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In the USA, as many as 20 % of recruits sustain stress fractures during basic training. In addition, approximately one-third of female recruits develop Fe deficiency upon completion of training. Fe is a cofactor in bone collagen formation and vitamin D activation, thus we hypothesised Fe deficiency may be contributing to altered bone microarchitecture and mechanics during 12-weeks of increased mechanical loading. Three-week old female Sprague Dawley rats were assigned to one of four groups: Fe-adequate sedentary, Fe-deficient sedentary, Fe-adequate exercise and Fe-deficient exercise. Exercise consisted of high-intensity treadmill running (54 min 3×/week). After 12-weeks, serum bone turnover markers, femoral geometry and microarchitecture, mechanical properties and fracture toughness and tibiae mineral composition and morphometry were measured. Fe deficiency increased the bone resorption markers C-terminal telopeptide type I collagen and tartate-resistant acid phosphatase 5b (TRAcP 5b). In exercised rats, Fe deficiency further increased bone TRAcP 5b, while in Fe-adequate rats, exercise increased the bone formation marker procollagen type I N-terminal propeptide. In the femur, exercise increased cortical thickness and maximum load. In the tibia, Fe deficiency increased the rate of bone formation, mineral apposition and Zn content. These data show that the femur and tibia structure and mechanical properties are not negatively impacted by Fe deficiency despite a decrease in tibiae Fe content and increase in serum bone resorption markers during 12-weeks of high-intensity running in young growing female rats.

To assess pregnancy outcomes following first trimester combined screening for preterm preeclampsia in Australia.We compared pregnancy outcomes of women with singleton pregnancies who underwent first trimester combined preeclampsia screening with the Fetal Medicine Foundation algorithm between 2014 and 2017 in Melbourne and Sydney, Australia, with those from women who received standard care. The primary outcomes were preterm preeclampsia and screening performance. Effect estimates were presented as risk ratios with 95% confidence intervals.A total of 29 618 women underwent combined screening and 301 566 women received standard care. Women who had combined screening were less likely to have preeclampsia, preterm birth, small neonates, and low Apgar scores than the general population. Women with high-risk results (≥1 in 100) were more likely to develop preterm preeclampsia (2.1% vs. 0.7%, risk ratio [RR] 3.04, 95% CI 2.46-3.77), while low-risk women (risk1 in 100) had lower rates of preterm preeclampsia (0.2% vs. 0.7%, RR 0.26, 95% CI 0.19-0.35) and other pregnancy complications. Screening detected 65.2% (95% CI 56.4-73.2%) of all preterm preeclampsia cases, with improved performance after adjustment for treatment effect.First trimester screening for preeclampsia in clinical practice identified a population at high risk of adverse pregnancy outcomes and low-risk women who may be suitable for less intensive antenatal care.

Elimination of dog-transmitted human rabies worldwide will require large-scale dog vaccination campaigns. However, this places participating vaccinators at increased risk. Data from the 2016–2017 Haitian mass rabies vaccination campaign was analyzed to determine dog bite incidence among vaccinators. A survey was then developed for completion by all identifiable bitten vaccinators covering demographics; experience and training; bite episode details; attitudes toward dogs and rabies; and medical care. A parallel group of unbitten vaccinators was also surveyed. Dog bite incidence was 0.03% (43/127,000) of all dogs vaccinated. The capture, vaccinate, and release method of vaccination carried a significantly higher risk of dog bite (0.35%, 6/1,739 vaccinations) than other methods (P < 0.001). Twenty-seven bitten vaccinators, and 54 control vaccinators were included in the survey analysis. No differences were found between groups in demographics, experience, or training. However, bitten vaccinators were significantly more likely than the control group to have experienced a dog bite before the study period (P < 0.001). This may be associated with a lesser appreciation of dogs, and/or a poorer ability to interpret dog behavioral signals within this group. Although 98% of the control group indicated they would seek medical care for a dog bite, only 35% of bitten vaccinators sought such care. On a yearly basis, for the Haitian campaign, a full series of postexposure rabies vaccinations for all bite victims would prove more cost-effective than preexposure vaccination of all vaccinators. These findings may prove useful for the planning and safety of future mass dog vaccination campaigns.

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms ‘graduate’ in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome., HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.

Background context Musculoskeletal (MSK) pain presents a global challenge. Individual and group pain management programmes (PMPs) are recommended approaches for patients with chronic MSK disorders. With advances in remote healthcare capability, telehealth, and the recent COVID-19 pandemic, the importance of telehealth PMPs has become even more evident. Nevertheless, it is not known how patients perceive PMPs for their MSK complaint when delivered via telehealth. Objective To synthesise the evidence of patients' experiences of group and individual telehealth PMPs for chronic MSK pain. Design A scoping review informed by the PRISMA extension for scoping reviews. Data sources Based on a planned search strategy, modified following initial searches, an electronic search was conducted of key databases: Cochrane Library, Medline, CINAHL, EMBASE, AMED, SportDiscus and APA PsychInfo from 2010 until 11 May 2021. Study selection Any qualitative or mixed methods study reporting patient experiences of telehealth PMPs for patients with MSK disorders. Data extraction and data synthesis Data were extracted and synthesised using thematic analysis. Results From 446 identified studies, 10 were included. Just two studies investigated group telehealth PMPs for patients with MSK disorders, with eight delivered individually. Four main themes emerged: (1) Usability of the technology, (2) Tailored care, (3) Therapeutic alliance and (4) Managing behaviour. The findings highlight patient acceptability of telehealth to support self-management for chronic MSK disorders, with appropriate clinical and technical support. Group telehealth has the potential to empower patients with peer support. Remote delivery of PMPs also impacts on how patients and providers interact, communicate and develop a therapeutic relationship. Conclusions and implications Barriers and enablers to engagement in telehealth PMPs for patients with chronic MSK disorders have been identified. Peer support and group cohesiveness can be achieved remotely to enhance the patient experience. There is a critical need for further research in this area.

PURPOSE Trials for DCIS have not explored whether outcomes for patients with large disease burden requiring mastectomy are comparable to those of patients with lumpectomy-amenable disease. We aim to identify whether patients with DCIS larger than 5 cm and diffuse-type DCIS differ in breast cancer mortality (BCM) from patients with disease less than 5 cm. METHODS Patients diagnosed with DCIS in the SEER program were assessed to identify factors prognostic of breast-cancer-specific survival using competing risks regression. RESULTS 44,849 patients met criteria for the cumulative incidence estimate. On competing risks cumulative incidence approximation, the 10-year estimate for BCM for each group was 1.3%, 1.3%, 2.3%, and 5.1%, respectively, and the difference among groups was significant (p = 0.017). On competing risks regression of patients with known covariates, both diffuse-type disease and disease larger than 5 cm (hazard ratio [HR] = 6.2 and 1.7, p = 0.013 and p = 0.042, respectively) were associated with increased risk of BCM. After matching, DCIS > 5 cm and diffuse disease were associated with increased BCM relative to disease

Objective:To compare the effect of comorbidities on the phenotype and outcomes of preeclampsia.Methods: A matched retrospective cohort study of women delivering at a tertiary maternity center following a diagnosis of preeclampsia. We collected data on signs and symptoms, biochemical markers, and maternal and perinatal outcomes.Results:We studied 474 women; 158 women with and 316 without comorbidities. Compared to women without comorbidities, women with comorbidities delivered earlier. They suffered fewer maternal but more neonatal complications.Conclusion: Women with comorbidities receive earlier intervention than women without comorbidities, which may lead to fewer maternal complications but worse neonatal outcomes.

Background Sentinel lymph node biopsy (SLNB) has been the standard of care for clinically node-negative women with invasive breast cancer (IBC); however, there is less agreement on whether to perform SLNB when the risk of metastasis is low or when it does not affect survival or locoregional control. Methods An Institutional Review Board-approved survey was sent to members of the American Society of Breast Surgeons asking in which scenarios surgeons would recommend SLNB. Descriptive statistics and multivariable analysis were performed using SPSS software. Results There was a 23% response rate; 68% identified as breast surgical oncologists, 6% as surgical oncologists, 24% as general surgeons, and 2% as other. The majority practiced in a community setting (71%) versus an academic setting (29%). In a healthy female with clinical T1N0 hormone receptor-positive (HR+) IBC, 83% favored SLNB if the patient was 75 years of age, versus 35% if the patient was 85 years of age. Academic surgeons were less likely to perform axillary staging in a healthy 75-year-old (odds ratio [OR] 0.51 [0.32–0.80], p = 0.004) or a healthy 85-year-old (OR 0.48 [0.31–0.74], p = 0.001). For DCIS, 32% endorsed SLNB in women undergoing lumpectomy, with breast surgical oncologists and academic surgeons being less likely to endorse this procedure (OR 0.54 [0.36–0.82], p = 0.028; and OR 0.53 [0.34–0.83], p = 0.005, respectively). Conclusions Despite studies showing that omitting SLNB in older patients with HR+ IBC does not impact regional control or survival, most surgeons are still opting for axillary staging. In addition, one in three are performing SLNB for lumpectomies for DCIS. Breast surgical oncologists and academic surgeons were more likely to be practicing based on recent data and guidelines. Practice patterns are changing but there is still room for improvement.

