Chromosomal microarray impacts clinical management.

Chromosomal microarray analysis (CMA) is standard of care, first-tier clinical testing for detection of genomic copy number variation among patients with developmental disabilities. Although diagnostic yield is higher than traditional cytogenetic testing, management impact has not been well studied. We surveyed genetic services providers regarding CMA ordering practices and perceptions about reimbursement. Lack of insurance coverage because of perceived lack of clinical utility was cited among the most frequent reasons why CMA was not ordered when warranted. We compiled a list of genomic regions where haploinsufficiency or triplosensitivity cause genetic conditions with documented management recommendations, estimating that at least 146 conditions potentially diagnosable by CMA testing have published literature supporting specific clinical management implications. Comparison with an existing clinical CMA database to determine the proportion of cases involving these regions showed that CMA diagnoses associated with such recommendations are found in approximately 7% of all cases (n = 28,526). We conclude that CMA impacts clinical management at a rate similar to other genetic tests for which insurance coverage is more readily approved. The information presented here can be used to address barriers that continue to contribute to inequities in patient access and care in regard to CMA testing.

Discharge Opioids are Unnecessary Following Radical Cystectomy.

OBJECTIVE: To show that zero-opioid discharges after both open and robotic cystectomy are feasible and to examine the impact of zero-opioid discharges on patient interaction with the physician's office. MATERIALS AND METHODS: One hundred seven patients who underwent either open or robotic radical cystectomy from March 1, 2020 to December 30, 2020 were identified. Patient demographics, perioperative data, and 30 day pain related outcomes including phone calls, office visits, requests for pain medication, emergency department visits, and readmissions were abstracted from the chart. We then examined variables associated with a zero-opioid discharge. RESULTS: Thirty-two patients were discharged with an opioid prescription (Median Oral Morphine Equivalents Prescribed = 90) and 75 were discharged without an opioid prescription. On regression analysis, age (OR 1.07, 95% CI [1.02-1.12]) and pathology (OR 0.36, 95% CI[0.14-0.9]) remained significantly associated with post-operative opioid prescriptions. There were no differences in the percent of patients presenting to the emergency department, being readmitted, calling the office, calling the office regarding pain, or requesting opioid prescriptions within 30 days of discharge, or the number of post-operative office visits (P >.05 for all). CONCLUSION: Patients can safely be discharged home without opioids following cystectomy, regardless of robotic or open approach. Age and pathology are predictors of the need for an opioid prescription on discharge. These patients did not have increased follow-up visits, phone calls, or requests for pain medication.

Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders.

BACKGROUND: Segmental duplications at breakpoints (BP4-BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram (EEG) abnormalities. PATIENTS: DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children's Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository. RESULTS: We report the clinical features of five patients with a BP4-BP5 deletion, three with a BP4-BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4-BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4-BP5 covers approximately 1.5 Mb (chr15:28.719-30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover approximately 500 kb (chr15:28.902-29.404 Mb) and contain three reference genes and one miRNA gene. The BP4-BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG. CONCLUSIONS: The phenotype of chromosome 15q13.2q13.3 BP4-BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.

Renal transplantation in patients with systemic lupus erythematosus.

The activity of systemic lupus erythematosus (SLE) was investigated in 18 recipients of 20 renal transplants by retrospective analysis of their medical records and by screening the ten patients with more than one year follow-up. Eight grafts were lost, all because of rejection occurring within the first year. From the 12 patients with functioning transplants, one was lost to follow-up at seven years and another had not completed one year. The remaining ten patients were studied, and no evidence of lupus nephritis was found despite serologically active SLE in four cases. Their follow-up was 4.5 +/- 1.3 years. Our study provides the relatively scarce literature on renal transplantation in patients with SLE with a series of 18 recipients of 20 allografts, confirms that the recurrence of lupus nephritis in the allografts is very rare, as previously suggested, and discloses that graft and patient survivals are comparable with those of the general nondiabetic transplant population.

Sex steroids and bone density in premenopausal and perimenopausal women.

