A cane toad (Rhinella marina) N-methyltransferase converts primary indolethylamines to tertiary psychedelic amines.

Psychedelic indolethylamines have emerged as potential medicines to treat several psychiatric pathologies. Natural sources of these compounds include 'magic mushrooms' (Psilocybe spp.), plants used to prepare ayahuasca, and toads. The skin and parotid glands of certain toads accumulate a variety of specialized metabolites including toxic guanidine alkaloids, lipophilic alkaloids, poisonous steroids, and hallucinogenic indolethylamines such as DMT, 5-methoxy-DMT, and bufotenin. The occurrence of psychedelics has contributed to the ceremonial use of toads, particularly among Mesoamerican peoples. Yet, the biosynthesis of psychedelic alkaloids has not been elucidated. Herein, we report a novel indolethylamine N-methyltransferase (RmNMT) from cane toad (Rhinella marina). The RmNMT sequence was used to identify a related NMT from the common toad, Bufo bufo. Close homologs from various frog species were inactive, suggesting a role for psychedelic indolethylamine biosynthesis in toads. Enzyme kinetic analyses and comparison with functionally similar enzymes showed that recombinant RmNMT was an effective catalyst and not product inhibited. The substrate promiscuity of RmNMT enabled the bioproduction of a variety of substituted indolethylamines at levels sufficient for purification, pharmacological screening, and metabolic stability assays. Since the therapeutic potential of psychedelics has been linked to activity at serotonergic receptors, we evaluated binding of derivatives at 5-HT1A and 5-HT2A receptors. Primary amines exhibited enhanced affinity at the 5-HT1A receptor compared with tertiary amines. With the exception of 6-substituted derivatives, N,N-dimethylation also protected against catabolism by liver microsomes.

The moderating effect of access to food facilities and recreational activity space on mHealth multiple health behavior change intervention.

OBJECTIVE: To evaluate whether the neighborhood social and built environment moderates response to a mobile health multiple health behavior change intervention targeting fruit/vegetable intake, sedentary behavior, and physical activity. METHODS: Participants were 156 Chicago-residing adults with unhealthy lifestyle behaviors. Using linear mixed models, we evaluated whether access to food facilities (fast food restaurants and grocery stores) and recreational activity spaces (gyms and parks) moderated the difference in behavior change between the active intervention condition relative to control. Using spatial data analysis (cross K functions), we also assessed whether participants who achieved goal levels of behaviors ("responders") were more or less likely than those who did not achieve intervention goals ("non-responders") to reside near fast food restaurants, grocery stores, gyms, or parks. RESULTS: According to linear mixed models, none of the neighborhood social and built environment factors moderated the difference in behavior change between the active intervention condition and the control condition (Likelihood Ratio (χ²[1] = 0.02-2.33, P-values > 0.05). Cross K functions showed that diet behavior change responders were more likely than non-responders to reside near fast food restaurants, but not grocery stores. The results for activity behavior change were more variable. Sedentary screen time responders were more likely to reside around recreational activity spaces than non-responders. Moderate-vigorous physical activity responders had greater and lesser clustering than non-responders around parks, dependent upon distance from the park to participant residence. CONCLUSIONS: A complex relationship was observed between residential proximity to Chicago facilities and response to multiple health behavior change intervention. Replication across diverse geographic settings and samples is necessary.

Cause of death during prostate cancer survivorship: A contemporary, US population-based analysis.

BACKGROUND: More than 3.6 million men in the United States harbor a diagnosis of prostate cancer (PCa). The authors sought to provide in-depth analyses of the causes of death for contemporary survivors. METHODS: The authors performed a population-based cohort study in the United States (2000-2016) to assess causes of death for men diagnosed with PCa stratified by demographics and tumor stage. Using general population data, they calculated standardized mortality ratios (SMRs) as observed-to-expected death ratios. RESULTS: In total, 752,092 men with PCa, including 200,302 who died (27%), were assessed. A total of 29,048 men with local/regional disease (17%) died of PCa, whereas more than 4-fold men died of other causes (n = 143,719 [83%]). SMRs for death from noncancer causes (0.77; 95% confidence interval [CI], 0.77-0.78) suggested that these men were less likely than the general population to die of most other causes. The most common noncancer cause of death was cardiac-related (23%; SMR, 0.76; 95% CI, 0.75-0.77). Among men with distant PCa, 90% of deaths occurred within 5 years of diagnosis. Although deaths due to PCa composed the majority of deaths (74%), SMRs suggested that men with distant PCa were at heightened risk for death from most other noncancer causes (1.50; 95% CI, 1.46-1.54) and, in particular, for cardiac-related death (SMR, 1.48; 95% CI, 1.41-1.54) and suicide (SMR, 2.32; 95% CI, 1.78-2.96). Further analyses demonstrated that causes of death varied by patient demographics. CONCLUSIONS: Causes of death during PCa survivorship vary by patient and tumor characteristics. These data provide valuable information regarding health care prioritization during PCa survivorship. LAY SUMMARY: Men with early-stage prostate cancer are 4-fold more likely to die of other causes, whereas those with advanced prostate cancer are at increased risk for several causes not related to prostate cancer in comparison with the general population. These findings can help guide physicians taking care of men with a diagnosis of prostate cancer.