Summary Background Little evidence is available on the use of telehealth for antenatal care. In response to the COVID-19 pandemic, we developed and implemented a new antenatal care schedule integrating telehealth across all models of pregnancy care. To inform this clinical initiative, we aimed to assess the effectiveness and safety of telehealth in antenatal care. Methods We analysed routinely collected health data on all women giving birth at Monash Health, a large health service in Victoria (Australia), using an interrupted time-series design. We assessed the impact of telehealth integration into antenatal care from March 23, 2020, across low-risk and high-risk care models. Allowing a 1-month implementation period from March 23, 2020, we compared the first 3 months of telehealth integrated care delivered between April 20 and July 26, 2020, with conventional care delivered between Jan 1, 2018, and March 22, 2020. The primary outcomes were detection and outcomes of fetal growth restriction, pre-eclampsia, and gestational diabetes. Secondary outcomes were stillbirth, neonatal intensive care unit admission, and preterm birth (birth before 37 weeks' gestation). Findings Between Jan 1, 2018, and March 22, 2020, 20 031 women gave birth at Monash Health during the conventional care period and 2292 women gave birth during the telehealth integrated care period. Of 20 154 antenatal consultations provided in the integrated care period, 10 731 (53%) were delivered via telehealth. Overall, compared with the conventional care period, no significant differences were identified in the integrated care period with regard to the number of babies with fetal growth restriction (birthweight below the 3rd percentile; 2% in the integrated care period vs 2% in the conventional care period, p=0·72, for low-risk care models; 5% in the integrated care period vs 5% in the conventional care period, p=0·50 for high-risk care models), number of stillbirths (1% vs 1%, p=0·79; 2% vs 2%, p=0·70), or pregnancies complicated by pre-eclampsia (3% vs 3%, p=0·70; 9% vs 7%, p=0·15), or gestational diabetes (22% vs 22%, p=0·89; 30% vs 26%, p=0·06). Interrupted time-series analysis showed a significant reduction in preterm birth among women in high-risk models (–0·68% change in incidence per week [95% CI −1·37 to −0·002]; p=0·049), but no significant differences were identified in other outcome measures for low-risk or high-risk care models after telehealth integration compared with conventional care. Interpretation Telehealth integrated antenatal care enabled the reduction of in-person consultations by 50% without compromising pregnancy outcomes. This care model can help to minimise in-person interactions during the COVID-19 pandemic, but should also be considered in post-pandemic health-care models. Funding None.

Timely delivery of infants suspected of having fetal growth restriction (FGR) is a balance between preventing stillbirth and minimizing prematurity, particularly because many infants with suspected FGR have normal growth.To explore the association between iatrogenic delivery for suspected FGR and childhood school outcomes.A retrospective whole-population cohort study linking perinatal data from births 32 weeks' or more gestation between January 1, 2003, to December 31, 2013, to developmental and educational test scores at preparatory school, and at school grades 3, 5, and 7 in Victoria, Australia. Follow-up was concluded in 2019.Suspicion or nonsuspicion of FGR, presence or absence of iatrogenic delivery (defined as early induction of labor or cesarean delivery prior to labor) for suspected FGR, and presence or absence of small for gestational age (SGA).The coprimary outcomes were being in the bottom 10th percentile on 2 or more of 5 developmental domains at school entry and being below the national minimum standard on 2 or more of 5 educational domains in grades 3, 5, or 7.In the birth population of 705 937 infants, the mean gestation at birth was 39.1 (SD, 1.5) weeks and the mean birth weight was 3426 (SD, 517) grams. The birth population linked to 181 902 children with developmental results and 425 717 children with educational results. Compared with infants with severe SGA (birth weight3rd percentile) not suspected of having FGR, infants with severe SGA delivered for suspected FGR were born earlier (mean gestation, 37.9 weeks vs 39.4 weeks). They also had a significantly increased risk of poor developmental outcome at school entry (16.2% vs 12.7%; absolute difference, 3.5% [95% CI, 0.5%-6.5%]); adjusted odds ratio [aOR], 1.36 [95% CI, 1.07-1.74]) and poor educational outcomes in grades 3, 5, and 7 (for example, in grade 7: 13.4% vs 10.5%; absolute difference, 2.9% [95% CI, 0.4%-5.5%]); aOR, 1.33 [95% CI, 1.04-1.70]). There was no significant difference between infants with normal growth (birth weight ≥10th percentile) delivered for suspected FGR and those not suspected of having FGR in developmental outcome (8.6% vs 8.1%; absolute difference, 0.5% [95% CI, -1.1% to 2.0%]); aOR, 1.17 [95% CI, 0.95-1.45]) or educational outcome in grade 3, 5 or 7, despite being born earlier (mean gestation, 38.0 weeks vs 39.1 weeks).In this exploratory study conducted in Victoria, Australia, iatrogenic delivery of infants with severe SGA due to suspected FGR was associated with poorer school outcomes compared with infants with severe SGA not suspected of having FGR. Iatrogenic delivery of infants with normal growth due to suspected FGR was not associated with poorer school outcomes compared with infants with normal growth not suspected of having FGR.

OBJECTIVE To provide epidemiological information on animal and human cases of rabies occurring in the United States during 2019 and summaries of 2019 rabies surveillance for Canada and Mexico. ANIMALS All animals submitted for laboratory diagnosis of rabies in the United States during 2019. PROCEDURES State and territorial public health departments and USDA Wildlife Services provided data on animals submitted for rabies testing in the United States during 2019. Data were analyzed temporally and geographically to assess trends in domestic and wildlife rabies cases. RESULTS During 2019, 53 jurisdictions submitted 97,523 animal samples for rabies testing, of which 94,770 (97.2%) had a conclusive (positive or negative) test result. Of these, 4,690 tested positive for rabies, representing a 5.3% decrease from the 4,951 cases reported in 2018. Texas (n = 565 [12.0%]), New York (391 [8.3%]), Virginia (385 [8.2%]), North Carolina (315 [6.7%]), California (276 [5.9%]), and Maryland (269 [5.7%]) together accounted for almost half of all animal rabies cases reported in 2019. Of the total reported rabid animals, 4,305 (91.8%) were wildlife, with raccoons (n = 1,545 [32.9%]), bats (1,387 [29.6%]), skunks (915 [19.5%]), and foxes (361 [7.7%]) as the primary species confirmed with rabies. Rabid cats (n = 245 [5.2%]) and dogs (66 [1.4%]) accounted for > 80% of rabies cases involving domestic animals in 2019. No human rabies cases were reported in 2019. CONCLUSIONS AND CLINICAL RELEVANCE The overall number of animal rabies cases decreased from 2018 to 2019. Laboratory diagnosis of rabies in animals is critical to ensure that human rabies postexposure prophylaxis is administered judiciously.

Comorbid insomnia and sleep apnea (COMISA) are the most common co-occurring sleep disorders and present many challenges to clinicians. This review provides an overview of the clinical challenges in the management of patients with COMISA, with a focus on recent evidence regarding the evaluation and treatment of COMISA. Innovations in the assessment of COMISA have used profile analyses or dimensional approaches to examine symptom clusters or symptom severity that could be particularly useful in the assessment of COMISA. Recent randomized controlled trials have provided important evidence about the safety and effectiveness of a concomitant treatment approach to COMISA using cognitive-behavioral therapy for insomnia (CBT-I) with positive airway pressure (PAP). Furthermore, patient-centered considerations that integrate patient characteristics, treatment preferences, and accessibility to treatment in the context of COMISA are discussed as opportunities to improve patient care. Based on these recent advances and clinical perspectives, a model for using multidisciplinary, patient-centered care is recommended to optimize the clinical management of patients with COMISA.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) affects over 15% of Americans and results in an increased risk of skeletal fractures and fracture-related mortality. However, there remain great challenges in estimating fracture risk in CKD patients, as conventional metrics such as bone density assess bone quantity without accounting for the material quality of the bone tissue. The purpose of this review is to highlight the detrimental effects of advanced glycation end products (AGEs) on the structural and mechanical properties of bone, and to demonstrate the importance of including bone quality when assessing fracture risk in CKD patients. RECENT FINDINGS: Increased oxidative stress and inflammation drive the production of AGEs in CKD patients which form non-enzymatic crosslinks between type I collagen fibrils in the bone matrix. Non-enzymatic crosslinks stiffen and embrittle the bone, reducing its ability to absorb energy and resist fracture. Clinical measurement of AGEs is typically indirect and fails to distinguish the identity and properties of the various AGEs. SUMMARY: Accounting for the impact of AGEs on the skeleton in CKD patients may improve our estimation of overall bone quality, fracture risk, and treatments to improve both bone quantity and quality by reducing AGEs in patients with CKD merit investigation in order to improve our understanding of the etiology of increased fracture risk.

