Five-Year Assessment of Multiple Gene Variants Associated with Bone Marrow Hypocellularity, Reduced Bone Density, and Ovarian Insufficiency in Adolescence.

This study covers the 5-year interval prior to COVID-19 admission for an otherwise healthy 46,XX adolescent expanding the developmental characterization of an unusual convergence of amenorrhea and genetic mutations. The patient experienced rapid collapse of endogenous estradiol output followed by secondary amenorrhea at 13 years of age. Euploid, diffusely hypocellular bone marrow was present on biopsy, although anemia or reduced total immunoglobulin production was not identified. Bone density was 1.5 years below mean; multiple dental anomalies were also documented. While alterations in "master regulator" genes RUNX2, SALL1, and SAMD9 are usually diagnosed in early childhood when missed milestones, dysmorphic features, or chronic infection/immune impairment warrant cross-disciplinary evaluation, this study is the first known report to associate ovarian failure with adolescence with such variants. Immunoglobulin patterns, osseous histomorphology, dentition, hematology/renal screening, pelvic anatomy, ovarian reserve data, and thyroid findings are also correlated. Although severe pathology is typically encountered when any of these genes are disrupted alone, this longitudinal survey reveals that a mild phenotype can prevail if these 3 variants occur simultaneously. Periodic monitoring is planned given the unclassified status of this unique mutation set.

Why might ovarian rejuvenation fail? Decision analysis of variables impacting reproductive response after autologous platelet-rich plasma.

Experience with platelet-rich plasma (PRP) has accumulated from use in dental restoration, postinfarct myocardial repair, tendon surgery, pain management, and aesthetic enhancements. Reproductive medicine joined this arena in 2016, beginning with reports of menopause reversal and fertility recovery after autologous PRP for senescent ovaries. Although recent publications have highlighted benefits of "ovarian rejuvenation," the absence of randomized placebo-controlled clinical trial data has limited its acceptance. Because selection bias tends to underreport negative outcomes, reliable estimates cannot be calculated for how often intraovarian PRP is unsuccessful. However, ample information is available to permit an operational root-cause analysis when failures are considered. This assessment uses a PRP treatment care path with a decision theory model to critique pre-intake screening, baseline audit, sample processing, ovarian tissue placement method, equipment selection, and follow-up monitoring. These branched choice points enable interventions likely to determine outcome. Specimen handling for intraovarian PRP merits particular scrutiny, since enormous variation in platelet protocols already exists across unrelated clinical areas. As a new addition to fertility practice, intraovarian PRP requires validation of safety and efficacy to gain wider support. Borrowing PRP knowledge from other domains can facilitate this goal, ideally with appreciation of aspects unique to intraovarian use.

The 500-year Cultural & Economic Trajectory of Tobacco: A Circle Complete.

Who smokes, and why do they do it? What factors discourage and otherwise reward or incentivize smoking? Tobacco use has been accompanied by controversy from the moment of its entry into European culture, and conflicting opinions regarding its potentially adverse influence on health have coexisted for hundreds of years. Its use in all forms represents the world's single greatest cause of preventable disease and death. Tobacco was introduced to Europe by Christopher Columbus, who in October 1492 discovered the crop in Cuba. While the next four centuries would see tobacco as the most highly traded economic commodity, by 1900, the now familiar cigarette remained obscure and accounted for only 2% of total tobacco sales. Global tobacco consumption rose sharply after 1914 and became especially prevalent following World War II, particularly among men. Indeed, overall tobacco sales increased by more than 60% by the mid-20th century, and cigarettes were a critical driver of this growth. Cigarettes dominated the tobacco market by 1950, by then accounting for more than 80% of all tobacco purchases. In the absence of clinical and scientific evidence against tobacco, moral and religious arguments dominated opposition voices against tobacco consumption in the 1800s. However, by the mid-20th century, advancements in medical research supported enhanced government and voluntary actions against tobacco advertising and also raised awareness of the dangers associated with passive tobacco smoke exposure. Solid epidemiological work connecting tobacco use with "the shortening of life span" began to appear in the medical literature in the 1950s, linking smoking with lung cancer and related conditions. In subsequent years, these developments led to significant curtailment of tobacco use. This monograph explores aspects of the intersection of tobacco with themes of behavioral incentives, religion, culture, literature, economics, and government over the past five centuries.