Bone density begins to decline in women before menopause, and the degree of bone loss is variable. We performed a cross-sectional analysis on the entry data of a 5-yr prospective study of risk factors for osteoporosis to determine the correlation of bone density with serum sex steroid concentrations and body weight. We studied 292 healthy white women, aged 35-50 yr, who were menstruating regularly or had had menses in the past 12 months. Blood samples were drawn in the early follicular phase for estradiol (E2), testosterone (T), dehydroepiandrosterone sulfate, and sex hormone-binding globulin (SHBG). Free levels of E2 (FE2) and T (FT) were calculated based on total T and E2, SHBG, and albumin levels. Women were classified as premenopausal (FSH, less than 12 U/L) and perimenopausal (FSH greater than or equal to 12 U/L; n = 46; 16%). Bone density was measured by dual photon absorptiometry of the lumbar spine (L2-L4) and hip and by single photon absorptiometry of the wrist. Perimenopausal women were older than premenopausal women (45.5 +/- 3.5 and 41.0 +/- 3.9 yr, respectively), but did not differ in height or weight. While bone density did not correlate with age in each group, perimenopausal women had significantly lower bone density at the L2-L4 and femoral neck (L2-L4, 1.18 +/- 0.14 in perimenopausal and 1.24 +/- 0.12 g/cm2 in premenopausal women; femur, 0.84 +/- 0.11 in perimenopausal and 0.90 +/- 0.11 g/cm2 in premenopausal women; P less than 0.005). Body weight showed the strongest positive correlation with bone density. Log FT, percent FT, and FE2 percent correlated positively with bone density, even after controlling for weight. Log SHBG was negatively correlated with bone density in premenopausal women at the hip and wrist after controlling for weight. FSH was inversely correlated with bone density, and E2 and T were lower in perimenopausal than premenopausal women. These data suggest that women who are still menstruating may have relative deficiencies in both E2 and T, with reduced bone densities as a consequence.

Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994)

Iodine deficiency in a population causes increased prevalence of goiter and, more importantly, may increase the risk for intellectual deficiency in that population. The National Health and Nutrition Examination Surveys [NHANES I (1971-1974) and (NHANES III (1988-1994)] measured urinary iodine (UI) concentrations. UI concentrations are an indicator of the adequacy of iodine intake for a population. The median UI concentrations in iodine-sufficient populations should be greater than 10 microg/dL, and no more than 20% of the population should have UI concentrations less than 5 microg/dL. Median UI concentrations from both NHANES I and NHANES III indicate adequate iodine intake for the overall U.S. population, but the median concentration decreased more than 50% between 1971-1974 (32.0+/-0.6 microg/dL) and 1988-1994 (14.5+/-0.3 microg/dL). Low UI concentrations (<5 microg/dL) were found in 11.7% of the 1988-1994 population, a 4.5-fold increase over the proportion in the 1971-1974 population. The percentage of people excreting low concentrations of iodine (UI, <5 microg/dL) increased in all age groups. In pregnant women, 6.7%, and in women of child-bearing age, 14.9% had UI concentrations below 5 microg/dL. The findings in 1988-1994, although not indicative of iodine deficiency in the overall U.S. population, define a trend that must be monitored.

The Drosophila primo locus encodes two low-molecular-weight tyrosine phosphatases.

The fine modulation of tyrosine phosphorylation by protein tyrosine phosphatases and protein tyrosine kinases is a key regulatory mechanism for many cell signaling pathways active during development. In a screen for genes with interesting expression patterns in the developing Drosophila pupal retina, we identified a novel pair of protein tyrosine phosphatases that exhibit an expression pattern suggesting a role in multiple steps of Drosophila neurogenesis. Together, these phosphatases define the primo locus. Their sequence is approx. 50% identical to each other and to low-molecular-weight protein tyrosine phosphatases (LMW-PTPs) identified in other species. Little is understood of the biological role of LMW-PTPs, and the powerful tools available in Drosophila should provide important insight into their role in signaling and development.

Blastic natural killer cell leukemia/lymphoma: a clinicopathologic study.