Background Increasing the detection of fetal growth restriction (FGR), while reducing stillbirth, also leads to unnecessary early intervention, and associated morbidity, for normally grown babies who are incorrectly suspected of FGR. Aims We sought to design a balance measure that addresses the specificity of FGR detection. Methods A retrospective cohort study on all singleton births ≥32 weeks gestation in 2016 and 2017 in Victoria. We compared two balance measures for the detection of FGR, defined as the proportion of all babies iatrogenically delivered before 39 weeks gestation for suspected FGR that had a birthweight ≥10th centile (balance measure 1) or ≥25th centile (balance measure 2). Hospital level performance on each balance measure was derived and compared to an existing performance measure for severe FGR detection in Victoria. Results Of the 38 hospitals analysed, 12 (32%) had a favourable performance on an existing indicator of FGR detection, seven (18%) hospitals had a favourable performance on balance measure 1, and 15 (39%) had a favourable performance on balance measure 2. There was a moderate correlation between hospital performance on the existing indicator and on balance measure 1 (r = 0.447, P = 0.005) but not balance measure 2 (r = -0.063, P = 0.71). There was no difference in perinatal mortality between high performing hospitals and low performing hospitals. Conclusion Introducing a balance measure into routine reporting may bring greater awareness to the unintended harm associated with increased detection of FGR.

Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/Tis ypN0). SGN-LIV1A is an investigational antibody drug conjugate consisting of an antibody to LIV1A, a zinc transporter highly prevalent in breast cancer, and a highly potent microtubule inhibitor, monomethyl auristatin E. Retrospective IHC analysis of LIV1A expression levels amongst tumor samples from 100 previous ISPY-2 patients showed 88% of breast tumor samples with moderate to high expression of LIV1A (Yau, C. et al SABCS 2018).Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone-receptor positive (HR+) patients had to have MP high molecular profile. Treatment included SGN-LIV1A 2.5 mg/kg (max dose 250 mg) every 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MR imaging where response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Analysis set was modified intention to treat with patients who switched to non-protocol therapy counted as non-pCR and not as their pCR status at time of surgery. The goal is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within signatures defined by HR & HER2 status & MP result. This investigational arm was eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Regimens may also leave the trial for futility (< 10% probability of success), maximum sample size accrual (10% < probability of success Results: Sixty patients were randomized and evaluable to SGN-LIV1A. The study arm was stopped due to reaching the predetermined time limit for patient accrual of 2 yrs. Final estimated pCR rates are below. The estimated pCR rates were similar between the SGN-LIV1A and control arms for any tumor subtype. Preliminary safety events for SGN-LIV1A include increased rates of transaminitis and hyperglycemia and reduced rates of peripheral neuropathy compared to control. One patient was removed from the analysis as she was determined to have angiosarcoma of the breast. Notably, this patient had a dramatic early response and subsequent pCR to SGN-LIV1A treatment. Conclusion: The value of I-SPY 2 is to give insight about the performance of an investigational agent’s likelihood of achieving pCR. SGN-LIV1A delivered every 3 weeks was comparable to paclitaxel for the primary endpoint of pCR in I-SPY2 and may have a similar side effect profile, however, with less peripheral neuropathy. Clinical trials evaluating weekly dosing of SGN-LIV1A are ongoing. A trial of SGN-LIV1A in the treatment of angiosarcoma is under consideration at this time. Final Estimated pCR Rates and Predictive ProbabilitiesEstimated pCR rate(95% prob interval)SignatureSGN-LIV1AControlProbability SGNLIV1A Superior to ControlPredictive Probability of Success in Phase 3HER2-0.16 (0.08-0.24) N= 600.20 (0.16-0.25) N= 3270.180.02HR-/HER2-0.25 (0.12-0.37) N=360.28 (0.21-0.35) N=1460.310.06HR+/HER2-0.09 (0-0.18) N=240.14 (0.09-0.19) N=1810.150.03 Citation Format: Heather Beckwith, Richard Schwab, Christina Yau, Erica Stringer-Reasor, Shi Wei, A. Jo Chien, Kathy S Albain, Kevin Kalinsky, Anne Wallace, Anthony Elias, Douglas Yee, Amy S Clark, Judy C Boughey, Heather Han, Rita Nanda, Claudine Isaacs, Zahi Mitri, Julie E Lang, Alexandra Thomas, Tara Sanft, Angela DeMichele, Jane Perlmutter, Hope S Rugo, Nola M Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, I-SPY 2 Consortium, Amy Wilson, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-10.

Background: Disseminated tumor cells (DTCs) in bone marrow detected after treatment may represent occult residual disease. We enumerated DTCs after neoadjuvant chemotherapy (NACT) in patients (pts) diagnosed with high-risk early stage breast cancer and examined the relationship of these cells with response and survival. Methods: I-SPY SURMOUNT is a sub-study of the I-SPY 2 TRIAL (NCT01042379). Pts enrolled on I-SPY 2, who signed consent for this sub-study, had bone marrow aspirates (BMA) collected after NACT at the time of surgery. DTCs were isolated and enumerated from BMA using immunomagnetic enrichment/flow cytometry (IE/FC). DTCs were defined as EPCAM-positive and CD45-negative nucleated cells. Samples were considered positive using a predetermined threshold of >4 DTCs per mL (Magbanua et al, unpublished data). Pathologic response was assessed using the residual cancer burden (RCB) method at local sites, and pts underwent standard adjuvant therapy if indicated and follow up for recurrence events and death. Relationship of DTCs with clinicopathologic variables was examined using Chi-squared test. Group means were compared using t tests. The log-rank test was used to compare survival curves. Results: A total of 73 patients were enrolled, 51 of whom had successful DTC assessment. The median DTC per mL was 4 (interquartile range 1.2-11.6). 24/51 (47%) were DTC-positive. Clinical characteristics by DTC status are shown in the table. DTC-positive pts were significantly younger (p=0.02) and had larger pretreatment tumors (longest diameter by magnetic resonance imaging) compared to DTC-negative pts (p=0.032). DTCs were not associated with receptor subtype. Thirty pts (41%) achieved a pathologic complete response (pCR). DTCs were not associated with pCR (p= 0.166); however, DTC-positive patients were significantly more likely to have residual cancer (RCB-II/III) after NACT compared to DTC-negative patients (OR 3.3, p=0.037). Median follow up of this cohort was 2.8 years (range: 0.9-4.8). Interim survival analysis showed that DTCs were not significantly correlated with EFS (p=0.6) or DRFS (p=0.41). Conclusions: Detection of DTCs at surgery after NACT is significantly more common in young patients, those with larger tumors, and those with residual disease at surgery. While these associations suggest higher risk for later recurrence, larger studies and longer follow up are necessary to determine if DTCs add prognostic value over pathologic evaluation alone for pts receiving NACT. Citation Format: Mark Jesus M Magbanua, Laura van 't Veer, Amy Clark, A. Jo Chien, Judy Boughey, Heather Han, Anne Wallace, Heather Beckwith, Minetta Liu, Christina Yau, E. Paul Wileyto, Lamorna Brown Swigart, Jane Perlmutter, Lauren Bayne, Shannon Deluca, Stephanie Yee, Erica Carpenter, Laura Esserman, John Park, Lewis Chodosh, Angela DeMichele. Outcomes associated with disseminated tumor cells at surgery after neoadjuvant chemotherapy in high-risk early stage breast cancer: The I-SPY SURMOUNT study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-07.

