Molecular Trojan Horses for treating lysosomal storage diseases.

Lysosomal storage diseases (LSDs) are caused by monogenic mutations in genes encoding for proteins related to the lysosomal function. Lysosome plays critical roles in molecule degradation and cell signaling through interplay with many other cell organelles, such as mitochondria, endoplasmic reticulum, and peroxisomes. Even though several strategies (i.e., protein replacement and gene therapy) have been attempted for LSDs with promising results, there are still some challenges when hard-to-treat tissues such as bone (i.e., cartilages, ligaments, meniscus, etc.), the central nervous system (mostly neurons), and the eye (i.e., cornea, retina) are affected. Consistently, searching for novel strategies to reach those tissues remains a priority. Molecular Trojan Horses have been well-recognized as a potential alternative in several pathological scenarios for drug delivery, including LSDs. Even though molecular Trojan Horses refer to genetically engineered proteins to overcome the blood-brain barrier, such strategy can be extended to strategies able to transport and deliver drugs to specific tissues or cells using cell-penetrating peptides, monoclonal antibodies, vesicles, extracellular vesicles, and patient-derived cells. Only some of those platforms have been attempted in LSDs. In this paper, we review the most recent efforts to develop molecular Trojan Horses and discuss how this strategy could be implemented to enhance the current efficacy of strategies such as protein replacement and gene therapy in the context of LSDs.

Monitoring policy in the context of preventive treatment of cardiovascular disease.

Preventing chronic diseases is an essential aspect of medical care. To prevent chronic diseases, physicians focus on monitoring their risk factors and prescribing the necessary medication. The optimal monitoring policy depends on the patient's risk factors and demographics. Monitoring too frequently may be unnecessary and costly; on the other hand, monitoring the patient infrequently means the patient may forgo needed treatment and experience adverse events related to the disease. We propose a finite horizon and finite-state Markov decision process to define monitoring policies. To build our Markov decision process, we estimate stochastic models based on longitudinal observational data from electronic health records for a large cohort of patients seen in the national U.S. Veterans Affairs health system. We use our model to study policies for whether or when to assess the need for cholesterol-lowering medications. We further use our model to investigate the role of gender and race on optimal monitoring policies.

Chondrocranial variation in chicken domestication.

The chondrocranium is a key structure of the skull, but our knowledge of its embryonic development is based mostly on investigations of few stages across taxa. Variation of chondrocranial features is known across species, but little is known about intraspecific variation, or its evolution in the context of domestication. Here, we investigated two specific structures of the chondrocranium in three windows of embryonic development. The anatomy of one of these structures was also compared among adult skulls of chickens and their wild ancestor (red junglefowl [RJF]). The proccesus tectalis and the prenasal process, along with the surrounding area of the orbitonasal foramina, presented variation throughout the ontogeny and in the adults. The processus tectalis showed distinct variation from the earliest stage studied to the adult. The numbers of orbitonasal foramina were also found to be variable in the ancestor and breeds studied. Furthermore, during early embryonic development, the prenasal process is similar across breeds and RJF, but later in embryonic development this structure presents variable states. The embryonic and adult variation found herein could be an example of intraspecific variation under domestication, resulting from different types of tissue interrelationship during development.

Risk Factors for Canalicular Injury After Mohs Micrographic Surgery.

BACKGROUND: There is a paucity of literature describing risk factors for canalicular injury (CI) during periocular Mohs micrographic surgery (Mohs). OBJECTIVE: This study aimed to determine factors associated with CI after Mohs. This information may inform patient counseling and surgical planning. MATERIALS AND METHODS: This case-control study compared subjects with canalicular injury after Mohs with subjects requiring ophthalmologic Mohs repair without canalicular injury. All subjects who had CI after Mohs were included in the control group. CI from other causes were excluded. RESULTS: Basal cell carcinoma was the most common etiologic tumor (p < .00001). Canalicular injury was associated with infiltrative, morpheaform, and/or micronodular-type basal cell carcinoma. Initial tumor location involving the medial canthus was not statistically different between cases and controls (32% vs 17%, p = .22). Having a final defect involving the medial canthus region was more likely in cases versus controls (55% vs 26%, p = .01952). CONCLUSION: Although most final defects involved the medial canthal region, a substantial number of tumors resulting in CI did not initially seem to involve the medial canthus. Surgeons cannot rely simply on anatomical location when assessing risk for CI, and anticipation of need for canalicular reconstruction is challenging.

