An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.

BACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).

Detecting cryptic clinically relevant structural variation in exome-sequencing data increases diagnostic yield for developmental disorders.

Structural variation (SV) describes a broad class of genetic variation greater than 50 bp in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DDs). Individuals presenting with DDs are often referred for diagnostic testing with chromosomal microarrays (CMAs) to identify large copy-number variants (CNVs) and/or with single-gene, gene-panel, or exome sequencing (ES) to identify single-nucleotide variants, small insertions/deletions, and CNVs. However, individuals with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the tool InDelible, which interrogates short-read sequencing data for split-read clusters characteristic of SV breakpoints. We applied InDelible to 13,438 probands with severe DDs recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 63 rare, damaging variants in genes previously associated with DDs missed by standard SNV, indel, or CNV discovery approaches. Clinical review of these 63 variants determined that about half (30/63) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21 and 500 bp in size and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.9%. Of particular interest were seven confirmed de novo variants in MECP2, which represent 35.0% of all de novo protein-truncating variants in MECP2 among DDD study participants. InDelible provides a framework for the discovery of pathogenic SVs that are most likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.

The Multiplicative Effects of Individual Risk Factors in the Development of Osteonecrosis of the Femoral Head.

BACKGROUND: While individual risk factors, including chronic corticosteroid use, alcohol abuse, and smoking, are implicated in osteonecrosis of the femoral head (ONFH), the degree to which multiple risk factors increase risk is unknown. This study aimed to: (1) identify the demographic characteristics of patients who have ONFH; (2) quantify the effects of individual risk factors on ONFH development; (3) quantify the effects of combined risk factors on ONFH development; and (4) determine the prognostic implications of combined risk factors on ONFH development. METHODS: This was a retrospective cohort study. A national insurance database was used to study a population of 2,612,383 adult patients who had a 10-year follow-up period. There were 10,233 patients identified who had a diagnosis of ONFH. We identified patients who had chronic corticosteroid use, tobacco use, and/or alcohol abuse and assessed the risk of developing ONFH over a 10-year period. Patients who had individual and multiple risk factors were grouped for comparison, and Chi-square analyses were performed. RESULTS: Higher proportions of patients who had each individual risk factor developed ONFH compared to proportions of patients who did not have risk factors. Patients who had combined risk factors were at greater risk of developing ONFH compared to patients who had no risk factors and those who had single risk factors. Combined risk factors demonstrated multiplicative effects on the development of ONFH: tobacco-alcohol risk ratio (RR) 5.25, corticosteroid-alcohol RR 10.20, tobacco-corticosteroid RR 8.69, and corticosteroid-tobacco-alcohol RR 12.54. Patients who had combined risk factors developed ONFH at younger ages than those who had single risk factors. Kaplan-Meier curve analyses demonstrated worse 10-year hip survival in the setting of combined risk factors. CONCLUSIONS: Combined risk factors have a multiplicative effect on the risk of developing of atraumatic ONFH. Orthopaedic surgeons may care for at-risk individuals through modulation of risk factors. LEVEL OF EVIDENCE: Retrospective Cohort Study, Level III.

Return to the Operating Room for Unplanned Pin Removal After Percutaneous Pinning of Supracondylar Humerus Fractures: A Retrospective Review.

