Rewiring of the phosphoproteome executes two meiotic divisions in budding yeast.

The cell cycle is ordered by a controlled network of kinases and phosphatases. To generate gametes via meiosis, two distinct and sequential chromosome segregation events occur without an intervening S phase. How canonical cell cycle controls are modified for meiosis is not well understood. Here, using highly synchronous budding yeast populations, we reveal how the global proteome and phosphoproteome change during the meiotic divisions. While protein abundance changes are limited to key cell cycle regulators, dynamic phosphorylation changes are pervasive. Our data indicate that two waves of cyclin-dependent kinase (Cdc28Cdk1) and Polo (Cdc5Polo) kinase activity drive successive meiotic divisions. These two distinct phases of phosphorylation are ensured by the meiosis-specific Spo13 protein, which rewires the phosphoproteome. Spo13 binds to Cdc5Polo to promote phosphorylation in meiosis I, particularly of substrates containing a variant of the canonical Cdc5Polo motif. Overall, our findings reveal that a master regulator of meiosis directs the activity of a kinase to change the phosphorylation landscape and elicit a developmental cascade.

Sleep Monitoring during Acute Stroke Rehabilitation: Toward Automated Measurement Using Multimodal Wireless Sensors.

Sleep plays a critical role in stroke recovery. However, there are limited practices to measure sleep for individuals with stroke, thus inhibiting our ability to identify and treat poor sleep quality. Wireless, body-worn sensors offer a solution for continuous sleep monitoring. In this study, we explored the feasibility of (1) collecting overnight biophysical data from patients with subacute stroke using a simple sensor system and (2) constructing machine-learned algorithms to detect sleep stages. Ten individuals with stroke in an inpatient rehabilitation hospital wore two wireless sensors during a single night of sleep. Polysomnography served as ground truth to classify different sleep stages. A population model, trained on data from multiple patients and tested on data from a separate patient, performed poorly for this limited sample. Personal models trained on data from one patient and tested on separate data from the same patient demonstrated markedly improved performance over population models and research-grade wearable devices to detect sleep/wake. Ultimately, the heterogeneity of biophysical signals after stroke may present a challenge in building generalizable population models. Personal models offer a provisional method to capture high-resolution sleep metrics from simple wearable sensors by leveraging a single night of polysomnography data.

Kinetochore-bound Mps1 regulates kinetochore-microtubule attachments via Ndc80 phosphorylation.

Dividing cells detect and correct erroneous kinetochore-microtubule attachments during mitosis, thereby avoiding chromosome missegregation. The Aurora B kinase phosphorylates microtubule-binding elements specifically at incorrectly attached kinetochores, promoting their release and providing another chance for proper attachments to form. However, growing evidence suggests that the Mps1 kinase is also required for error correction. Here we directly examine how Mps1 activity affects kinetochore-microtubule attachments using a reconstitution-based approach that allows us to separate its effects from Aurora B activity. When endogenous Mps1 that copurifies with kinetochores is activated in vitro, it weakens their attachments to microtubules via phosphorylation of Ndc80, a major microtubule-binding protein. This phosphorylation contributes to error correction because phospho-deficient Ndc80 mutants exhibit genetic interactions and segregation defects when combined with mutants in other error correction pathways. In addition, Mps1 phosphorylation of Ndc80 is stimulated on kinetochores lacking tension. These data suggest that Mps1 provides an additional mechanism for correcting erroneous kinetochore-microtubule attachments, complementing the well-known activity of Aurora B.

Usability, functionality, and efficacy of a custom myoelectric elbow-wrist-hand orthosis to assist elbow function in individuals with stroke.

INTRODUCTION: After stroke, upper limb impairment affects independent performance of activities of daily living. We evaluated the usability, functionality, and efficacy of a myoelectric elbow-wrist-hand orthosis to provide support, limit unsafe motion, and enhance the functional motion of paralyzed or weak upper limbs. METHODS: Individuals with stroke participated in a single-session study to evaluate the device. Ability to activate the device was tested in supported and unsupported shoulder position, as well as the elbow range of motion, ability to maintain elbow position, and ability to lift and hold a range of weights while using the device. RESULTS: No adverse events were reported. 71% of users were able to operate the device in all three active myoelectric activation modes (Biceps, Triceps, Dual) during testing. Users were able to hold a range of wrist weights (0.5-2 lbs) for 10-120 seconds, with the largest percentage of participants able to hold weights with the device in Biceps Mode. CONCLUSIONS: The myoelectric elbow-wrist-hand orthosis improved range of motion during use and was efficacious at remediating upper extremity impairment after stroke. All users could operate the device in at least one mode, and most could lift and hold weights representative of some everyday objects using the device.

