Association between prepartum body condition score and prepartum and postpartum dry matter intake and energy balance in multiparous Holstein cows.

The objectives of this retrospective observational study were to investigate the association between BCS at 21 d before calving with prepartum and postpartum DMI, energy balance (EB), and milk yield. Data from 427 multigravid cows from 11 different experiments conducted at the University of Florida (Gainesville, FL) were used. Cows were classified according to their BCS at 21 d before calving as fat (BCS ≥ 4.00; n = 83), moderate (BCS = 3.25-3.75; n = 287), and thin (BCS ≤ 3.00; n = 57). Daily DMI from -21 to -1 and from +1 to +28 DIM was individually recorded. Energy balance was calculated as the difference between net energy for lactation consumed and required. Dry matter intake in fat cows was lower than that in moderate and thin cows both prepartum (fat = 9.97 ± 0.21, moderate = 11.15 ± 0.14, and thin = 11.92 ± 0.22 kg/d) and postpartum (fat = 14.35 ± 0.49, moderate = 15.47 ± 0.38, and thin = 16.09 ± 0.47 kg/d). Dry matter intake was also lower for moderate cows compared with thin cows prepartum, but not postpartum. Energy balance in fat cows was lower than in moderate and thin cows both prepartum (fat = -4.16 ± 0.61, moderate = -1.20 ± 0.56, and thin = 0.88 ± 0.62 Mcal/d) and postpartum (fat = -12.77 ± 0.50, moderate = -10.13 ± 0.29, and thin = -6.14 ± 0.51 Mcal/d). Energy balance was also lower for moderate cows compared with thin cows both prepartum and postpartum. There was a quadratic association between BCS at 21 d before calving and milk yield. Increasing BCS from 2.5 to 3.5 was associated with an increase in daily milk yield of 6.0 kg and 28 d cumulative milk of 147 kg. Increasing BCS from 3.5 to 4.5 was associated with a decrease in daily milk yield of 4.4 kg and 28 d cumulative milk of 116 kg. In summary, a moderate BCS at 21 d before calving was associated with intermediate DMI and EB pre- and postpartum but greater milk yield compared with thinner and fatter cows. Our findings indicate that a moderate BCS is ideal for ensuring a successful lactation.

Effects of progesterone concentrations and follicular wave during growth of the ovulatory follicle on conceptus and endometrial transcriptome in dairy cows.

Objectives were to evaluate the effects of follicular wave and progesterone concentration on growth of the ovulatory follicle, conceptus elongation, uterine IFN-τ concentration, and transcriptome of conceptus and endometrium of pregnant cows on d 17 of gestation. Nonlactating nonpregnant Holstein cows were assigned randomly to one of 3 treatments: ovulation of a first-wave follicle (FW, n = 15); ovulation of a first-wave follicle and progesterone supplementation (FWP4, n = 12); and ovulation of a second-wave follicle (SW, n = 19). Ovulation of a first- or second-wave follicle was achieved by initiating the Ovsynch protocol (d -9 GnRH, d -2 and -1 PGF2α, d 0 GnRH and artificial insemination, d 0.7 artificial insemination) on d 0 or 6 of a presynchronized estrous cycle, respectively. Cows in FWP4 received 3 intravaginal inserts containing progesterone at 12, 24, and 48 h after the first GnRH injection that were removed on d -2. Cows were killed on d 17 for collection of the reproductive tract. Transcriptome was evaluated by microarray using the Affymetrix Bovine Array. Orthogonal contrasts were built to assess the effects of progesterone concentration during follicle growth (FW vs. FWP4 + SW) and follicular wave (FWP4 vs. SW). Progesterone concentrations (LSM ± SEM) from d -9 to -2 were greater for SW, followed by FWP4 and FW (5.38 ± 0.24, 4.26 ± 0.28, and 1.17 ± 0.27 ng/mL). Diameter of the ovulatory follicle (FW = 19.6 ± 0.6; FWP4 = 15.6 ± 0.6; SW = 15.2 ± 0.5 mm) and concentrations of estradiol from d -2 to 1 (FW = 4.05 ± 0.33; FWP4 = 2.73 ± 0.35; SW = 2.48 ± 0.30 pg/mL) were greater for FW compared with FWP4 and SW. Progesterone concentrations from d 3 to 16 were greater for FW compared with FWP4 and SW. A total of 28 singleton conceptuses were collected (FW, n = 8; FWP4, n = 8; SW, n = 12) and only intact conceptuses were included in the analyses of length (FW, n = 8; FWP4, n = 6; SW, n = 12). Although conceptuses were longer for FW compared with FWP4 and SW (FW = 16.6 ± 2.3; FWP4 = 9.8 ± 2.2; SW = 9.6 ± 2.0 cm), treatment did not affect the amount of IFN-τ in uterine flushing. Transcriptome of conceptuses and endometrium of pregnant cows was not extensively affected by follicular wave (8 and 1 differentially expressed transcripts) or concentration of progesterone during follicle growth (0 and 3 differentially expressed transcripts), showing that these factors did not affect conceptuses and endometrium transcriptome in pregnancies that are maintained to d 17.