Introduction Preterm birth is a major cause of perinatal morbidity and mortality worldwide. In many countries preterm birth rates are increasing, largely as a result of increases in iatrogenic preterm birth, whereas in other countries rates are stable or even declining. The objective of the study is to describe trends in singleton preterm births in Victoria from 2007 to 2017 in relation to trends in perinatal mortality to identify opportunities for improvements in clinical care. Material and methods We conducted a consecutive cross‐sectional study in all women with a singleton pregnancy giving birth at ≥20 weeks of pregnancy in Victoria, Australia, between 2007 and 2017, inclusive. Rates of preterm birth and perinatal mortality were calculated and trends were analyzed in all pregnancies, in pregnancies complicated by fetal growth problems, hypertension, (pre)eclampsia or prelabor rupture of membranes (PROM), and in (low‐risk) pregnancies not complicated by any of these conditions. Results There were 811 534 singleton births between 2007 and 2017. Preterm birth increased from 5.9% (4074 births) to 6.4% (4893 births; P

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Graphical abstract, Highlights • The COVID-19 pandemic has challenged the healthcare capacity of many countries. • Strict, horizontal lockdowns have adverse social, economic and health effects that have not been fully considered. • Primary and community care have multiple roles in COVID-19 pandemic mitigation. • Greece is a case example of a country which neglected primary and community care, and in November 2020 implemented a second horizontal lockdown. • Primary and community care, represents the only realistic strategy for successful COVID-19 pandemic mitigation in the long-term., COVID-19 pandemic mitigation strategies are mainly based on social distancing measures and healthcare system reinforcement. However, many countries in Europe and elsewhere implemented strict, horizontal lockdowns because of extensive viral spread in the community which challenges the capacity of the healthcare systems. However, strict lockdowns have various untintended adverse social, economic and health effects, which have yet to be fully elucidated, and have not been considered in models examining the effects of various mitigation measures. Unlike commonly suggested, the dilemma is not about health vs wealth because the economic devastation of long-lasting lockdowns will definitely have adverse health effects in the population. Furthermore, they cannot provide a lasting solution in pandemic containment, potentially resulting in a vicious cycle of consecutive lockdowns with in-between breaks. Hospital preparedness has been the main strategy used by governments. However, a major characteristic of the COVID-19 pandemic is the rapid viral transmission in populations with no immunity. Thus, even the best hospital system could not cope with the demand. Primary, community and home care are the only viable strategies that could achieve the goal of pandemic mitigation. We present the case example of Greece, a country which followed a strategy focused on hospital preparedness but failed to reinforce primary and community care. This, along with strategic mistakes in epidemiological surveillance, resulted in Greece implementing a second strict, horizontal lockdown and having one of the highest COVID-19 death rates in Europe during the second wave. We provide recommendations for measures that will reinstate primary and community care at the forefront in managing the current public health crisis by protecting hospitals from unnecessary admissions, providing primary and secondary prevention services in relation to COVID-19 and maintaining population health through treatment of non−COVID-19 conditions. This, together with more selective social distancing measures (instead of horizontal lockdowns), represents the only viable and realistic long-term strategy for COVID-19 pandemic mitigation.

Primary cutaneous anaplastic large-cell lymphoma and breast implant-associated ALCL (BIA-ALCL) are rare subtypes of anaplastic lymphoma kinase (ALK)-negative ALCLs originating from skin and breast implants, respectively. Herein, we report a unique case of cutaneous ALK-negative ALCL occurring in the skin of left medial breast from a patient with multiple rounds of bilateral breast implants and a history of breast carcinoma. The lymphoma cells are entirely confined to the lymphatic channels in the dermis, and the patient has no other areas of skin abnormality, no lymphadenopathy, peri-implant fluid accumulation, or masses from the bilateral capsules of implants. The differential diagnosis and its relationship with breast implants are further explored.

AIM: Timely delivery of fetal growth restriction (FGR) is a balance between avoiding stillbirth and minimising prematurity. We sought to assess the neonatal outcomes for babies suspected of FGR, both true and false positives. METHODS: This population cohort study examined all singleton births in Victoria, Australia from 2000 to 2017 (n = 1 231 415). Neonatal morbidities associated with neonatal intensive care unit (NICU) admission were assessed for babies born ≥32 weeks' with severe FGR (

PURPOSE: To use the National Cancer Database to assess treatment patterns in very young women with ductal carcinoma in situ (DCIS) given their propensity for higher risk features and increased risk of recurrence. METHODS: We used the NCDB to identify female patients who underwent surgery for a first cancer diagnosis of DCIS within three different age groups: ≤30, 31–50, and >50. Demographic information, tumor characteristics, and initial treatment patterns were characterized and compared. Univariable and multivariable logistic regression of individuals with hormone-receptor positive disease who underwent breast conserving surgery (BCS) was conducted to assess for group differences in adjuvant endocrine therapy utilization. Survival analysis was conducted via Kaplan-Meier method and Cox Regression. RESULTS: We identified 236,832 patients meeting inclusion criteria. Individuals in the youngest group were more likely to be a minority, had better Charlson-Deyo scores, lived further from their treatment facility, and were less often insured. This group also had more unfavorable tumor features and were more likely to undergo bilateral mastectomy. In subgroup analysis of patients with hormone-receptor positive disease who underwent BCS, the youngest group was significantly less likely to have received endocrine therapy. There was also a trend towards worse overall survival in the youngest group. CONCLUSION: We report differences in demographics, tumor characteristics, and treatment of very young women with DCIS. Given the known reduction in recurrence with use of adjuvant endocrine therapy, there may be room for increasing therapy rates or otherwise altering guidelines for treatment of young women with hormone-receptor positive DCIS who undergo BCS.

Introduction The widespread maternal endothelial dysfunction that underlies the manifestations of preeclampsia is thought to arise from excessive placental production of antiangiogenic factors and enhanced oxidative stress. Therefore, we assessed whether the natural antioxidant sulforaphane could improve vascular function. Methods Cell viability of human umbilical vein endothelial cells (HUVECs) was assessed after 24 or 48 h in normoxia (20% O2) or hypoxia (1% O2) with or without sulforaphane. To model vascular dysfunction associated with preeclampsia, mouse mesenteric arteries were incubated in trophoblast conditioned media (TCM), and human omental arteries incubated in preeclamptic explant media (PEM) with or without sulforaphane. Both media are rich in antiangiogenic compounds associated with preeclampsia. TCM was generated from primary cytotrophoblast cells from term placentae of normotensive, while PEM was generated from explants from preeclamptic women. Reactivity was assessed by wire myography. sulforaphane's actions as a vasodilator were also investigated. Results Under conditions of hypoxia, sulforaphane improved HUVEC viability. In mouse mesenteric arteries, sulforaphane reduced contraction evoked by potassium (p Discussion Sulforaphane causes relaxation in arteries and protects against arterial dysfunction induced by placental-derived antiangiogenic factors, which are known to contribute to the preeclampsia.

Although canine rabies virus variant (CRVV) was successfully eliminated from the United States after approximately 6 decades of vaccination campaigns, licensing requirements, and stray animal control, dogs remain the principal source of human rabies infections worldwide. A rabies vaccination certificate is required for dogs entering the United States from approximately 100 countries with endemic CRVV, including Egypt (1). On February 25, 2019, rabies was diagnosed in a dog imported from Egypt, representing the third canine rabies case imported from Egypt in 4 years (2,3). This dog and 25 others were imported by a pet rescue organization in the Kansas City metropolitan area on January 29. Upon entry into the United States, all 26 dogs had certificates of veterinary inspection, rabies vaccination certificates, and documentation of serologic conversion from a government-affiliated rabies laboratory in Egypt. CDC confirmed that the dog was infected with a CRVV that circulates in Egypt, underscoring the continued risk for CRVV reintroduction and concern regarding the legitimacy of vaccine documentation of dogs imported from countries considered at high risk for CRVV. Vaccination documentation of dogs imported from these countries should be critically evaluated before entry into the United States is permitted, and public health should be consulted upon suspicion of questionable documents.

