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The summary presented herein represents Part II of the two-part series dedicated to the Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Part II outlines the appropriate management of the male in an infertile couple. Medical therapies, surgical techniques, as well as use of intrauterine insemination (IUI)/in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) are covered to allow for optimal patient management. Please refer to Part I for discussion on evaluation of the infertile male and discussion of relevant health conditions that are associated with male infertility.The Emergency Care Research Institute Evidence-based Practice Center team searched PubMed®, Embase®, and Medline from January 2000 through May 2019. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (table[Table: see text]). This summary is being simultaneously published in Fertility and Sterility and The Journal of Urology.This Guideline provides updated, evidence-based recommendations regarding management of male infertility. Such recommendations are summarized in the associated algorithm (figure[Figure: see text]).Male contributions to infertility are prevalent, and specific treatment as well as assisted reproductive techniques are effective at managing male infertility. This document will undergo additional literature reviews and updating as the knowledge regarding current treatments and future treatment options continues to expand.

Thunderstorm ground enhancement (TGE) is a phenomenon that enhances radiation background on the ground related to thunderstorm activity and charge structure of the thundercloud. On the other hand, the rise of gamma background is connected with precipitation by the washout of radon progeny from the atmosphere. In our analysis, we examined known enhancements of gamma background, previously attributed solely to radon progeny, using data from the Czech Radiation Monitoring Network (RMN) to investigate the enhancements with respect to thunderstorms and TGE phenomena. We also used radar precipitation data and data from the lightning location network to analyze their influences on the radiation background enhancement during three thunderstorm events that occurred in summer 2016 over the Czech Republic (Central Europe). We state that the RMN might have detected TGE over the Czech Republic.

Context Progress has been made in determining the fertility timeline and potential in adolescents with Klinefelter syndrome; however, medical professionals are currently without protocols to guide treatment. Objective To evaluate the current practices regarding fertility and andrology care in adolescent males with Klinefelter syndrome. Design A 24-question survey was developed to elicit practitioner background/expertise and management practices. This was distributed to members of the Society for the Study of Male Reproduction, the Pediatric Endocrine Society, and the Endocrine Society. Setting N/A. Patients Adolescent males with Klinefelter syndrome. Intervention None. Main Outcome Measured Current practices regarding fertility and andrology care. Results 232 responses were received from 133 (57%) adult endocrinologists, 60 (26%) pediatric endocrinologists, and 39 (17%) urologists. Among these, 69% of respondents were in academics, 62% practiced for > 10 years, and 65% received formal training in Klinefelter syndrome. All specialties encouraged sperm banking in late puberty, however most disagreed with the practice in early puberty. Seventy-eight percent agreed that testicular biopsy should be offered if no sperm was found in the ejaculate. The perceived optimal age for testicular biopsy varied among specialists. Clinical symptoms of hypogonadism (28%), rising gonadotropin levels (15%), and testosterone levels (15%) were the most commonly cited reasons for initiation of testosterone replacement therapy. Conclusion Fertility preservation practices in adolescents with Klinefelter syndrome vary greatly within and among the specialties caring for these patients. These findings should guide future research and highlight the importance of establishing clinical practice guidelines.

Purpose The summary presented herein represents Part I of the two-part series dedicated to the Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Part I outlines the appropriate evaluation of the male in an infertile couple. Recommendations proceed from obtaining an appropriate history and physical exam ( Appendix I ), as well as diagnostic testing, where indicated. Materials/Methods The Emergency Care Research Institute Evidence-based Practice Center team searched PubMed®, Embase®, and Medline from January, 2000 through May, 2019. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. ( Table 1 ) This summary is being simultaneously published in Fertility and Sterility and The Journal of Urology. Results This Guideline provides updated, evidence-based recommendations regarding evaluation of male infertility as well as the association of male infertility with other important health conditions. The detection of male infertility increases the risk of subsequent development of health problems for men. In addition, specific medical conditions are associated with some causes for male infertility. Evaluation and treatment recommendations are summarized in the associated algorithm. ( Figure 1 ) Conclusion The presence of male infertility is crucial to the health of patients and its effects must be considered for the welfare of society. This document will undergo updating as the knowledge regarding current treatments and future treatment options continues to expand.

Clinicians should encourage disclosure between intimate partners but must maintain confidentiality in cases where there is no prospect of harm to the partner and/or offspring. In cases where one member of a couple refuses to disclose relevant health information to the other partner and there exists a risk of harm to the unaware partner and/or offspring, clinicians may refuse to offer care and should decline to treat if full informed consent is not possible due to lack of disclosure.