The classification of natural killer (NK)-cell and NK-like T-cell malignancies has undergone significant evolution in recent years. Although examples of NK-cell tumors resembling acute leukemia have been described anecdotally as blastic, blastoid, or monomorphic NK-cell leukemia/lymphoma (NKL/L), the clinical and pathologic features of these tumors have not been systematically defined. We report four patients with blastic NKL/L and describe the clinical, pathologic, and immunophenotypic findings in these cases. All patients were elderly (58-82 years) and presented with cutaneous plaques. Two patients also had adenopathy, and three patients had marrow involvement at presentation. Biopsy of cutaneous lesions showed atypical superficial and deep dermal lymphoid infiltrates. Involved lymph nodes were architecturally effaced by an interfollicular infiltrate with blastic cytologic features. In Wright-Giemsa-stained blood or marrow smears, tumor cells had finely distributed nuclear chromatin, many with nucleoli, and variable amounts of cytoplasm. In contrast to many NK and NK-like T-cell disorders, azurophilic cytoplasmic granules were absent or inconspicuous. The tumor cells were immunophenotypically distinctive. They expressed intermediate density CD45, as is characteristic of blasts; in addition, the cells were positive for HLA-DR, CD2, CD4, and the NK-associated antigen CD56. Surface CD3, cytoplasmic CD3, and CD5 were negative in all cases tested, whereas CD7 was expressed in two cases. In formalin-fixed tissue, tumor cells marked with antibodies to CD43, but not with other T- or B-lineage-related antibodies. All three cases studied for Epstein-Barr viral RNA by in situ hybridization were negative. Although treatments varied, all three patients with clinical follow-up died within months of the diagnosis. The clinical course in two patients culminated in an overtly leukemic phase. These findings suggest that blastic NKL/L represents a distinct clinicopathologic entity, characterized by cutaneous, nodal, and marrow involvement by blastic cells with immunophenotypic characteristics of true NK cells. The disease afflicts elderly patients, pursues an aggressive course, and may culminate in overt leukemia.

Comparative analysis of the DST and Imuran-plus-DST protocols for live donor renal transplantation.

We have done a comparative analysis of two consecutive clinical trials at our center: the first in 56 patients who received blood transfusions from their prospective donors (DST group), and the second in 36 patients who received such transfusions while they were taking Imuran in an attempt to reduce the incidence of sensitization against the donor (IM + DST group). The major findings of our study are: (1) Imuran significantly (P less than .05) reduced the rate of sensitization from 27% to 11%; (2) Patients who had prolonged dialysis before entering one of these protocols were significantly more likely to become sensitized against their living donors, and had significantly higher sensitization against the leukocyte panel, although panel-reactive antibodies were not significantly changed by transfusions from the live donor; (3) MLC reactivity against the living donor was not significantly altered by donor transfusions, and was also not different for sensitized and transplanted patients; (4) Results of transplantation were excellent in both patient groups, with only two grafts and two patients lost in 68 transplants (actuarial one-year survival of 97% and 93% of patients alive and with functional grafts at one year in the DST and IM + DST groups, respectively); (5) Rejection episodes occurred in about 50% of each group, but were of a special type (DST-type rejection) in about 30% of the DST patients and 10% of the IM + DST patients (P = .07); (6) The probability of transplantation, and the results of transplantation after unsuccessful entry into one of these protocols was not adversely affected. We think that primarily because of the low rate of sensitization the IM + DST protocol is superior to the DST protocol. Both, however, are established clinical tools that have increased our clinical transplant volume by a large number of highly successful transplants.

A four-year experience with donor blood transfusion protocols for living-donor renal transplantation.