Synthetic Access to Benzimidacarbocyanine Dyes to Tailor Their Aggregation Properties.

Developing structure-aggregation relationships of cyanine dyes is crucial for controlling their optical properties for various uses. This study develops a synthetic route and the structure-dependent self-assembly of a family of benzimidacarbocyanine dyes for J- or H-aggregation properties. It was found that both the presence and placement of halogen atoms play a defining role in the resulting supramolecular interactions of these compounds.

Community clinical practice patterns and mortality in patients with intermediate oncotype DX recurrence scores: Who benefits from chemotherapy?

BACKGROUND: The Oncotype DX recurrence score (RS) is used as a tool for making decisions about chemotherapy for patients who have hormone receptor (estrogen receptor or progesterone receptor)-positive, HER2-negative breast cancer. There is no benefit from chemotherapy among patients aged ≥50 years who have lymph node-negative disease and an RS from 11 to 25, but the benefit of chemotherapy in the lymph node-positive group remains unknown. METHODS: On the basis of data from the National Cancer Data Base between 2010 and 2014, a nationwide, retrospective cohort study included 73,185 women who had stage I through IIIA breast cancer and an RS between 11 and 30. RESULTS: Receipt of chemotherapy was associated with a reduced risk of death among patients who had lymph node-positive breast cancer (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.45-0.74; P < .001) after adjusting for other prognostic factors in a multivariable Cox model. The 5-year survival gain ranged from 1.3% (RS 11-17 subgroup), to 3.3% (RS 18-25 subgroup), and to 6.7% (RS 26-30 subgroup). Among patients who had lymph node-negative disease, chemotherapy was associated with a reduced risk of death for those with an RS from 25 to 30 (HR, 0.68; 95% CI, 0.48-0.96; P = .03; 5-year survival gain, 1.8%), but there was no benefit from chemotherapy for patients who had an RS from 11 to 17 (HR, 0.97; 95% CI, 0.61-1.55; P = .90), and there was a marginally significant benefit for women who had an RS from 18 to 25 (HR, 0.79; 95% CI, 0.62-1.00; P = .05). Similar results were observed using propensity score-matching method. CONCLUSIONS: The benefit of chemotherapy for patients with breast cancer who have an intermediate RS is driven in a nonlinear fashion by RS: the higher the RS, the larger the absolute benefit. Findings from this study underscore the utility of real-world data to inform joint decision making in practice.

Racial disparities in omission of oncotype DX but no racial disparities in chemotherapy receipt following completed oncotype DX test results.

PURPOSE: To examine racial/ethnic disparities in Oncotype DX (ODX) testing among patients with node-negative, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers and possible racial/ethnic disparities in chemotherapy receipt following ODX testing within Recurrence Score (RS) category (Not Done, Low, Intermediate, High), as well as chemotherapy receipt time trends within RS categories. METHODS: A retrospective cohort list of 125,288 women who were potentially indicated for ODX testing from 2010 to 2014 was obtained using the National Cancer Database. We fit multivariate logistic regression predicting chemotherapy receipt, adjusting for clinical factors, patient demographic factors, and hospital-level factors, separately by RS category, and calculated odds ratios (OR) and 95% confidence intervals (CI), as well as time trends. RESULTS: Overall, ODX testing was completed for 46.1% of Non-Hispanic (NH) Whites, 43.9% of NH Blacks, and 41.7% of Hispanics. Among patients who did not receive ODX testing, NH Black and Hispanic women both experienced statistically significant increases in chemotherapy receipt relative to NH White women (NH Black OR 1.23; 95% CI 1.11-1.37; Hispanic OR 1.23; 95% CI 1.07-1.42). However, among patients with ODX results, no statistically significant racial/ethnic differences in chemotherapy receipt were observed within strata of RS category. Trend analyses demonstrated increasing adherence to national guidelines for ODX testing. CONCLUSIONS: We identified racial disparities in omission of ODX testing but no differences in chemotherapy receipt if ODX test results were obtained, suggesting increasing access to ODX testing may improve racial equality in efficacious use of adjuvant chemotherapy for ER-positive HER2-negative breast cancer.