STUDY QUESTION\ud \ud Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems?\ud \ud \ud \ud SUMMARY ANSWER\ud \ud A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders.\ud \ud \ud \ud WHAT IS KNOWN ALREADY\ud \ud In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues.\ud \ud \ud \ud STUDY DESIGN, SIZE, DURATION\ud \ud Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions.\ud \ud \ud \ud PARTICIPANTS/MATERIALS, SETTING, METHODS\ud \ud Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations.\ud \ud \ud \ud MAIN RESULTS AND THE ROLE OF CHANCE\ud \ud A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as ‘fertility care’ and ‘fertility awareness’ together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of ‘infertility’ has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion.\ud \ud \ud \ud LIMITATIONS, REASONS FOR CAUTION\ud \ud All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary.\ud \ud \ud \ud WIDER IMPLICATIONS OF THE FINDINGS\ud \ud Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide.

Patient requests for transfer of embryos with genetic anomalies linked to serious health-affecting disorders detected in preimplantation testing are rare but do exist. This Opinion sets out the possible rationales for a provider's decision to assist or decline to assist in such transfers. The Committee concludes in most clinical cases it is ethically permissible to assist or decline to assist in transferring such embryos. In circumstances in which a child is highly likely to be born with a life-threatening condition that causes severe and early debility with no possibility of reasonable function, provider transfer of such embryos is ethically problematic and highly discouraged.

While venous thromboembolism (VTE) is rare in young women of reproductive age, combined oral contraceptives increase the risk of VTE. In the patient in whom combined hormonal contraception is appropriate, it is reasonable to use any currently available preparation.

This opinion addresses the ethics of providing fertility treatment to women at elevated risk from fertility treatment or pregnancy. Providers ethically may treat women at elevated risk provided that they are carefully assessed; that specialists in their medical condition are consulted as appropriate; and that patients are fully informed about risks, benefits, and alternatives, including oocyte and embryo donation, use of a gestational surrogate, not undergoing fertility care, and adoption. Providers also may conclude that the risks are too high for them to treat particular patients ethically; such determinations must be made in a medically objective and unbiased manner and patients must be fully informed of the decision. Counseling of women who wish to initiate fertility treatment with underlying medical conditions that confer increased risk during treatment or pregnancy should incorporate the most current knowledge available, being cognizant of the woman's personal determinants in relation to her reproductive desires. In such a way, both physician and patient will optimize decision making in an ethically sound, patient-supportive context.

Financial "risk-sharing" fee structures in assisted reproduction programs charge patients a higher initial fee but provide reduced fees for subsequent cycles and often a partial or complete refund if treatment fails. This opinion of the ASRM Ethics Committee analyzes the ethical issues raised by these fee structures, including patient selection criteria, conflicts of interest, success rate transparency, and patient informed consent. This document replaces the document of the same name, last published in 2013 (Fertil Steril 2013;100:334-6).

Luteal phase deficiency (LPD) has been described in healthy normally menstruating women and in association with other medical conditions. Although progesterone is important for the process of implantation and early embryonic development, LPD, as an independent entity causing infertility, has not been proven. This document replaces the document by the same name, last published in 2012 (Fertil Steril 2012;98:1112-7).

The purpose of this ASRM Practice Committee report is to provide clinicians with principles and strategies for the evaluation of couples with male infertility problems. This revised document replaces the document of the same name, last published in 2012 (Fertil Steril 2012;98:294-301).

Fertility programs may withhold services from prospective patients on the basis of well-grounded reasons that those patients will be unable to provide minimally adequate or safe care for offspring. This document was reviewed and updated; this version replaces the previous version of this document, last published July 2013 (Fertil Steril 2013;100:50-53).

Presented paper describes the behaviour of simply supported single ply glass beam with discontinuities in its geometry. Discontinuity is introduced by four openings symmetrically placed over the beam. This type of simplified structure represents cut out of real constructions where similar glass components are used as primary load bearing structures supporting glazing of roofs or decks of pedestrian bridges. The main focus of this article is in research of stress distribution around openings and how different diameter of a hole influences stresses in its close proximity. As Eurocode standards for glass structures are still not codified and most of the nowadays literature only provide suggested diameters of holes based on the thickness of the glass pane, this paper will provide the future designers of glass load bearing structures with closer look at stress distribution around mentioned area. In order to bring those informations to theirs seekers, both experimental analysis and numerical analysis together with parametric study were used.