Our experience over the last 4 years with HLA-identical, donor-specific transfusion (DST), and Imuran (IM) + DST living-donor transplants in 206 patients is presented. Transplants from 8 completely incompatible sibling donors, 4 distantly related donors, and 7 unrelated donors are included. Except for a slightly higher average serum creatinine, and a markedly reduced rate of donor-specific sensitization in the IM + DST group when compared with the DST group (14% vs. 31%, P less than .005), the results of transplantation using these 3 protocols have been equivalent. Actuarial one-year survival was 97% for patients and 93% for grafts for the combined group of 206 patients. Of the 44 patients who entered the DST or IM + DST protocols but were not transplanted, 31 patients (70%) have subsequently been transplanted, and all 5 recipients of living-donor kidneys and 20 of 26 recipients of cadaveric kidneys (77%) have functioning grafts. Because it optimizes the availability of transplantable living-donor kidneys, gives results equivalent to those obtained with HLA-identical donors and the DST protocol, and is not associated with clinically apparent adverse effects, we now use the IM + DST protocol for all living-donor transplants except those between HLA-identical donor-recipient pairs.

Influence of pre- and perioperative blood transfusions on renal allograft survival.

One hundred and seventy-nine patients who received transplants between January 1975 and May 1980 have been studied retrospectively in order to elucidate the effect of pre- and perioperative random third-party blood transfusions on first cadaveric renal allograft survival. The 179 patients were approximately evenly divided into four groups; those who received blood transfusions preoperatively only (group 1, n = 45), received blood both pre- and perioperatively (group 2, n = 48), received blood perioperatively only (group 3, n = 37), or were never transfused before transplantation or perioperatively (group 4, n = 49). Actuarial graft survival for group 1 was 73% at 1 to 4 years, which was significantly better (P less than or equal to 0.02) than each of the other three groups at all four intervals. Groups 2, 3, and 4 were statistically identical to each other and had graft survivals of 52% or less at 1 to 4 years. From our study we conclude that: (1) Preoperative transfusions confer significant benefit on recipients of first cadaveric renal allografts. (2) Perioperative blood transfusions are without significant benefit in previously untransfused patients, and significantly lower allograft survival in previously transfused patients. A rational blood transfusion policy based on these results would be to transfuse renal allograft recipients preoperatively and avoid perioperative blood transfusions as much as possible.

Beneficial effects of adenosine and phosphate in kidney preservation.

A new perfusate developed in the animal laboratory has been used in our clinical transplantation program in the last year. This perfusate provides excellent clinical results even with less-than-ideal kidneys, as manifested by an 83% immediate function rate and a 96.5% one-month graft survival. Optimum utilization of all donors referred to a transplant center may lessen the problem of insufficient donor organs. Continued basic research in the laboratory to optimize perfusion preservation may produce even better perfusates that can be adapted to the clinical situation and further improve graft survival.

Can the results of live donor kidney transplantation be improved?

According to an analysis of 100 consecutive kidney transplants from live donors performed at our center over a 25-month period beginning in June 1980, only two patients have died, and five other patients had graft loss from acute or chronic rejection; this resulted in an overall actuarial 2-year patient survival rate of 98% and a graft survival rate of 90%. Eighty-five of the 93 patients with functioning grafts have excellent renal function, with serum creatinine levels less than or equal to 2 mg/dl. Complications occurred in 24 patients but rarely jeopardized the patients' lives or grafts or resulted in permanent disability. The functional capacity of most of the patients was improved by transplantation or was excellent both before and after transplantation. Forty-three transplants were possible through the use of the original or Imuran-modified donor-specific transfusion protocol, so that the lack of compatible donors rarely limited the availability of this therapy. New therapies that might improve graft or patient survival rate cannot reasonably be evaluated in recipients of live donor kidney transplants, because these results are already good. We have estimated that as much as $3.6 million in health care funds could be saved every 2 years at our center if we offered kidney transplants from healthy willing donors to all recipients before instituting dialysis. From our study we conclude that live donor kidney transplantation is an available, highly effective, and cost-efficient form of therapy for patients with end-stage renal disease.

Obstetric care of the affected carrier of hemophilia B.