Risk of a Second Skin Cancer in a Cohort of Patients With Nonmelanoma Skin Cancer -Basal Cell Carcinoma or Squamous Cell Carcinoma-Treated With Mohs Micrographic Surgery: A National Prospective Cohort Study. / Riesgo de aparición de segundas neoplasias cutáneas en una cohorte de pacientes diagnosticados de carcinoma queratinocítico (carcinoma basocelular y carcinoma epidermoide) tratados con cirugía de Mohs. Estudio de cohortes prospectivo nacional.

OBJECTIVE: Patients with nonmelanoma skin cancer (NMSC)-ie, basal cell carcinoma (BCC) or squamous cell carcinoma (SCC)-have an increased risk of developing a second skin cancer. The aim of this study was to describe the frequency, incidence per 1000 person-years, and predictors of a second skin cancer in a cohort of patients with NMSC treated with Mohs micrographic surgery (MMS). MATERIAL AND METHODS: Prospective study of a national cohort of patients with NMSC who underwent MMS at 22 Spanish hospitals between July 2013 and February 2020; case data were recorded in the REGESMOHS registry. The study variables included demographic characteristics, frequency and incidence per 1000 person-years of second skin cancers diagnosed during the study period, and risk factors identified using mixed-effects logistic regression. RESULTS: We analyzed data for 4768 patients who underwent MMS; 4397 (92%) had BCC and 371 (8%) had SCC. Mean follow-up was 2.4 years. Overall, 1201 patients (25%) developed a second skin cancer during follow-up; 1013 of the tumors were BCCs (21%), 154 were SCCs (3%), and 20 were melanomas (0.4%). The incidence was 107 per 1000 person-years (95% CI, 101-113) for any cancer, 90 per 1000 person-years (95% CI, 85-96) for BCC, 14 (95% CI, 12-16) per 1000 person-years for SCC, and 2 (95% CI, 1-3) per 1000 person-years for melanoma. More men than women developed a subsequent skin cancer (738 [61%] vs 463 [39%]). The main risk factors were a history of multiple tumors before diagnosis (relative risk [RR], 4.6; 95% CI, 2.9-7.1), immunosuppression (RR, 2.1; 95% CI, 1.4-3.1), and male sex (RR, 1.6; 95% CI, 1.4-1.9). CONCLUSION: Patients have an increased risk of developing a second tumor after MMS treatment of NMSC. Risk factors are a history of multiple tumors at diagnosis, immunosuppression, and male sex.

Non-invasive clinical and microscopic evaluation of the response to treatment with clobetasol cream vs. calcipotriol/betamethasone dipropionate foam in mild to moderate plaque psoriasis: an investigator-initiated, phase IV, unicentric, open, randomized clinical trial.

