Personalized Embryo Transfer Outcomes in Recurrent Implantation Failure Patients Following Endometrial Receptivity Array With Pre-Implantation Genetic Testing.

Introduction Implantation failure is a trending problem for pregnancy outcomes. Women's reproduction rates can increase by in-vitro fertilization, which comes with frequent implantation failures. These failures can be mitigated by the personalization of embryo transfer depending on the patient's implantation window. The study aimed to assess the importance of using an endometrial receptivity array (ERA) combined with pre-implantation genetic testing in patients with recurrent implantation failure (RIF) and the significant role of personalized embryo transfer (PET) after ERA in patients with a displaced window of implantation. The study also determined the efficacy of this approach in improving clinical outcomes. Methods We conducted this observational retrospective study following approval by the Ethics Committee of Wings In-Vitro Fertilization (IVF) Women's Hospital, a unit of Reveba Infertility Clinics Pvt. Ltd., Ahmadabad (Approval No. 2019/002/31B). Two hundred ninety-one RIF patients were recruited and categorized into Group I (patients without ERA group) and Group II (ERA study group). Patients in the ERA study group were screened for ERA and subclassified into receptive and nonreceptive ERA groups. PET was performed for all subjects in the ERA study group according to their receptivity as assessed by ERA. We also screened some of the patients for ploidy (genetic) status of embryos by pre-implantation genetic testing for aneuploidy (PGT-A) before embryo transfer. The study had a power of 95% and an alpha of 0.05; therefore, 80 ± 2 subjects were required to conduct the study.  Results The primary outcome was the clinical pregnancy rate followed by the implantation rate. We found an improved clinical pregnancy rate and implantation rate (73.5% and 78.6%) in the nonreceptive endometrial group after adjusting their embryo transfer schedule to their endometrial receptivity. The clinical pregnancy rate (64% and 65%) and implantation rate (65% and 74%) in receptive and nonreceptive ERA (respectively) were high in subjects with donor oocytes for IVF/intracytoplasmic sperm injection. In addition, patients who opted for PGT-A to eliminate the risk of transferring aneuploidy embryos had significantly better implantation (88% and 95% receptive and nonreceptive, respectively) and clinical pregnancy rates (100% in both groups) compared to non-PGT-A screened patients (p<0.05; 34% and 37% clinical pregnancy rate, 96% and 57% implantation rate in receptive and nonreceptive groups, respectively). Conclusion Endometrial receptivity assessment is a highly beneficial method to assess the genetic expression of the endometrium and embryo transfer timing. In our study, in patients with recurrent implantation failure, this technology found receptivity issues and provided a chance to plan embryo transfer according to the window of implantation. The combination of PGT-A with ERA rules out the genetic issues related to embryos. In RIF patients, ERA results-guided PET improved the implantation rate and reproductive outcomes.

CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice.

As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.

Environmental enrichment improves metabolic and behavioral health in the BTBR mouse model of autism.

BTBR T + Itpr3tf/J (BTBR) mice are an Autism Spectrum Disorder (ASD)-like model that exhibit behavioral and physiological deficits similar to those observed in patients with ASD. While behavioral therapy is a first line of treatment in ASD patients, comparable non-pharmacological treatments are less explored in murine models. Here, we administer a bio-behavioral intervention for BTBR mice by way of environmental enrichment (EE) - an experimental housing paradigm previously shown to improve systemic metabolism, learning/memory, anxious behavior, neurogenesis, locomotion, and immunocompetence in C57BL/6 mice. Juvenile BTBR mice were randomized to standard or EE housing and were subjected to metabolic and behavioral assessments up to 17 weeks. Following EE exposure, we report an EE-induced metabolic and behavioral phenotype. Male BTBR mice responded metabolically to EE, displaying reduced adiposity, increased lean mass, improved glycemic control, and decreased circulating leptin. The gene expressions of brain-derived neurotrophic factor (Bdnf) and its receptor (Ntrk2/TrkB) were upregulated in several brain areas in EE-BTBR males. EE-BTBR females showed modest reduction of adiposity and no changes in glycemic control, circulating leptin, or Bdnf/Ntrk2 gene expression. With regard to behavior, EE resulted in decreased anxiety, and increased social affiliation. Together, these results suggest that EE improves metabolic and behavioral health in BTBR mice.

Long-term environmental enrichment affects microglial morphology in middle age mice.

Aging is associated with increased central nervous system inflammation, in large part due to dysfunctional microglia. Environmental enrichment (EE) provides a model for studying the dynamics of lifestyle factors in the development of age-related neuroinflammation and microglial dysfunction. EE results in improvements in learning and memory, metabolism, and mental health in a variety of animal models. We recently reported that implementing EE in middle age promotes healthy aging. In the present study, we investigated whether EE influences microglial morphology, and whether EE is associated with changes in expression of microglial and neuroinflammatory markers. Inflammatory cytokines and MHC-II were reduced following 12-month EE in 10-month-old mice. Long-term EE for 7.5 months resulted in broad increases in Iba1 expression in hippocampus, hypothalamus, and amygdala detected by immunohistochemistry. Quantification of microglial morphology reveal both hypertrophy and ramification in these three brain regions, without increases in microglial cell density. These data indicate that long-term EE implemented in middle age results in a microglial state distinct from that of normal aging in standard laboratory housing, in specific brain regions, associated with reduced neuroinflammatory markers and improvement of systemic metabolism.

Heterotopic Ossification in Primary Total Hip Arthroplasty Using the Direct Anterior vs Direct Lateral Approach.

