A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair-Proficient Colorectal or Pancreatic Cancer.

BACKGROUND: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib). METHODS: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. RESULTS: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. CONCLUSIONS: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.

Dose-response of inactivated yeast in diets of late gestating and lactating gilts on immunoglobulin transfer and offspring pre-weaning growth performance.

Fifty gilts [initial BW 190.7 ± 4.2 kg] were recruited on d 85 of gestation and were used until d 19 of lactation to assess the dose-response of inactivated yeast via hydrolyzation (HY) inclusion on offspring growth and immunoglobulin (Ig) transfer prior to weaning. Gilts were assigned to one of five experimental diets: a control with no HY (HY0) or inclusion of 0.25% (HY0.25), 0.5% (HY0.5), 1.0% (HY1.0) or 1.2% (HY1.2) HY. Gilts were weighed on d 85 and 110 of gestation and d 1 and 19 (weaning) after farrowing. Offspring were weighed on d 1 and 19 of age. On lactation d 1 (approx. 24 h after farrowing), colostrum, gilt plasma, and plasma from two median body weight (BW) piglets were collected and on d 19, plasma from each gilt and two median BW piglets per litter were collected for determination of Ig concentrations. Contrast statements were used to assess linear, quadratic cubic, and quartic effects of HY inclusion. The inclusion of HY had minimal effects on gilt BW or litter characteristics at birth (total number born and born alive, piglet birth weight). Lactation average daily feed intake of the gilts tended to increase then decrease with increasing HY inclusion (quadratic; P = 0.085). Piglet pre-weaning average daily gain (linear, quadratic, and quartic; P < 0.05) and BW at weaning (quadratic and quartic; P < 0.05) increased then decreased with increasing HY inclusion. On lactation d 1, colostrum and gilt plasma Ig concentrations were not affected by dietary treatment (P > 0.10) but piglet IgA and IgM decreased then increased with HY inclusion level (cubic; P < 0.05). On lactation d 19, piglet plasma IgG tended to increase with HY inclusion (linear; P = 0.099). In summary, increasing HY inclusion in late gestating and lactating gilt diets improved immune transfer in the first 24 h after birth and piglet pre-weaning growth rates and body weight at weaning. Therefore, maternal feeding of HY could be used as a strategy to improve offspring immunocompetence and BW at weaning, with possible carry-over benefits for the post-weaning phase.

Psychological, Psychiatric, and Organic Brain Manifestations of Celiac Disease.

Celiac disease is an autoimmune condition that affects approximately 1% of the population worldwide. Although its main impact often concerns the small intestine, resulting in villous atrophy and nutrient malabsorption, it can also cause systemic manifestations, particularly when undiagnosed or left untreated. Here, attention is paid to the possible psychological, psychiatric, and organic brain manifestations of celiac disease. Specific topics related to the influence and risk of such manifestations with respect to celiac disease are defined and discussed. Overall, eighteen main topics are considered, sifted from over 500 references. The most often studied topics were found to be the effect on quality of life, organic brain dysfunction and ataxia, epilepsy, Down syndrome, generalized psychological disorders, eating dysfunction, depression, and schizophrenia. For most every topic, although many studies report a connection to celiac disease, there are often one or more contrary studies and opinions. A bibliographic analysis of the cited articles was also done. There has been a sharp increase in interest in this research since 1990. Recently published articles tend to receive more referencing, up to as many as 15 citations per year, suggesting an increasing impact of the topics. The number of manuscript pages per article has also tended to increase, up to as many as 12 pages. The impact factor of the publishing journal has remained level over the years. This compendium may be useful in developing a consensus regarding psychological, psychiatric, and organic brain manifestations that can occur in celiac disease, and for determining the best direction for ongoing research focus.

Neighborhood Racialized Economic Polarization, Home Visiting Coverage, and Adverse Birth Outcomes in a Medicaid-eligible Population.