BACKGROUND: Treatment response for psoriasis is typically evaluated using clinical scores. However, patients can relapse after clinical clearance, suggesting persistent inflammation. Dermoscopy, reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) can non-invasively improve treatment response assessment. OBJECTIVES: To compare the clinical and non-invasive microscopic features in a psoriatic target lesion treated with clobetasol cream or calcipotriol/betamethasone dipropionate foam (Cal/BD foam). METHODS: Prospective, unicentric, open, randomized clinical trial comparing clinical data [total clinical score (TCS)] and microscopic data (dermoscopy, RCM and OCT) in psoriasis patients treated with clobetasol or Cal/BD foam. RESULTS: We included 36 adult patients (22 men). At week 4, more patients treated with Cal/BD foam achieved TCS ≤1 than with clobetasol (63.2% vs. 18.8%, P = 0.016). Treatment satisfaction was higher with Cal/BD foam (P < 0.03). Microscopically, Cal/BD foam induced more reduction in epidermal thickness at week 4 (P < 0.049). Dilated horizontal blood vessels were more common with clobetasol than with Cal/BD foam at week 8 (69.2% vs. 31.2%, P = 0.159). If epidermal hyperplasia was noted at baseline, the response was poorer with clobetasol (P = 0.029). LIMITATIONS: Small sample size, open study, imaging sampling bias. CONCLUSION: Cal/BD foam is more effective than clobetasol, has better patient satisfaction and induces greater reduction in the hyperkeratosis/acanthosis, regardless of baseline epidermal hyperplasia.

Parental Age in Relation to Offspring's Neurodevelopment.

Objective: Advanced parenthood increases the risk of severe neurodevelopmental disorders like autism, Down syndrome and schizophrenia. Does advanced parenthood also negatively impact offspring's general neurodevelopment?Method: We analyzed child-, father-, mother- and teacher-rated attention-problems (N = 38,024), and standardized measures of intelligence (N = 10,273) and educational achievement (N = 17,522) of children from four Dutch population-based cohorts. The mean age over cohorts varied from 9.73-13.03. Most participants were of Dutch origin, ranging from 58.7%-96.7% over cohorts. We analyzed 50% of the data to generate hypotheses and the other 50% to evaluate support for these hypotheses. We aggregated the results over cohorts with Bayesian research synthesis.Results: We mostly found negative linear relations between parental age and attention-problems, meaning that offspring of younger parents tended to have more attention problems. Maternal age was positively and linearly related to offspring's IQ and educational achievement. Paternal age showed an attenuating positive relation with educational achievement and an inverted U-shape relation with IQ, with offspring of younger and older fathers at a disadvantage. Only the associations with maternal age remained after including SES. The inclusion of child gender in the model did not affect the relation between parental age and the study outcomes.Conclusions: Effects were small but significant, with better outcomes for children born to older parents. Older parents tended to be of higher SES. Indeed, the positive relation between parental age and offspring neurodevelopmental outcomes was partly confounded by SES.

Study on the dopant concentration ratio in thulium-holmium doped silica fibers for lasing at 2.1µm.

We present the fabrication and laser performance of thulium-holmium co-doped silica fibers when cladding pumped at ∼790 nm. By using the hybrid gas phase-solution doping process in conjunction with the MCVD preform fabrication technique, the doping concentration and the Tm:Ho ratio were varied to study the energy transfer efficiency from Tm3+ to Ho3+. Our study indicates that for a thulium concentration that has resulted in an efficient two-for-one cross- relaxation process with 790 nm pumping, and while maintaining a Tm:Ho concentration ratio in the range ∼ 10 to 20, the energy transfer efficiency has reached above 75%. In a free-running laser cavity, the pump power limited laser output of 38W with a slope efficiency of 56% at 2.1 microns is demonstrated.

Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways.