Anaplastic large cell lymphoma in human immunodeficiency virus-infected people and solid organ transplant recipients.

Human immunodeficiency virus (HIV)-infected people and solid organ transplant recipients have elevated risk of anaplastic large cell lymphoma (ALCL). Little is known regarding ALCL risk factors in immunosuppressed populations. We used data from US cancer registries linked to HIV registries (1996-2016) and to the national transplant registry (1992-2017). ALCL risk in HIV-infected people and transplant recipients relative to the general population was calculated as a standardized incidence ratio (SIR). ALCL risk factors were evaluated using Poisson regression. We identified 121 incident ALCL cases in the HIV (n = 86) and transplant (n = 35) populations. We reviewed pathology reports for 45 cases and most (86·7%) were confirmed as ALCL. Epstein-Barr virus tested positive in 1/8 (12·5%) cases. Compared to the general population, ALCL risk was strongly elevated among HIV-infected people [SIR 5·43; 95% confidence interval (CI) 4·27-6·81] and transplant recipients (5·96; 4·03-8·49). Among HIV-infected people, ALCL incidence was strongly related to CD4 count [adjusted incidence rate ratio (aIRR) 0·15 for ≥500 vs. <200 cells/µl; P trend < 0·001]. Among transplant recipients, risk was highest within the first year (aIRR 6·82) and 10+ years post-transplant (5·99). In conclusion, ALCL risk is strongly increased in these immunosuppressed populations but may be unrelated to EBV infection based on limited reports.

Automating sleep stage classification using wireless, wearable sensors.

Polysomnography (PSG) is the current gold standard in high-resolution sleep monitoring; however, this method is obtrusive, expensive, and time-consuming. Conversely, commercially available wrist monitors such as ActiWatch can monitor sleep for multiple days and at low cost, but often overestimate sleep and cannot differentiate between sleep stages, such as rapid eye movement (REM) and non-REM. Wireless wearable sensors are a promising alternative for their portability and access to high-resolution data for customizable analytics. We present a multimodal sensor system measuring hand acceleration, electrocardiography, and distal skin temperature that outperforms the ActiWatch, detecting wake and sleep with a recall of 74.4% and 90.0%, respectively, as well as wake, non-REM, and REM with recall of 73.3%, 59.0%, and 56.0%, respectively. This approach will enable clinicians and researchers to more easily, accurately, and inexpensively assess long-term sleep patterns, diagnose sleep disorders, and monitor risk factors for disease in both laboratory and home settings.

Autophosphorylation is sufficient to release Mps1 kinase from native kinetochores.

Accurate mitosis depends on a surveillance system called the spindle assembly checkpoint. This checkpoint acts at kinetochores, which attach chromosomes to the dynamic tips of spindle microtubules. When a kinetochore is unattached or improperly attached, the protein kinase Mps1 phosphorylates kinetochore components, catalyzing the generation of a diffusible "wait" signal that delays anaphase and gives the cell time to correct the error. When a kinetochore becomes properly attached, its checkpoint signal is silenced to allow progression into anaphase. Recently, microtubules were found to compete directly against recombinant human Mps1 fragments for binding to the major microtubule-binding kinetochore element Ndc80c, suggesting a direct competition model for silencing the checkpoint signal at properly attached kinetochores. Here, by developing single-particle fluorescence-based assays, we tested whether such direct competition occurs in the context of native kinetochores isolated from yeast. Mps1 levels were not reduced on kinetochore particles bound laterally to the sides of microtubules or on particles tracking processively with disassembling tips. Instead, we found that Mps1 kinase activity was sufficient to promote its release from the isolated kinetochores. Mps1 autophosphorylation, rather than phosphorylation of other kinetochore components, was responsible for this dissociation. Our findings suggest that checkpoint silencing in yeast does not arise from a direct competition between Mps1 and microtubules, and that phosphoregulation of Mps1 may be a critical aspect of the silencing mechanism.

Association of In Vitro Fertilization With Childhood Cancer in the United States.