Leveraging weakness into strength: how neo-patrimonial oil-producing countries survive economic crises.

Most scholarship on major oil-producing countries (OPCs) focuses on their illiberal characteristics, but scant research explores how these regimes react to periodic oil price collapses, particularly neo-patrimonial OPCs with relatively low state capacity, herein termed gatekeeper OPCs. These OPCs should be extremely vulnerable to regime change during economic crises. However, since the most recent collapse in international oil markets in 2014, almost all neo-patrimonial OPCs have managed to weather the ensuing fallout, thereby begging the question of how these seemingly vulnerable regimes manage to survive extended periods of economic crises. We hypothesise that the likelihood of regime survival in neo-patrimonial OPCs depends on a strategic calibration of domestic neo-patrimonial policies, such as clientelism and executive aggrandisement, and the skilled navigation of global geopolitics. We find evidence that incumbent governments leverage international geopolitical tensions during economic crises to secure valuable foreign aid from key allies, which allows them to maintain the domestic neo-patrimonial strategies required to safeguard their power. We reached the above finding through a nested mixed-methods research design combining quantitative analysis of 35 major OPCs from 2011 to 2018 using Cox proportional hazards models with the qualitative comparison of two gatekeeper OPCs-Chad and Venezuela.

Shifts in growth, but not differentiation, foreshadow the formation of exaggerated forms under chicken domestication.

Domestication provides an outstanding opportunity for biologists to explore the underpinnings of organismal diversification. In domesticated animals, selective breeding for exaggerated traits is expected to override genetic correlations that normally modulate phenotypic variation in nature. Whether this strong directional selection affects the sequence of tightly synchronized events by which organisms arise (ontogeny) is often overlooked. To address this concern, we compared the ontogeny of the red junglefowl (RJF) (Gallus gallus) to four conspecific lineages that underwent selection for traits of economic or ornamental value to humans. Trait differentiation sequences in embryos of these chicken breeds generally resembled the representative ancestral condition in the RJF, thus revealing that early ontogeny remains highly canalized even during evolution under domestication. This key finding substantiates that the genetic cost of domestication does not necessarily compromise early ontogenetic steps that ensure the production of viable offspring. Instead, disproportionate beak and limb growth (allometry) towards the end of ontogeny better explained phenotypes linked to intense selection for industrial-scale production over the last 100 years. Illuminating the spatial and temporal specificity of development is foundational to the enhancement of chicken breeds, as well as to ongoing research on the origins of phenotypic variation in wild avian species.

CYP2D6 genotype and reduced codeine analgesic effect in real-world clinical practice.

Cytochrome P450 2D6 (CYP2D6) O-demethylates codeine to the active drug, morphine. However, the utility of testing for CYP2D6 metabolizer status in patients receiving codeine in real-world clinical practice is poorly defined. Using data from a DNA bank linked to de-identified electronic health records, we studied 157 patients with a baseline pain score higher than 4 (0-10 scale) who received codeine. Based on CYP2D6 genotyping, 69 were classified as poor/intermediate and 88 as normal/ultrarapid CYP2D6 metabolizers. Pain response was defined as a score of 4 or lower while receiving codeine. In a propensity-score adjusted model, poor/intermediate metabolizers had lower odds (OR = 0.35, p = 0.02) of achieving a pain response than normal/ultrarapid metabolizers. To discriminate between codeine responders and nonresponders, a score including CYP2D6 phenotype and clinical variables was built. The response rate was 38.5% among patients in the high, 17.3% in the intermediate, and 9.4% in the low-score groups, respectively (p = 0.001).

Management of blood products: Nursing knowledge and practices at an academic hospital.