The impact of HER2 status in ductal carcinoma in situ (DCIS) on the risk of progression to invasive ductal carcinoma (IDC) has been debated. We aim to use a national database to identify patients with known HER2 status to elucidate the effect of HER2 overexpression on ipsilateral IDC (iIDC) development. We performed survival analysis on patient-level data using the U.S. NCI's Surveillance Epidemiology and End Results program. We identified patients diagnosed with DCIS who underwent lumpectomy and had known HER2 status. Competing risks analysis was performed. A total of 1,540 patients had known HER2 status and met inclusion criteria. Median age at diagnosis was 60, median follow-up time was 44.5 months. A total of 417 (27.1%) patients were HER2 positive and 1,035 (67.2%) were HER2 negative. Twenty-two (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% for HER2-negative and borderline patients, and 3.9% for HER2-positive patients. On multivariate competing risks regression, two factors were significant for iIDC: radiation (protective) therapy within 24 months (HR, 0.05; P = 0.00006) and HER2 overexpression (increased likelihood; HR, 2.72; P = 0.044). Patients with HER2-positive DCIS were more likely to have recurrences with receptor discordance. HER2 may serve as a prognostic factor for invasive recurrence and was the only lesion-related factor to significantly relate to iIDC development. It may also be associated with receptor discordance of recurrences. Further large studies will be needed to confirm these results.

Magnetic resonance imaging (MRI) is used for preoperative evaluation, high-risk screening, and other select indications for breast cancer. However, the interpretation of breast MR images in pregnant and lactating women is complicated by physiologic changes of the breast that may result in marked background enhancement. Breast MRI with contrast administration is contraindicated in pregnancy. Restriction spectrum imaging (RSI) is an advanced diffusion-weighted (DW)-MRI method that theoretically reflects signal from cells with high nuclear-to-cytoplasm ratio without gadolinium-based contrast. This report describes a case in which RSI notably increased tumor conspicuity in a lactating woman, compared to contrast-enhanced (CE)-MRI and conventional DW-MRI.

Background Clinical trial transparency is important for scientific research and for the good of the general public. Diversity of study samples by race/ethnicity, gender, and age is important to ensure that results are generalizable. Moreover, reporting results might also be necessary to engage racial/ethnic minorities in clinical research. The primary objective of this study was to describe the results of clinical studies conducted for obstructive sleep apnea (OSA) and insomnia, two of the most prevalent sleep disorders. The secondary objective was to identify which factors were associated with voluntarily reporting the results. Methods We reviewed ClinicalTrials.gov , the public database of biomedical and behavioral research operated by the United States (U.S.) National Library of Medicine at the National Institutes of Health to ascertain the reports of demographic variables, including race/ethnicity of the studies conducted for OSA and insomnia. Since reporting race/ethnicity was an optional data feature, we searched for publications in PubMed using the unique national clinical trial identification number (NCTID). The national clinical trial identification number is assigned as soon as the trial is registered. The article extraction was conducted by graduate students and supervised by N.J.W. Results We identified 427 studies on OSA and 404 studies on insomnia. Results were reported for 122 studies. Based on the 122 studies with results that included studies that were terminated (n = 16) and/or completed (n = 105), and one study was listed as “active” but not recruiting. 46.7% studies involved drugs, 30.3% studied a medical device, and 8.2% investigated behavioral interventions. The age range of subjects was 2–99 years of age and 16.4% included an age range of 35-50 years. Twenty-nine studies (23.8%) reported race/ethnicity in ClinicalTrials.gov . Of these, 74% of subjects were white (n = 2,953); 20% black (n = 822); 1% Asian American (n = 40); 2% Hispanic/Latino (n = 77); and 3% of study subjects identified race/ethnicity as “other” (n = 118). With the PubMed search, we found an additional 24 studies that reported race/ethnicity. There was no difference in reports of race/ethnicity between studies for insomnia and studies for OSA. The intervention type labeled as “behavioral” was a significant predictor (odds ratio: 12.49, P-value ≤ .05, confidence interval: 1.002-155.62) for reporting results. Conclusion The National Institutes of Health has mandated federally funded research include women and minorities and that they are representative of the U.S. population. Though gender was reported, few investigators and study sponsors reported the results of race/ethnicity, which begs the question about trial transparency for the future of sleep research. Presumably, the lack of reporting is related to low enrollment of ethnic/minorities included in these studies. Nonetheless, our key finding warrants increased attention to minority participation in sleep clinical studies and trial transparency.

On November 7, 2018, the Utah Department of Health (UDOH) reported the first confirmed human rabies death in the state since 1944 (1). The case occurred in a person who had been treated over a period of 19 days at four health care facilities and an emergency medical transport service across three counties and two states. Human rabies is preventable through preexposure or postexposure vaccination but is invariably fatal upon symptom onset. Timely identification of persons who might have been exposed to rabies virus is therefore crucial to administer postexposure prophylaxis (PEP). Because of the large number of health care workers who had been involved in the patient's care, a standardized online risk assessment survey was developed by UDOH based on Advisory Committee on Immunization Practices recommendations (2). This online tool was evaluated for accuracy, acceptability, and administrative obligation by reviewing the results from the tool and conducting focus group discussions and a follow-up survey. Among 90 health care workers initially identified by the online risk assessment as being potentially exposed to infectious material, 74 were classified as exposed. All 74 health care workers received PEP following consultation with occupational health staff members, indicating a positive predictive value of the assessment tool of 82%. In a follow-up survey, 42 (76%) of the 55 respondents reported that they were satisfied with the assessment process. In focus group discussions, participants suggested that the survey could be improved by providing additional information about rabies exposures because many of them were unfamiliar with human-to-human rabies transmission. This evaluation highlighted the importance of adopting clear communication strategies, demonstrated the benefits of using an online risk assessment during a mass rabies exposure, and provided specific feedback for CDC to improve resources available for states and health care facilities after mass rabies exposures.

Telepsychotherapy (also referred to as telehealth or telemental health), the use of videoconferencing to deliver psychotherapy services, offers an innovative way to address significant gaps in access to care and is being used to deliver a variety of treatments for youth. Although recent research has supported the effectiveness of telehealth delivery of a variety of interventions for children, the literature has focused very little on childhood posttraumatic stress disorder. This pilot study examined the feasibility and potential effectiveness of trauma-focused cognitive- behavioral therapy (TF-CBT) delivered via telepsychotherapy in community-based locations of either schools or patient homes. Telepsychotherapy treatment was delivered to 70 traumaexposed youth in 7 underserved communities. Of these, 88.6% completed a full course of TF-CBT and 96.8% of these treatment completers no longer met diagnostic criteria for a trauma-related disorder at posttreatment. Results demonstrated clinically meaningful symptom change posttreatment, with large effect sizes evident for both youthand caregiver-reported reduction in posttraumatic stress disorder symptoms. The results observed in this pilot evaluation are promising and provide preliminary evidence of the feasibility and effectiveness of this novel treatment format. The COVID-19 global pandemic has resulted in an unprecedented need to rethink how mental health services are delivered, which is particularly applicable to high base rate conditions related to posttraumatic stress. Given the existing network of nationally certified TF-CBT therapists, and many international TF-CBT therapists, these findings suggest the potential for providing effective and accessible telepsychotherapy intervention during this public health crisis (as well as those that will occur in the future).

Objective An estimated two billion people worldwide live with hepatitis B virus (HBV) infection. Many of these are women of reproductive age. Studies that have examined pregnancy outcomes in women living with HBV have reported conflicting results in relation to the incidence of gestational diabetes (GDM). The aim of this study is to examine if gestational diabetes is more common in women with chronic HBV residing in a non-Asian country. Design Cross-sectional study. Setting Victoria, Australia. Population All singleton births between 2009 and 2017. Methods Poisson regression was performed to determine whether gestational diabetes is more common in women with HBV than in women without HBV taking into account other risk factors such as maternal age, body mass index (BMI), parity and country of birth. Main outcome measure Gestational diabetes diagnosis in women with chronic HBV infection. Results For women with HBV, the unadjusted incidence risk ratio for GDM was 1.75 (95% CI 1.6-1.9). After adjusting for region of birth, BMI, parity, age and smoking, the adjusted incidence risk ratio was 1.2 (95% CI 1.1-1.3). The highest incidence (37.1%) of GDM was in women with HBV and a BMI of >40. Conclusions The findings from this study confirm an association between HBV and GDM. Tweetable abstract HBV is associated with GDM with an incidence risk ratio for GDM of 1.75 (95% CI 1.6-1.9).