A decade of health assessments in Appalachia.

Purpose The purpose of this paper is to describe standardized clinical process of care and quality performance metrics at Roane Medical Center (RMC) and compare data from 2005 to 2015. Design/methodology/approach Information was extracted from a nationwide sample of short-term acute care hospitals using the Hospital Quality Alliance (HQA) database, evaluating multiple parameters measured at RMC. HQA data from RMC were matched against state and national benchmarks; findings were also compared with similar reports from the same facility in 2005. Findings Information collected by HQA expanded substantially in ten years and queried different parameters over time, thus exact comparisons between 2005 and 2015 cannot be easily calculated. Nevertheless, analysis of process of care data for 2015 placed RMC at or above state- and national-average performance in 64.9 percent (24 of 37) and 56.5 percent (26 of 46) categories, respectively. RMC registered superior process of care scores in heart failure care, pneumonia care, thrombus prevention and care, as well as stroke care. While RMC continues to perform favorably against state and national reference groups, the differences between RMC vs state and RMC vs national averages using current reporting metrics were both statistically smaller in 2015 compared to 2005 ( p<0.05). Research limitations/implications Perhaps the most significant interval health event for the RMC service area since 2005 was a coal ash spill at the nearby Tennessee Valley Authority facility in December 2008. Although reports on environmental and health effects following one of the largest domestic industrial toxin releases reached a number of important conclusions, the consequences for RMC in terms of potential added clinical burden on emergency services and impact on chronic health conditions have not been specifically studied. This could explain data reported on emergency department services at RMC but additional research will be needed to establish causality. Practical implications While tracking of care processes at all US hospitals will be facilitated by refinements in HQA tools, longitudinal evaluations for any specific unit will be more meaningful if the assessment instrument undergoes limited change over time. Social implications Appalachia remains one of several regions in the USA often identified as medically underserved. Hospitals here have confronted the challenge of diminished reimbursement, high expenses, limited staffing and other financial hardships in a variety of ways. Since the last published report on RMC, a particularly severe global recession has placed additional stress on organizations offering crucial health services in the region. Originality/value As a follow-up study to track potential changes which have been registered in the decade 2005-2015, this is the first report to provide original, longitudinal analysis on RMC, an institution operating in a rural and underserved area.

Cost Implications for Subsequent Perinatal Outcomes After IVF Stratified by Number of Embryos Transferred: A Five Year Analysis of Vermont Data.

BACKGROUND: In states in the USA without in vitro fertilzation coverage (IVF) insurance coverage, more embryos are transferred per cycle leading to higher risks of multi-fetal pregnancies and adverse pregnancy outcomes. OBJECTIVE: To determine frequency and cost of selected adverse perinatal complications based on number of embryos transferred during IVF, and calculate incremental cost per IVF live birth. METHODS: Medical records of patients who conceived with IVF (n = 116) and delivered at >20 weeks gestational age between 2007 and 2011 were evaluated. Gestational age at delivery, low birth weight (LBW) term births, and delivery mode were tabulated. Healthcare costs per cohort, extrapolated costs assuming 100 patients per cohort, and incremental costs per infant delivered were calculated. RESULTS: The highest prematurity and cesarean section rates were recorded after double embryo transfers (DET), while the lowest rates were found in single embryo transfers (SET). Premature singleton deliveries increased directly with number of transferred embryos [6.3 % (SET), 9.1 % (DET) and 10.0 % for ≥3 embryos transferred]. This trend was also noted for rate of cesarean delivery [26.7 % (SET), 36.6 % (DET), and 47.1 % for ≥3 embryos transferred]. The proportion of LBW infants among deliveries after DET and for ≥3 embryos transferred was 3.9 and 9.1 %, respectively. Extrapolated costs per cohort were US$718,616, US$1,713,470 and US$1,227,396 for SET, DET, and ≥3 embryos transferred, respectively. CONCLUSION: Attempting to improve IVF pregnancy rates by permitting multiple embryo transfers results in sharply increased rates of multiple gestation and preterm delivery. This practice yields a greater frequency of adverse perinatal outcomes and substantially increased healthcare spending. Better efforts to encourage SET are necessary to normalize healthcare expenditures considering the frequency of very high cost sequela associated with IVF where multiple embryo transfers occur.