BACKGROUND: Pin migration is a common complication associated with closed reduced and percutaneous pinning (CRPP) of supracondylar humerus fractures (SCHF) in children. Though this complication occurs frequently, little work has been done to elicit circumstances surrounding this complication. The purpose of this study was to evaluate patients with SCHF treated with percutaneous pins who needed to return to the operating room for pin removal. METHODS: This was a multicenter study involving children treated at 6 pediatric tertiary care centers between 2010 and 2020. Retrospective chart review was performed to identify children aged 3 to 10 years of age with a diagnosis of a SCHF. Current Procedural Terminology (CPT) codes were used to identify patients who underwent CRPP of their injuries. CPT codes for deep hardware removal requiring procedural sedation or anesthesia were used to identify patients who needed to return to the operating room for hardware removal. RESULTS: Between 2010 and 2020, 15 out of 7862 patients who were treated for SCHF at our 6 participating study centers experienced pin migration requiring a return to the operating room for pin removal, yielding a complication rate of 0.19%. Twelve (80%) of these injuries were Wilkins modification of the Gartland classification Type III, while the remaining injuries were Type II. 2-pin fixation constructs were used in nine (60%) children; 3-pin fixation constructs were used in 6 (40%) children. Pin migration was noted 23.2±7.0 days postoperatively at clinic follow-up. Four patients were noted to have multiple pins buried at follow-up. Four patients required 1-centimeter incisions for exposure of the buried pins, while surgeons were able to remove the buried pin with just a needle driver and blunt dissection in the remainder of patients. CONCLUSIONS: Pin migration is a common complication of closed reduction and percutaneous pinning of SCHF. There is variation in pin site management to prevent migration in the absence of underlying risk factors. LEVEL OF EVIDENCE: Level III.

Elastomeric Porous Poly(glycerol sebacate) Methacrylate (PGSm) Microspheres as 3D Scaffolds for Chondrocyte Culture and Cartilage Tissue Engineering.

Cartilage defects can be difficult to treat; therefore, tissue engineering of cartilage is emerging as a promising potential therapy. One interesting area of research explores the delivery of cells to the cartilage defect via scaffold-based cell delivery vehicles and microsurgery. This study explores the use of novel poly(glycerol sebacate) methacrylate (PGSm)-polymerised high internal phase emulsion (polyHIPE) microspheres as scaffolds with embedded cells for cartilage tissue engineering. Porous microsphere scaffolds (100 µm-1 mm diameter) were produced from emulsions consisting of water and a methacrylate-based photocurable resin of poly(glycerol sebacate). These resins were used in conjunction with a T-junction fluidic device and an ultraviolet (UV) curing lamp to produce porous microspheres with a tuneable size. This technique produced biodegradable PGSm microspheres with similar mechanical properties to cartilage. We further explore these microspheres as scaffolds for three-dimensional culture of chondrocytes. The microspheres proved to be very efficient scaffolds for primary chondrocyte culture and were covered by a dense extracellular matrix (ECM) network during the culture period, creating a tissue disk. The presence of glycosaminoglycans (GAGs) and collagen-II was confirmed, highlighting the utility of the PGSm microspheres as a delivery vehicle for chondrocytes. A number of imaging techniques were utilised to analyse the tissue disk and develop methodologies to characterise the resultant tissue. This study highlights the utility of porous PGSm microspheres for cartilage tissue engineering.

Decision Making and Cost in Healthcare: The Patient Perspective.

Unsustainable spending and unsatisfactory outcomes have prompted a reanalysis of healthcare policy towards value. Several strategies have been proposed as part of this effort including cost sharing plans to shift costs to patients and gain-sharing models to shift risk to health systems. The patient perspective is rarely elicited in policy formation despite efforts to increase patient-centered care. We conducted a prospective study of 118 patients presenting to hand clinic to assess patient perspective of who should constrain treatment options (patient, physician, insurance company, hospital) and be responsible for costs in scenarios of clinical equipoise. We found that patients believed that insurance companies and hospitals should not constrain which treatment options are available to a patient and that physicians and patients should together influence the availability of treatment options. Patients were willing to cost share with insurance companies when choosing more expensive treatments or in the setting of non-life-threatening diseases. In addressing rising healthcare costs, patient perspectives can inform policies designed to increase value. Asking patients to cost share when choosing a more expensive treatment option in the setting of clinical equipoise could be a strategy for health systems to increase value. Level of Evidence: III (Journal of Surgical Orthopaedic Advances 32(1):023-027, 2023).