The use of adult intrafamilial gamete donors and gestational surrogates is generally ethically acceptable when all participants are fully informed and counseled, but consanguineous arrangements or ones that simulate incestuous unions should be prohibited. Adult child-to-parent arrangements require caution in order to avoid coercion, and parent-to-adult child arrangements are acceptable in limited situations. Programs that choose to participate in intrafamilial arrangements should be prepared to spend additional time counseling participants and ensuring that they have made free, informed decisions. This document replaces the document of the same name, last published in 2012 (Fertil Steril 2012;98:797–803).

Financial compensation of women donating oocytes for infertility therapy or for research is justified on ethical grounds and should acknowledge the time, inconvenience, and discomfort associated with screening, ovarian stimulation, and oocyte retrieval, and not vary according to the planned use of the oocytes, the number or quality of oocytes retrieved, the number or outcome of prior donation cycles, or the donor's ethnic or other personal characteristics. This document replaces the document of the same name, last published in 2007 (Fertil Steril 2007;88:305-9).

Cross-border reproductive care (CBRC) is a growing worldwide phenomenon, raising questions about why assisted reproductive technology (ART) patients travel abroad, what harms and benefits may result, and what duties health-care providers may have in advising and treating patients who travel for reproductive services. Cross-border care offers benefits and poses harms to ART stakeholders, including patients, offspring, providers, gamete donors, gestational carriers, and local populations in destination countries. This document replaces the previous document of the same name, last published in 2013 (Fertil Steril 2013;100:645–50).

Medical providers have an ethical duty to disclose clinically significant errors involving gametes and embryos as soon as they are discovered. Clinics also should have written policies in place for reducing and disclosing errors. This document was reviewed and affirmed in 2015 and replaces the earlier document of the same name (Fertil Steril 2011;96:1312–4).

Building families through the adoption of children has been supported by human society throughout history. The ethical appropriateness of patients donating embryos to other patients for family building, or for research, is well established and is affirmed by this Committee. The use of the term ‘‘adoption'' for embryos is inaccurate and should be avoided. This document replaces the ASRM Ethics Committee statement by the same name, last published in 2013 (Fertil Steril 2013;99:1846–7).

A normal functioning reproductive endocrine system is a prerequisite for normal male fertility. Any disruption of the delicately coordinated interaction between the components of the hypothalamic-pituitary-testicular axis may lead to hypogonadism and/or infertility. The goal of the clinical evaluation is to determine if the patient has an abnormality of testosterone production or action, the etiology of the abnormality, and if hormone therapy will correct the infertility. Based on a careful history, physical examination, and evaluation of the hormones of the reproductive axis, the physician will ascertain if the patient's hypogonadism is (1) prepubertal or postpubertal in onset; (2) the result of an abnormality in the hypothalamic-pituitary axis, the testes, or the androgen receptor; or (3) associated with another underlying medical condition. This information will place the patient into one of four diagnostic categories: hypogonadotropic hypogonadism, testicular failure, 5alpha-reductase deficiency, or androgen resistance. Within each category are disorders with identifiable pathogenic mechanisms. Recent studies have added to these lists and have provided insights into the molecular basis and inheritance patterns of several of these endocrinopathies.

Many studies have investigated the association between male infertility and trinucleotide repeat polymorphisms in the androgen receptor (AR) gene, but no comprehensive meta-analysis of all published studies has been conducted.Our goals were to summarize published data on associations between AR CAG and GGC repeat lengths and male infertility and investigate sources of variation between study results.We searched for reports published before October 2006 using Medline, PubMed, and Web of Science.All selected studies included the following: a case group with infertility as measured by semen parameters, a control group of known or presumed fertile men, and measurement of CAG and/or GGC repeat lengths among cases and controls. Thirty-nine reports were selected based on these criteria, and 33 were ultimately included in the meta-analysis.One investigator extracted data on sample size, mean and sd of trinucleotide repeat length, and study characteristics.Estimates of the standardized mean difference (95% confidence interval) were 0.19 (0.09-0.29) for the 33 studies and 0.31 (0.14-0.47) for a subset of 13 studies that used more stringent case and control selection criteria. Thus, in both groups, cases had statistically significantly longer CAG repeat length than controls. Publication date appeared to be a significant source of variation between studies.This meta-analysis provides support for an association between increased androgen receptor CAG length and idiopathic male infertility, suggesting that even subtle disruptions in the androgen axis may compromise male fertility.