OBJECTIVE: The purpose of this study was to determine the knowledge and practice of nurses at an academic hospital regarding the handling of red blood cells (RBCs) and platelets. METHODS: A descriptive study was performed using a paper-based questionnaire. Nurses from 12 wards where these products are frequently transfused were purposefully selected to participate. RESULTS: Ninety-nine questionnaires were analysed. While 78.9 % respondents reported that their knowledge regarding the handling of RBCs and platelets was adequate, 81.7 % still stated that they would like more training on this subject. Almost half (45.2 %) reported that the time of arrival of RBCs and platelets on the ward was not charted, while 25.5 % indicated that they warm all these blood products before transfusion. About eighty percent (80.8 %) did not know where to store platelets in the ward and 37.4 % knew the average duration of a platelet transfusion. The term, blood on returnable basis was correctly interpreted by 6.1 % of respondents. CONCLUSION: Gaps exist in the knowledge and practice of nursing staff regarding the correct handling of RBCs and platelets, specifically discarding, storage and warming of these products. Addressing such gaps would improve patient care and contribute towards patient blood management.

Pharmacogenetics of hypoglycemia associated with sulfonylurea therapy in usual clinical care.

Hypoglycemia is a common complication among type 2 diabetes mellitus (T2DM) patients receiving sulfonylurea therapy. The aim of this study was to determine if genetic contributions to sulfonylurea pharmacokinetics or pharmacodynamics substantially affect the risk of hypoglycemia in these patients. In a retrospective case-control study in European American patients with T2DM, we examined the potential association between CYP2C9 reduced-function variants and sulfonylurea-related hypoglycemia. We also explored the relationship between sulfonylurea-related hypoglycemia and several candidate genetic variants previously reported to alter the response to sulfonylureas. We detected no evidence of association between CYP2C9 reduced-function alleles or any of the candidate genetic variants and sulfonylurea-related hypoglycemia. In conclusion, we identified no clinically significant predictors of hypoglycemia among genes associated with sulfonylurea pharmacokinetics or pharmacodynamics.

Ambulatory blood pressure in patients with systemic lupus erythematosus: Association with markers of immune activation.

Objectives: Ambulatory blood pressure monitoring measures 24-hour blood pressure, night-time blood pressure, and impaired dipping of nocturnal blood pressure, parameters that better predict cardiovascular risk than standard office blood pressure measurements. Systemic lupus erythematosus is characterized by immune system hyperactivity, elevated cardiovascular risk and high prevalence of hypertension; however, little is known about ambulatory blood pressure in lupus patients and its relationship to immune activation. Methods: We studied 26 patients with lupus and 26 control subjects. We obtained ambulatory 24-hour blood pressure measurements and report plasma concentrations of 77 markers of immune activation using a multiplex immunoassay and assessed their association with blood pressure measurements. Results: Despite similar office blood pressure measurements in patients with lupus and controls, lupus patients had higher 24-hour systolic [median (interquartile range) 129 (113 - 140) vs. 116 (111 - 121) mmHg, p = 0.03] and diastolic blood pressure [80 (69 - 86) vs. 72 (64 - 75) mmHg, p = 0.006] as well as less nocturnal dipping [7.8% (5.1 - 14.2%) vs. 12.0% (8.1 20.0%)] p = 0.03], compared to controls. In patients with lupus, markers of the innate (monocyte chemotactic protein-3) and adaptive immune systems [CUB domain-containing protein-1 and Interleukin-15 receptor subunit-α,] were associated with nocturnal blood pressure measurements and attenuated nocturnal dipping. In conclusion, 24-hour systolic and diastolic blood pressure was higher and nocturnal blood pressure dipping was attenuated in patients with lupus compared to control subjects. Conclusion: In patients with SLE, nocturnal blood pressure and attenuated nocturnal blood pressure dipping were significantly associated with several innate and adaptive immune system biomarkers.

A Human-Derived, Collagen-Rich Hydrogel Augments Wound Healing in a Diabetic Animal Model.