BACKGROUND: Residential polarization shaped by racial segregation and concentrations of wealth (hereafter neighborhood racialized economic polarization) results in both highly deprived and highly privileged neighborhoods. Numerous studies have found a negative relationship between neighborhood racialized economic polarization and birth outcomes. We investigated whether community-informed home visiting programs achieve high rates of service coverage in highly deprived neighborhoods and can attenuate the deleterious effect of neighborhood polarization on birth outcomes. METHODS: We used 2016-2019 data from Michigan's statewide database that links birth records, Medicaid claims, and program participation (N = 211,412). We evaluated whether 1) home visiting programs achieved high rates of service coverage in highly deprived neighborhoods, 2) participation in home visiting may help to mitigate the negative relationship between neighborhood polarization and birth outcomes, and 3) the reductions in preterm birth and low birthweight were larger among Black birthing individuals. Data were examined using multilevel generalized linear models and mediation analysis. RESULTS: The statewide home visiting program achieved higher rates of coverage in the most deprived neighborhoods (21.0% statewide, 28.3% in the most deprived vs. 10.4% in the most privileged neighborhoods). For all, home visiting participation was associated with a decrease in the relationship between neighborhood polarization and preterm birth by 6.8% (mean indirect effect, -0.008; 95% confidence interval, -0.011 to -0.005), and by 5.2% (mean indirect effect, -0.013; 95% confidence interval, -0.017 to -0.009) for low birthweight, adjusting for individual-level risk factors. The decrease was larger among Black individuals. CONCLUSIONS: A statewide Medicaid-sponsored home visiting program achieved high rates of service coverage in highly deprived neighborhoods. Program participation may help to mitigate the negative relationship between neighborhood polarization and birth outcomes, and more so among Black individuals. Continued support for home visiting services is required to better engage birthing individuals in neighborhoods with concentrated deprivation and to decrease disparities.

Exploring the Nature of Arhopalus ferus (Coleoptera: Cerambycidae: Spondylidinae) Pheromone Attraction.

Cerambycid species of the Spondylidinae subfamily are distributed worldwide and are known for being prolific invaders that infest conifers. In New Zealand, Arhopalus ferus (Mulsant), the burnt pine longhorn beetle, is well-established and requires monitoring at high-risk sites such as ports, airports, and sawmills as part of the requirements to meet pine log export standards set by the New Zealand Ministry of Primary Industries (MPI). Currently, its surveillance relies on traps baited with host volatiles (i.e., ethanol and α-pinene). We used volatile collections from adult beetles, electroantennograms, and field trapping bioassays to identify the pheromones emitted by the burnt pine longhorn beetle A. ferus and their effects on its behaviour. We show that A. ferus males emit mainly (E)-fuscumol and geranylacetone, as well as the minor components, α-terpinene and p-mentha-1,3,8-triene, and that all four compounds elicit a dose-dependent response in antennae of both sexes. Traps baited with the binary combination of geranylacetone plus fuscumol captured significantly more female A. ferus than did unbaited traps in two of three field experiments. α-Terpinene did not affect A. ferus trap catches and effects of p-mentha-1,3,8-triene on trap catch were not determined. Our findings provide further evidence of the use of fuscumol and geranylacetone as aggregation-sex pheromones by longhorn beetles in the Spondylidinae subfamily, and suggest that their deployment in survey traps may improve the efficacy of A. ferus monitoring in New Zealand and elsewhere.

Neuroradiological features of contrast-induced neurotoxicity: A systematic review and pooled analysis.

BACKGROUND: Contrast-induced neurotoxicity (CIN), is an increasingly recognised complication of endovascular procedures, presenting as a spectrum of neurological symptoms that mimic ischaemic stroke. The diagnosis of CIN remains a clinical challenge, and stereotypical imaging findings are not established. This study was conducted to characterise the neuroimaging findings in patients with CIN, to raise diagnostic awareness and improve decision making. METHODS: We performed a systematic review of PubMed and Embase databases from inception (1946/1947) to June 2023 for reports of CIN following administration of iodinated contrast media. Studies with a final diagnosis of CIN, which provided details of neuroimaging were included. All included cases were pooled and descriptive analysis was conducted. RESULTS: A total of 84 patients were included, with a median age of 64 years. A large proportion of patients had normal imaging (CT 40.8 %, MRI 53.1 %). CT abnormalities included cortical/subarachnoid hyperattenuation (42.1 %), cerebral oedema/sulcal effacement (26.3 %), and loss of grey-white differentiation (7.9 %). Frequently reported MRI abnormalities included brain parenchymal MRI signal change (40.8 %) and cerebral oedema (12.2 %), most commonly observed on FLAIR sequences (26.5 %). Characterisation of imaging findings according to anatomical location and clinical symptoms has been conducted. CONCLUSIONS: Neuroimaging is an essential part of the diagnostic workup of CIN. Analysis of the anatomical location and laterality of imaging abnormalities may suggest relationship between radiological features and actual clinical symptoms, although this remains to be confirmed with dedicated study. Radiological abnormalities, particularly CT, appear to be transient and reversible in most patients.