Background: Patients who achieve a pathological complete response (pCR- defined as no invasive cancer) after neoadjuvant chemotherapy (NAC) for breast cancer (BC) have improved outcomes, but there is still controversy about the significance of residual ductal carcinoma in situ (DCIS) on local recurrence rate (LRR). The I-SPY 2 TRIAL is an adaptive neoadjuvant platform trial evaluating novel experimental regimens in comparison to standard chemotherapy in women with high-risk breast cancer. The purpose of this study is to determine if residual DCIS after NAC in early BC affects LRR in patients with or without residual invasive disease in the I-SPY 2 TRIAL. Methods: 933 I-SPY 2 patients with residual cancer burden (RCB) and follow-up data were included in this analysis. Residual DCIS was defined as any carcinoma in situ > 0% on RCB evaluation. Local recurrence was defined as recurrence in breast, chest wall or locoregional nodes and/or skin and subcutaneous tissue. We stratified our cohort into four groups: those without residual invasive disease (defined as RCB0) ± residual DCIS, and those with residual invasive disease (RCB>0) ± residual DCIS. We estimated LRR within each group using the Kaplan Meier method; and used Cox proportional hazards models to assess LRR differences between groups, with: patients with no residual disease (invasive or in situ) as reference group. Results: Among 933 patients assessed, median follow up time was 3.9 years. RCB 0 status was achieved in 337 patients (36%). Of these, 267 (29%) had no residual DCIS, which represents our reference group, and 70 (7%) had residual DCIS. Among 596 (64%) patients who had RCB>0, 296 (32%) had residual DCIS. For patients with RCB0 without DCIS and RCB0 with DCIS, the LRR at 3 years were similar: 2% vs 3% respectively (Hazard ratio: 1.29 [0.26-6.39]). Results were also similar in the RCB>0 group, with a LRR of 10% at 3 years in those without residual DCIS, and 11% in those with residual DCIS. Both RCB>0 groups had significantly higher LRR when compared to the patients with RCB0 without DCIS (Hazard ratio: 5.25 [2.20-12.5]) and HR 5.85 [2.47-13.9] respectively). Conclusion: There was no association between residual DCIS and LRR after neoadjuvant chemotherapy, regardless of resolution of invasive disease. Further work is needed to determine whether residual DCIS should drive locoregional therapy decisions after neoadjuvant chemotherapy for invasive breast cancer. Citation Format: Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Smita M. Asare, Ron Balassanian, Jodi M. Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Gretchen Ahrendt, Akiko Chiba, Cheryl Ewing, Constantine Godellas, Nora Jaskowiak, Brigid Killelea, Helen Krontiras, Rachael Lancaster, Julie Lang, M. Catherine Lee, Arpana Naik, Roshni Rao, Julia Tchou, Shannon Tierney, Eleni Tousimis, Tod Tuttle, Anne Wallace, I-SPY 2 TRIAL Consortium, Bev Parker, Laura J. Esserman, Rita A. Mukhtar. The impact of residual ductal carcinoma in situ on breast cancer recurrence in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-16.

Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-02.

Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify (graduate) regimens with ≥ 85% Bayesian predictive probability of success (i.e., demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with pCR endpoint within signatures defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status. Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or safety concerns as recommended by the independent DSMB. For HER2+ patients, the I-SPY2 control arm was 12 weekly cycles of paclitaxel+trastuzumab (TH, control) followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x4 and surgery. Patritumab is a fully human monoclonal antibody that inhibits HER3. In this experimental arm for HER2+ patients, patritumab was given q3w x 4 cycles (18mg/kg loading dose followed by 9mg/kg/dose) concurrent with paclitaxel and trastuzumab q1w x 12 weeks (PTH, treatment), followed by AC q2-3w. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 weeks after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Analysis was intention to treat. Patients who switched to non-protocol therapy count as non-pCR. Patients on treatment arm therapy at the time of arm closure are non-evaluable. Graduation potential was in 3 of 10 pre-defined signatures: all HER2+, HR-/HER2+, and HR+/HER2+. Results: The PTH regimen was stopped at the recommendation of the Safety Working Group and DSMB based on a safety event (bilateral sensorineural hearing loss, Gr 3) observed in one patient. At the time of arm closure, N=31 patients had received PTH treatment; 4 patients receiving PTH were changed to non-protocol therapy and removed from the analysis. The final estimated pCR report will consider 27 PTH and 31 TH as evaluable patients. Accrual was insufficient to assess graduation, however, there appears to be good signal in the HER2+HR- but not HER2+HR+ signatures. I-SPY 2 TRIAL Est. pCR at time of arm closureSignaturesPTH (Treatment)N= 31TH (Control)N = 31All (HER2+)0.40 (0.22 - 0.59), n=310.23 (0.09 - 0.37), n=31HR-/HER2+0.64 (0.36 - 0.91), n=110.30 (0.12 - 0.47), n=12HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19 HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19The patient who developed Gr3 sensorineural hearing loss 6 days after the 2nd patritumab (and 4th paclitaxel/trastuzumab) treatment, did not recover her hearing after patritumab was stopped, and also reported Gr3 vulvovaginal pain, vulvitis, and vaginal inflammation. Other gynecological symptoms in the PTH arm include: 1 pt with Gr1 vaginal hemorrhage, and 1 pt with Gr2 dyspareunia. There was a higher frequency of Gr3 hypokalaemia (12.5% vs. 3.2%). One pt in the PTH arm reported Gr3 small intestinal obstruction which resolved with conservative management. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial; PTH was stopped due to safety concerns, although there was activity in the HER2+ HR- signature. This is the first report of Gr3 hearing loss associated with patritumab/paclitaxel/trastuzumab, and thus attribution is uncertain. Citation Format: Teresa L Helsten, Shelly S Lo, Christina Yau, Kevin Kalinsky, Anthony D Elias, Anne M Wallace, A. Jo Chien, Janice Lu, Julie E Lang, Kathy S Albain, Erica Stringer-Reasor, Amy S Clark, Judy C Boughey, Erin D Ellis, Douglas Yee, Angela DeMichele, Claudine Isaacs, Jane Perlmutter, Hope S Rugo, Richard Schwab, Nola M. Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, Amy Wilson, Ruby Singhrao, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of patritumab/paclitaxel/trastuzumab over standard paclitaxel/trastuzumab in early stage, high-risk HER2 positive breast cancer: Results from the neoadjuvant I-SPY 2 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-02.

Background: I-SPY2 is a multicenter, response-adaptive randomization phase 2 trial to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - weekly paclitaxel + investigational treatment x 12 wks followed by doxorubicin & cyclophosphamide(AC) q3 wks x 4 vs. weekly paclitaxel/AC (control). The primary endpoint is pathologic complete response (pCR). The goal for all investigational arms is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with a pCR endpoint within signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Findings from the graduated, previously reported Pembro4 arm (Nanda et al, ASCO 2017) supported investigation of de-escalating therapy, and determining if pembrolizumab (an anti-PD-1 antibody) alone q3 wks x 4 after weekly paclitaxel x 12 wks + pembrolizumab q3 wks x 4 was sufficient to sustain response without AC. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ were ineligible. MRI scans (at baseline, 3 wks, 12 wks, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients (pts). Pts who receive non-protocol therapy (e.g., carboplatin or AC for the Pembro8-noAC arm) count as non-pCR. Pembro8-noAC was open to HER2- pts for evaluation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2-, and HR-/HER2-. Regimens exit the trial for futility ( Results: Pembro8-noAC was randomized to 73 pts, 3 of whom progressed while receiving pembrolizumab alone on study. Randomization to this arm continued after the first report because the rate of progression during AC over the course of the trial was estimated to be 6.5% based on serial MRI studies. However, notification of the third case prompted the study team to ask the DSMB for the summary response for this arm. Although it did not meet formal stopping rules for either graduation or futility, Pembro8-noAC was not near the target threshold pCR rates of 60% for HR-/HER2- and 30% for HR+/HER2+. As a result of this information, combined with the on-treatment progressions, assignment to Pembro8-noAC was discontinued. Treatment with pembrolizumab alone was no longer allowed due to the potential concern for progression, and investigators were given the option to administer AC with pembrolizumab or proceed with definitive surgery following the 12 weeks of paclitaxel + pembrolizumab. 34 pts had surgery results at the time the study was closed. Of the remaining 39 pts, 34 pts have on-therapy MRI assessments. Estimated pCR rates were based on all pts with information at the time (see table). Immune-related adverse events included grade 3 colitis (n=2), grade 3 pneumonitis (n=1), grade 3 transaminitis (n=1), grade 3 hypothyroidism (n=1), and grade 1-2 adrenal insufficiency (n=5). Conclusion: Although Pembro8-noAC is performing at least as well as standard paclitaxel/AC, the likelihood is very low that the regimen would be successful in a phase 3 trial. Pembrolizumab alone following 12 weeks of paclitaxel + pembrolizumab was not sufficient to sustain a response. This was quickly assessed with a small number of patients. Estimated pCR rateSignature(95% prob interval)Pembro8-noACControlHER2-0.210.2(0.09-0.32)(0.15-0.25)HR-/HER2-0.270.27(0.09-0.45)(0.19-0.35)HR+/HER2-0.150.15(0.01-0.29)(0.09-0.20) Citation Format: Minetta C. Liu, Patricia A Robinson, Christina Yau, Anne M Wallace, A. Jo Chien, Erica Stringer-Reasor, Rita Nanda, Douglas Yee, Kathy S Albain, Judy C Boughey, Heather S Han, Anthony D Elias, Kevin Kalinsky, Amy S Clark, Kathleen Kemmer, Claudine Isaacs, Julie E Lang, Janice Lu, Tara Sanft, Angela DeMichele, Nola M Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Patricia K Haugen, Amy Wilson, Ruby Singhrao, Smita Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of a novel agent plus standard neoadjuvant therapy in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-02.

