Rapid Whole-Genome Sequencing and Clinical Management in the PICU: A Multicenter Cohort, 2016-2023.

OBJECTIVES: Analysis of the clinical utility of rapid whole-genome sequencing (rWGS) outside of the neonatal period is lacking. We describe the use of rWGS in PICU and cardiovascular ICU (CICU) patients across four institutions. DESIGN: Ambidirectional multisite cohort study. SETTING: Four tertiary children's hospitals. PATIENTS: Children 0-18 years old in the PICU or CICU who underwent rWGS analysis, from May 2016 to June 2023. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 133 patients underwent clinical, phenotype-driven rWGS analysis, 36 prospectively. A molecular diagnosis was identified in 79 patients (59%). Median (interquartile range [IQR]) age was 6 months (IQR 1.2 mo-4.6 yr). Median time for return of preliminary results was 3 days (IQR 2-4). In 79 patients with a molecular diagnosis, there was a change in ICU management in 19 patients (24%); and some change in clinical management in 63 patients (80%). Nondiagnosis changed management in 5 of 54 patients (9%). The clinical specialty ordering rWGS did not affect diagnostic rate. Factors associated with greater odds ratio (OR [95% CI]; OR [95% CI]) of diagnosis included dysmorphic features (OR 10.9 [95% CI, 1.8-105]) and congenital heart disease (OR 4.2 [95% CI, 1.3-16.8]). Variables associated with greater odds of changes in management included obtaining a genetic diagnosis (OR 16.6 [95% CI, 5.5-62]) and a shorter time to genetic result (OR 0.8 [95% CI, 0.76-0.9]). Surveys of pediatric intensivists indicated that rWGS-enhanced clinical prognostication (p < 0.0001) and contributed to a decision to consult palliative care (p < 0.02). CONCLUSIONS: In this 2016-2023 multiple-PICU/CICU cohort, we have shown that timely genetic diagnosis is feasible across institutions. Application of rWGS had a 59% (95% CI, 51-67%) rate of diagnostic yield and was associated with changes in critical care management and long-term patient management.

Rapid genome sequencing identifies novel variants in complement factor I.

Complement factor I deficiency (CFID; OMIM #610984) is a rare immunodeficiency caused by deficiencies in the serine protease complement factor I (CFI). CFID is characterized by predisposition to severe pneumococcal infection, often in infancy. We report a previously healthy adolescent male who presented with respiratory failure secondary to pneumococcal pneumonia and severe systemic inflammatory response. Rapid genome sequencing (rGS) identified compound heterozygous variants in CFI in the proband, with a novel maternally inherited likely pathogenic variant, a single nucleotide deletion resulting in premature stop (c.1646del; p.Asn549ThrfsTer25) and a paternally inherited novel likely pathogenic deletion (Chr 4:110685580-110692197del).

Plasma cell free next-generation sequencing detects an unusual pneumonia pathogen in an immunocompetent adolescent with acute respiratory distress syndrome.

This case details a rapid diagnosis of legionella pneumonia causing severe acute respiratory distress syndrome (ARDS) in an otherwise healthy adolescent through plasma microbial cell-free DNA next generation sequencing (mcfDNA-NGS). Diagnosis by mcfDNA-NGS of this unexpected pathogen led to narrowing of antimicrobials and the addition of glucocorticoids as adjunctive therapy for ARDS.

Adrenal pheochromocytoma in a patient with Lynch Syndrome.

Lynch Syndrome (LS), or hereditary non-polyposis colorectal cancer, is the most common cause of hereditary colorectal cancer. There are well described extra-colonic manifestations of LS, including gynecologic and upper urinary tract malignancies. Other extra-colonic manifestations of LS are less understood. Here we present an unusual case of a functional adrenal pheochromocytoma in a 31-year old man with LS.

A Curious Case of Croup: Laryngotracheitis Caused by COVID-19.

We describe a case of croup in a 14-month-old boy caused by severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019. The patient presented with classic signs and symptoms consistent with croup. Workup was remarkable for a positive point-of-care test for severe acute respiratory syndrome coronavirus 2. This case represents recognition of a new clinical entity caused by coronavirus disease 2019.

Shift Work Sleep Disorder and Night Shift Work Significantly Impair Erectile Function.

