A Review of Deep Learning Methods for Antibodies.

Driven by its successes across domains such as computer vision and natural language processing, deep learning has recently entered the field of biology by aiding in cellular image classification, finding genomic connections, and advancing drug discovery. In drug discovery and protein engineering, a major goal is to design a molecule that will perform a useful function as a therapeutic drug. Typically, the focus has been on small molecules, but new approaches have been developed to apply these same principles of deep learning to biologics, such as antibodies. Here we give a brief background of deep learning as it applies to antibody drug development, and an in-depth explanation of several deep learning algorithms that have been proposed to solve aspects of both protein design in general, and antibody design in particular.

Role of family caregivers regarding sexual and reproductive health for women and girls with intellectual disability: A scoping review.

BACKGROUND: While people with intellectual disability (ID) face disparities relating to sexual and reproductive health (SRH) services, little is known about the role of family caregivers who assist women and girls with ID access SRH services. This scoping review examined the findings of studies to elucidate the role of family caregivers with regard to SRH for women and girls with ID. METHOD: We used Arksey and O'Malley's six-stage scoping framework, with Levac, Colquhoun and O'Brien's revisions, to evaluate identified sources. We searched three electronic databases, six ID journals and reference lists in full-text articles. Inclusion criteria included (1) primary and secondary source research studies in peer-reviewed journals; (2) published in English; (3) all research methodologies (i.e. qualitative, quantitative, mixed methods and systematic reviews or commentaries); (4) published between 2000 and 2016; and (5) studies from any country. RESULTS: The search yielded 2062 studies; 57 articles met inclusion criteria. Most studies employed purposive, convenience or criterion sampling. Participants included people with ID, family caregivers, paid caregivers and health-care professionals. Findings were summarised thematically: (1) menstruation and menopause; (2) vaccinations and preventive screenings; (3) supporting sexuality and healthy relationships; (4) coordinating with health-care providers and (5) contraception and sterilisation. CONCLUSIONS: Findings from this scoping review underscore the need for more and better-quality research, including how family caregivers assist women and girls with ID access perinatal and preventive SRH services and sexual abuse education. Family caregivers, women and girls with ID and health-care providers need increased access to information about SRH.

Racial and ethnic disparities in birth outcomes and labour and delivery-related charges among women with intellectual and developmental disabilities.

BACKGROUND: Women with intellectual and developmental disabilities (IDD) in the USA are bearing children at increasing rates. However, very little is known whether racial and ethnic disparities in birth outcomes and labour and delivery-related charges exist in this population. This study investigated racial and ethnic disparities in birth outcomes and labour and delivery-related charges among women with IDD. METHODS: The study employed secondary analysis of the 2004-2011 Healthcare Cost and Utilization Project National Inpatient Sample, the largest all-payer, publicly available US inpatient healthcare database. Hierarchical mixed-effect logistic and linear regression models were used to compare the study outcomes. RESULTS: We identified 2110 delivery-associated hospitalisations among women with IDD including 1275 among non-Hispanic White women, 527 among non-Hispanic Black women and 308 among Hispanic women. We found significant disparities in stillbirth among non-Hispanic Black and Hispanic women with IDD compared with their non-Hispanic White peers [odds ratio = 2.50, 95% confidence interval (CI): 1.16-5.28, P < 0.01 and odds ratio = 2.53, 95% CI: 1.08-5.92, P < 0.01, respectively]. There were no racial and ethnic disparities in caesarean delivery, preterm birth and small-for-gestational-age neonates among women with IDD. The average labour and delivery-related charges for non-Hispanic Black and Hispanic Women with IDD ($18 889 and $22 481, respectively) exceeded those for non-Hispanic White women with IDD ($14 886) by $4003 and $7595 or by 27% and 51%, respectively. The significant racial and ethnic differences in charges persisted even after controlling for a range of individual-level and institutional-level characteristics and were 6% (ln(ß) = 0.06, 95% CI: 0.01-0.11, P < 0.05) and 9% (ln(ß) = 0.09, 95% CI: 0.03-0.14, P < 0.01) higher for non-Hispanic Black and Hispanic Women with IDD compared with non-Hispanic White women with IDD. CONCLUSIONS: Our findings highlight the need for an integrated approach to the delivery of comprehensive perinatal services for racial and ethnic minority women with IDD to reduce their risk of having a stillbirth. Additionally, further research is needed to examine the causes of racial and ethnic disparities in hospital charges for labour and delivery admission among women with IDD and ascertain whether price discrimination exists based on patients' racial or ethnic identities.

Sexual well-being after menopause: An International Menopause Society White Paper.

Sexual well-being frequently declines following the menopause transition and can be associated with significant personal and relationship distress. This distress is the hallmark of female sexual dysfunction (FSD). FSD is highly prevalent in postmenopausal women. The prevalence of sexual problems increases with age, but conversely this is associated with decreasing distress with advancing age. This pattern has been seen across multiple international populations with varied cultural norms. While the etiology of FSD is multifactorial, the physiological changes of sex hormone insufficiency and postmenopausal symptoms, such as dyspareunia, are primary factors contributing to FSD at midlife. The International Menopause Society is working to increase awareness of FSD and to provide a framework for practitioners to address sexual medicine concerns. This White Paper aims to review the process of care for female sexual well-being following menopause, from initially approaching the discussion of FSD, to identifying clinical signs and symptoms, and ultimately determining the best available biopsychosocial therapies. As with most processes of care, the first step is often the most difficult. Health-care practitioners need to broach the topic of sexuality in the clinical setting. Lack of information on, comfort with, and biases about the topic of sexuality after menopause are significant hurdles that the International Menopause Society addresses in this document. Each member of the Writing Group remains committed to continued advocacy for the validity of FSD as a diagnosis, the need for therapies for women to be both available and included in health insurance coverage, and continued therapeutic research to provide evidence-based solutions.