What Is the Economic Cost of Unplanned Pregnancy Following Hysteroscopic Sterilization in the US? A New National Estimate Based on Essure® Procedure Prevalence, Failure Rates and Workforce Productivity.

OBJECTIVE: Although hysteroscopic sterilization (HS) (Essure ®) has been available in the US since 2002, there is disagreement regarding its efficacy, and there has been no study of the economic impact of HS failure. Our investigation examined the economic consequences of contraceptive failure with Essure in the US. METHODS: Contraceptive failure rates (CFR) of 5.7%, 7.7% and 9.6% were applied to the US cohort of HS patients (n = 600,000). Direct economic impact of productivity losses resulting from unplanned conceptions after HS was calculated by factoring Essure failure rate, the exposed population, US female labour force participation, unemployment rate, time away from work owing to vaginal delivery or pregnancy termination and weekly wages. RESULTS: For the 9.6% CFR scenario, US workforce productivity loss from unplanned pregnancy and delivery was estimated at 771,065 days (2,112 years). Productivity loss secondary to conception and subsequent termination of pregnancy after Essure was approximately 23,725 days (65 years). Assuming CFR at 5.7%, livebirth delivery with total time missed from work at 65 days, this was associated with an aggregate economic impact of $49.2M in lost annual wages. Direct economic impact of unplanned pregnancy after Essure irrespective of outcome (terminations and deliveries) was estimated to result in US productivity losses valued at ~$130M. CONCLUSION: Although not all unplanned pregnancy costs are attributable to failed HS, estimates derived from earlier surveys have not considered this contraceptive method, and the economic consequences of unplanned pregnancy after Essure are not trivial. Quantifying the economic consequences of HS failure would be improved with specific ICD-10 coding for Essure-associated symptoms.

A Time-motion Comparison of Itemized Treatment Costs in First and Second In Vitro Fertilization Attempts: A United Kingdom Fertility Centre Experience.

Objective: To assess the difference in cost between initial and second in vitro fertilization (IVF) cycles in the United Kingdom. Methods: This prospective time-motion analysis captured data on average time spent on 31 representative components of the IVF sequence as provided by clinical team members in seven categories. Audits of consumables and observations on personnel costs were made from total of 120 fertility patients undergoing initial or second IVF cycles (n=736) between 1 January 2002 and 31 December 2002 at a UK assisted fertility unit. Results: Patients spent an average of 16.71±4.3 hrs with staff during an initial IVF cycle, resulting in direct personnel costs of £577.05±151.01. When consumables were included, each initial cycle cost the clinic approximately £2246.57±151.01. For second IVF cycles, patients spent significantly less time with staff compared to their first IVF cycle (6.94±2.44 hrs; p<0.05), corresponding to £257.53±90.77 in personnel cost. Conclusions: This is the first economic appraisal of the IVF treatment sequence in the UK using a timemotion analysis model. Our study found that when combined with consumables, total institutional costs for second IVF cycles were significantly reduced when compared to initial cycles (£1813.12±90.77; p<0.05). Aggregating data from all IVF cycles performed within the fertility centre during the study interval, initial cycles were found to be front-loaded, resulting in £252,420 more in institutional costs as compared with subsequent IVF cycles. While these observations were registered in 2003, an inflation adjustment using recent European Commission Eurostat data for healthcare finds the difference between initial and subsequent fresh IVF cycles in present currency to be approximately £579.14 per cycle. Time-motion analysis can identify episodes of care that can be streamlined to improve outcomes and reduce cost.

Balancing selected medication costs with total number of daily injections: a preference analysis of GnRH-agonist and antagonist protocols by IVF patients.