Acid-Catalyzed Electron Transfer Processes in Naphthalene peri-Dichalcogenides.

1,8-Naphthalene peri-dichalcogenides undergo protonation by Bronsted acids to produce electrophilic cations. Single electron transfer (SET) from the remaining unprotonated electron-rich peri-dichalcogenide to the cation then generates a radical cation and a radical. Thus, the formation of radical species results in severe peak broadening and coalescence of NMR signals when trifluoroacetic acid or other strong acids are added to the peri-dichalcogenide, and the process can be reversed by treatment with base. Further evidence for the formation of radicals stems from EPR, radical quencing with sodium dithionite, and computational experiments. The electron transfer is enhanced by the presence of 2,7-dialkoxy substituents that further increase the electron-donating ability of the dichalcogenides. This is an unusual example of a proton-coupled electron transfer process where an electron-rich molecule reacts with its own conjugate acid via a single electron transfer process.

Residential cancer cluster investigation nearby a Superfund Study Area with trichloroethylene contamination.

PURPOSE: Trichloroethylene (TCE) is an industrial solvent associated with liver cancer, kidney cancer, and non-Hodgkin's lymphoma (NHL). It is unclear whether an excess of TCE-associated cancers have occurred surrounding the Middlefield-Ellis-Whisman Superfund site in Mountain View, California. We conducted a population-based cancer cluster investigation comparing the incidence of NHL, liver, and kidney cancers in the neighborhood of interest to the incidence among residents in the surrounding four-county region. METHODS: Case counts and address information were obtained using routinely collected data from the Greater Bay Area Cancer Registry, part of the Surveillance, Epidemiology, and End Results program. Population denominators were obtained from the 1990, 2000, and 2010 US censuses. Standardized incidence ratios (SIRs) with two-sided 99 % confidence intervals (CIs) were calculated for time intervals surrounding the US Censuses. RESULTS: There were no statistically significant differences between the neighborhood of interest and the larger region for cancers of the liver or kidney. A statistically significant elevation was observed for NHL during one of the three time periods evaluated (1996-2005: SIR = 1.8, 99 % CI 1.1-2.8). No statistically significant NHL elevation existed in the earlier 1988-1995 (SIR = 1.3, 99 % CI 0.5-2.6) or later 2006-2011 (SIR = 1.3, 99 % CI 0.6-2.4) periods. CONCLUSION: There is no evidence of an increased incidence of liver or kidney cancer, and there is a lack of evidence of a consistent, sustained, or more recent elevation in NHL occurrence in this neighborhood. This evaluation included existing cancer registry data, which cannot speak to specific exposures incurred by past or current residents of this neighborhood.

Enhanced Glutathione Peroxidase Activity of Water-Soluble and Polyethylene Glycol-Supported Selenides, Related Spirodioxyselenuranes, and Pincer Selenuranes.

Diaryl selenides containing o-hydroxymethylene substituents function as peroxide-destroying mimetics of the antioxidant selenoenzyme glutathione peroxidase (GPx), via oxidation to the corresponding spirodioxyselenuranes with hydrogen peroxide and subsequent reduction back to the original selenides with glutathione. Parent selenides with 3-hydroxypropyl or 2,3-dihydroxypropyl groups produced the novel compounds 10 and 11, respectively, with greatly improved aqueous solubility and catalytic activity. The phenolic derivative 28 displayed similarly ameliorated properties and also modest radical-inhibiting antioxidant activity, as evidenced by an assay based on phenolic hydrogen atom transfer to the stable free radical DPPH. In contrast, several selenides that afford pincer selenuranes (e.g., 20 and 21) instead of spiroselenuranes upon oxidation showed inferior catalytic activity. Several selenide analogues were attached to polyethylene glycol (PEG) oligomers, as PEG substituents can improve water solubility and bioavailability, while retarding clearance. Again, the PEG derivatives afforded remarkable activity when oxidation generated spirodioxyselenuranes and diminished activity when pincer compounds were produced. Several such compounds proved to be ca. 10- to 100-fold catalytically superior to the diaryl selenides and their spirodioxyselenurane counterparts investigated previously. Finally, an NMR-based assay employing glutathione in D2O was designed to accommodate the faster reacting water-soluble mimetics and to more closely duplicate in vivo conditions.