Overview of the Global and US Burden of Preterm Birth.

Preterm birth (PTB) is the leading cause of morbidity and mortality in children globally, yet its prevalence has been difficult to accurately estimate due to unreliable methods of gestational age dating, heterogeneity in counting, and insufficient data. The estimated global PTB rate in 2020 was 9.9% (95% confidence interval: 9.1, 11.2), which reflects no significant change from 2010, and 81% of prematurity-related deaths occurred in Africa and Asia. PTB prevalence in the United States in 2021 was 10.5%, yet with concerning racial disparities. Few effective solutions for prematurity prevention have been identified, highlighting the importance of further research.

The Clinical and Radiological Outcomes of the Multimodal Use of the Woven EndoBridge Device: A Large Multicenter Study.

BACKGROUND: The Woven EndoBridge (WEB) is a device used for intrasaccular flow diversion, designed for the elimination of wide-necked bifurcation aneurysms from the circulation. In this study, we aim to assess the safety and efficacy of the WEB and its uses in treating aneurysms of different morphologies and locations. METHODS: In a retrospective analysis, we compiled a comprehensive dataset from patients treated with the WEB device across three major Australian neurovascular centers from May 2017 to September 2023. The case series encompassed a spectrum of aneurysm types, including wide-necked bifurcation, sidewall, and irregularly shaped aneurysms, as well as cases previously managed with alternative therapeutic strategies. This study additionally encompasses cases where aneurysms were managed using the WEB device in combination with supplementary endovascular devices. RESULTS: The study included 169 aneurysms in 161 patients. The rate of satisfactory aneurysm occlusion was 85.6%, with 86.7% of patients maintaining good functional status at their most recent follow-up. The procedure exhibited a low mortality rate of 0.6% and a thromboembolic complication rate of 7.1% (n = 12/161). There were no instances of postoperative re-rupture and the procedure-related hemorrhage rate was low (1.2%, n = 2/169), aligning with the literature regarding the safety and efficacy of the WEB device. CONCLUSIONS: Our multicenter trial reinforces the WEB device's role as an effective and safe modality for intracranial aneurysm management, supporting its expanded application beyond wide-necked bifurcation aneurysms. Further prospective studies are required to delineate its evolving role fully.

Severe Maternal Morbidity Disparities Before and During the COVID Pandemic in a Medicaid Population.

This study assessed racial and ethnic disparities in severe maternal mortality during delivery through 6 weeks postpartum, before and during the COVID pandemic, in a statewide Medicaid population. This retrospective, population-based, cohort study used Medicaid claims data linked to birth certificates from the Michigan Department of Health and Human Services Health Services Data Warehouse that included all individuals giving birth between January 1, 2017, and October 31, 2021, in Michigan who had Medicaid insurance during the month of childbirth. The SMM rate increased more during the COVID pandemic for Black (1.36 [1.26-1.46]) compared to White individuals (1.17 [1.09-1.26], p-value<0.01 Black vs White). The Black-White and Hispanic-White disparities in severe maternal morbidity, already high in the Medicaid population, widened during the COVID pandemic. Multilevel interventions are needed to reduce disparities in maternal morbidity and mortality. Conflict of interest disclosure: No conflicts to disclose.

Comparative effect of Tai Chi and aerobic exercise on cognitive function in advanced lung cancer survivors with perceived cognitive impairment: a three-arm randomized controlled trial with mediation analysis.