BACKGROUND: Application of collagen products to wounds has been shown to improve wound healing. Using a collagen-based hydrogel (cHG) capable of cellular support previously developed by our laboratory, we hypothesize that our hydrogel will increase the speed of wound healing by providing a 3-dimensional framework for cellular support, increasing angiogenesis and cell-proliferation at the wound bed. METHODS: Two, 10-mm excisional wounds were created over the dorsum of 12 male, genetically modified Zucker diabetic rats. Wounds were splinted open to limit healing by wound contracture. One wound was treated with an occlusive dressing (OD), whereas the adjacent wound was treated with an OD plus cHG. Occlusive dressings were changed every other day. Hydrogel was applied on day 2 and every 4 days after until complete wound closure. Rate of wound closure was monitored with digital photography every other day. Wounds were harvested at days 10 and 16 for histological and immunohistochemical analysis. RESULTS: Wound closure was significantly faster in cHG-treated wounds compared with OD-treated wounds. By day 10, cHG-treated wounds achieved 63% wound closure, compared with 55% wound closure in OD-treated wounds (P < 0.05). By day 16, cHG-treated wounds achieved 84% wound closure, compared with 68% wound closure in OD-treated wounds (P < 0.05).Histologically, wound depth was not different between the cHG and OD groups on days 10 and 16. However, wound length was significantly less in the cHG group compared with the OD group (P < 0.05) consistent with digital photographic analysis. Immunohistochemical analysis for RECA-1 demonstrated that blood vessel density in the wound bed was 2.3 times higher in the cHG group compared with the OD group (P = 0.01) on day 16. Cell proliferation was 3.8 times higher in the cHG group versus the OD group (P < 0.05) on day 10. CONCLUSIONS: Collagen-based hydrogel-treated wounds demonstrated significantly improved healing compared with control. The thermoresponsive feature of collagen hydrogel and its structural stability at body temperature demonstrate promising clinical potential as a vehicle for the delivery of therapeutic cells to the wound bed.

Morphological diversity of integumentary traits in fowl domestication: Insights from disparity analysis and embryonic development.

The domestication of the fowl resulted in a large diversity of integumental structures in chicken breeds. Several integumental traits have been investigated from a developmental genetics perspective. However, their distribution among breeds and their developmental morphology remain unexplored. We constructed a discrete trait-breed matrix and conducted a disparity analysis to investigate the variation of these structures in chicken breeds; 20 integumental traits of 72 chicken breeds and the red junglefowl were assessed. The analyses resulted in slight groupings of breed types comparable to standard breed classification based on artificial selection and chicken type use. The red junglefowl groups together with bantams and European breeds. We provide new data on the red junglefowl and four chicken breeds, demonstrating where and when variation arises during embryonic development. We document variation in developmental timing of the egg tooth and feather formation, as well as other kinds of developmental patterning as in the anlagen of different type of combs. Changes in epithelial-mesenchymal signaling interactions may drive the highly diverse integument in chickens. Experimental and comparative work has revealed that the cranial neural crest mesenchyme mediates its interactions with the overlying epithelium and is the likely source of patterning that generates diversity in integumental structures.

Implications of bipolar voltage mapping and magnetic resonance imaging resolution in biventricular scar characterization after myocardial infarction.

AIMS: We aimed to study the differences in biventricular scar characterization using bipolar voltage mapping compared with state-of-the-art in vivo delayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging and ex vivo T1 mapping. METHODS AND RESULTS: Ten pigs with established myocardial infarction (MI) underwent in vivo scar characterization using LGE-CMR imaging and high-density voltage mapping of both ventricles using a 3.5-mm tip catheter. Ex vivo post-contrast T1 mapping provided a high-resolution reference. Voltage maps were registered onto the left and right ventricular (LV and RV) endocardium, and epicardium of CMR-based geometries to compare voltage-derived scars with surface-projected 3D scars. Voltage-derived scar tissue of the LV endocardium and the epicardium resembled surface projections of 3D in vivo and ex vivo CMR-derived scars using 1-mm of surface projection distance. The thinner wall of the RV was especially sensitive to lower resolution in vivo LGE-CMR images, in which differences between normalized low bipolar voltage areas and CMR-derived scar areas did not decrease below a median of 8.84% [interquartile range (IQR) (3.58, 12.70%)]. Overall, voltage-derived scars and surface scar projections from in vivo LGE-CMR sequences showed larger normalized scar areas than high-resolution ex vivo images [12.87% (4.59, 27.15%), 18.51% (11.25, 24.61%), and 9.30% (3.84, 19.59%), respectively], despite having used optimized surface projection distances. Importantly, 43.02% (36.54, 48.72%) of voltage-derived scar areas from the LV endocardium were classified as non-enhanced healthy myocardium using ex vivo CMR imaging. CONCLUSION: In vivo LGE-CMR sequences and high-density voltage mapping using a conventional linear catheter fail to provide accurate characterization of post-MI scar, limiting the specificity of voltage-based strategies and imaging-guided procedures.