Trends in Management of Pediatric Distal Radius Buckle Fractures.

BACKGROUND: Distal radius buckle fractures (DRBFx) represent nearly half of the pediatric wrist injuries. DRBFx are stable injury patterns that can typically be successfully managed with brief immobilization. The purpose of this study was to evaluate opinions and preferences of pediatric orthopaedic specialists regarding the management of DRBFx. METHODS: The POSNA Trauma Quality, Safety, and Value Initiative (QSVI) Committee developed a 20-question survey regarding the treatment of DRBFx in children. The survey was sent twice to all active and candidate POSNA members in June 2020 (n=1487). Questions focused on various aspects of treatment, including type and length of immobilization, follow-up, and radiographs and on potential concerns regarding patient/family satisfaction and pain control, medicolegal concerns, misdiagnosis, and mismanagement. RESULTS: A total of 317 participants completed the survey (response rate=21.3%). In all, 69% of all respondents prefer to use a removable wrist splint, with 76% of those in practice <20 years preferring removable wrist splints compared with 51% of those in practice >20 years (χ 2 =21.7; P <0.01). Overall, 85% of participants utilize shared decision-making in discussing management options with patients and their families. The majority of participants felt that the risk of complications associated with DRBFx was very low, but concern for misdiagnosis and mismanagement have required some respondents to perform closed or open reductions. CONCLUSIONS: In 2020, the majority of respondents treat DRBFx with removable splints (69%) for 3 or fewer weeks (55%), minimal follow-up (85%), and no reimaging (64%). This marks a dramatic shift from the 2012 POSNA survey when only 29% of respondents used removable splinting for DRBFx. LEVEL OF EVIDENCE: Level II.

Patient-Reported Outcome Measurement Information System (PROMIS) Scores in Pediatric Idiopathic Toe Walkers.

BACKGROUND: Idiopathic toe walking (ITW) can result in early contact with the health care system and be distressing for patients and their families. The natural history of ITW is poorly characterized. Deciding how and when to intervene can be difficult.Patient-reported outcomes are utilized in the clinical setting to assess patient factors and indications that may better inform treatment plans. Patient-Reported Outcomes Measurement Information System (PROMIS) is an instrument designed to collect patient-reported outcomes. Minimum clinically important differences in PROMIS metrics have been established to facilitate clinical relevance and utility of these metrics. The purpose of this study was to characterize the patient perspective of ITW by utilizing the PROMIS scores. METHODS: Retrospective chart review was performed to identify children aged 5 to 17 with a diagnosis of ITW treated at a single tertiary care center between 2017 and 2020. Inclusion criteria were a diagnosis of ITW and completion of a PROMIS questionnaire. Exclusion criteria were neurologic disease, autism, and previous surgical treatment. Demographic, physical exam, treatment, and available motion analysis data were collected. PROMIS scores for the following domains were available: Mobility, Peer Relationships, and Pain Interference. RESULTS: Forty-five children were enrolled. Seventy-three percent of PROMIS scores were patient reported while the remainder were parent reported. PROMIS score means for the cohort by domain were Mobility: 45.2±8.2 ( P <0.000); Peer Relationships: 46.4±11.6 ( P =0.047); and Pain Interference: 47.4±9.5 ( P =0.67). Motion analysis data, available for 11 children, noted age-matched gait velocity negatively correlated ( rs =-0.652, P =0.03) with Peer Relationships. No correlations were found between other aspects of gait, body mass index, or limitations in dorsiflexion and PROMIS domains. Parents reported lower Mobility scores than children did. There were no other significant differences between patient-reported and parent-reported PROMIS scores. PROMIS scores did not differ significantly between those <10 years and those ≥10 years. CONCLUSION: In this cohort of 45 otherwise healthy children without other neurologic diagnoses, there are both clinically and statistically significant differences in PROMIS means between our cohort and the healthy age-matched population. These differences manifested in worse peer relationships and mobility scores. LEVEL OF EVIDENCE: Level IV.