OBJECTIVES: Here we examine the association between shift work sleep disorder (SWSD) and erectile dysfunction (ED) in shift workers. METHODS: Men presenting to a single andrology clinic between January 2014 and July 2017 completed validated questionnaires: International Index of Erectile Function (IIEF), Patient Health Questionnaire-9 (PHQ-9), and the nonvalidated SWSD Questionnaire. Men were also asked about shift work schedule, comorbidities, phosphodiesterase 5 (PDE5) inhibitor use, and testosterone use. Serum total testosterone values were determined for each visit. Linear regression was performed controlling for testosterone use, testosterone levels, PDE5 inhibitor use, age, and comorbidities to determine the effect of SWSD on ED as assessed using the IIEF. RESULTS: Of the 754 men completing questionnaires, 204 reported nonstandard shift work (begins before 7 am or after 6 pm, regularly extends out of that frame, or rotates frequently) and 48 were found to have SWSD using a screening questionnaire. Nonstandard shift work alone did not result in worse IIEF-EF scores (P = .31), but those who worked nonstandard shifts and had SWSD demonstrated IIEF-EF scores 2.8 points lower than men without SWSD (P < .01). When assessing for the type of shift work performed, men who worked night shifts had IIEF-EF scores 7.6 points lower than men who worked during the day or evening (P < .01). Testosterone use improved IIEF-EF scores for men with SWSD by 2.9 points, ameliorating the effect of SWSD on ED. However, baseline testosterone levels were not associated with worse erectile function in this cohort. CONCLUSION: Men with SWSD have worse erectile function, with men who work night shifts having even poorer erectile function. These findings suggest that circadian rhythm disturbance may significantly impact erectile function. While testosterone therapy may partly reverse the effects of SWSD, shift work is a potential risk factor for ED and should be assessed for as part of the evaluation of men with ED. Rodriguez KM, Kohn TP, Kohn JR, et al. Shift Work Sleep Disorder and Night Shift Work Significantly Impair Erectile Function. J Sex Med 2020;17:1687-1693.

Varicocele Repair Prior to Assisted Reproductive Technology: Patient Selection and Special Considerations.

Clinical varicoceles are one of the most commonly identified physical exam abnormalities in men presenting with infertility. Clinical varicoceles can cause impaired spermatogenesis and surgical correction can improve semen parameters in select men. Increasingly, andrologists are performing varicocele repairs prior to intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) to boost male fertility potential. In this review, we evaluated the available literature 1) to determine if varicocelectomy prior to IUI or assisted reproductive technologies proved to improve sperm production or pregnancy outcomes; and 2) to identify who may be the ideal candidate for pre-IUI/ART varicocelectomy. Overall, few studies have explored this topic and little can be concluded about the impact of varicocelectomy prior to IUI. The evidence, however, does support that correcting a clinical varicocele can increase pregnancy outcomes in couples who plan to pursue IVF or ICSI. When selecting patients for varicocelectomy prior to IUI or ART, clinicians should evaluate female age as improvement in semen parameters can take 6 months after varicocelectomy and this duration of time may be deleterious in cases of advanced maternal age when each cycle becomes increasingly important. Overall, the currently limited literature regarding clinical varicoceles correction demonstrates that pregnancy rates can be increased when comparing patients who have undergone varicocelectomy prior to ART with those who had clinical varicocele but did not undergo surgery.

The History of Estrogen Therapy.

INTRODUCTION: Menopausal hormone therapy (MHT) has proven an effective treatment for the amelioration of symptoms of menopause. The idea that a substance was the missing factor in a woman's body after menopause dates to the 1800s, when cow ovarian tissue was injected into German women in a successful attempt to reverse the sexual symptoms of menopause. The early 1900s saw the rise of commercialized menopause "treatments" that ranged in substance and even theoretical efficacy. The role of estrogen was first accurately described in Guinea pigs in 1917 by Dr. Papanicolaou. AIM: To tell the detailed history of how estrogen was discovered and the controversy surrounding MHT. METHODS: A literature search was conducted using PubMed to identify relevant studies and historical documents regarding the history of estrogen therapy. RESULTS: The history of estrogen supplementation and its controversies are interesting stories and relevant to today's ongoing investigation into hormone replacement. CONCLUSION: The controversy of MHT remained until the first randomized trials examining MHT in the early 1990s that suggested MHT is cardioprotective in postmenopausal women, although this conclusion was contradicted in subsequent trials. In the present day, MHT is approved only for short-term use for the symptomatic treatment of menopause. Kohn GE, Rodriguez KM, Hotaling J, et al. The History of Estrogen Therapy. Sex Med Rev 2019;7:416-421.