Three-dimensional cardiac fibre disorganization as a novel parameter for ventricular arrhythmia stratification after myocardial infarction.

AIMS: Myocardial infarction (MI) alters cardiac fibre organization with unknown consequences on ventricular arrhythmia. We used diffusion tensor imaging (DTI) of three-dimensional (3D) cardiac fibres and scar reconstructions to identify the main parameters associated with ventricular arrhythmia inducibility and ventricular tachycardia (VT) features after MI. METHODS AND RESULTS: Twelve pigs with established MI and three controls underwent invasive electrophysiological characterization of ventricular arrhythmia inducibility and VT features. Animal-specific 3D scar and myocardial fibre distribution were obtained from ex vivo high-resolution contrast-enhanced T1 mapping and DTI sequences. Diffusion tensor imaging-derived parameters significantly different between healthy and scarring myocardium, scar volumes, and left ventricular ejection fraction (LVEF) were included for arrhythmia risk stratification and correlation analyses with VT features. Ventricular fibrillation (VF) was the only inducible arrhythmia in 4 out of 12 infarcted pigs and all controls. Ventricular tachycardia was also inducible in the remaining eight pigs during programmed ventricular stimulation. A DTI-based 3D fibre disorganization index (FDI) showed higher disorganization within dense scar regions of VF-only inducible pigs compared with VT inducible animals (FDI: 0.36; 0.36-0.37 vs. 0.32; 0.26-0.33, respectively, P = 0.0485). Ventricular fibrillation induction required lower programmed stimulation aggressiveness in VF-only inducible pigs than VT inducible and control animals. Neither LVEF nor scar volumes differentiated between VF and VT inducible animals. Re-entrant VT circuits were localized within areas of highly disorganized fibres. Moreover, the FDI within heterogeneous scar regions was associated with the median VT cycle length per animal (R2 = 0.5320). CONCLUSION: The amount of scar-related cardiac fibre disorganization in DTI sequences is a promising approach for ventricular arrhythmia stratification after MI.

The Power of Patient Norms: Postoperative Pathway Associated With Shorter Hospital Stay After Free Autologous Breast Reconstruction.

INTRODUCTION: Enhanced recovery after surgery pathways designed to optimize postoperative care have become increasingly popular across multiple surgical specialties with proven benefits. In this retrospective cohort study, we present a comparative evaluation of the impact of protocol-based postoperative care on free autologous breast reconstruction patients. METHODS: With institutional review board approval, we performed a chart review of patients who underwent breast reconstruction with free autologous tissue transfer by a single surgeon from 2006 to 2017. Patients were managed according to a postoperative protocol since 2006 that initially called for discharge home on postoperative day (POD) 4 for unilateral cases and POD 5 for bilateral cases. In May 2015, the protocol was revised to discharge home on POD 3 for all cases. Patients who underwent reconstruction before (2006 to April 2015) and after (May 2015 to 2017) the change in postoperative protocol were compared. RESULTS: A total of 432 patients (647 breasts) underwent free autologous breast reconstruction during the study period. Flaps were predominantly muscle-sparing transverse rectus abdominis myocutaneous (56.3%) or deep inferior epigastric perforator (30.3%) flaps. Average patient age was 51.6 years (range, 29.7-80.3 years). Unilateral reconstructions were performed for 167 patients before and 50 patients after the protocol change; average hospital length of stay (LOS) was 4.5 and 3.4 days, respectively (P < 0.001). Bilateral reconstructions were performed for 153 patients before and 62 patients after the protocol change; average hospital LOS was 5.1 and 3.5 days, respectively (P < 0.001). There was no significant increase in patients with major or minor complications. CONCLUSIONS: Revising our postoperative protocol to reduce expected LOS was associated with an overall faster time to discharge without negative consequences in patients who underwent unilateral and bilateral free autologous breast reconstruction. Use of protocols to guide behavior not only can improve the patient experience by promoting a quicker return home, but may also have the added benefit of decreasing healthcare expenditures through reduced inpatient utilization.

Upper Extremity Angiographic Patterns in Systemic Sclerosis: Implications for Surgical Treatment.