Training the next generation of global health experts: experiences and recommendations from Pacific Rim universities.

BACKGROUND: Finding solutions to global health problems will require a highly-trained, inter-disciplinary workforce. Global health education and research can potentially have long-range impact in addressing the global burden of disease and protecting and improving the health of the global population. METHODS: We conducted an online survey of twelve higher education institutions in the Pacific Rim that spanned the period 2005-2011. Program administrators provided data on program concentrations, student enrollment and student funding opportunities for 41 public health programs, including those specific to global health. RESULTS: The Master of Public Health (MPH) was the most common degree offered. A growing demand for global health education was evident. Enrollment in global health programs increased over three-fold between 2005-2011. Very few institutions had specific global health programs or offered training to undergraduates. Funding for student scholarships was also lacking. CONCLUSIONS: The growing demand for global health education suggests that universities in the Pacific Rim should increase educational and training opportunities in this field. Schools of medicine may not be fully equipped to teach global health-related courses and to mentor students who are interested in global health. Increasing the number of dedicated global health research and training institutions in the Pacific Rim can contribute to building capacity in the region. Faculty from different departments and disciplines should be engaged to provide multi-disciplinary global health educational opportunities for undergraduate and graduate students. New, innovative ways to collaborate in education, such as distance education, can also help universities offer a wider range of global health-related courses. Additional funding of global health is also required.

Immigration factors and prostate cancer survival among Hispanic men in California: does neighborhood matter?

BACKGROUND: Hispanics are more likely than other racial/ethnic groups in the United States to be diagnosed with later stage of prostate cancer, yet they have lower prostate cancer mortality rates. The authors evaluated the impact of nativity and neighborhood-level Hispanic ethnic enclave on prostate cancer survival among Hispanics. METHODS: A total of 35,427 Hispanic men diagnosed with invasive prostate cancer from 1995 through 2008 in the California Cancer Registry were studied; vital status data were available through 2010. Block group-level neighborhood measures were developed from US Census data. Stage-stratified Cox proportional hazards models were used to assess the effect of nativity and ethnic enclave on prostate cancer survival. RESULTS: In models adjusted for neighborhood socioeconomic status and other individual factors, foreign-born Hispanics were found to have a significantly lower risk of prostate cancer survival (hazards ratio [HR], 0.81; 95% confidence interval [95% CI], 0.75-0.87). Living in an ethnic enclave appeared to modify this effect, with the survival advantage slightly more pronounced in the high ethnic enclave neighborhoods (HR, 0.78; 95% CI, 0.71-0.86) compared with low ethnic enclave neighborhoods (HR, 0.86; 95% CI, 0.76-0.98). CONCLUSIONS: Despite lower socioeconomic status, Hispanic immigrants have better survival after prostate cancer than US-born Hispanics and this pattern was more striking among those living in ethnic enclaves. Identifying the modifiable individual and neighborhood-level factors that facilitate this survival advantage in Hispanic immigrants may help to inform specific interventions to improve survival among all patients.

Colorectal cancer incidence in Asian populations in California: effect of nativity and neighborhood-level factors.