PURPOSE: Cancer-related cognitive impairment is prevalent in metastatic lung cancer survivors. This study aimed to compare the effectiveness of aerobic exercise and Tai Chi on perceived cognitive function and the mediating role of psychoneurological symptoms with perceived cognitive impairment. METHODS: In a subgroup of a parent randomized clinical trial, participants who reported cognitive impairment underwent a 16-week aerobic exercise (n = 49), Tai Chi (n = 48), and control (n = 54) groups. Measures included perceived cognitive function and psychoneurological symptoms (sleep disturbance, fatigue, anxiety, and depression) assessed at baseline (T0), 16-week (T1), and 1 year (T2). RESULTS: Participants in Tai Chi showed significant improvements compared to aerobic exercise and control groups in perceived cognitive function at T1 (AE: between-group difference, 6.52; P < 0.001; CG: 8.34; P < 0.001) and T2 (AE: between-group difference, 3.55; P = 0.05; CG: 5.94; P < 0.001). Sleep disturbance, fatigue, anxiety, and depression at month 12 explained 24%, 31%, 32%, and 24% of the effect of the intervention on cognitive function at month 12, respectively. Only anxiety at month 4 explained 23% of the intervention effect at month 12. CONCLUSIONS: Tai Chi demonstrated beneficial effects on cognitive function in advanced lung cancer survivors with perceived cognitive impairment. Improvement in cognitive function was mediated by reducing sleep disturbance, fatigue, anxiety, and depression, highlighting the importance of addressing these symptoms in future interventions to improve cognitive function, with anxiety playing a significant role at an earlier stage. IMPLICATIONS FOR CANCER SURVIVORS: Tai Chi is a potentially safe complementary therapeutic option for managing cognitive impairment in this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04119778; retrospectively registered on 8 October 2019.

Interpretable deep learning insights: Unveiling the role of 1 Gy volume on lymphopenia after radiotherapy in breast cancer.

BACKGROUND: Lymphopenia is known for its significance on poor survivals in breast cancer patients. Considering full dosimetric data, this study aimed to develop and validate predictive models for lymphopenia after radiotherapy (RT) in breast cancer. MATERIAL AND METHODS: Patients with breast cancer treated with adjuvant RT were eligible in this multicenter study. The study endpoint was lympopenia, defined as the reduction in absolute lymphocytes and graded lymphopenia after RT. The dose-volume histogram (DVH) data of related critical structures and clinical factors were taken into account for the development of dense neural network (DNN) predictive models. The developed DNN models were validated using external patient cohorts. RESULTS: A total of 918 consecutive patients with invasive breast cancer enrolled. The training, testing, and external validating datasets consisted of 589, 203, and 126 patients, respectively. Treatment volumes at nearly all dose levels of the DVH were significant predictors for lymphopenia following RT, including volumes at very low-dose 1 Gy (V1) of organs at risk (OARs) including lung, heart and body, especially ipsilateral-lung V1. A final DNN model, combining full DVH dosimetric parameters of OARs and three key clinical factors, achieved a predictive accuracy of 75 % or higher. CONCLUSION: This study demonstrated and externally validated the significance of full dosimetric data, particularly the volume of low dose at as low as 1 Gy of critical structures on lymphopenia after radiation in patients with breast cancer. The significance of V1 deserves special attention, as modern VMAT RT technology often has a relatively high value of this parameter. Further study is warranted for RT plan optimization.

Tai Chi and Aerobic Exercise on Cancer-Related Dyspnea in Advanced Lung Cancer Patients: A Randomized Clinical Trial.

CONTEXT: Dyspnea, a prevalent and debilitating symptom in patients with advanced lung cancer, negatively affects symptom burden and prognosis. Physical activity has emerged as a promising non-pharmacological intervention for managing dyspnea. OBJECTIVES: This study compared the effectiveness of two widely-recognized physical activity modalities, namely Tai Chi (TC) and aerobic exercise (AE) for treating dyspnea in patients with advanced lung cancer. METHODS: Patients with advanced lung cancer (n=226) were randomized into TC, AE, or control groups. There was no baseline dyspnea requirement for patients. The AE group received two 60-minute supervised sessions and home-based exercises per month, the TC group received 60-minute sessions twice weekly, and the control group received exercise guidelines for 16 weeks. The primary outcome (sleep quality) of the study has been previously reported. In this secondary analysis, we focused on dyspnea outcomes, including overall and lung cancer-specific dyspnea. Assessments were conducted at baseline (T0), 16 weeks (T1), and one year (T2). RESULTS: Compared to the control group, TC significantly improved overall dyspnea at T1 (between-group difference, -8.69; P=0.03) and T2 (between-group difference, -11.45; P=0.01), but not AE. Both AE (between-group difference, -11.04; P=0.01) and TC (between-group difference, -14.19; P<0.001) significantly alleviated lung cancer-specific dyspnea at T2 compared with the control group. CONCLUSION: Both TC and AE alleviate dyspnea severity in patients with advanced lung cancer, and continuous exercise can yield substantial improvements. Due to its multi-component nature, Tai Chi has a greater effect on dyspnea.