BACKGROUND: The malignant mechanisms that control the development of cutaneous T-cell lymphoma (CTCL) are beginning to be identified. Recent evidence suggests that disturbances in specific intracellular signalling pathways, such as RAS-mitogen-activated protein kinase, T-cell receptor (TCR)-phospholipase C gamma 1 (PLCG1)-nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL. OBJECTIVES: To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL. METHODS: We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin-fixed paraffin-embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR-PLCG1-NFAT, JAK-STAT and NF-κB pathways. Folliculotropism and large-cell transformation were also examined. RESULTS: NFAT and nuclear factor kappa B (NF-κB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large-cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF-negative cases. A significant association of NFAT with NF-κB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T-cell leukaemia/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell-survival pathways. A higher mutational allele frequency was detected in advanced stages. CONCLUSIONS: Our results show that STAT3 is activated in advanced cases and is associated with large-cell transformation, while the activation of NFAT and NF-κB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications. What's already known about this topic? Mycosis fungoides is characterized by a clonal expansion of T cells in the skin. The mechanisms controlling disease development and progression are not fully understood. What does this study add? An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level. Signal transducer and activator of transcription 3 activation was associated with large-cell transformation and was more frequent in advanced stages. A genomic analysis of cutaneous T-cell lymphoma-associated genes was performed. Nine mutations were detected. What is the translational message? These results could have important implications for the treatment of MF in the near future.

Management strategies to minimize the use of synthetic chemical acaricides in the control of the cattle tick Rhipicephalus (Boophilus) microplus (Canestrini, 1888) in an area highly favourable for its development in Argentina.

The aim of this work was to test the efficacy of winter-spring control strategies against Rhipicephalus (Boophilus) microplus (Canestrini, 1888) (Ixodida: Ixodidae) in an area highly favourable for its development in Argentina. Control schemes using three or four annual applications of synthetic acaricides were evaluated. Furthermore, the dynamics of the non-parasitic phases of R. microplus were analysed to provide a framework for the application of pasture spelling as a tool for tick control. The treatment schemes provided appropriate levels of efficacy against R. microplus and also prevented the occurrence of the major peak in abundance of this tick in autumn. A significant overall effect against R. microplus can be achieved when the control strategies tested in this study are applied within the area most ecologically favourable for this tick in Argentina. Analysis of the dynamics of the non-parasitic phase of R. microplus indicates that the spelling period required to achieve a significant reduction of larvae in pastures fluctuates between 12 and 17 weeks if spelling is initiated in spring or early summer, but between 20 and 28 weeks if spelling is started in late summer, autumn or winter.

Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms.

Human induced pluripotent stem cells (hiPSCs) have transformed conventional drug discovery pathways in recent years. In particular, recent advances in hiPSC biology, including organoid technologies, have highlighted a new potential for neural drug discovery with clear advantages over the use of primary tissues. This is important considering the financial and social burden of neurological health care worldwide, directly impacting the life expectancy of many populations. Patient-derived iPSCs-neurons are invaluable tools for novel drug-screening and precision medicine approaches directly aimed at reducing the burden imposed by the increasing prevalence of neurological disorders in an aging population. 3-Dimensional self-assembled or so-called 'organoid' hiPSCs cultures offer key advantages over traditional 2D ones and may well be gamechangers in the drug-discovery quest for neurological disorders in the coming years.

Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial.

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.

Highly efficient thulium-doped high-power laser fibers fabricated by MCVD.

We report a hybrid process by combining both vapor-phase and solution-doping techniques of rare-earth doped preform fabrication in conjunction with the MCVD technique, in order to fabricate highly efficient Tm-doped laser fibers. The proposed fabrication route takes advantage of co-doping silica with high alumina content through the vapor-phase doping process, which is otherwise difficult to achieve using conventional solution doping technique. In addition, by employing the solution doping method, high-purity thulium halide precursors that have low vapor pressures up to several hundred degree Celsius. These high-purity thulium halide precursors can be used to dope the fiber core region with a high thulium concentration that is optimized for an efficient two-for-one cross-relaxation process for 79xnm diode pumped thulium-doped fiber laser. Fibers fabricated using the hybrid approach show more homogeneous and flat-top dopant profiles, compared with the conventional approach, where both aluminum and thulium are incorporated in the core through solution doping. This will ensure that more doped region will take part in the cross-relaxation process. Superior laser performance with a slope efficiency of >70% in the two-micron band has been demonstrated when diode pumped at ~790nm.