Importance: In vitro fertilization (IVF) is associated with birth defects and imprinting disorders. Because these conditions are associated with an increased risk of childhood cancer, many of which originate in utero, descriptions of cancers among children conceived via IVF are imperative. Objective: To compare the incidence of childhood cancers among children conceived in vitro with those conceived naturally. Design, Setting, and Participants: A retrospective, population-based cohort study linking cycles reported to the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System from January 1, 2004, to December 31, 2012, that resulted in live births from September 1, 2004, to December 31, 2013, to the birth and cancer registries of 14 states, comprising 66% of United States births and 75% of IVF-conceived births, with follow-up from September 1, 2004, to December 31, 2014. The study included 275 686 children conceived via IVF and a cohort of 2 266 847 children, in which 10 births were randomly selected for each IVF birth. Statistical analysis was performed from April 1, 2017, to October 1, 2018. Exposure: In vitro fertilization. Main Outcomes and Measures: Cancer diagnosed in the first decade of life. Results: A total of 321 cancers were detected among the children conceived via IVF (49.1% girls and 50.9% boys; mean [SD] age, 4.6 [2.5] years for singleton births and 5.9 [2.4] years for multiple births), and a total of 2042 cancers were detected among the children not conceived via IVF (49.2% girls and 50.8% boys; mean [SD] age, 6.1 [2.6] years for singleton births and 4.7 [2.6] years for multiple births). The overall cancer rate (per 1 000 000 person-years) was 251.9 for the IVF group and 192.7 for the non-IVF group (hazard ratio, 1.17; 95% CI, 1.00-1.36). The rate of hepatic tumors was higher among the IVF group than the non-IVF group (hepatic tumor rate: 18.1 vs 5.7; hazard ratio, 2.46; 95% CI, 1.29-4.70); the rates of other cancers did not differ between the 2 groups. There were no associations with specific IVF treatment modalities or indication for IVF. Conclusions and Relevance: This study found a small association of IVF with overall cancers of early childhood, but it did observe an increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility. Continued follow-up for cancer occurrence among children conceived via IVF is warranted.

Survival after a cancer diagnosis among solid organ transplant recipients in the United States.

BACKGROUND: Transplant recipients have an elevated risk of cancer because of immunosuppressive medications used to prevent organ rejection, but to the authors' knowledge no study to date has comprehensively examined associations between transplantation status and mortality after a cancer diagnosis. METHODS: The authors assessed cases in the US general population (N=7,147,476) for 16 different cancer types as ascertained from 11 cancer registries. The presence of a solid organ transplant prior to diagnosis (N=11,416 cancer cases) was identified through linkage with the national transplantation registry (1987-2014). Cox models were used to examine the association between transplantation status and cancer-specific mortality, adjusting for demographic characteristics and cancer stage. RESULTS: For the majority of cancers, cancer-specific mortality was higher in transplant recipients compared with other patients with cancer. The increase was particularly pronounced for melanoma (adjusted hazard ratio [aHR], 2.59; 95% confidence interval [95% CI], 2.18-3.00) and cancers of the breast (aHR, 1.88; 95% CI, 1.61-2.19), bladder (aHR, 1.85; 95% CI, 1.58-2.17), and colorectum (aHR, 1.77; 95% CI, 1.60-1.96), but it also was increased for cancers of the oral cavity/pharynx, stomach, pancreas, kidney, and lung as well as diffuse large B-cell lymphoma (aHR range, 1.21-1.47). Associations remained significant after adjustment for first-course cancer treatment and generally were stronger among patients with local-stage cancers for whom potentially curative treatment was provided, including patients with melanoma (aHR, 3.82; 95% CI, 2.94-4.97) and cancers of the colorectum (aHR, 2.77; 95% CI, 2.07-3.70), breast (aHR, 2.08; 95% CI, 1.50-2.88), and prostate (aHR, 1.60; 95% CI, 1.12-2.29), despite the lack of an association for prostate cancer overall. CONCLUSIONS: For multiple cancer types, transplant recipients with cancer appear to have an elevated risk of dying of their cancer, even after adjustment for stage and treatment, which may be due to impaired immunity.

Purification of kinetochores from the budding yeast Saccharomyces cerevisiae.