The standardized ileal digestible lysine-to-net energy ratio in the diets of sows to optimize milk nitrogen retention is dynamic during lactation.

Fifty-two multiparous sows (average parity 3.1 ±â€…0.9 and initial BW 245.6 ±â€…32.5 kg) were used to evaluate the effects of dietary standardized ileal digestible (SID) Lys-to-net energy (NE) ratios on nitrogen (N) utilization throughout a 24-d lactation period. Sows were randomly assigned to one of five isoenergetic feeding programs that provided equally spaced and increasing SID Lys-to-NE ratios between 2.79 and 5.50 g SID Lys/Mcal NE. The feeding programs were generated by blending the two extreme diets in varying proportions and were provided to sows immediately after farrowing (day 1) and until weaning at day 24 ±â€…1. Nitrogen balances were conducted between days 4 and 7, 12 and 15, and 20 and 23 ±â€…1 of lactation to represent weeks 1, 2, and 3, respectively, using total urine collection and fecal grab sampling. Contrast statements were used to determine the linear and quadratic effects of increasing Lys-to-NE ratios. Linear and quadratic broken-line and polynomial quadratic (QPM) models were used to determine the optimum dietary Lys-to-NE ratios for N retention in milk. The Bayesian information criterion was used to assess the best fit. Feeding program did not influence sow average daily feed intake (5.8 ±â€…0.1 kg), BW change (-8.2 ±â€…3.1 kg), or change in back fat thickness (-2.6 ±â€…0.7 mm) over the 24-d lactation period, but piglet average daily gain increased with dietary SID Lys-to-NE ratio (linear; P < 0.05). Sow N intake increased with increasing dietary Lys-to-NE ratio in weeks 2 and 3 (linear; P < 0.001). Whole-body N retention (N intake - N output in urine and feces) increased with increasing dietary Lys-to-NE ratio in all weeks (linear; P < 0.05). The N retention in milk tended to increase then decrease with increasing dietary Lys-to-NE ratio in weeks 1 and 2 (quadratic; P = 0.051 and P = 0.081) and the QPM showed optimal milk N retention at 4.28, 4.42, and 4.67 g Lys/Mcal NE for weeks 1, 2, and 3, respectively. Maternal N retention (N intake - N output in urine, feces, and milk) decreased and then increased in week 1 (quadratic; P < 0.01) and increased in weeks 2 and 3 (linear; P < 0.01) with increasing dietary Lys-to-NE ratio. Therefore, the SID Lys-to-NE ratio necessary to optimize milk N output is dynamic throughout lactation. A two-diet feeding program could be created to match optimal weekly or daily SID Lys-to-NE ratios, which could lead to improved piglet ADG and body weights at weaning.

Despite significant changes in nutrient and energy requirements as well as voluntary feed intake during lactation, sows are typically fed a single diet with a static nutrient and energy composition throughout the entire lactation period, which may not optimize milk output. Fifty-two sows were used to explore how various ratios of standardized ileal digestible (SID) Lys to net energy (NE) in lactating sow diets affect the growth of piglets and nitrogen utilization during a 24-d lactation period. Sows were randomly assigned to one of five feeding programs that contained equal amounts of energy and provided equally spaced and increasing Lys-to-NE ratios between 2.79 and 5.50 g SID Lys/Mcal NE immediately after farrowing. The dietary Lys-to-NE ratio did not influence sow daily feed intake, body weight change, or change in backfat thickness over the 24-d lactation period; however, piglet growth rate and body weight at weaning increased with increasing Lys-to-NE ratio. The SID Lys-to-NE ratio necessary to optimize milk nitrogen output was 4.28, 4.42, and 4.67 g SID Lys/Mcal NE during weeks one, two, and three of lactation, respectively. Therefore, it is possible to create a two-diet feeding program offering dynamic SID Lys-to-NE ratios as lactation progresses, which could lead to improved piglet average daily gain and body weights at weaning.