Hemophilia B (factor IX deficiency) is an X-linked recessive clotting disorder similar to hemophilia A. In both diseases, phenotypic expression of the disorder may occur in significant numbers of heterozygous carriers. This is presumably due to random inactivation of one of the two X chromosomes of the female carrier as described by the Lyon hypothesis. Described herein is the obstetric care of a severely affected heterozygous carrier of hemophilia B. Predelivery automated plasma exchange was used to raise factor IX levels successfully. Commercial factor concentrates were avoided. The Lyon hypothesis is discussed in detail, and recommendations are made for the care of the clotting factor-deficient gravid woman.

Automation of diphenylhydantoin and phenobarbital measurements using the ABA-100 with emit reagents.

1. The EMIT-AED procedures for phenobarbital and diphenylhydantoin have been adapted for use on the ABA-100. 2. A basic language computer program has been developed for data reduction and quality control. 3. Within-run and run-to-run coefficients of variations were, in general, less than 8% across the concentration range tested. 4. Performance data on agreement of duplicates and recovery from "spiked" samples were aceptable. 5. The automated procedure provides a two-thirds savings in reagents.

Images of cone photoreceptors in the living human eye.

Though the photoreceptor mosaic has been imaged through the intact optics of the eyes of several species, it has not been clear whether individual photoreceptors can be resolved in the living human eye. We have constructed a high-resolution fundus camera and have resolved cones with a spacing as small as 3.5 microns in single images of the fundus. The high contrast of these images implies that almost all the light returning from the retina at this wavelength (555 nm) has passed through the apertures of foveal cones. The average power spectra of our retinal images show that it is possible to recover spatial frequencies as high as 150 c/deg in eyes with normal optical quality, a conclusion that was confirmed with estimates of the optical quality of these eyes obtained with a Hartmann-Shack wavefront sensor. These results emphasize the superiority of the eye's optics over the spatial sampling limits of the retina when the eye's optical quality is optimized. They also show that it would be possible to routinely resolve retinal structures as small as photoreceptors in the normal living eye if its aberrations could be corrected.

Pluralistic ignorance and alcohol use on campus: some consequences of misperceiving the social norm.

Four studies examined the relation between college students' own attitudes toward alcohol use and their estimates of the attitudes of their peers. All studies found widespread evidence of pluralistic ignorance: Students believed that they were more uncomfortable with campus alcohol practices than was the average student. Study 2 demonstrated this perceived self-other difference also with respect to one's friends. Study 3 traced attitudes toward drinking over the course of a semester and found gender differences in response to perceived deviance: Male students shifted their attitudes over time in the direction of what they mistakenly believed to be the norm, whereas female students showed no such attitude change. Study 4 found that students' perceived deviance correlated with various measures of campus alienation, even though that deviance was illusory. The implications of these results for general issues of norm estimation and responses to perceived deviance are discussed.

Failure to recognize the effect of implicit social influence on the presentation of self.

Two studies demonstrated that individuals can fail to detect changes in their actions that are induced by implicit social influence. In both studies, observers' impressions indicated that actors matched the positivity of their remarks about themselves to the positivity of another person's self-description. However, actors' own judgments of the types of impressions they conveyed revealed that they did not perceive the effect of the other's self-description on their self-presentation. Study 1 suggested that actors' relatively poor access to their own nonverbal behavior could not fully account for their failure to perceive how they were influenced. Study 2 indicated that actors' metaperceptions were connected to actors' general beliefs about themselves, whereas observers' impressions were not. The "blindness" effect was driven primarily by actors low in self-esteem. Implications for self-presentation and other social phenomena are discussed.

The disparity between the actual and assumed power of self-interest.

Five studies examined the hypothesis that people overestimate the influence of self-interest on attitudes and behaviors. The results strongly supported the hypothesis. In Study 1, participants overestimated the impact that financial reward exerted on their peers' willingness to donate blood. In 4 subsequent studies, participants overestimated the impact that group membership had on their peers' attitudes (Studies 2, 3, and 4) and behaviors (Study 5). The tendency to overestimate the impact of self-interest on others was largely unrelated to the impact that it had on participants' own attitudes and behaviors. Implications of the lay person's belief in the power of self-interest are discussed.