Chromosome segregation relies on forces generated by spindle microtubules that are translated into chromosome movement through interactions with kinetochores, highly conserved macromolecular machines that assemble on a specialized centromeric chromatin structure. Kinetochores not only have to stably attach to growing and shrinking microtubules, but they also need to recruit spindle assembly checkpoint proteins to halt cell cycle progression when there are attachment defects. Even the simplest kinetochore in budding yeast contains more than 50 unique components that are present in multiple copies, totaling more than 250 proteins in a single kinetochore. The complex nature of kinetochores makes it challenging to elucidate the contributions of individual components to its various functions. In addition, it is difficult to manipulate forces in vivo to understand how they regulate kinetochore-microtubule attachments and the checkpoint. To address these issues, we developed a technique to purify kinetochores from budding yeast that can be used to analyze kinetochore functions and composition as well as to reconstitute kinetochore-microtubule attachments in vitro.

Variables influencing wearable sensor outcome estimates in individuals with stroke and incomplete spinal cord injury: a pilot investigation validating two research grade sensors.

BACKGROUND: Monitoring physical activity and leveraging wearable sensor technologies to facilitate active living in individuals with neurological impairment has been shown to yield benefits in terms of health and quality of living. In this context, accurate measurement of physical activity estimates from these sensors are vital. However, wearable sensor manufacturers generally only provide standard proprietary algorithms based off of healthy individuals to estimate physical activity metrics which may lead to inaccurate estimates in population with neurological impairment like stroke and incomplete spinal cord injury (iSCI). The main objective of this cross-sectional investigation was to evaluate the validity of physical activity estimates provided by standard proprietary algorithms for individuals with stroke and iSCI. Two research grade wearable sensors used in clinical settings were chosen and the outcome metrics estimated using standard proprietary algorithms were validated against designated golden standard measures (Cosmed K4B2 for energy expenditure and metabolic equivalent and manual tallying for step counts). The influence of sensor location, sensor type and activity characteristics were also studied. METHODS: 28 participants (Healthy (n = 10); incomplete SCI (n = 8); stroke (n = 10)) performed a spectrum of activities in a laboratory setting using two wearable sensors (ActiGraph and Metria-IH1) at different body locations. Manufacturer provided standard proprietary algorithms estimated the step count, energy expenditure (EE) and metabolic equivalent (MET). These estimates were compared with the estimates from gold standard measures. For verifying validity, a series of Kruskal Wallis ANOVA tests (Games-Howell multiple comparison for post-hoc analyses) were conducted to compare the mean rank and absolute agreement of outcome metrics estimated by each of the devices in comparison with the designated gold standard measurements. RESULTS: The sensor type, sensor location, activity characteristics and the population specific condition influences the validity of estimation of physical activity metrics using standard proprietary algorithms. CONCLUSIONS: Implementing population specific customized algorithms accounting for the influences of sensor location, type and activity characteristics for estimating physical activity metrics in individuals with stroke and iSCI could be beneficial.

Contribution of solid organ transplant recipients to the pediatric non-hodgkin lymphoma burden in the United States.

BACKGROUND: Pediatric solid organ transplant recipients have a 100 to 200 times higher risk of non-Hodgkin lymphoma (NHL) than the general pediatric population. Consequently, transplant-related NHL may contribute considerably to the pediatric NHL burden in the United States. METHODS: A cohort study using a linkage between the US transplant registry and 16 cancer registries was conducted. Cancer incidence rates were calculated for people less than 20 years old in the transplant and general populations. Rates were applied to transplant registry and US census data to estimate pediatric NHL counts for transplant recipients and the general population. RESULTS: During 1990-2012, an estimated 22,270 NHLs were diagnosed in US children and adolescents; they included 628 cases diagnosed in transplant recipients. Thus, 2.82% of pediatric NHL diagnoses in the general population (95% confidence interval [CI], 2.45%-3.19%) occurred in transplant recipients. Among transplant recipients, the most common subtypes were diffuse large B-cell lymphoma (DLBCL; 64.5% of cases) and Burkitt lymphoma (BL; 8.6%). For DLBCL and BL, transplant recipients contributed 7.62% (95% CI, 6.35%-8.88%) and 0.87% (95% CI, 0.51%-1.23%) of diagnoses, respectively. The proportion of NHLs that occurred in transplant recipients was highest among children less than 5 years old (4.46%; 95% CI, 3.24%-5.69%) and in more recent calendar years (3.73% in 2010-2012; 95% CI, 2.07%-5.39%). DLBCL patterns were similar, with transplant recipients contributing 19.78% of cases among children less than 5 years old (95% CI, 12.89%-26.66%) and 11.4% of cases in 2010-2012 (95% CI, 5.54%-17.28%). CONCLUSIONS: Among children and adolescents, solid organ transplant recipients contribute a substantial fraction of NHL diagnoses, particularly DLBCL diagnoses. This fraction has increased over time. Prevention efforts targeted toward this group could reduce the overall pediatric NHL burden. Cancer 2017;123:4663-4671. © 2017 American Cancer Society.