The Role of Testosterone Therapy in the Setting of Prostate Cancer.

PURPOSE OF REVIEW: The role of testosterone in the development of prostate cancer and the safety of testosterone therapy (TTh) after prostate cancer treatment, or in the setting of active surveillance, remains controversial. There are many concerns about using TTh in men, particularly those with a history of prostate cancer, ranging from a possible increased risk of cardiovascular disease to cancer progression or recurrence. With many prostate cancer patients living longer, and hypogonadism having significant morbidity, much care must go into the decision to treat. Here, we review the literature investigating the effects of testosterone on the prostate as well as the efficacy and safety of exogenous testosterone in men with a history of prostate cancer. RECENT FINDINGS: The improvement in quality of life with TTh is well studied and understood, while the argument for significantly increased risk of cancer or other adverse effects is much less robust. Neither increased rates of prostate cancer, cancer recurrence, or cardiovascular risk have been well established. In men with high-risk prostate cancer, evidence in the setting of TTh is very limited, and TTh should be used with caution. The fears of TTh causing or worsening prostate cancer do not appear to be well supported by available data. Though more studies are needed to definitively determine the safety of TTh in men with prostate cancer, consideration should be given to treatment of hypogonadal men with a history of CaP.

Increased Risk of Incident Disease in Men with Peyronie's Disease: Analysis of U.S. Claims Data.

BACKGROUND: The subsequent health risks associated with Peyronie's disease (PD) are unknown. AIM: This cohort study assesses the risk of developing auto-immune conditions and common chronic health conditions after a diagnosis of PD. We hypothesize that an increase in auto-immune disease will be evident in men with PD, as has been suggested in smaller studies. METHODS: We determined the longitudinal incidence of 13 auto-immune diseases and 25 common chronic conditions in a cohort from the Truven Health Analytics (Ann Arbor, Michigan, USA) database from 2007-2013. The cohort included men with 1 of 3 exposures in 2007: (1) men with PD, (2) men with erectile dysfunction (ED) but not PD, and (3) men without PD or ED, matched on age and follow-up duration. OUTCOMES: To assess incidence, we utilized a Cox regression model adjusting for age, smoking, obesity, health care visits per year, urology visits per year, and years of follow-up. RESULTS: We included 8,728 men with PD; 204,147 men with ED; and 87,280 controls. Men with PD had an increased risk of developing benign prostatic hyperplasia (hazard ratio [HR] 1.21, 95% CI 1.16-1.27), prostatitis (HR 1.21, 95% CI 1.12-1.31), and lower urinary tract symptoms (HR 1.10, 95% CI 1.05-1.16) when compared to both men with ED and age-matched controls without ED or PD even when controlling for the number of urology visits per year. Compared to controls, men with PD also had an increased risk of developing keloids. No significant risk for any auto-immune disease was observed. CLINICAL IMPLICATIONS: Clinicians should have heightened awareness for these relevant co-morbidities when treating men with PD. STRENGTHS & LIMITATIONS: Utilizing a claims database provides one of the largest cohorts of men with PD ever published but claims databases lack some individual patient data such as risk factors and demographic information relevant to PD, including: penile injury, history of urologic procedures, and other lifestyle factors. CONCLUSION: Men with PD had a higher risk of benign prostatic hyperplasia, lower urinary tract symptoms, prostatitis, and keloids after a diagnosis of PD, but no increased risk of auto-immune conditions. These findings suggest a common etiology for these conditions that may manifest itself in diseases at different times in men's life cycle. Pastuszak AW, Rodriguez KM, Solomon ZJ, et al. Increased Risk of Incident Disease in Men with Peyronie's Disease: Analysis of U.S. Claims Data. J Sex Med 2018;15:894-901.

Alternatives to Testosterone Therapy: A Review.