Association of dry matter intake and energy balance prepartum and postpartum with health disorders postpartum: Part II. Ketosis and clinical mastitis.

The main objective of this study was to determine the association of dry matter intake as percentage of body weight (DMI%BW) and energy balance (EB) prepartum (-21 d relative to parturition) and postpartum (28 d) with ketosis (n = 189) and clinical mastitis (n = 79). For this, DMI%BW and EB were the independent variables and ketosis and clinical mastitis were the dependent variables. A secondary objective was to evaluate prepartum DMI%BW and EB as predictors of ketosis and clinical mastitis. For this, ketosis and clinical mastitis were the independent variables and DMI%BW and EB were the dependent variables. Data from 476 cows from 9 experiments were compiled. Clinical mastitis was diagnosed if milk from 1 or more quarters was abnormal in color, viscosity, or consistency, with or without accompanying heat, pain, redness, or swelling of the quarter or generalized illness, during the first 28 d postpartum. Ketosis was defined as the presence of acetoacetate in urine that resulted in any color change [5 mg/dL (trace) or higher] in the urine test strip (Ketostix, Bayer, Leverkusen, Germany). Cows that developed ketosis had lesser DMI%BW and lesser EB on d -5, -3, -2, and -1 than cows without ketosis. Each 0.1-percentage point decrease in the average DMI%BW and each 1-Mcal decrease in the average of EB in the last 3 d prepartum increased the odds of having ketosis by 8 and 5%, respectively. Cut-offs for DMI%BW and EB during the last 3 d prepartum to predict ketosis were established and were ≤1.5%/d and ≤1.1 Mcal/d, respectively. Cows that developed ketosis had lesser postpartum DMI%BW and EB and greater energy-corrected milk (ECM) than cows without ketosis. Cows that developed clinical mastitis had lesser DMI%BW but similar prepartum EB compared with cows without clinical mastitis. Each 0.1-percentage point decrease in the average DMI%BW and each 1-Mcal decrease in the average EB in the last 3 d prepartum increased the odds of having clinical mastitis by 10 and 8%, respectively. The average DMI%BW and EB during the last 3 d prepartum produced significant cut-offs to predict clinical mastitis postpartum, which were ≤1.2%/d and ≤1.0 Mcal/d, respectively. Cows that developed clinical mastitis had lesser postpartum DMI%BW from d 3 to 15 and on d 17; greater EB on d 18, from d 21 to 23, and on d 26; and lesser ECM. The main limitation in this study is that the time-order of disease relative to DMI%BW and ECM is inconsistent such that postpartum outcomes were measured before and after disease, which was diagnosed at variable intervals after calving. In summary, measures of prepartum DMI were associated with and were predictors of ketosis and clinical mastitis postpartum, although the effect sizes were small.

Association of dry matter intake and energy balance prepartum and postpartum with health disorders postpartum: Part I. Calving disorders and metritis.

The main objective of this study was to determine the association of dry matter intake as percentage of body weight (DMI%BW) and energy balance (EB) prepartum (-21 d relative to parturition) and postpartum (28 d) with calving disorders (CDZ; dystocia, twins, and stillbirths; n = 101) and metritis (n = 114). For this, DMI%BW and EB were the independent variables and CDZ and metritis were the dependent variables. A secondary objective was to evaluate prepartum DMI%BW and EB as predictors of CDZ and metritis. For this, CDZ and metritis were the independent variables and DMI%BW and EB were the dependent variables. Data from 476 cows from 9 experiments were compiled. Cows that developed CDZ had lesser postpartum DMI%BW from d 3 to 12 and lesser energy-corrected milk (ECM) than cows that did not develop CDZ. Dry matter intake as percentage of BW and EB prepartum did not affect the odds of CDZ. Cows with metritis had lesser prepartum DMI%BW and EB. Each 0.1-percentage point decrease in the average DMI%BW and each 1-Mcal decrease in the average EB in the last 3 d prepartum increased the odds of having metritis by 8%. The average DMI%BW and EB during the last 3 d prepartum produced significant cut-offs to predict metritis postpartum, which were ≤1.6%/d and ≤2.5 Mcal/d, respectively. Cows that developed metritis had lesser overall postpartum DMI%BW and ECM and lesser EB from d 2 to 5 and from d 7 to 11 than cows that did not develop metritis. The main limitation in this study is that the time-order of disease relative to DMI%BW and ECM is inconsistent such that postpartum outcomes were measured before and after disease, which was diagnosed at variable intervals after calving. In summary, prepartum DMI%BW and EB were associated with and were predictors of metritis although the effect sizes were small for metritis, and calving disorders and metritis were associated with decreased DMI%BW and ECM postpartum.