Cancer Risk After Pediatric Solid Organ Transplantation.

BACKGROUND: The effects of pediatric solid organ transplantation on cancer risk may differ from those observed in adult recipients. We described cancers in pediatric recipients and compared incidence to the general population. METHODS: The US transplant registry was linked to 16 cancer registries to identify cancer diagnoses among recipients <18 years old at transplant. Standardized incidence ratios (SIRs) were estimated by dividing observed cancer counts among recipients by expected counts based on the general population rates. Cox regression was used to estimate the associations between recipient characteristics and non-Hodgkin's lymphoma (NHL) risk. RESULTS: Among 17 958 pediatric recipients, 392 cancers were diagnosed, of which 279 (71%) were NHL. Compared with the general population, incidence was significantly increased for NHL (SIR = 212, 95% confidence interval [CI] = 188-238), Hodgkin's lymphoma (SIR = 19, 95% CI = 13-26), leukemia (SIR = 4, 95% CI = 2-7), myeloma (SIR = 229, 95% CI = 47-671), and cancers of the liver, soft tissue, ovary, vulva, testis, bladder, kidney, and thyroid. NHL risk was highest during the first year after transplantation among recipients <5 years old at transplant (SIR = 313), among recipients seronegative for Epstein-Barr virus (EBV) at transplant (SIR = 446), and among intestine transplant recipients (SIR = 1280). In multivariable analyses, seronegative EBV status, the first year after transplantation, intestine transplantation, and induction immunosuppression were independently associated with higher NHL incidence. CONCLUSIONS: Pediatric recipients have a markedly increased risk for many cancers. NHL constitutes the majority of diagnosed cancers, with the highest risk occurring in the first year after transplantation. NHL risk was high in recipients susceptible to primary EBV infection after transplant and in intestine transplant recipients, perhaps due to EBV transmission in the donor organ.

Embryo banking among women diagnosed with cancer: a pilot population-based study in New York, Texas, and Illinois.

PURPOSE: The purpose of the present study is to estimate the proportion of women with cancer who return to use the embryos that they have banked and to compare this proportion to that of women without cancer who bank embryos. METHODS: This is a cohort study of three groups of women from New York, Texas, and Illinois who used embryo banking in their first assisted reproductive technology (ART) treatment cycle: two groups with cancer (222 women without an infertility diagnosis and 48 women with an infertility diagnosis) and a control group without cancer (68 women with the infertility diagnosis of male factor only). Women were included only if their first ART cycle reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) occurred between 2004 and 2009. Cancer cases were identified from each State Cancer Registry from 5 years prior to initiation of ART treatment to 6 months post-initiation; mean follow-up after the first ART cycle was 2.0 years. RESULTS: Women with cancer without an infertility diagnosis returned for a subsequent ART cycle at a lower rate (10.8 %) than those with an infertility diagnosis (31.3 %, p = 0.0010) or the control group (85.3 %, p < 0.0001). Among those who returned for a subsequent cycle, women with cancer waited a longer time to return (14.3 months without an infertility diagnosis and 8.3 months with an infertility diagnosis, p = 0.13) compared to the control group (2.8 months, p = 0.0007). The live birth rate among women who did not utilize embryo banking in their second cycle did not differ significantly across the three study groups, ranging from 25.0 and 42.9 % for women with cancer with and without an infertility diagnosis, respectively, to 36.2 % for women in the control group. CONCLUSIONS: Women with cancer without an infertility diagnosis are either less likely to return for subsequent treatment or will wait a longer time to return than women with an infertility diagnosis or those that do not have cancer. A longer-term study is necessary to assess whether these women return to use their frozen embryos after cancer treatment or are able to spontaneously conceive and if those subsequent pregnancies are adversely affected by the cancer diagnosis or therapy.