INTRODUCTION: Although testosterone therapy (TTh) is an effective treatment for hypogonadism, recent concerns regarding its safety have been raised. In 2015, the US Food and Drug Administration issued a warning about potential cardiovascular risks resulting from TTh. Fertility preservation is another reason to search for viable alternative therapies to conventional TTh, and in this review we evaluate the literature examining these alternatives. AIMS: To review the role and limitations of non-testosterone treatments for hypogonadism. METHODS: A literature search was conducted using PubMed to identify relevant studies examining medical and non-medical alternatives to TTh. Search terms included hypogonadism, testosterone replacement therapy, testosterone therapy, testosterone replacement alternatives, diet and exercise and testosterone, varicocele repair and testosterone, stress reduction and testosterone, and sleep apnea and testosterone. MAIN OUTCOME MEASURES: Review of peer-reviewed literature. RESULTS: Medical therapies examined include human chorionic gonadotropins, aromatase inhibitors, and selective estrogen receptor modulators. Non-drug therapies that are reviewed include lifestyle modifications including diet and exercise, improvements in sleep, decreasing stress, and varicocele repair. The high prevalence of obesity and metabolic syndrome in the United States suggests that disease modification could represent a viable treatment approach for affected men with hypogonadism. CONCLUSIONS: These alternatives to TTh can increase testosterone levels and should be considered before TTh. Lo EM, Rodriguez KM, Pastuszak AW, Khera M. Alternatives to Testosterone Therapy: A Review. Sex Med Rev 2018;6:106-113.

A history of penile implants.

Erectile dysfunction (ED) has long been described by physicians and patients, with treatments for ED proposed starting in the 8th century BC. In the last 50 years, however, there have been many advances in medical and surgical management of ED, notably the introduction of the inflatable penile prosthesis (IPP) in 1973 and phosphodiesterase type 5 inhibitors (PDE5Is) in 1998. Here we review the evolution of the IPP from 1973 through the current day. The 3-piece device was first described in 1973 by Dr. F. Brantley Scott, who helped found American Medical Systems (AMS) to market and sell the device. In 1983, Mentor (now Coloplast) started marketing a competing device. AMS and Mentor have made multiple modifications to the device over the years, which have increased rigidity, durability and patient satisfaction, and have decreased surgical variability, post-operative infection and spontaneous inflation. Today, the IPP is a safe and effective option for many men who have failed medical therapies, with high satisfaction from both patients and partners.

Penile implants: a look into the future.

Inflatable penile prosthesis (IPP) has been around since the 1970's as a durable and one-time cure for erectile dysfunction (ED). For the past 40 years, many changes have been made to make the device better and currently IPP boasts a high percentage of long-term patient satisfaction. The next paradigm shift in IPP treatment for ED is upon us. Funding for ED related medications and devices has been a hot topic in health policy over the last 10 years. This suggests that the device must improve and patient advocacy and education must increase for IPP to remain as a viable solution for ED. In this paper, we conduct a literature search for innovations in IPP and argue that IPP must constantly improve to compete with oral, injectable, shockwave, and potentially gene therapies.

Carcinoma gástrico con estroma linfoide: 3 entidades clínico-patológicas / Gastric carcinoma with lymphoid stroma: 3 clinicopathological entities

Los carcinomas gástricos con estroma linfoide son un grupo heterogéneo de neoplasias mal caracterizadas que históricamente no se han clasificado en entidades clínico-patológicas distintas. Conocer los criterios diagnósticos e identificarlos tiene una importancia relevante tanto clínica como pronóstica. Analizamos 13 casos de pacientes con carcinomas gástricos con estroma linfoide. Con criterios histopatológicos, inmunofenotípicos y moleculares, se definieron 3 subtipos (patrón 1, 2 y 3). Realizamos inmunohistoquímica para caracterizar las poblaciones linfoides (CD3, CD4, CD8 y CD20), para analizar la expresión de virus de Epstein-Barr (VEB) y la expresión de proteínas reparadoras del ADN. El objetivo de este estudio es definir criterios útiles que permitan distinguir estas inusuales lesiones y estudiar el inmunofenotipo de las poblaciones linfoides (AU)