Perinatal inflammation, fetal growth restriction, and long-term neurodevelopmental impairment in Bangladesh.

BACKGROUND: There are limited data on the impact of perinatal inflammation on child neurodevelopment in low-middle income countries and among growth-restricted infants. METHODS: Population-based, prospective birth cohort study of 288 infants from July 2016-March 2017 in Sylhet, Bangladesh. Umbilical cord blood was analyzed for interleukin(IL)-1α, IL-1ß, IL-6, IL-8, and C-reactive protein(CRP). Child neurodevelopment was assessed at 24 months with Bayley-III Scales of Infant Development. We determined associations between cord blood inflammation and neurodevelopmental outcomes, controlling for potential confounders. RESULTS: 248/288 (86%) live born infants were followed until 24 months, among whom 8.9% were preterm and 45.0% small-for-gestational-age(SGA) at birth. Among all infants, elevated concentrations (>75%) of CRP and IL-6 at birth were associated with increased odds of fine motor delay at 24 months; elevated CRP was also associated with lower receptive communication z-scores. Among SGA infants, elevated IL-1α was associated with cognitive delay, IL-8 with language delay, CRP with lower receptive communication z-scores, and IL-1ß with lower expressive communication and motor z-scores. CONCLUSIONS: In rural Bangladesh, perinatal inflammation was associated with impaired neurodevelopment at 24 months. The associations were strongest among SGA infants and noted across several biomarkers and domains, supporting the neurobiological role of inflammation in adverse fetal development, particularly in the setting of fetal growth restriction. IMPACT: Cord blood inflammation was associated with fine motor and language delays at 24 months of age in a community-based cohort in rural Bangladesh. 23.4 million infants are born small-for-gestational-age (SGA) globally each year. Among SGA infants, the associations between cord blood inflammation and adverse outcomes were strong and consistent across several biomarkers and neurodevelopmental domains (cognitive, motor, language), supporting the neurobiological impact of inflammation prominent in growth-restricted infants. Prenatal interventions to prevent intrauterine growth restriction are needed in low- and middle-income countries and may also result in long-term benefits on child development.

Using the genomic adjusted radiation dose (GARD) to personalize the radiation dose in nasopharyngeal cancer.

BACKGROUND: Locally advanced nasopharyngeal cancer (NPC) patients undergoing radiotherapy are at risk of treatment failure, particularly locoregional recurrence. To optimize the individual radiation dose, we hypothesize that the genomic adjusted radiation dose (GARD) can be used to correlate with locoregional control. METHODS: A total of 92 patients with American Joint Committee on Cancer / International Union Against Cancer stage III to stage IVB recruited in a randomized phase III trial were assessed (NPC-0501) (NCT00379262). Patients were treated with concurrent chemo-radiotherapy plus (neo) adjuvant chemotherapy. The primary endpoint is locoregional failure free rate (LRFFR). RESULTS: Despite the homogenous physical radiation dose prescribed (Median: 70 Gy, range 66-76 Gy), there was a wide range of GARD values (median: 50.7, range 31.1-67.8) in this cohort. In multivariable analysis, a GARD threshold (GARDT) of 45 was independently associated with LRFFR (p = 0.008). By evaluating the physical dose required to achieve the GARDT (RxRSI), three distinct clinical subgroups were identified: (1) radiosensitive tumors that RxRSI at dose < 66 Gy (N = 59, 64.1 %) (b) moderately radiosensitive tumors that RxRSI dose within the current standard of care range (66-74 Gy) (N = 20, 21.7 %), (c) radioresistant tumors that need a significant dose escalation above the current standard of care (>74 Gy) (N = 13, 14.1 %). CONCLUSION: GARD is independently associated with locoregional control in radiotherapy-treated NPC patients from a Phase 3 clinical trial. GARD may be a potential framework to personalize radiotherapy dose for NPC patients.

The Economic Iceberg of Celiac Disease: More Than the Cost of Gluten-Free Food.