Maximization Personality, Disability and Symptoms of Psychosocial Disease in Hand Surgery Patients.

There are different frameworks to describe how people make decisions. One framework, maximization, is an approach where individuals approach choices with a goal of finding the 'best' possible alternative. We sought to determine the relationship between maximization and patient reported disability in patients with hand problems. We performed a cross-sectional study of 119 patients who presented to a hand surgery clinic. Patients completed a questionnaire that included sociodemographics, QuickDASH, Decisional Conflict Scale, Pain Catastrophizing Scale, Patient Health Questionnaire, Health Anxiety Inventory and General Self-Efficacy. Maximization did not correlate with subjective disability in patients with hand problems. Depression, pain catastrophizing and a diagnosis of upper extremity fracture had the greatest independent association with disability.In patients presenting for an initial hand surgery consultation, maximization was not associated with variation in patient reported disability or symptoms of psychosocial disease. Alternative factors influencing patient decision-making and outcomes should be explored. (Journal of Surgical Orthopaedic Advances 29(2):106-111, 2020).

Evidence to Action: The 10th International Conference on Typhoid and Other Invasive Salmonelloses.

Typhoid and other invasive salmonelloses continue to cause a significant burden of disease, including morbidity, mortality, and financial cost, in low- and middle-income countries. Prevention and control efforts for these diseases encounter challenges and require a coordinated global response. To organize this effort, share breakthrough research, and discuss innovative solutions, the Coalition Against Typhoid, based at the Sabin Vaccine Institute, convened the 10th International Conference on Typhoid and Other Invasive Salmonelloses in Kampala, Uganda, from 4-6 April 2017. Here, we review the significant topics and research discussed at the conference, including disease burden, diagnosis and detection, antimicrobial resistance, and prevention and control methods.

The Coalition Against Typhoid: Mobilizing a Community for a Global Fight.

Typhoid became a low priority on the global public health agenda when it was largely eliminated from developed countries in the 1940s. However, communities in South Asia and sub-Saharan Africa continue to bear the brunt of the disease burden. One strategy to increase attention and coordinate action is the creation of a coalition to act as a steward for typhoid. The Coalition against Typhoid (CaT) was created in 2010 with the mission of preventing typhoid among vulnerable populations through research, education, and advocacy. CaT successfully raised the profile of typhoid through convening the community with a biennial international conference that has experienced growing participation, disseminating data and news through a website and newsletter with increasing readership, and advocating through social media and a blog reaching a diverse audience. In 2017, CaT joined forces with the Typhoid Vaccine Acceleration Consortium to "Take on Typhoid," combining advocacy and communications efforts to mobilize researchers, clinicians, and decision makers at the global, regional, and local levels to introduce the new typhoid conjugate vaccine. As a result, the knowledge base, political will, and momentum are increasingly in place to implement prevention and control interventions including the typhoid conjugate vaccine in the poor communities that have historically been left behind.

Absence of heterozygosity due to template switching during replicative rearrangements.

We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

Postincident Support for Healthcare Workers Experiencing Occupational Violence and Aggression.

PURPOSE: To investigate the relative contributions of workplace type, occupational violence and aggression (OVA) strategies and interventions along with perceptions of the occupational health and safety (OHS) environment on the likelihood of receiving postincident support following the experience of OVA. DESIGN: We used a cross-sectional study design with an online survey to collect data from employees in nursing and midwifery in Victoria, Australia. METHODS: Survey data collected from 3,072 members of the Australian Nursing and Midwifery Federation (Victorian branch) were analyzed using logistic regression. FINDINGS: Of the 3,072 respondents who had experienced OVA in the preceding 12 months, 1,287 (42%) reported that they had received postincident support. Hierarchical logistic regression revealed that the OHS environment was the dominant factor that predicted the likelihood of workers receiving postincident support. Working in a positive OHS environment characterized by higher levels of leading indicators of OHS, prioritization of OHS, supervisor support for safety, and team psychological safety was the stronger predictor of postincident support. Being employed in a workplace that offered training in the management and prevention of OVA also increased the likelihood of receiving postincident support. CONCLUSIONS: While training in the management and prevention of OVA contributed to the likelihood of receiving postincident support, a greater emphasis on the OHS environment was more important in predicting the likelihood that workers received support. CLINICAL RELEVANCE: This study identifies workplace practices that facilitate the provision of postincident support for healthcare workers. Facilitating effective postincident support could improve outcomes for workers, their patients and workplaces, and society in general.