PURPOSE: Conventional angiography is often used in the preoperative work-up of hand surgery patients with systemic sclerosis. The goal of this study was to propose a classification system based on the pattern of arterial involvement in a series of upper extremity angiograms. The authors hypothesized that this classification system would demonstrate high inter- and intrarater reliability. METHODS: A retrospective review of 110 upper extremity angiograms in patients with systemic sclerosis (obtained between 1996 and 2017) was performed. Images were classified into 4 types based on the patency of the radial and ulnar arteries at the wrist, and into 3 subtypes based on the patency of the superficial and deep palmar arches. Classification reliability was compared with Fleiss' Kappa (for inter-rater) and Cohen's (for intrarater) coefficient between 4 fellowship-trained hand surgeons and a hand fellow. RESULTS: The inter-rater reliability between all 5 observers using types alone was 0.83 (0.80-0.85), whereas the inter-rater reliability using subtypes was 0.64 (confidence interval [CI] 95%, 0.62-0.65). The intrarater reliability using types alone ranged from 0.80 to 0.95, whereas intrarater reliabilities using subtypes were 0.81 (CI 95%, 0.72-0.90), 0.78 (CI 95%, 0.69-0.87), 0.87 (CI 95%, 0.80-0.95), 0.64 (CI 95%, 0.53-0.75), and 0.92 (CI 95%, 0.86-0.98) for the 4 attendings and a hand fellow, respectively. Fifty-seven percent of angiograms were interpreted as having loss of ulnar artery patency at the wrist (type 2) with 77% having additional loss of superficial palmar arch patency (type 2A). CONCLUSIONS: This large series of angiograms in patients with systemic sclerosis demonstrates a classification system for conventional angiography that shows high inter-rater and intrarater reliability using type alone. When subtypes were used, the inter-rater and intrarater reliabilities decreased to moderate and moderate-to-high, respectively. CLINICAL RELEVANCE: This study represents the first step in establishing a classification system that, by grouping patients with similar angiogram findings, may allow for targeted research into risk stratification, monitoring, and treatment in systemic sclerosis.

Threshold-Based Quantification in a Multiline Lateral Flow Assay via Computationally Designed Capture Efficiency.

Lateral flow assays (LFAs) are widely used for yes/no detection of analytes, but they are not well-suited for quantification. We show that the sensitivity of the test line in a lateral flow assay can be tuned to appear at a specific sample concentration by varying the density of capture molecules at the test line and that when test lines tuned for different responses are combined into a single test strip, lines appear at specific thresholds of sample concentration. We also developed a model based on mass-action kinetics that accurately described test line signal and shape over a wide matrix of capture molecules and sample concentrations in single-line strips. The model was used to design a three-line test strip with lines designed to appear at logarithmically spaced sample concentrations, and the experiments showed a remarkable match to predictions. The response of this "graded ladder bar" format is due to the effect of test line concentration on capture efficiency at each test line, not on sample depletion effects, and the effect is maintained whether a system is under kinetic or equilibrium control. These features enable design of nonlinear responses (logarithmic here) and suggest robustness for different systems. Thus, the graded ladder bar format could be a useful tool for applications requiring quantification of sample concentrations over a wide dynamic range.

Using Mesh to Reinforce the Abdominal Wall in Abdominal Free Flaps for Breast Reconstruction: Is There a Benefit? What are the Risks?