OBJECTIVES: Heritable and environmental factors may contribute to differences in colorectal cancer (CRC) incidence across populations. We capitalized on the resources of the California Cancer Registry (CCR) and California's diverse Asian population to perform a cohort study exploring the relationships between CRC incidence, nativity, and neighborhood-level factors across Asian subgroups. METHODS: We identified CRC cases in the CCR from 1990 to 2004 and calculated age-adjusted CRC incidence rates for non-Hispanic Whites and US-born vs. foreign-born Asian ethnic subgroups, stratified by neighborhood socioeconomic status (SES) and "ethnic enclave." Trends were studied with joinpoint analysis. RESULTS: CRC incidence was lowest among foreign-born South Asians (22.0/100,000; 95% confidence interval (CI): 19.7-24.5/100,000) and highest among foreign-born Japanese (74.6/100,000; 95% CI: 70.1-79.2/100,000). Women in all Asian subgroups except Japanese, and men in all Asian subgroups except Japanese and US-born Chinese, had lower CRC incidence than non-Hispanic Whites. Among Chinese men and Filipino women and men, CRC incidence was lower among foreign-born than US-born persons; the opposite was observed for Japanese women and men. Among non-Hispanic Whites, but not most Asian subgroups, CRC incidence decreased over time. CRC incidence was inversely associated with neighborhood SES among non-Hispanic Whites, and level of ethnic enclave among Asians. CONCLUSIONS: CRC incidence rates differ substantially across Asian subgroups in California. The significant associations between CRC incidence and nativity and residence in an ethnic enclave suggest a substantial effect of acquired environmental factors. The absence of declines in CRC incidence rates among most Asians during our study period may point to disparities in screening compared with Whites.

Effects of methoxy substituents on the glutathione peroxidase-like activity of cyclic seleninate esters.

Cyclic seleninate esters function as mimetics of the antioxidant enzyme glutathione peroxidase and catalyze the reduction of hydrogen peroxide with a stoichiometric thiol. While a single electron-donating methoxy substituent para to the selenium atom enhances the catalytic activity, m-methoxy groups have little effect and o-methoxy substituents suppress activity. The effects of multiple methoxy groups are not cumulative. This behavior can be rationalized by opposing mesomeric and steric effects. Oxidation of the product disulfide via its thiolsulfinate was also observed.

Complete quantum control of a single quantum dot spin using ultrafast optical pulses.

A basic requirement for quantum information processing systems is the ability to completely control the state of a single qubit. For qubits based on electron spin, a universal single-qubit gate is realized by a rotation of the spin by any angle about an arbitrary axis. Driven, coherent Rabi oscillations between two spin states can be used to demonstrate control of the rotation angle. Ramsey interference, produced by two coherent spin rotations separated by a variable time delay, demonstrates control over the axis of rotation. Full quantum control of an electron spin in a quantum dot has previously been demonstrated using resonant radio-frequency pulses that require many spin precession periods. However, optical manipulation of the spin allows quantum control on a picosecond or femtosecond timescale, permitting an arbitrary rotation to be completed within one spin precession period. Recent work in optical single-spin control has demonstrated the initialization of a spin state in a quantum dot, as well as the ultrafast manipulation of coherence in a largely unpolarized single-spin state. Here we demonstrate complete coherent control over an initialized electron spin state in a quantum dot using picosecond optical pulses. First we vary the intensity of a single optical pulse to observe over six Rabi oscillations between the two spin states; then we apply two sequential pulses to observe high-contrast Ramsey interference. Such a two-pulse sequence realizes an arbitrary single-qubit gate completed on a picosecond timescale. Along with the spin initialization and final projective measurement of the spin state, these results demonstrate a complete set of all-optical single-qubit operations.

Population-level impact of adjuvant trastuzumab emtansine on the incidence of metastatic breast cancer: an epidemiological prediction model of women with HER2-positive early breast cancer and residual disease following neoadjuvant therapy.

PURPOSE: Treating early-stage breast cancer (eBC) may delay or prevent subsequent metastatic breast cancer (mBC). In the phase 3 KATHERINE study, women with human epidermal growth factor receptor 2 (HER2)-positive eBC with residual disease following neoadjuvant therapy containing trastuzumab and a taxane experienced 50% reductions in disease recurrence or death when treated with adjuvant trastuzumab emtansine (T-DM1) vs adjuvant trastuzumab. We predicted the population-level impact of adjuvant T-DM1 on mBC occurrence in five European countries (EU5) and Canada from 2021-2030. METHODS: An epidemiological prediction model using data from national cancer registries, observational studies, and clinical trials was developed. Assuming 80% population-level uptake of adjuvant treatment, KATHERINE data were extrapolated prospectively to model projections. Robustness was evaluated in alternative scenarios. RESULTS: We projected an eligible population of 116,335 women in Canada and the EU5 who may be diagnosed with HER2-positive eBC and have residual disease following neoadjuvant therapy from 2021-2030. In EU5, the cumulative number of women projected to experience relapsed mBC over the 10-year study period was 36,009 vs 27,143 under adjuvant trastuzumab vs T-DM1, a difference of 8,866 women, equivalent to 25% fewer cases with the use of adjuvant T-DM1 in EU5 countries from 2021-2030. Findings were similar for Canada. CONCLUSION: Our models predicted greater reductions in the occurrence of relapsed mBC with adjuvant T-DM1 vs trastuzumab in the indicated populations in EU5 and Canada. Introduction of T-DM1 has the potential to reduce population-level disease burden of HER2-positive mBC in the geographies studied.

Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders.

The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite positive clinical end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chemical entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacological exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long-term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.

Impact of breast cancer subtypes on 3-year survival among adolescent and young adult women.

INTRODUCTION: Young women have poorer survival after breast cancer than do older women. It is unclear whether this survival difference relates to the unique distribution of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2)-defined molecular breast cancer subtypes among adolescent and young adult (AYA) women aged 15 to 39 years. The purpose of our study was to examine associations between breast cancer subtypes and short-term survival in AYA women, as well as to determine whether the distinct molecular subtype distribution among AYA women explains the unfavorable overall breast cancer survival statistics reported for AYA women compared with older women. METHODS: Data for 5,331 AYA breast cancers diagnosed between 2005 and 2009 were obtained from the California Cancer Registry. Survival by subtype (triple-negative; HR+/HER2-; HR+/HER2+; HR-/HER2+) and age-group (AYA versus 40- to 64-year-olds) was analyzed with Cox proportional hazards regression with follow-up through 2010. RESULTS: With up to 6 years of follow-up and a mean survival time of 3.1 years (SD = 1.5 years), AYA women diagnosed with HR-/HER + and triple-negative breast cancer experienced a 1.6-fold and 2.7-fold increased risk of death, respectively, from all causes (HR-/HER + hazard ratio: 1.55; 95% confidence interval (CI): 1.10 to 2.18; triple-negative HR: 2.75; 95% CI, 2.06 to 3.66) and breast cancer (HR-/HER + hazard ratio: 1.63; 95% CI, 1.12 to 2.36; triple-negative hazard ratio: 2.71; 95% CI, 1.98 to 3.71) than AYA women with HR+/HER2- breast cancer. AYA women who resided in lower socioeconomic status neighborhoods, had public health insurance, and were of Black, compared with White, race/ethnicity experienced worse survival. This race/ethnicity association was attenuated somewhat after adjusting for breast cancer subtypes (hazard ratio, 1.33; 95% CI, 0.98 to 1.82). AYA women had similar all-cause and breast cancer-specific short-term survival as older women for all breast cancer subtypes and across all stages of disease. CONCLUSIONS: Among AYA women with breast cancer, short-term survival varied by breast cancer subtypes, with the distribution of breast cancer subtypes explaining some of the poorer survival observed among Black, compared with White, AYA women. Future studies should consider whether distribution of breast cancer subtypes and other factors, including differential receipt of treatment regimens, influences long-term survival in young compared with older women.

Ultrafast optical control of individual quantum dot spin qubits.

Single spins in semiconductor quantum dots form a promising platform for solid-state quantum information processing. The spin-up and spin-down states of a single electron or hole, trapped inside a quantum dot, can represent a single qubit with a reasonably long decoherence time. The spin qubit can be optically coupled to excited (charged exciton) states that are also trapped in the quantum dot, which provides a mechanism to quickly initialize, manipulate and measure the spin state with optical pulses, and to interface between a stationary matter qubit and a 'flying' photonic qubit for quantum communication and distributed quantum information processing. The interaction of the spin qubit with light may be enhanced by placing the quantum dot inside a monolithic microcavity. An entire system, consisting of a two-dimensional array of quantum dots and a planar microcavity, may plausibly be constructed by modern semiconductor nano-fabrication technology and could offer a path toward chip-sized scalable quantum repeaters and quantum computers. This article reviews the recent experimental developments in optical control of single quantum dot spins for quantum information processing. We highlight demonstrations of a complete set of all-optical single-qubit operations on a single quantum dot spin: initialization, an arbitrary SU(2) gate, and measurement. We review the decoherence and dephasing mechanisms due to hyperfine interaction with the nuclear-spin bath, and show how the single-qubit operations can be combined to perform spin echo sequences that extend the qubit decoherence from a few nanoseconds to several microseconds, more than 5 orders of magnitude longer than the single-qubit gate time. Two-qubit coupling is discussed, both within a single chip by means of exchange coupling of nearby spins and optically induced geometric phases, as well as over longer-distances. Long-distance spin-spin entanglement can be generated if each spin can emit a photon that is entangled with the spin, and these photons are then interfered. We review recent work demonstrating entanglement between a stationary spin qubit and a flying photonic qubit. These experiments utilize the polarization- and frequency-dependent spontaneous emission from the lowest charged exciton state to single spin Zeeman sublevels.