Gastric carcinomas with lymphoid stroma comprise a heterogeneous group of incompletely characterized neoplasms that have not as yet been classified as different clinico-pathological entities. We analysed 13 cases of gastric carcinoma with lymphoid stroma in order to establish diagnostic criteria for their identification. We defined 3 different subtypes (patterns 1, 2 and 3) based on histopathologic, immunophenotypic and molecular criteria. Immunohistochemistry was performed to identify lymphoid populations (CD 3, CD4, CD8 and CD20), the presence of Epstein-Barr Virus (EBV) and the expression of DNA mismatch repair proteins. Our aim is to define criteria that are helpful in the differential diagnosis of these unusual lesions and to clarify the immunophenotype of their lymphoid population (AU)

Carcinoma gástrico de tipo linfoepitelioma: criterios diagnósticos / Gastric lymphoepithelioma-like carcinoma: diagnostic criteria

El carcinoma gástrico tipo linfoepitelioma es una entidad poco frecuente y mal caracterizada. Históricamente no se ha considerado una entidad como tal y frecuentemente se ha utilizado como sinónimo del carcinoma medular y del carcinoma gástrico convencional con estroma linfoide. Diferenciar esta entidad tiene mucha relevancia tanto clínica como pronóstica. Se describe un caso de un hombre de 77 años con una lesión ulcerada en fundus. El examen histológico reveló unas estructuras neoplásicas glandulares acompañadas de un marcado estroma linfoide. Dicha lesión presentó intensa expresión del virus de Epstein-Barr, expresión de las proteínas reparadoras del ADN y una distribución característica de las poblaciones linfoides. El objetivo de este estudio es definir criterios útiles que permitan distinguir esta inusual lesión y estudiar el inmunofenotipo de las poblaciones linfoides (AU9

Gastric lymphoepithelioma-like carcinoma is a rare and poorly characterized condition which historically has not been considered a specific entity, usually being considered synonymous with medullary carcinoma and conventional gastric carcinoma with lymphoid stroma. However, the differentiation of this entity is of clinical and prognostic importance. We report a case of a 77 year old man who presented with a gastric ulcer in the fundus. Histological examination revealed the presence of neoplastic glandular structures with marked lymphoid stroma. The immunohistochemical staining showed strong expression for Epstein-Barr virus and DNA repair proteins with a distinctive lymphoid cell distribution. The aim of our study is to determine criteria useful in the recognition of this unusual condition and assess the inmunophenotype of the lymphoid population (AU)

Enclomiphene citrate for the treatment of secondary male hypogonadism.

INTRODUCTION: Hypogonadism is a growing concern in an aging male population. Historically treated using exogenous testosterone, concerns about possible adverse effects of testosterone have led physicians to seek alternative treatment approaches. AREAS COVERED: Enclomiphene citrate is the trans isomer of clomiphene citrate, a non-steroidal estrogen receptor antagonist that is FDA-approved for the treatment of ovarian dysfunction in women. Clomiphene citrate has also been used off-label for many years to treat secondary male hypogonadism, particularly in the setting of male infertility. Here we review the literature examining the efficacy and safety of enclomiphene citrate in the setting of androgen deficiency. EXPERT OPINION: Initial results support the conclusion that enclomiphene citrate increases serum testosterone levels by raising luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, without negatively impacting semen parameters. The ability to treat testosterone deficiency in men while maintaining fertility supports a role for enclomiphene citrate in the treatment of men in whom testosterone therapy is not a suitable option.

Testosterone therapy and prostate cancer.

The use of exogenous testosterone to treat hypogonadism in the men with a history of prostate cancer (CaP) remains controversial due to fears of cancer recurrence or progression. Due to the detrimental impact of hypogonadism on patient quality of life, recent work has examined the safety of testosterone therapy (TTh) in men with a history of CaP. In this review, we evaluate the literature with regards to the safety of TTh in men with a history of CaP. TTh results in improvements in quality of life with little evidence of biochemical recurrence or progression in men with a history of CaP, or de novo cancer in unaffected men. An insufficient amount of evidence is currently available to truly demonstrate the safe use of TTh in men with low risk CaP. In men with high-risk cancer, more limited data suggest that TTh may be safe, but these findings remain inconclusive. Despite the historic avoidance of TTh in men with a history of CaP, the existing body of evidence largely supports the safe and effective use of testosterone in these men, although additional study is needed before unequivocal safety can be demonstrated.