified. Average age was 44.3 years (SD 17.5); most patients were male (n = 110, 66.3%). Achilles defect was mostly reported (n = 151, 86.8%), followed by patellar (n = 17, 9.8%) and other tendon defects (n = 6, 3.4%). Average tendon defect size was 8.4 cm (SD 4.0), average soft tissue loss was 80.2 cm2 (SD 40.0). Most employed composite flap was anterolateral thigh and fascia lata (ALT + FL) (n = 101, 58.0%). Most patients (n = 134, 99.3%) returned to ambulation in an average 123.1 days (SD 78.3). Average reconstructive joint degree of motion was 62.1 degrees compared with normal degree of motion 62.3 degrees. Patient-reported outcomes demonstrated increased satisfaction after reconstruction. CONCLUSION: Composite flaps effectively reconstruct a variety of tendon and soft tissue defects; the most reported flap is ALT + FL, which provides large flap territories and rapid healing in Achilles, patellar, and other tendon defects. In this review, patients with composite flaps demonstrated return to ambulation, minimal impairment in range of motion, and notable postoperative satisfaction.

Painful Unilateral Knee Snapping after Hyperextension Injury and Meniscus Tear.

This case involves a healthy male with painful lateral knee pain and snapping after a hyperextension injury. Initially, this was felt to be from a displaced lateral meniscus tear; however, he failed to improve after meniscal debridement. Further workup with an ultrasound and magnetic resonance imaging identified an aberrant biceps femoris anatomy. He was taken to the operating room and the aberrant slip was identified. A tenodesis of the aberrant slip to the biceps femoris was completed. This resolved the patient's pain and snapping, and he was able to return to all activities.

Trans-regulatory changes underpin the evolution of the Drosophila immune response.

When an animal is infected, the expression of a large suite of genes is changed, resulting in an immune response that can defend the host. Despite much evidence that the sequence of proteins in the immune system can evolve rapidly, the evolution of gene expression is comparatively poorly understood. We therefore investigated the transcriptional response to parasitoid wasp infection in Drosophila simulans and D. sechellia. Although these species are closely related, there has been a large scale divergence in the expression of immune-responsive genes in their two main immune tissues, the fat body and hemocytes. Many genes, including those encoding molecules that directly kill pathogens, have cis regulatory changes, frequently resulting in large differences in their expression in the two species. However, these changes in cis regulation overwhelmingly affected gene expression in immune-challenged and uninfected animals alike. Divergence in the response to infection was controlled in trans. We argue that altering trans-regulatory factors, such as signalling pathways or immune modulators, may allow natural selection to alter the expression of large numbers of immune-responsive genes in a coordinated fashion.

Outcomes Between Stemmed and Stemless Total Shoulder Arthroplasty: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: Both stemmed and stemless designs for total shoulder arthroplasty (TSA) have demonstrated efficacious outcomes for the surgical treatment of primary glenohumeral joint osteoarthritis. The purpose of this systematic review and meta-analysis was to compare the clinical outcomes of stemmed versus stemless TSA in randomized controlled trials. We hypothesized that there would be no differences in Constant Score (CS), range of motion, or adverse events, such as periprosthetic fracture and/or revision surgery. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic review of the literature was done using MEDLINE, SPORTDiscus, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Registry of Controlled Trials, Embase, and Web of Science databases. Outcomes of interest included CS, range of motion, and adverse events (periprosthetic fracture and revision). Summary effect estimates of the mean difference between stemmed and stemless TSA for each outcome were estimated in random effects models. RESULTS: The search yielded 301 articles with 4 appropriate for qualitative analysis, including the results of 229 stemmed and 358 stemless TSAs. No significant difference was observed in postoperative CS (P = 0.36), forward flexion (P = 0.93), abduction (P = 0.30), or external rotation (P = 0.34) between stemmed and stemless TSA. No significant difference was observed in change in CS (P = 0.27), forward flexion (P = 0.25), or external rotation (P = 0.74). A change in abduction was significantly different between stemmed and stemless TSA (standardized mean difference = -0.64; 95% confidence interval, -1.20 to -0.08) in favor of stemmed TSA (P = 0.02), attributed to preoperative differences. No significant difference was observed in periprosthetic fractures (P = 0.07) or revision (P = 0.90). CONCLUSION: TSA with stemless versus stemmed humeral components was not associated with notable differences in functional and clinical outcomes. No difference was observed between stemmed and stemless designs in postoperative forward flexion, abduction, or external rotation. Similarly, there was no difference in change in forward flexion or external rotation. A markedly greater improvement in abduction was observed with stemmed TSA, likely due to the lower preoperative motion in the stemmed cohort in one of the studies. No differences were observed between stemmed and stemless designs in the rate of humeral fracture or risk of revision. LEVEL OF EVIDENCE: Level II; systematic review and meta-analysis of prospective randomized controlled trials.