Microdeletion 22q11.2 syndrome: Does thymus incidental surgical resection affect its immunological profile?

BACKGROUND: The del22q11 syndrome patients present immunological abnormalities associated to thymus alterations. Up to 75% of them present cardiopathies and thymus is frequently removed during surgery. The thymectomy per se has a deleterious effect concerning lymphocyte subpopulations, and T cell function. When compared to healthy controls, these patients have higher infections propensity of variable severity. The factors behind these variations are unknown. We compared immunological profiles of del22q11.2 Syndrome patients with and without thymectomy to establish its effect in the immune profile. METHODS: Forty-six del22q11.2 syndrome patients from 1 to 16 years old, 19 of them with partial or total thymectomy were included. Heart disease type, heart surgery, infections events and thymus resection were identified. Immunoglobulin levels, flow cytometry for lymphocytes subpopulations and TREC levels were determined, and statistical analyses were performed. RESULTS: The thymectomy group had a lower lymphocyte index, both regarding total cell count and when comparing age-adjusted Z scores. Also, CD3+, CD4+ and CD8+ lower levels were observed in this group, the lowest count in those patients who had undergone thymus resection during the first year of life. Their TREC level median was 23.6/µL vs 16.1µL in the non-thymus group (p=0.22). No differences were identified regarding immunoglobulin levels or infection events frequencies over the previous year. CONCLUSION: Patients with del22q11.2 syndrome subjected to thymus resection present lower lymphocyte and TREC indexes when compared to patients without thymectomy. This situation may be influenced by the age at the surgery and the time elapsed since the procedure.

Hippocampal mechanisms in impaired spatial learning and memory in male offspring of rats fed a low-protein isocaloric diet in pregnancy and/or lactation.

Maternal nutritional challenges during fetal and neonatal development result in developmental programming of multiple offspring organ systems including brain maturation and function. A maternal low-protein diet during pregnancy and lactation impairs associative learning and motivation. We evaluated effects of a maternal low-protein diet during gestation and/or lactation on male offspring spatial learning and hippocampal neural structure. Control mothers (C) ate 20% casein and restricted mothers (R) 10% casein, providing four groups: CC, RR, CR, and RC (first letter pregnancy, second lactation diet). We evaluated the behavior of young adult male offspring around postnatal day 110. Corticosterone and ACTH were measured. Males were tested for 2 days in the Morris water maze (MWM). Stratum lucidum mossy fiber (MF) area, total and spine type in basal dendrites of stratum oriens in the hippocampal CA3 field were measured. Corticosterone and ACTH were higher in RR vs. CC. In the MWM acquisition test CC offspring required two, RC three, and CR seven sessions to learn the maze. RR did not learn in eight trials. In a retention test 24 h later, RR, CR, and RC spent more time locating the platform and performed fewer target zone entries than CC. RR and RC offspring spent less time in the target zone than CC. MF area, total, and thin spines were lower in RR, CR, and RC than CC. Mushroom spines were lower in RR and RC than CC. Stubby spines were higher in RR, CR, and RC than CC. We conclude that maternal low-protein diet impairs spatial acquisition and memory retention in male offspring, and that alterations in hippocampal presynaptic (MF), postsynaptic (spines) elements and higher glucocorticoid levels are potential mechanisms to explain these learning and memory deficits.