This document presents arguments that conclude that it is unethical to use somatic cell nuclear transfer (SCNT) for infertility treatment due to concerns about safety; the unknown impact of SCNT on children, families, and society; and the availability of other ethically acceptable means of assisted reproduction. This document replaces the ASRM Ethics Committee report titled, "Human somatic cell nuclear transfer and cloning," last published in Fertil Steril 2012;98:804–7.

Idiopathic male infertility may be due to exposure to environmental toxicants that alter spermatogenesis or sperm function. We studied the relationship between air pollutant levels and semen quality over a 2-year period in Los Angeles, California, by analyzing repeated semen samples collected by sperm donors. Semen analysis data derived from 5,134 semen samples from a sperm donor bank were correlated with air pollutant levels (ozone, nitrogen dioxide, carbon monoxide, and particulate matter < 10 microm in aerodynamic diameter) measured 0-9, 10-14, and 70-90 days before semen collection dates in Los Angeles between January 1996 and December 1998. A linear mixed-effects model was used to model average sperm concentration and total motile sperm count for the donation from each subject. Changes were analyzed in relationship to biologically relevant time points during spermatogenesis, 0-9, 10-14, and 70-90 days before the day of semen collection. We estimated temperature and seasonality effects after adjusting for a base model, which included donor's date of birth and age at donation. Forty-eight donors from Los Angeles were included as subjects. Donors were included if they collected repeated semen samples over a 12-month period between January 1996 and December 1998. There was a significant negative correlation between ozone levels at 0-9, 10-14, and 70-90 days before donation and average sperm concentration, which was maintained after correction for donor's birth date, age at donation, temperature, and seasonality (p < 0.01). No other pollutant measures were significantly associated with sperm quality outcomes. Exposure to ambient ozone levels adversely affects semen quality.

Given that only an estimated 24% of infertile couples in the United States can fully engage in the medical care required to successfully conceive, the American Society for Reproductive Medicine (ASRM) has incorporated improved access to the full gamut of fertility therapies as an integral component of the Society's strategic plan that was launched in 2014. Toward this end, the ASRM hosted a two-day summit held in Washington D.C. in September 2015 that attracted thought leaders, both speakers and attendees, from around the world. This issue's Views and Reviews focuses on several key areas integral to this effort: an appreciation of the economic challenges to access, as well as the impact and interplay of racial, ethnic, emotional and gender-specific issues in the treatment of infertility. The potential to broaden access to care through modification of existing assisted reproductive techniques is also explored.

Two methods estimating areal precipitation for selected river basins in the Czech Republic are compared. The methods use radar precipitation (the radar-derived precipitation estimate based on column maximum reflectivity) and data from 81 on-line rain gauges routinely provided by the Czech Hydrometeorological Institute. Data from a dense network of climatological rain gauges (the average inter-station distance is approximately 8 km), the measurements of which are not available in real time, are utilized for the verification. The mean areal precipitation, which is used as the ground truth, is obtained by the weighted interpolation of the dense rain gauge network. The accuracy of the methods is evaluated by the root-mean-square-error.

BACKGROUND: Bladder exstrophy is an uncommon anomaly rarely associated with uterus didelphys. Fertility is limited by associated vaginal malformations, which have traditionally required surgical reconstruction. CASE: A woman with a history of bladder exstrophy and hypoplastic vagina presented complaining of painful intercourse. The patient underwent vaginal dilator treatment after corrective surgery for the bladder defect. Without any further fertility therapy she subsequently conceived twins, with one implantation in each horn of a didelphic uterus. CONCLUSION: Bladder exstrophy, uterus didelphys, and vaginal hypoplasia share a common embryological devel-opment, and the finding of one anomaly can alert to the presence of another. Vaginal dilators may be used in place of surgical reconstruction to allow conception.

The majority of men with cystic fibrosis (CF) have associated congenital bilateral absence of the vas deferens (CBVAD). This congenital defect results in the absence of the anatomic ducts through which spermatozoa pass from the testes to the urethra. No spermatozoa are found in the semen, a condition referred to as obstructive azoospermia. This abnormality of the genital-urinary system is associated with the same genetic mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR ), which leads to the classic presentation of a patient with CF. However, patients may have CBVAD and CFTR mutations without symptoms of CF. Screening for the common mutations may miss a milder rare gene alteration: a DNA variant in the 5T allele. With the advent of assisted reproductive technologies, fertility is now possible for these men. The National Institutes of Health recommend genetic counseling for any couple attempting assisted reproductive techniques when the man has CF or presents with obstructive azoospermia and is positive for a CF mutation.