Patients Should Define Value in Health Care: A Conceptual Framework.

The main tenet of value-based health care is delivering high-quality care that is centered on the patient, improving health, and minimizing cost. Collaborative decision-making frameworks have been developed to help facilitate delivering care based on patient preferences (patient-centered care). The current value-based health care model, however, focuses on improving population health and overlooks the individuality of patients and their preferences for care. We highlight the importance of eliciting patient preferences in collaborative decision making and describe a conceptual framework that incorporates individual patients' preferences when defining value.

Rare variants in NR2F2 cause congenital heart defects in humans.

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters.

The rate of nonallelic homologous recombination in males is highly variable, correlated between monozygotic twins and independent of age.

Nonallelic homologous recombination (NAHR) between highly similar duplicated sequences generates chromosomal deletions, duplications and inversions, which can cause diverse genetic disorders. Little is known about interindividual variation in NAHR rates and the factors that influence this. We estimated the rate of deletion at the CMT1A-REP NAHR hotspot in sperm DNA from 34 male donors, including 16 monozygotic (MZ) co-twins (8 twin pairs) aged 24 to 67 years old. The average NAHR rate was 3.5 × 10(-5) with a seven-fold variation across individuals. Despite good statistical power to detect even a subtle correlation, we observed no relationship between age of unrelated individuals and the rate of NAHR in their sperm, likely reflecting the meiotic-specific origin of these events. We then estimated the heritability of deletion rate by calculating the intraclass correlation (ICC) within MZ co-twins, revealing a significant correlation between MZ co-twins (ICC = 0.784, p = 0.0039), with MZ co-twins being significantly more correlated than unrelated pairs. We showed that this heritability cannot be explained by variation in PRDM9, a known regulator of NAHR, or variation within the NAHR hotspot itself. We also did not detect any correlation between Body Mass Index (BMI), smoking status or alcohol intake and rate of NAHR. Our results suggest that other, as yet unidentified, genetic or environmental factors play a significant role in the regulation of NAHR and are responsible for the extensive variation in the population for the probability of fathering a child with a genomic disorder resulting from a pathogenic deletion.

Emerging therapy for endometriosis.

INTRODUCTION: Endometriosis is a chronic disease manifested by pain and infertility due to ectopic implantation of endometrial glands and stroma causing inflammation. Treatment of endometriosis utilizes a significant amount of health-care resources and requires chronic therapy. Management involves a combination of surgical and medical interventions and requires long-term treatment to avoid repeated surgeries. AREAS COVERED: Whereas medical therapies exist for management of endometriosis-related pain, each class has its limitations including side effects, cost, and known duration of relief of symptoms. Development of effective, well-tolerated medical therapies that are appropriate for long-term use is crucial to provide adequate treatment for this chronic disease. This review discusses the various medical therapies available, their limitations, and emerging therapies being developed to address many of these concerns. EXPERT OPINION: The authors recommend chronic suppressive therapy for management of endometriosis symptoms, particularly in the postoperative setting. Empiric treatment is appropriate for those patients without evidence of severe disease. Currently available option may not be effective for nor tolerated by all patients. Newer compounds, including gonadotropin-releasing antagonists and aromatase inhibitors combined with hormonal contraceptives, offer possible alternatives to currently available therapies.