Background Insomnia is one of the most common nonmotor features of Parkinson's disease (PD). However, there are few practical guidelines for providers on how to best evaluate and treat this problem. Methods and Findings This review was developed to provide clinicians with a pragmatic approach to assessing and managing insomnia in PD. Recommendations were based on literature review and expert opinion. We addressed the following topics in this review: prevalence of insomnia in PD, sleep–wake mechanisms, theoretical models of insomnia, risk factors, assessment, pharmacologic and nonpharmacologic treatments. Insomnia treatment choices may be guided by PD severity, comorbidities, and patient preference. However, there is limited evidence supporting pharmacotherapy and nonpharmacologic treatments of insomnia in PD. Conclusions We provide a pragmatic algorithm for evaluating and treating insomnia in PD based on the literature and our clinical experience. We propose personalized insomnia treatment approaches based on age and other issues. Gaps in the existing literature and future directions in the treatment of insomnia in PD are also highlighted.

CDC, the Food and Drug Administration (FDA), state and local health departments, and public health and clinical stakeholders continue to investigate a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) (1). EVALI patients in Illinois, Utah, and Wisconsin acquired tetrahydrocannabinol (THC)-containing products primarily from informal sources (2,3). This report updates demographic characteristics and self-reported sources of THC- and nicotine-containing e-cigarette, or vaping, products derived from EVALI patient data reported to CDC by state health departments. As of January 7, 2020, among 1,979 (76%) patients with available data on substance use, a total of 1,620 (82%) reported using any THC-containing products, including 665 (34%) who reported exclusive THC-containing product use. Use of any nicotine-containing products was reported by 1,128 (57%) patients, including 264 (13%) who reported exclusive nicotine-containing product use. Among 809 (50%) patients reporting data on the source of THC-containing products, 131 (16%) reported acquiring their products from only commercial sources (i.e., recreational dispensaries, medical dispensaries, or both; vape or smoke shops; stores; and pop-up shops), 627 (78%) from only informal sources (i.e., friends, family, in-person or online dealers, or other sources), and 51 (6%) from both types of sources. Among 613 (54%) EVALI patients reporting nicotine-containing product use with available data on product source, 421 (69%) reported acquiring their products from only commercial sources, 103 (17%) from only informal sources, and 89 (15%) from both types of sources. Adolescents aged 13-17 years were more likely to acquire both THC- and nicotine-containing products from informal sources than were persons in older age groups. The high prevalence of acquisition of THC-containing products from informal sources by EVALI patients reinforces CDC's recommendation to not use e-cigarette, or vaping, products that contain THC, especially those acquired from informal sources. Although acquisition of nicotine-containing products through informal sources was not common overall, it was common among persons aged

To investigate whether earlier “post-term” monitoring of South Asian (SA) pregnancies from 39 weeks’ gestation with amniotic fluid index (AFI) and cardiotocography (CTG) detected suspected fetal compromise. Retrospective cohort study of all SA-born women at an Australian health service with uncomplicated, singleton pregnancies following the introduction of twice-weekly AFI and CTG monitoring from 39 weeks. Monitoring results, and their association with a perinatal compromise composite (including assisted delivery for fetal compromise, stillbirth, and NICU admission) were determined. 771 SA-born women had earlier monitoring, triggering delivery in 82 (10.6%). 31 (4%) had a non-reassuring antepartum CTG (abnormal fetal heart rate or variability, or decelerations) and 21 (2.7%) had an abnormal AFI (≤ 5 cm). Women with abnormal monitoring were 53% (95% CI 1.2–1.9) more likely to experience perinatal compromise and 83% (95% CI 1.2–2.9) more likely to experience intrapartum compromise than women with normal monitoring. Monitoring from 39 weeks identified possible fetal compromise earlier than it otherwise would have been, and triggered intervention in 10% of women. Without robust evidence to guide timing of birth in SA-born women to reduce rates of stillbirth, earlier monitoring provides an alternative to routine induction of labour.

Background: Robust dog vaccination coverage is the primary way to eliminate canine rabies. Haiti conducts annual canine mass vaccination campaigns, but still has the most human deaths in the Latin American and Caribbean region. We conducted an evaluation of dog vaccination methods in Haiti to determine if more intensive, data-driven vaccination methods, using smartphones for data reporting and geo-communication, could increase vaccination coverage to a level capable of disrupting rabies virus transmission.Methods: Two cities were designated into “Traditional” and “Technology-aided” vaccination areas. Traditional areas utilized historical methods of vaccination staff management, whereas Technology-aided areas used smartphone-supported spatial coordination and management of vaccination teams. Smartphones enabled real time two-way geo-communication between campaign managers and vaccinators. Campaign managers provided geographic instruction to vaccinators by assigning mapped daily vaccination boundaries displayed on phone handsets, whilst vaccinators uploaded spatial data of dogs vaccinated for review by the campaign manager to inform assignment of subsequent vaccination zones. The methods were evaluated for vaccination effort, coverage, and cost.Results: A total of 11,420 dogs were vaccinated during the 14-day campaign. The technology-aided approach achieved 80% estimated vaccination coverage as compared to 44% in traditional areas. Daily vaccination rate was higher in Traditional areas (41.7 vaccinations per team-day) compared to in technology-aided areas (26.8) but resulted in significantly lower vaccination coverages. The cost per dog vaccinated increased exponentially with the associated vaccination coverage, with a cost of $1.86 to achieve 25%, $2.51 for 50% coverage, and $3.19 for 70% coverage.Conclusions: Traditional vaccination methods failed to achieve sufficiently high vaccination coverages needed to interrupt sustained rabies virus transmission, whilst the technology-aided approach increased coverage above this critical threshold. Over successive campaigns, this difference is likely to represent the success or failure of the intervention in eliminating the rabies virus. Technology-aided vaccination should be considered in resource limited settings where rabies has not been controlled by Traditional vaccination methods. The use of technology to direct health care workers based on near-real-time spatial data from the field has myriad potential applications in other vaccination and public health initiatives.

Objectives: In July 2017, Victoria’s largest maternity service implemented a new clinical guideline aimed to reduce the rates of stillbirth at term for South Asian-born women. Here we present the evaluation of the change in care on rates of stillbirth, neonatal and obstetric interventions. Design: Cohort Study Setting: Victoria’s largest metropolitan university-affiliated teaching hospital. Population: All women receiving antenatal care who gave birth in the term period between January 2016 and December 2020. Methods: Differences in rates of stillbirths, neonatal deaths, perinatal morbidities, and interventions after July 2017 were determined. Multigroup interrupted time-series analysis was used to assess changes in rates of induction of labour. Main Outcome Measures: Rates of stillbirths, neonatal deaths, perinatal morbidities, and obstetric interventions. Results: 3506 south Asian-born women gave birth prior to, and 8532 after the change. There was a 64% reduction in term stillbirth (95%CI 87% to 2%; p=0.047) for south Asian-born women after the change in practice from 2.3 per 1000 births to 0.8 per 1000 births. The rates of early neonatal death (3.1 per 1000 vs 1.3 per 1000; p=0.03) and SCN admission (16.5% vs 11.1%; p

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY’s prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