Assisted reproductive technology use and outcomes among women with a history of cancer.

STUDY QUESTION: How do the assisted reproductive technology (ART) outcomes of women presenting for ART after cancer diagnosis compare to women without cancer? SUMMARY ANSWER: The likelihood of a live birth after ART among women with prior cancer using autologous oocytes is reduced and varies by cancer diagnosis but is similar to women without cancer when donor oocytes are used. WHAT IS KNOWN ALREADY: Premenopausal patients faced with a cancer diagnosis frequently present for fertility preservation. STUDY DESIGN, SIZE, DURATION: Population-based cohort study of women treated with ART in NY, TX and IL, USA. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with their first ART treatment between 2004 and 2009 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database and linked to their respective State Cancer Registries based on name, date of birth and social security number. Years were rounded, i.e. year 1 = 6-18 months before treatment. This study used reports of cancer from 5 years, 6 months prior to treatment until 6 months after first ART treatment. Women who only presented for embryo banking were omitted from the analysis. The likelihood of pregnancy and of live birth with ART using autologous oocytes was modeled using logistic regression, with women without prior cancer as the reference group, adjusted for woman's age, parity, cumulative FSH dosage, infertility diagnosis, number of diagnoses, number of ART cycles, State of residency and year of ART treatment. Results of the modeling are reported as adjusted odds ratios (AORs) and (95% confidence intervals). MAIN RESULTS AND THE ROLE OF CHANCE: The study population included 53 426 women; 441 women were diagnosed with cancer within 5 years prior to ART cycle start. Mean (±SD) age at cancer diagnosis was 33.4 ± 5.7 years; age at start of ART treatment was 34.9 ± 5.8 for women with cancer compared with 35.3 ± 5.3 years for women without cancer (P = 0.03). Live birth rates among women using autologous oocytes differed substantially by cancer status (47.7% without cancer versus 24.7% with cancer, P < 0.0001), and cancer diagnosis (ranging from 53.5% for melanoma to 14.3% for breast cancer, P < 0.0001. The live birth rates among women using donor oocytes did not vary significantly by cancer status (60.4% for women with any cancer versus 64.5% for women without cancer), or by cancer diagnosis (ranging from 57.9% for breast cancer to 63.6% for endocrine cancer). Women with breast cancer make up about one-third of all cancers in this cohort. Among women with breast cancer, 2.8% of the 106 women who underwent ART within 6 months of being diagnosed with cancer used donor oocytes compared with 34.8% of the 46 women who received ART treatment a longer time after being diagnosed with cancer (P < 0.0001). We conjecture that the former group were either unaware that they had cancer or decided to undergo ART therapy prior to cancer treatment. However, their live birth rate was only 11.7% compared with 28.8%, the overall live birth rate for all women with cancer using autologous oocytes (P < 0.0001). The live birth rate for women diagnosed with breast cancer more than 6 months before ART (23.3%) did not differ significantly from the overall live birth rate for cancer (P = 0.49). If this difference is substantiated by a larger study, it would indicate a negative effect of severe recent illness itself on ART success, rather than the poor outcome being only related to the destructive effects of chemotherapies on ovarian follicles. Alternatively, because of the short time difference between cancer diagnosis and ART treatment, these pre-existing cancers may have been detected due to the increased medical surveillance during ART therapy. In women who only used autologous oocytes, women with prior cancers were significantly less likely to become pregnant and to have a live birth than those without cancer (adjusted odds ratio (AOR): 0.34, [95% confidence interval (CI): 0.27, 0.42] and 0.36 [0.28, 0.46], respectively). This was also evident with specific cancer diagnoses: breast cancer (0.20 [0.13, 0.32] and 0.19 [0.11, 0.30], respectively), cervical cancer (0.36 [0.15, 0.87] and 0.33 [0.13, 0.84], respectively) and all female genital cancers (0.49 [0.27, 0.87] and 0.47 [0.25, 0.86], respectively). Of note, among women with cancer who became pregnant, their likelihood of having a live birth did not differ significantly from women without cancer (85.8 versus 86.7% for women using autologous oocytes, and 85.3 versus 86.9% for women using donor oocytes). LIMITATIONS, REASONS FOR CAUTION: Women may not have been residents of the individual States for the entire 5-year pre-ART period, and therefore some cancers may not have been identified through this linkage. As a result, the actual observed number of cancers may be an underestimate. In addition, the overall prevalence is low due to the age distributions. Also, because we restricted the pre-ART period to 5 years prior, we would not have identified women who were survivors of early childhood cancers (younger than age 13 years at cancer diagnosis), or who had ART more than 5 years after being diagnosed with cancer. Additional analyses are currently underway evaluating live birth outcomes after embryo banking among women with cancer prior to ART, cycles which were excluded from the analyses in this paper. Future studies are planned which will include more States, as well as linkages to vital records to obtain information on spontaneous conceptions and births, to further clarify some of the issues raised in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: Since the live birth rates using donor oocytes were not reduced in women with a prior cancer, but were reduced with autologous cycles, this suggests that factors acting in the pre- or peri-conceptional periods may be responsible for the decline. STUDY FUNDING/COMPETING INTERESTS: The study was funded by grant R01 CA151973 from the National Cancer Institute, National Institutes of Health, USA. B.L. is a research consultant for the Society for Assisted Reproductive Technology. All other authors report no conflict of interest.