Celiac disease (CeD) is a chronic autoimmune disorder of global relevance, with the potential for acute and long-term complications. However, the economic burden of CeD is rarely considered and largely thought of as limited to the cost of gluten-free food. Fortunately, recent research has shed light on the various societal costs of CeD across the health care continuum. This article summarizes the current evidence on the economic impacts of CeD, which suggest that the societal economic burden of CeD stretches beyond the cost of gluten-free food. This review provides ample evidence of larger but hidden costs related to excess health care use for complications and comorbidities, as well as reduced productivity. Although significant advances are expected in the management of CeD, their effect on the economic burden of CeD remain uncertain. The aim of this review was to inform stakeholders across society and contribute to improved policies to support patients with CeD.

A biosocial analysis of perinatal and late neonatal mortality among Indigenous Maya Kaqchikel communities in Tecpán, Guatemala: a mixed-methods study.

INTRODUCTION: Neonatal mortality is a global public health challenge. Guatemala has the fifth highest neonatal mortality rate in Latin America, and Indigenous communities are particularly impacted. This study aims to understand factors driving neonatal mortality rates among Maya Kaqchikel communities. METHODS: We used sequential explanatory mixed methods. The quantitative phase was a secondary analysis of 2014-2016 data from the Global Maternal and Newborn Health Registry from Chimaltenango, Guatemala. Multivariate logistic regression models identified factors associated with perinatal and late neonatal mortality. A number of 33 in-depth interviews were conducted with mothers, traditional Maya midwives and local healthcare professionals to explain quantitative findings. RESULTS: Of 33 759 observations, 351 were lost to follow-up. There were 32 559 live births, 670 stillbirths (20/1000 births), 1265 (38/1000 births) perinatal deaths and 409 (12/1000 live births) late neonatal deaths. Factors identified to have statistically significant associations with a higher risk of perinatal or late neonatal mortality include lack of maternal education, maternal height <140 cm, maternal age under 20 or above 35, attending less than four antenatal visits, delivering without a skilled attendant, delivering at a health facility, preterm birth, congenital anomalies and presence of other obstetrical complications. Qualitative participants linked severe mental and emotional distress and inadequate maternal nutrition to heightened neonatal vulnerability. They also highlighted that mistrust in the healthcare system-fueled by language barriers and healthcare workers' use of coercive authority-delayed hospital presentations. They provided examples of cooperative relationships between traditional midwives and healthcare staff that resulted in positive outcomes. CONCLUSION: Structural social forces influence neonatal vulnerability in rural Guatemala. When coupled with healthcare system shortcomings, these forces increase mistrust and mortality. Collaborative relationships among healthcare staff, traditional midwives and families may disrupt this cycle.

Outcomes of iStent inject combined with cataract surgery in Asian eyes: Australian data from the Fight Glaucoma Blindness international registry.

PURPOSE: To analyse real-world outcomes in Asian eyes of iStent inject, a second-generation trabecular micro-bypass stent, combined with phacoemulsification. METHODS: This is a multi-centre, observational study of glaucomatous Asian eyes that have undergone iStent inject implantation combined with cataract surgery. Patient data were extracted from the Fight Glaucoma Blindness! Registry. Outcome measures included those of IOP reduction, glaucoma medication reduction, and adverse events including the need for secondary surgery. RESULTS: 123 eyes of 86 patients with a mean age of 68.4 ± 9.3 years underwent iStent inject implantation with phacoemulsification. At baseline, the mean ± SD preoperative intraocular pressure (IOP) was 16.0 ± 4.4 mmHg, and the mean preoperative number of topical glaucoma medications was 1.9 ± 1.4. At 12 months 30.8% of eyes demonstrated a reduction in IOP greater than 20%, the mean IOP reduction was 12.5% with an additional reduction of 0.7 glaucoma medications. 40% of eyes were using no medications at 12 months compared to 16.3% preoperatively. 8.2% of eyes required a subsequent procedure within the 12-month follow-up window. CONCLUSION: iStent inject implantation combined with phacoemulsification in Asian eyes showed a reduction of IOP and glaucoma medication use in a real-world clinical setting. The safety profile of the device is good with minimal adverse outcomes, however, a subset of patients required secondary procedures within the 12 month follow up.

Parity affects mammary development in late-pregnant swine.