Trisomy 21 (Ts21) causes alterations in skeletal development resulting in decreased bone mass, shortened stature and weaker bones in individuals with Down syndrome (DS). There is a sexual dimorphism in bone mineral density (BMD) deficits associated with DS with males displaying earlier deficits than females. The relationships between causative trisomic genes, cellular mechanisms, and influence of sex in DS skeletal abnormalities remain unknown. One hypothesis is that the low bone turnover phenotype observed in DS results from attenuated osteoblast function, contributing to impaired trabecular architecture, altered cortical geometry, and decreased mineralization. DYRK1A, found in three copies in humans with DS, Ts65Dn, and Dp1Tyb DS model mice, has been implicated in the development of postnatal skeletal phenotypes associated with DS. Reduced copy number of Dyrk1a to euploid levels from conception in an otherwise trisomic Ts65Dn mice resulted in a rescue of appendicular bone deficits, suggesting DYRK1A contributes to skeletal development and homeostasis. We hypothesized that reduction of Dyrk1a copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed Dyrk1a gene (Ts65Dn,Dyrk1afl/wt) were mated with male Osx-Cre+ (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced Dyrk1a copy number in mature osteoblasts in Ts65Dn,Dyrk1a+/+/Osx-Cre P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn,Dyrk1a+/+/+ (3 copies of DYRK1A in osteoblasts) and Ts65Dn,Dyrk1a+/+/Osx-Cre (2 copies of Dyrk1a in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced Dyrk1a in osteoblasts. This suggests that trisomic DYRK1A does not affect osteoblast function in a cell-autonomous manner at or before P42. Although male Dp1Tyb and Ts65Dn mice exhibit similar skeletal deficits at P42 in both trabecular and cortical bone compartments between euploid and trisomic mice, female Ts65Dn mice exhibit significant cortical and trabecular deficits at P42, in contrast to an absence of genotype effect in female Dp1Tyb mice in trabecular bone. Taken together, these data suggest skeletal deficits in DS mouse models and are sex and age dependent, and influenced by strain effects, but are not solely caused by the overexpression of Dyrk1a in osteoblasts. Identifying molecular and cellular mechanisms, disrupted by gene dosage imbalance, that are involved in the development of skeletal phenotypes associated with DS could help to design therapies to rescue skeletal deficiencies seen in DS.

Importance Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. Objective To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. Design, Setting, and Participants The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) andERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Interventions Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Main Outcomes and Measures Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). Results A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) andERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. Conclusions and Relevance In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. Trial Registration ClinicalTrials.gov Identifier:NCT01042379

Approximately 67% of U.S. households have pets. Limited data are available on SARS-CoV-2 in pets. We assessed SARS-CoV-2 infection in pets during a COVID-19 household transmission investigation. Pets from households with ≥1 person with laboratory-confirmed COVID-19 were eligible for inclusion from April–May 2020. We enrolled 37 dogs and 19 cats from 34 households. All oropharyngeal, nasal, and rectal swabs tested negative by rRT-PCR, one dog’s fur swabs (2%) tested positive by rRT-PCR at the first sampling. Among 47 pets with serological results, eight (17%) pets (four dogs, four cats) from 6/30 (20%) households had detectable SARS-CoV-2 neutralizing antibodies. In households with a seropositive pet, the proportion of people with laboratory-confirmed COVID-19 was greater (median 79%, range: 40–100%) compared to households with no seropositive pet (median 37%, range: 13–100%) (p = 0.01). Thirty-three pets with serologic results had frequent daily contact (≥1 h) with the index patient before the person’s COVID-19 diagnosis. Of these 33 pets, 14 (42%) had decreased contact with the index patient after diagnosis and none were seropositive, of the 19 (58%) pets with continued contact, four (21%) were seropositive. Seropositive pets likely acquired infection after contact with people with COVID-19. People with COVID-19 should restrict contact with pets and other animals.

Stillbirth and preterm birth (PTB) remain two of the most important, unresolved challenges in modern pregnancy care. Approximately 10% of all births are preterm with nearly one million children dying each year due to PTB. It remains the most common cause of death among children under five years of age. The numbers for stillbirth are no less shocking with 2.6 million babies stillborn each year. With minimal impact on the rate of these adverse birth outcomes over the past decade there is an urgent need to identify more effective interventions to tackle these problems. In this retrospective cohort study, we used whole-of-population data, to determine if maternal immunization during pregnancy against influenza and/or pertussis, is associated with a lower risk of PTB, delivering a small-for-gestational age (SGA) infant, developing preeclampsia or stillbirth. Women with a singleton pregnancy at 28 or more weeks’ gestation delivering in Victoria, Australia from July 2015 to December 2018 were included in the analysis. Log-binomial regression was used to measure the relationship between vaccination during pregnancy against influenza and against pertussis, with preterm birth, SGA, preeclampsia and stillbirth. Variables included in the adjusted model were maternal age, body mass index, first or subsequent birth, maternal Indigenous status, socio-economic quintile, smoking, public or private maternity care and metropolitan or rural location of the hospital. Women who received influenza vaccine were 75% less likely to have a stillbirth (aRR 025; 95% CI 0.20, 0.31), and 31% less likely to birth

Background Universal screening has been proposed as a strategy to identify asymptomatic individuals infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mitigate transmission. Aim To investigate the rate of positive tests among pregnant women in Melbourne, Australia. Methods We performed a cross-sectional prevalence study at three maternity hospitals (one tertiary referral hospital and two secondary maternities) in Melbourne, Australia. SARS-CoV-2 testing was offered to all pregnant women attending face-to-face antenatal visits and to those attending the hospital with symptoms of possible coronavirus disease, between 6th and 19th of May 2020. Testing was performed by multiplex-tandem polymerase chain reaction (PCR) on combined oropharyngeal and nasopharyngeal swabs. The primary outcome was the proportion of positive SARS-CoV-2 tests. Findings SARS-CoV-2 testing was performed in 350 women, of whom 19 had symptoms of possible COVID-19. The median maternal age was 32 years (IQR 28–35 years), and the median gestational age at testing was 33 weeks and four days (IQR 28 weeks to 36 weeks and two days). All 350 tests returned negative results (p = 0%, 95% CI 0–1.0%). Conclusion In a two-week period of low disease prevalence, the rate of asymptomatic coronavirus infection among pregnant women in Australia during the study period was negligible, reflecting low levels of community transmission.

Purpose Chronic kidney disease (CKD) and aging are each independently associated with higher fracture risk. Although CKD is highly prevalent in the aging population, the interaction between these two conditions with respect to bone structure and mechanics is not well understood. The purpose of this study was to examine cortical porosity and mechanical properties in skeletally mature young and aging mice with CKD. Methods CKD was induced by feeding 16-week and 78-week male mice 0.2% adenine (AD) for six weeks followed by two weeks of maintenance on a control diet for a total study duration of eight weeks of CKD; control (CON) animals of each age were fed a standard diet. Serum biochemistries, μCT imaging, and mechanical properties via four-point bending were assessed at the endpoint. Results Phosphorus, parathyroid hormone, and blood urea nitrogen were elevated in both ages of AD mice compared to age-matched CON; aging AD mice had PTH and BUN values higher than all other groups. Femoral cortical porosity was more than four-fold higher in aging AD mice compared to young AD mice and more than two-fold higher compared to age-matched controls. Structural and estimated material mechanical properties were both lower in aging mice, but there were no significant interactions between AD treatment and age. Conclusion These data show an interaction between CKD and aging that produces a more severe biochemical and cortical bone phenotype. This highlights the importance of studying mechanisms and potential interventions in both young and aged animals to translate to a broader spectrum of CKD patients.

OBJECTIVE To assess the impact of publicly reporting a statewide fetal growth restriction (FGR) performance indicator. DESIGN Retrospective cohort study from 2000 to 2017. SETTING All maternity services in Victoria, Australia. POPULATION A total of 1 231 415 singleton births at ≥32 weeks of gestation. METHODS We performed an interrupted time-series analysis to assess the impact of publicly reporting an FGR performance indicator on the rate of detection for severe cases of small for gestational age (SGA). Rates of perinatal mortality and morbidity and obstetric intervention were assessed for severe SGA pregnancies and pregnancies delivered for suspected SGA. MAIN OUTCOME MEASURES Gestation at delivery, obstetric management and perinatal outcome. RESULTS The public reporting of a statewide FGR performance indicator was associated with a steeper reduction per quarter in the percentage of severe SGA undelivered by 40 weeks of gestation, from 0.13 to 0.51% (P = 0.001), and a decrease in the stillbirth rate by 3.3 per 1000 births among those babies (P = 0.01). Of babies delivered for suspected SGA, the percentage with birthweights ≥ 10th centile increased from 41.4% (n = 307) in 2000 to 53.3% (n = 1597) in 2017 (P

Study Objectives:The Insomnia Severity Index (ISI) has been used to define insomnia symptoms in individuals with obstructive sleep apnea (OSA). However, whether distinct ISI profiles exist in indiv...