A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade.

Background: The presence of stromal tumor-infiltrating lymphocytes (TILs) is associated with increased pathologic complete response (pCR) and improved outcomes in HER2-positive early-breast cancer (BC) treated with anti-HER2-based chemotherapy. In the absence of chemotherapy, the association of TILs with pCR following anti-HER2 therapy-only is largely unknown. Patients and methods: The PAMELA neoadjuvant trial treated 151 women with HER2-positive BC with lapatinib and trastuzumab [and hormonal therapy if hormone receptor (HR)-positive] for 18 weeks. Percentage of TILs and tumor cellularity were determined at baseline (N = 148) and at day 15 (D15) of treatment (N = 134). Associations of TILs and tumor cellularity with pCR in the breast were evaluated. A combined score based on tumor cellularity and TILs (CelTIL) measured at D15 was derived in PAMELA, and validated in D15 samples from 65 patients with HER2-positive disease recruited in the LPT109096 neoadjuvant trial, where anti-HER2 therapy-only was administer for 2 weeks, then standard chemotherapy was added for 24 weeks. Results: In PAMELA, baseline and D15 TILs were significantly associated with pCR in univariate analysis. In multivariable analysis, D15 TILs, but not baseline TILs, were significantly associated with pCR. At D15, TILs and tumor cellularity were found independently associated with pCR. A combined score (CelTIL) taking into account both variables was derived. CelTIL at D15 as a continuous variable was significantly associated with pCR, and patients with CelTIL-low and CelTIL-high scores had a pCR rate of 0% and 33%, respectively. In LPT109096, CelTIL at D15 was found associated with pCR both as a continuous variable and as group categories using a pre-defined cut-off (75.0% versus 33.3%). Conclusions: On-treatment TILs, but not baseline TILs, are independently associated with response following anti-HER2 therapy-only. A combined score of TILs and tumor cellularity measured at D15 provides independent predictive information upon completion of neoadjuvant anti-HER2-based therapy. Clinical trial number: NCT01973660.

Van der Waals Spin Valves.

We propose spin valves where a 2D nonmagnetic conductor is intercalated between two ferromagnetic insulating layers. In this setup, the relative orientation of the magnetizations of the insulating layers can have a strong impact on the in-plane conductivity of the 2D conductor. We first show this for a graphene bilayer, described with a tight-binding model, placed between two ferromagnetic insulators. In the antiparallel configuration, a band gap opens at the Dirac point, whereas in the parallel configuration, the graphene bilayer remains conducting. We then compute the electronic structure of graphene bilayer placed between two monolayers of the ferromagnetic insulator CrI_{3}, using density functional theory. Consistent with the model, we find that a gap opens at the Dirac point only in the antiparallel configuration.

The effect of pH on the dynamics of natural membranes.

Pure phospholipids and membrane fragments from bacterial cells living under various conditions were studied against the influence of the surrounding acidity on the internal dynamics. For that we compared mean square displacements extracted from elastic incoherent neutron scattering data, measured both at low and at neutral pH, of the phospholipids 1,2-dimyristoyl-sn-glycero-3-phosphocholine and of samples from neutralophilic and acidophilic micro-organisms (some being hyperthermophilic and others mesophilic). The lipids showed a slight shift in the phase transition temperature of about 4 degrees under pH variation and became slightly more mobile at lower pH. The membrane fragments not used to extreme acidic conditions were significantly more sensitive to variations in the pH values, whereas the acidophilic and -tolerant samples were much less influenced by this parameter. They presented the higher softness at low pH, which was closer to their native condition. Such findings might be a hint for adaptation mechanisms to different acidity conditions.

Mohs micrographic surgery in the elderly: comparison of tumours, surgery and first-year follow-up in patients younger and older than 80 years old in REGESMOHS.