Objective: This study was undertaken to determine the effect of male aging on sperm quality as determined by semen analysis, the fertilization rate of human oocytes in vitro, and live birth rates. Study Design: Retrospective analysis correlating outcome measures with male age was performed for 558 oocyte donation cycles in 441 couples. The oocyte donation model was chosen because it controls for oocyte quality and endometrial receptivity, which allows variations in sperm quality as a function of male age to be the only dependent variable. Outcome measures analyzed were semen analysis, fertilization rates in vitro, pregnancy rates, live birth rates, and cumulative live birth rates by life-table analysis. Results: There was a negative correlation between male age and total sperm count, but there was no correlation between male age and any of the other parameters in the semen analysis. There was no association between male age and the fertilization rate of donated oocytes in vitro, pregnancy rates, or live birth rates. Recipient couples were grouped by quartiles of male age, and cumulative live birth rates were the same in the 4 groups. Conclusion: Whereas male aging is associated with a significant decline in total sperm count, this change is not reflected in a decreased fertilization rate or a decreased live birth rate in the oocyte donation model. (Am J Obstet Gynecol 2001;184:818-24.)

Animal and clinical studies suggest that lead exposure disrupts the hypothalamic-pituitary axis. To define more precisely the toxic action of lead on the hypothalamic-pituitary unit, a series of in vivo and in vitro experiments were performed. The first experiment was designed to determine whether lead exposure exerts an inhibitory effect on GnRH secretion as reflected by an enhanced inhibition of luteinizing hormone (LH) secretion in response to the tyrosine hydroxylase inhibitor methyl-p-tyrosine (AMPT). In the control animals, the AMPT dose had no significant effect on LH secretion, whereas LH fell significantly in the lead-treated animals. In experiments designed to evaluate the effects of lead exposure on the pattern of pulsatile release of gonadotropins castrated control and lead-dosed animals were cannulated, and serial blood sampling was performed. Baseline LH and follicle-stimulating hormone values were not statistically different between the control and lead-treated group. There were no significant differences noted in pulsatile patterns when the data were analyzed as groups. Pituitary cells harvested from lead-treated animals released significantly more LH that did the control animals. These data are consistent with the hypothesis that the signals between the hypothalamus and pituitary gland are disrupted by lead exposure in the intact animal. However, the lead-exposed castrated rat's hypothalamic-pituitary unit is able to adapt to the toxic effects of lead.

Important medical conditions associated with Klinefelter syndrome (KS) are categorized as: 1) motor, cognitive, and behavioral dysfunction; 2) tumors; 3) vascular disease; and 4) endocrine/metabolic and autoimmune diseases. Earlier diagnosis of KS may lead to earlier intervention with effective treatment.

Lead is a male reproductive toxicant. Lead exposure results in a general suppression of the hypothalamic-pituitary-testicular (HPT) axis in male rats. The mechanism(s) for this disruption by lead is unknown. Toxic lead levels seem to disrupt central nervous system (CNS) control of the HPT system, resulting in a decrease in serum testosterone levels and sperm concentrations. A study designed to elucidate the mechanisms accounting for the disruption of the normal function of the male axis by toxic lead levels at the molecular level demonstrated a 2-3-fold enhancement of mRNA levels of GnRH and the tropic hormone LH. A 3-fold increase of intracellular stores of LH was also found. Because mRNA levels of LH and GnRH and pituitary levels of stored LH are proportional to blood levels of lead, we hypothesize that lead interferes with the normal release of tropic hormones and disrupts hormonal feedback mechanisms. The observed pleiotropic effects of lead upon the male axis and other systems may be explained by simple and unique competition by lead with normal metal ion binding sites that govern genetic control of specific genes.

Because of a subtle anomaly we encountered upon an analytical gel while characterizing a point mutation in an exon of a patient, we decided to perform expensive and time-consuming procedures to characterize the anomaly. Although initial and subsequent Southern blots and PCR analyses of this patient's mutation suggested that his mutation lay directly within a TaqI recognition site, further characterization revealed that the mutation actually lay in a base immediately outside the recognition site. Had we included an appropriate double-stranded DNA control in the restriction enzyme digestion of this patient's PCR-amplified exon, we could have arrived at the correct conclusion as to the location of the mutation without incurring high costs and time loss. This brief report depicts the use of DNA controls of appropriate length and base composition as a means of avoiding erroneous conclusions and expense in routine mutational analyses in the clinical setting.