Invited commentary: reproductive organ surgeries and breast cancer risk--apples, oranges, or fruit cocktail?

Case-control and cohort studies are almost always complicated by nonrandom exposure allocation, which must be minimized in the design and analysis phases. Tubal sterilization is a common gynecological procedure that may be associated with other reproductive organ surgeries, which in turn may be associated with breast cancer risk. In this issue of the Journal, Gaudet et al. (Am J Epidemiol. 2013;177(6):492-499) argue successfully that tubal sterilization is unassociated with breast cancer risk. Scrutiny of the heterogeneous studies included in their meta-analysis underscores the role of confounding and effect modification in observational epidemiologic studies. Specifically, tubal sterilization is unassociated with breast cancer risk, but either oophorectomy or hysterectomy, or both, and the timing of these procedures warrant careful consideration in the design, analysis, and interpretation of observational research on reproductive factors.

Impact of Pertuzumab and Ado-Trastuzumab Emtansine on Cumulative Avoidance of Recurrence Among Women Treated for Locally Advanced, Inflammatory, or Early-Stage Nonmetastatic HER2-Positive Breast Cancer in the United States.

INTRODUCTION: We assessed the impact of HER2-positive early breast cancer (EBC) treatment landscape changes following the introduction of pertuzumab and ado-trastuzumab emtansine (T-DM1) on cumulative population-level recurrences avoided since 2013 (first pertuzumab approval for EBC in the United States; US). METHODS: We constructed a multi-year epidemiologic population treatment-impact model to estimate annual recurrences between 2013 and 2031. Parameters were: BC incidence; stage I-III proportion; HER2-positive disease proportion; treatment proportions for neoadjuvant-only, adjuvant-only, and neoadjuvant-adjuvant continuation; and therapeutic agent proportions within each of those settings (chemotherapy only, trastuzumab ± chemotherapy, pertuzumab with trastuzumab ± chemotherapy, or T-DM1). The primary endpoint was cumulative recurrences, estimated by incorporating extrapolated clinical trial data for each regimen of interest into the model under four scenarios. RESULTS: Approximately 889,057 women were predicted to be diagnosed with stage I-III HER2-positive BC from 2006 to 2031 in the US and potentially indicated for HER2-targeted treatment. In steady-state equilibrium, the model estimated that real-world utilization of pertuzumab and T-DM1 will reduce the population-level number of recurrences by approximately 32%, with 7226 recurrences predicted in 2031 based on current utilization rates. In different modeled scenarios, use of neoadjuvant pertuzumab, continuation of pertuzumab in the adjuvant setting, and T-DM1 in the adjuvant setting in women with residual disease after neoadjuvant treatment were all predicted to reduce the number of recurrences. CONCLUSION: Given the improvement of HER2-targeted treatments, alongside increases in BC disease burden, we expect that the population-level impact of HER2-targeted treatments will accelerate over the next decade. Our results suggest that utilization of HER2-targeted treatments in the US has the potential to change the epidemiology of HER2-positive EBC by preventing a substantial number of women from experiencing disease recurrence. These improvements may help to inform our understanding of the future disease and economic burden of HER2-positive BC in the US.

We predicted whether two treatments for a type of breast cancer called "HER2-positive," that had not yet spread from the breast, could be used to avoid the cancer coming back in women in the United States (US), using computer modeling. The model estimated that approximately 889,057 women were predicted to be diagnosed with this type of breast cancer from 2006 to 2031, and that use of the treatments pertuzumab and ado-trastuzumab emtansine (T-DM1) would reduce the number of breast cancers that came back by around 32%. Treating with pertuzumab before surgery, continuing pertuzumab treatment after surgery, and giving T-DM1 after surgery (in the event that some of the breast cancer remained after being treated before surgery) were all predicted to reduce the number of breast cancers that come back. Overall, we expect use of pertuzumab and T-DM1 to keep lowering the number of breast cancers that come back over the next decade in the US.