INTRODUCTION: Abdominal wall integrity may be compromised after abdominal flap harvest for breast reconstruction, leading to bulging or herniation due to weakening of the abdominal wall and dissection through the rectus muscle. Mesh can be used to reinforce the abdominal wall to reduce the risk of hernia formation postoperatively, especially in patients who may be at high risk. In this study, we describe this institution's experience with the use of mesh in the abdominal wall and critically evaluate its impact on patient outcomes and complications. METHODS: We retrospectively reviewed all patients with an abdominal free flap harvested for breast reconstruction at Stanford Health Care from 2005 to 2015. Multivariate-adjusted logistic regression analysis was used to compare the odds of abdominal complications-infection, bulging, and herniation-between patients with and without an abdominal mesh implanted during breast reconstruction. RESULTS: Three hundred eighty patients met inclusion criteria. One hundred sixty-one patients received mesh, whereas 219 received no reinforcement. In the mesh group, there were 7 (4.3%) cases of postoperative abdominal bulging, 11 (6.8%) cases of abdominal infection, and no (0.0%) cases of herniation. In the group without mesh, there were 17 (7.8%) cases of abdominal bulging, 11 (5.0%) cases of abdominal infection, and 5 (2.3%) cases of herniation. There was a significant difference in the odds of bulging (odds ratio [OR], 0.30; P = 0.01). There was not a significant difference in the odds of herniation (OR, 2.26E-10; P = 0.99) or infection (OR, 1.21; P = 0.69). CONCLUSIONS: In our current treatment algorithm, patients who received mesh were selected based upon several criteria, including obesity, weak fascia identified during surgery, and extensive muscle dissection. We confirm that the risk of bulging and herniation is decreased in patients receiving mesh. Furthermore, the risk of wound infection was not associated with the use of mesh; instead, a patient's elevated body mass index, as well as tension of closure, and other comorbidities are more likely causes of superficial wound complications. We find the use of mesh to be safe and beneficial in select patients undergoing abdominal free flap breast reconstruction who are at risk for hernias and bulges.

Greater Growth of Proximal Metatarsals in Bird Embryos and the Evolution of Hallux Position in the Grasping Foot.

In early theropod dinosaurs-the ancestors of birds-the hallux (digit 1) had an elevated position within the foot and had lost the proximal portion of its metatarsal. It no longer articulated with the ankle, but was attached at about mid-length of metatarsal 2 (mt2). In adult birds, the hallux is articulated closer to the distal end of mt2 at ground level with the other digits. However, on chick embryonic day 7, its position is as in early theropods at half-length of mt2. The adult distal location is acquired during embryonic days 8-10. To assess how the adult phenotype is acquired, we produced fate maps of the metatarsals of day 6 chicken embryos injecting the lipophilic tracer DiI. The fates of these marks indicate a larger expansion of the metatarsals at their proximal end, which creates the illusory effect that d1 moves distally. This larger proximal expansion occurs concomitantly with growth and early differentiation of cartilage. Histological analysis of metatarsals shows that the domains of flattened and prehypertrophic chondrocytes are larger toward the proximal end. The results suggest that the distal position of the hallux in the avian foot evolved as a consequence of an embryological period of expansion of the metatarsus toward the proximal end. It also brings attention to the developmental mechanisms leading to differential growth between epiphyses and their evolutionary consequences.

New developmental evidence clarifies the evolution of wrist bones in the dinosaur-bird transition.

From early dinosaurs with as many as nine wrist bones, modern birds evolved to develop only four ossifications. Their identity is uncertain, with different labels used in palaeontology and developmental biology. We examined embryos of several species and studied chicken embryos in detail through a new technique allowing whole-mount immunofluorescence of the embryonic cartilaginous skeleton. Beyond previous controversy, we establish that the proximal-anterior ossification develops from a composite radiale+intermedium cartilage, consistent with fusion of radiale and intermedium observed in some theropod dinosaurs. Despite previous claims that the development of the distal-anterior ossification does not support the dinosaur-bird link, we found its embryonic precursor shows two distinct regions of both collagen type II and collagen type IX expression, resembling the composite semilunate bone of bird-like dinosaurs (distal carpal 1+distal carpal 2). The distal-posterior ossification develops from a cartilage referred to as "element x," but its position corresponds to distal carpal 3. The proximal-posterior ossification is perhaps most controversial: It is labelled as the ulnare in palaeontology, but we confirm the embryonic ulnare is lost during development. Re-examination of the fossil evidence reveals the ulnare was actually absent in bird-like dinosaurs. We confirm the proximal-posterior bone is a pisiform in terms of embryonic position and its development as a sesamoid associated to a tendon. However, the pisiform is absent in bird-like dinosaurs, which are known from several articulated specimens. The combined data provide compelling evidence of a remarkable evolutionary reversal: A large, ossified pisiform re-evolved in the lineage leading to birds, after a period in which it was either absent, nonossified, or very small, consistently escaping fossil preservation. The bird wrist provides a modern example of how developmental and paleontological data illuminate each other. Based on all available data, we introduce a new nomenclature for bird wrist ossifications.