BACKGROUND: During in vitro fertilization (IVF), fertility patients are expected to self-administer many injections as part of this treatment. While newer medications have been developed to substantially reduce the number of these injections, such agents are typically much more expensive. Considering these differences in both cost and number of injections, this study compared patient preferences between GnRH-agonist and GnRH-antagonist based protocols in IVF. METHODS: Data were collected by voluntary, anonymous questionnaire at first consultation appointment. Patient opinion concerning total number of s.c. injections as a function of non-reimbursed patient cost associated with GnRH-agonist [A] and GnRH-antagonist [B] protocols in IVF was studied. RESULTS: Completed questionnaires (n = 71) revealed a mean +/- SD patient age of 34 +/- 4.1 yrs. Most (83.1%) had no prior IVF experience; 2.8% reported another medical condition requiring self-administration of subcutaneous medication(s). When out-of-pocket cost for [A] and [B] were identical, preference for [B] was registered by 50.7% patients. The tendency to favor protocol [B] was weaker among patients with a health occupation. Estimated patient costs for [A] and [B] were $259.82 +/- 11.75 and $654.55 +/- 106.34, respectively (p < 0.005). Measured patient preference for [B] diminished as the cost difference increased. CONCLUSIONS: This investigation found consistently higher non-reimbursed direct medication costs for GnRH-antagonist IVF vs. GnRH-agonist IVF protocols. A conditional preference to minimize downregulation (using GnRH-antagonist) was noted among some, but not all, IVF patient sub-groups. Compared to IVF patients with a health occupation, the preference for GnRH-antagonist was weaker than for other patients. While reducing total number of injections by using GnRH-antagonist is a desirable goal, it appears this advantage is not perceived equally by all IVF patients and its utility is likely discounted heavily by patients when nonreimbursed medication costs reach a critical level.

Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study.

BACKGROUND: Single embryo transfer (SET) remains underutilized as a strategy to reduce multiple gestation risk in IVF, and its overall lower pregnancy rate underscores the need for improved techniques to select one embryo for fresh transfer. This study explored use of comprehensive chromosomal screening by array CGH (aCGH) to provide this advantage and improve pregnancy rate from SET. METHODS: First-time IVF patients with a good prognosis (age <35, no prior miscarriage) and normal karyotype seeking elective SET were prospectively randomized into two groups: In Group A, embryos were selected on the basis of morphology and comprehensive chromosomal screening via aCGH (from d5 trophectoderm biopsy) while Group B embryos were assessed by morphology only. All patients had a single fresh blastocyst transferred on d6. Laboratory parameters and clinical pregnancy rates were compared between the two groups. RESULTS: For patients in Group A (n = 55), 425 blastocysts were biopsied and analyzed via aCGH (7.7 blastocysts/patient). Aneuploidy was detected in 191/425 (44.9%) of blastocysts in this group. For patients in Group B (n = 48), 389 blastocysts were microscopically examined (8.1 blastocysts/patient). Clinical pregnancy rate was significantly higher in the morphology + aCGH group compared to the morphology-only group (70.9 and 45.8%, respectively; p = 0.017); ongoing pregnancy rate for Groups A and B were 69.1 vs. 41.7%, respectively (p = 0.009). There were no twin pregnancies. CONCLUSION: Although aCGH followed by frozen embryo transfer has been used to screen at risk embryos (e.g., known parental chromosomal translocation or history of recurrent pregnancy loss), this is the first description of aCGH fully integrated with a clinical IVF program to select single blastocysts for fresh SET in good prognosis patients. The observed aneuploidy rate (44.9%) among biopsied blastocysts highlights the inherent imprecision of SET when conventional morphology is used alone. Embryos randomized to the aCGH group implanted with greater efficiency, resulted in clinical pregnancy more often, and yielded a lower miscarriage rate than those selected without aCGH. Additional studies are needed to verify our pilot data and confirm a role for on-site, rapid aCGH for IVF patients contemplating fresh SET.

Preimplantation genetic diagnosis for elective sex selection, the IVF market economy, and the child--another long day's journey into night?

The promise of medical innovation has long evoked social commentary, particularly when personal reproductive autonomy may be involved. Development of the oral contraceptive, effective and safe surgical sterilization, and later IVF and ICSI are among the revolutionary developments where the initial reactions were dubious but were accorded mainstream status with sufficient clinical experience. In each instance, debate about the moral and social implications of these treatments accompanied their introduction into the medical marketplace. This pattern appears to be repeating itself in connection with the use of preimplantation genetic diagnosis (PGD) for elective sex selection of human embryos. As with prior challenges in reproductive medicine, the development of meaningful "guidelines" for this latest controversy has proven to be a contentious task. Indeed, the progression of ethics committee reports from the American Society for Reproductive Medicine seems to echo the ambivalence within society at large regarding this issue. In this report, we chronicle sex selection claims based on sperm sorting, and describe how flow cytometry and especially PGD have facilitated this selection at the gamete and embryo stage, respectively. In doing so, we also explore market forces and practitioner considerations associated with the application of PGD for this; related ethical issues with particular emphasis on the progeny derived from such treatment are also reviewed.