BACKGROUND: The formation and severity of heterotopic ossification (HO) may be influenced by type of surgical approach. Our hypothesis was that because of differences in soft tissue dissection, differences exist in HO formation in primary total hip arthroplasty using direct anterior (DA) vs direct lateral (DL) approach. METHODS: A total of 1482 consecutive patients with DL (736) or DA (746) approach and similar perioperative care protocol during 2009-2011 were retrospectively studied. No patient received prophylactic radiotherapy. Preoperative and 6-month postoperative radiographs were reviewed based on Brooker classification. RESULTS: The incidence of overall HO was higher in DL (36.1%) vs DA group (19.4%, P < .001) but high-grade HO (Brooker ≥3) was not significantly different among the groups (3.9% for DL and 3.0% for DA groups). No patient required further surgery for HO resection. CONCLUSION: The type of approach (DA vs DL) did not seem to have a major influence on the short-term incidence of high-grade HO based on this radiographic analysis.

Recurrent Periprosthetic Joint Infection After Irrigation and Debridement With Component Retention Is Most Often Due to Identical Organisms.

BACKGROUND: Irrigation and debridement with prosthetic retention (I&D) is an oft-utilized treatment option for PJI, despite its known limited success. While it is known that nearly half of all patients treated with I&D have recurrent infection, the organism persistence between infection events remains unreported. In addition, identifying those cases in which I&D routinely failed to eradicate the infection (not simply prevent recurrent infection) may allow improved patient selection for this less morbid procedure-a difficult task to date. METHODS: Using an institutional database, 146 patients (153 joints) undergoing I&D between April 2000 and July 2013 were identified. There were 60 hips (40%). The overall success rate of I&D in this group was 52% (80/153). The failure group was limited to those patients with growth on culture at both initial failure and recurrent failure (46 cases). Analyses were performed to identify potential predictors of failed I&D and organism persistence in those cases. RESULTS: In the study group, 83.7% (36/43) of cases failed with the same organism. Knees with failed I&D had an organism persistence of 92.3% (24/26) compared with 70.5% (12/17; P = .09) for the hip. Patients initially infected with Staphylococcus aureus (specifically methicillin-resistant [13/13]) had a higher risk of persistent PJI (96%; 24/25) compared to other organisms (66.7%; 12/18; P = .01). CONCLUSION: I&D had a success rate of approximately 50% and typically failed due to organism persistence rather than a new infection. Given that persistent infection was most common in knees and S aureus, I&D should have a limited role in treating PJI, especially in these cases.

Advancements in Diagnosing Periprosthetic Joint Infections after Total Hip and Knee Arthroplasty.

Periprosthetic joint infection (PJI) is a complication of total joint arthroplasty that is challenging to diagnose. Currently, there is no "gold standard" for definite diagnosis of PJI. A multi-criteria definition has been described for PJI based on microbiology cultures, serum markers, such as erythrocyte sedimentation rate and C-reactive protein (CRP), synovial fluid biomarkers, such as leukocyte esterase and histopathology assessment of the periprosthetic tissue. The conventional serum markers are generally nonspecific and can be elevated in inflammatory conditions. Therefore, they cannot be relied on for definite diagnosis of PJI. Hence, with the use of proteomics, synovial fluid biomarkers such as α-defensin, IL-6, and CRP have been proposed as more accurate biomarkers for PJI. Current methods to culture micro-organisms have several limitations, and can be false-negative and false-positive in a considerable number of cases. In an attempt to improve culture sensitivity, diagnostic methods to target biofilms have recently been studied. The understanding of the concept of biofilms has also allowed for the development of novel techniques for PJI diagnosis, such as visualizing biofilms with fluorescent in-situ hybridization and detection of bacteria via DNA microarray. Lastly, the use of amplification-based molecular techniques has provided methods to identify specific species of bacteria that cause culture-negative PJI. While diagnosing PJI is difficult, these advances could be valuable tools for clinicians.

Increased FGF-2 secretion and ability to support neurite outgrowth by astrocytes cultured on polyamide nanofibrillar matrices.

An electrospun nonwoven matrix of polyamide nanofibers was employed as a new model for the capillary basement membrane at the blood-brain barrier (BBB). The basement membrane separates astrocytes from endothelial cells and is associated with growth factors, such as fibroblast growth factor-2 (FGF-2). FGF-2 is produced by astrocytes and induces specialized functions in endothelial cells, but also has actions on astrocytes. To investigate potential autocrine actions of FGF-2 at the BBB, astrocytes were cultured on unmodified nanofibers or nanofibers covalently modified with FGF-2. The former assumed an in vivo-like stellate morphology that was enhanced in the presence of cross-linked FGF-2. Furthermore, astrocyte monolayers established on unmodified nanofibers were more permissive for neurite outgrowth when cultured with an overlay of neurons than similar monolayers established on standard tissue culture surfaces, while astrocytes cultured on FGF-2-modifed nanofibers were yet more permissive. The observed differences were due in part to progressively increasing amounts of FGF-2 secreted by the astrocytes into the medium; hence FGF-2 increases its own expression in astrocytes to modulate astrocyte-neuron interactions. Soluble FGF-2 was unable to replicate the effects of cross-linked FGF-2. Nanofibers alone up-regulated FGF-2, albeit to a lesser extent than nanofibers covalently modified with FGF-2. These results underscore the importance of both surface topography and growth factor presentation on cellular function. Moreover, these results indicate that FGF-2-modified nanofibrillar scaffolds may demonstrate utility in tissue engineering applications for replacement and regeneration of lost tissue following central nervous system (CNS) injury or disease.