BACKGROUND: The elderly population is increasing and more patients in this group undergo Mohs micrographic surgery (MMS). The few publications investigating MMS in elderly people conclude that it is a safe procedure; however, these are single-centre studies without a comparison group. OBJECTIVE: To compare the characteristics of patients, tumours, MMS and 1-year follow-up in patients younger than 80 years, with patients older than 80 years at the time of surgery. METHODS: Data was analysed from REGESMOHS, a prospective cohort study of patients treated with MMS. The participating centres were 19 Spanish hospitals where at least one MMS is performed per week. Data on characteristics of the patient, tumour and surgery were recorded. Follow-up data were collected from two visits; the first within 1 month postsurgery and the second within the first year. RESULTS: From July 2013 to October 2016, 2575 patients that underwent MMS were included in the registry. Of them, 1942 (75.4%) were aged <80 years and 633 (24.6%) were ≥80 years old. In the elderly, the tumour size was significantly higher with a higher proportion of squamous cell carcinoma. Regarding surgery, elderly more commonly had tumours with deeper invasion and required a higher number of Mohs surgery stages, leaving larger defects and requiring more time in the operating room. Despite this, the incidence of postoperative complications was the same in both groups (7%) and there were no significant differences in proportion of relapses in the first-year follow-up. CONCLUSION: The risk of short-term complications and relapses were similar in elderly and younger groups. MMS is a safe procedure in the elderly.

Effects of prepartum dietary cation-anion difference and source of vitamin D in dairy cows: Lactation performance and energy metabolism.

The objectives of this experiment were to evaluate the effects of feeding diets with 2 dietary cation-anion difference (DCAD) levels and supplemented with either cholecalciferol (CH) or calcidiol (CA) during late gestation on lactation performance and energetic metabolism in dairy cows. The hypothesis was that combining a prepartum acidogenic diet with calcidiol supplementation would benefit peripartum Ca metabolism and, thus, improve energy metabolism and lactation performance compared with cows fed an alkalogenic diet or cholecalciferol. Holstein cows at 252 d of gestation were blocked by parity (28 nulliparous and 51 parous cows) and milk yield within parous cows, and randomly assigned to 1 of 4 treatments arranged as a 2 × 2 factorial, with 2 levels of DCAD (positive, +130, and negative, -130 mEq/kg) and 2 sources of vitamin D, CH or CA, fed at 3 mg per 11 kg of diet dry matter (DM). The resulting treatment combinations were positive DCAD with CH (PCH), positive DCAD with CA (PCA), negative DCAD with CH (NCH), or negative DCAD with CA (NCA), which were fed for the last 21 d of gestation. After calving, cows were fed the same lactation diet. Body weight and body condition were evaluated prepartum and for the first 49 d postpartum. Blood was sampled thrice weekly prepartum, and on d 0, 1, 2, 3, and every 3 d thereafter until 30 d postpartum for quantification of hormones and metabolites. Lactation performance was evaluated for the first 49 d postpartum. Feeding a diet with negative DCAD reduced DM intake in parous cows by 2.1 kg/d, but no effect was observed in nulliparous cows. The negative DCAD reduced concentrations of glucose (positive = 4.05 vs. negative = 3.95 mM), insulin (positive = 0.57 vs. negative = 0.45 ng/mL), and insulin-like growth factor-1 (positive = 110 vs. negative = 95 ng/mL) prepartum. Treatments did not affect DM intake postpartum, but CA-supplemented cows tended to produce more colostrum (PCH = 5.86, PCA = 7.68 NCH = 6.21, NCA = 7.96 ± 1.06 kg) and produced more fat-corrected milk (PCH = 37.0, PCA = 40.1 NCH = 37.5, NCA = 41.9 ± 1.8 kg) and milk components compared with CH-supplemented cows. Feeding the negative DCAD numerically increased yield of fat-corrected milk by 1.0 kg/d in both nulliparous and 1.4 kg/d in parous cows. Minor differences were observed in postpartum concentrations of hormones and metabolites linked to energy metabolism among treatments. Results from this experiment indicate that replacing CH with CA supplemented at 3 mg/d during the prepartum period improved postpartum lactation performance in dairy cows.