The goal of this project was to determine whether various measures of mammary development differed between gilts and multiparous sows at the end of gestation. During gestation, Yorkshire × Landrace gilts (n = 19) and sows (second and third gestations, n = 17) were fed one daily meal of a conventional corn-based diet, where the amount fed was based on body weight (BW) and backfat thickness (BF) at mating. On day 110 ±â€…1 of gestation, a jugular blood sample was obtained from all gilts and sows to measure insulin-like growth factor-1 (IGF-1), glucose, free fatty acids, and urea. On that same day, BW and BF were measured and animals were euthanized. Mammary glands from one side of the udder were dissected for compositional analyses. The fifth gland of the contralateral row of mammary glands was sampled for histology and immunohistochemical localization of Ki67. There was less total parenchyma (1,437.4 vs. 2,004.7 ±â€…127.1 g; P < 0.001) and total extraparenchymal tissue (1,691.0 vs. 2,407.0 ±â€…125.3 g; P < 0.001) in mammary glands of gilts compared to those from sows. When these values were expressed per kg BW (226.0 and 284.0 ±â€…2.7 kg for gilts and sows, respectively), parenchymal mass did not differ (P > 0.10), while extraparenchymal tissue weight tended to be less in gilts than sows (P = 0.07). All components within the parenchyma differed by parity (P < 0.001). Specifically, parenchymal tissue from gilts contained a greater proportion of fat and dry matter (DM), a lower proportion of protein, and lower concentrations of DNA (6.59 vs. 9.35 ±â€…0.53 mg/g DM) and RNA (7.76 vs. 12.33 ±â€…0.70 mg/g DM) than that from sows. On the other hand, the circumference of alveolar lumens was greater in gilts than sows (P < 0.001), while the percentage of epithelial cells that were positive for Ki67, a marker of cell proliferation, was greater in sows than gilts (P < 0.05). Circulating concentrations of IGF-1 were greater in gilts than in multiparous sows (45.0 vs. 27.3 ±â€…2.8 ng/mL, P < 0.001). None of the other blood variables were changed by parity. Results show a marked effect of parity on mammary gland development in swine. At the end of gestation, the mammary glands of gilts had less parenchyma with lower epithelial proliferation than glands from multiparous sows. These differences could alter the response of mammary tissue to various nutritional or endocrine signals. This information is crucial for the development of management strategies designed to maximize sow milk yield.

The Association Between Breastfeeding and Growth Among Infants with Moderately Low Birth Weight: A Prospective Cohort Study.

OBJECTIVE: To assess the association between breastfeeding competency, as determined by Latch, Audible swallowing, Type of nipple, Comfort, and Hold (LATCH) and Preterm Infant Breastfeeding Behavior Scale (PIBBS) scores, and exclusive breastfeeding and growth among infants with low birth weight (LBW) in India, Malawi, and Tanzania. STUDY DESIGN: We conducted LATCH and PIBBS assessments among mother-infant dyads enrolled in the Low Birthweight Infant Feeding Exploration (LIFE) observational study of infants with moderately LBW (1500g-2499 g) in India, Malawi, and Tanzania. We analyzed feeding and growth patterns among this cohort. RESULTS: We observed 988 infants. We found no association between LATCH or PIBBS scores and rates of exclusive breastfeeding at 4 or 6 months. Higher week 1 LATCH and PIBBS scores were associated with increased likelihood of regaining birth weight by 2 weeks of age [LATCH: aRR 1.42 (95% CI 1.15, 1.76); PIBBS: aRR 1.15 (95% CI 1.07, 1.23); adjusted for maternal age, parity, education, residence, delivery mode, LBW type, number of offspring, and site]. Higher PIBBS scores at 1 week were associated with improved weight gain velocity (weight-for-age z-score change) at 1, 4, and 6 months [adjusted beta coefficient: 1 month 0.04 (95% CI 0.01, 0.06); 4 month 0.04 (95% CI 0.01, 0.06); and 6 month 0.04 (95% CI 0.00, 0.08)]. CONCLUSION: Although week 1 LATCH and PIBBS scores were not associated with rates of exclusive breastfeeding, higher scores were positively associated with growth metrics among infants with LBW, suggesting that these tools may be useful to identify dyads who would benefit from early lactation support.