Cancer in women after assisted reproductive technology.

OBJECTIVE: To evaluate the risk of cancer after assisted reproductive technology (ART) therapy. DESIGN: Longitudinal cohort study. SETTING: Not applicable. PATIENT(S): New York, Texas, and Illinois residents between 2004 and 2009, treated with ART, comprising cycles of 113,226 women, including 53,859 women without prior ART treatment, who were linked to their respective state cancer registries and whose cycles were reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System (SART CORS). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Diagnosis of cancer, as reported to the state cancer registry; standardized incidence ratios (SIR) and their 95% confidence intervals, comparing the observed to expected cancer cases based on age-specific cancer rates in the general population of each state. RESULT(S): Among the cohort of women without prior ART therapy, hazard ratios (HR) and 95% confidence intervals (CI) were calculated for treatment parameters and reproductive history factors. The mean follow-up period was 4.87 years; among women without prior ART, 450 women developed 460 cancers. Women treated with ART had a statistically significantly lower risk for all cancers (for all women: SIR 0.78; CI, 0.73-0.83; women without prior ART: SIR 0.75; CI, 0.68-0.82), breast cancer, and all female genital cancers; a non-statistically-significant lower risk for endocrine and uterine cancer; and a non-statistically-significant higher risk for melanoma and ovarian cancer. Among women without prior ART, we found no statistically significant increased HR by parity, number of cycles, cumulative follicle-stimulating hormone dosage, or cycle outcome. CONCLUSION(S): Women initiating ART treatment have no greater risk for developing cancer after nearly 5 years of follow-up compared with the general population and with other women treated with ART.

Spectrum of cancer risk among US solid organ transplant recipients.

CONTEXT: Solid organ transplant recipients have elevated cancer risk due to immunosuppression and oncogenic viral infections. Because most prior research has concerned kidney recipients, large studies that include recipients of differing organs can inform cancer etiology. OBJECTIVE: To describe the overall pattern of cancer following solid organ transplantation. DESIGN, SETTING, AND PARTICIPANTS: Cohort study using linked data on solid organ transplant recipients from the US Scientific Registry of Transplant Recipients (1987-2008) and 13 state and regional cancer registries. MAIN OUTCOME MEASURES: Standardized incidence ratios (SIRs) and excess absolute risks (EARs) assessing relative and absolute cancer risk in transplant recipients compared with the general population. RESULTS: The registry linkages yielded data on 175,732 solid organ transplants (58.4% for kidney, 21.6% for liver, 10.0% for heart, and 4.0% for lung). The overall cancer risk was elevated with 10,656 cases and an incidence of 1375 per 100,000 person-years (SIR, 2.10 [95% CI, 2.06-2.14]; EAR, 719.3 [95% CI, 693.3-745.6] per 100,000 person-years). Risk was increased for 32 different malignancies, some related to known infections (eg, anal cancer, Kaposi sarcoma) and others unrelated (eg, melanoma, thyroid and lip cancers). The most common malignancies with elevated risk were non-Hodgkin lymphoma (n = 1504; incidence: 194.0 per 100,000 person-years; SIR, 7.54 [95% CI, 7.17-7.93]; EAR, 168.3 [95% CI, 158.6-178.4] per 100,000 person-years) and cancers of the lung (n = 1344; incidence: 173.4 per 100,000 person-years; SIR, 1.97 [95% CI, 1.86-2.08]; EAR, 85.3 [95% CI, 76.2-94.8] per 100,000 person-years), liver (n = 930; incidence: 120.0 per 100,000 person-years; SIR, 11.56 [95% CI, 10.83-12.33]; EAR, 109.6 [95% CI, 102.0-117.6] per 100,000 person-years), and kidney (n = 752; incidence: 97.0 per 100,000 person-years; SIR, 4.65 [95% CI, 4.32-4.99]; EAR, 76.1 [95% CI, 69.3-83.3] per 100,000 person-years). Lung cancer risk was most elevated in lung recipients (SIR, 6.13 [95% CI, 5.18-7.21]) but also increased among other recipients (kidney: SIR, 1.46 [95% CI, 1.34-1.59]; liver: SIR, 1.95 [95% CI, 1.74-2.19]; and heart: SIR, 2.67 [95% CI, 2.40-2.95]). Liver cancer risk was elevated only among liver recipients (SIR, 43.83 [95% CI, 40.90-46.91]), who manifested exceptional risk in the first 6 months (SIR, 508.97 [95% CI, 474.16-545.66]) and a 2-fold excess risk for 10 to 15 years thereafter (SIR, 2.22 [95% CI, 1.57-3.04]). Among kidney recipients, kidney cancer risk was elevated (SIR, 6.66 [95% CI, 6.12-7.23]) and bimodal in onset time. Kidney cancer risk also was increased in liver recipients (SIR, 1.80 [95% CI, 1.40-2.29]) and heart recipients (SIR, 2.90 [95% CI, 2.32-3.59]). CONCLUSION: Compared with the general population, recipients of a kidney, liver, heart, or lung transplant have an increased risk for diverse infection-related and unrelated cancers.

Cognition in circadian rhythm sleep disorders.

Circadian rhythms in physiology and behavior exist in all living organisms, from cells to humans. The most evident rhythms are the recurrent cycles of sleep and wake as well as changes in alertness and cognitive performance across the 24h. Clearly, sleep pressure can exert a strong influence on cognitive performance, but the influence of circadian modulation of alertness and cognitive function is evident even when the pressure for sleep is high. Circadian rhythms also influence more complex cognitive tasks, such as selective attention and executive function, which are important for work performance and safety. The circadian timekeeping system also ensures that circadian rhythms are appropriately synchronized to the external physical environment and work and social schedules. Circadian misalignment is the basis for all circadian rhythm sleep disorders. These disorders are often associated with impairments of cognitive performance that can have adverse effects on school and work performance, overall quality of life, and safety.

Interferon-gamma receptors in HIV-1 infection.

We studied in vitro production of interferon-gamma and expression of interferon-gamma receptors (R1 and R2) by the peripheral blood mononuclear cells of 24 HIV-1-infected patients and 12 healthy volunteers. Interferon-gamma production was lower in HIV-1-infected patients compared with healthy volunteers (p < 0.05), and it further declined in patients with lower CD4+ T-cell counts. In contrast, expression of interferon-gamma R1 by CD4+ T lymphocytes was higher in HIV-infected patients than healthy volunteers (25% versus 10%, p < 0.05). In the HIV-infected group, interferon-gamma R1 expression increased with a decline in CD4+ T-cell count (r = -0.64, p < 0.001). Interferon-gamma R2 expression directly correlated with interferon-gamma R1 expression (p < 0.001). When stimulated with heat-killed Mycobacterium avium complex (MAC) and phorbol myristic acetate (PMA), the mononuclear cells of patients with advanced HIV-1 infection had lowered ability to produce additional interferon-gamma (either MAC or PMA) and interferon-gamma receptors (MAC). In conclusion, with progression of HIV-1 infection, interferon-gamma production declines whereas expression of interferon-gamma receptors (R1 and R2) increases. Persistent upregulation of both interferon-gamma R1 and R2 receptors probably favors development of type 2 T-helper cells environment and promotes viral replication. This dysfunction in the interferon-gamma pathway contributes to a further impairment in cellular immune function in patients with advanced HIV-1 infection, which may further increase susceptibility to opportunistic infections.