Reduced satellite cell density and myogenesis in Wagyu compared with Angus cattle as a possible explanation of its high marbling.

Mechanisms responsible for excellent marbling in Japanese black cattle, Wagyu, remain to be established. Because both muscle cells and intramuscular adipocytes are developed from mesenchymal progenitor cells during early muscle development, we hypothesized that intramuscular progenitor cells in Wagyu cattle have attenuated myogenic capacity in favor of adipogenesis, leading to high marbling but reduced muscle growth. Biceps femoris muscle biopsy samples were obtained from both Angus (n=3) and Wagyu (n=3) cattle at 12 months of age. Compared with Angus, the density of satellite cells was much lower in Wagyu muscle (by 45.8±10%, P<0.05). Consistently, the formation of myotubes from muscle-derived progenitor cells was also lower (by 64.2±12.9%, P<0.05), but adipogenic capacity was greater in Wagyu. The average muscle fiber diameter was larger in Wagyu (by 23.9±6.8%, P=0.089) despite less muscle mass, suggesting less muscle fiber formation in Wagyu compared with Angus cattle. Because satellite cells are derived from fetal myogenic cells, the reduction in satellite cell density together with lower muscle fiber formation suggests that myogenesis was attenuated during early muscle development in Wagyu cattle. Given the shared pool of mesenchymal progenitor cells, the attenuated myogenesis likely shifts progenitor cells to adipogenesis during early development, which may contribute to high intramuscular adipocyte formation in Wagyu cattle.

Behavioural and cognitive outcomes in young children of mothers with intellectual impairments.

BACKGROUND: Despite an increase in international studies examining the experiences of parents with intellectual impairments and their children, few have utilised population-based data. This study investigated the behavioural and cognitive outcomes of 3-year-old US children of mothers with intellectual impairments compared with children of mothers without intellectual impairments. METHODS: This study employed a secondary analysis of the Fragile Families Child and Wellbeing Study, a longitudinal birth cohort study in the US. Our analytic sample included mothers with intellectual impairments (n = 263) and a comparison group of mothers without intellectual impairments (n = 1298), as well as each sampled mother's focal child. When weighted, Fragile Families is representative of all births in US cities with populations over 200 000. RESULTS: Children of mothers with intellectual impairments had poorer behavioural and cognitive outcomes in comparison to same-age children of mothers without intellectual impairments. Notably, however, children of mothers with intellectual impairments were not at increased risk of being aggressive unless their family income was below 200% of the federal poverty level. Further, families headed by mothers with intellectual impairments experienced multiple hardships related to socioeconomic factors, limited social supports and poor self-reported health. CONCLUSION: Appropriate policies and programmes must be developed and implemented to effectively support these families, such as increased financial benefits.

Functional severity and Latino ethnicity in specialty services for children with autism spectrum disorder.

BACKGROUND: Children with autism spectrum disorder (ASD) experience a range of severity levels characterised as levels of support they need for everyday functioning. By this definition, greater levels of severity should warrant greater use of services and supports among children with ASD. In previous studies, Latino children with ASD in the USA have been shown to have lower access to diagnosis and treatment services than White children. However, none have examined service use in relation to severity. In this study, we examined whether there are ethnic disparities between Latino and White children with ASD in specialty autism-related services, and whether functional severity moderates the relationship between ethnicity and receipt of autism services. METHODS: We used data from the Survey of Pathways to Diagnosis and Services, a supplement to the National Survey of Children with Special Health Care Needs and analysed four specialty services commonly used by children with ASD, adjusting for demographic variables. RESULTS: We found that Latino children with ASD who had severe limitations received fewer specialty autism-related services than White children with similarly severe conditions. These disparities were evident despite the fact that the sample of Latino children in these data were more privileged than the general US Latino population. CONCLUSION: Assertive policy initiatives are needed to address these disparities and ensure that these highly vulnerable children with severe functional limitations receive appropriate services and supports.

Enhanced mitogenesis in stromal vascular cells derived from subcutaneous adipose tissue of Wagyu compared with those of Angus cattle.

Japanese Wagyu cattle are well known for their extremely high marbling and lower subcutaneous adipose tissue compared with Angus cattle. However, mechanisms for differences in adipose deposition are unknown. The objective of this paper was to evaluate breed differences in the structure of subcutaneous adipose tissue, adipogenesis, and mitogenesis of stromal vascular (SV) cells between Wagyu and Angus cattle. Subcutaneous biopsy samples were obtained from 5 Wagyu (BW = 302 ± 9 kg) and 5 Angus (BW = 398 ± 12 kg) heifers at 12 mo of age, and samples were divided into 3 pieces for histological examination, biochemical analysis, and harvest of SV cells. Adipogenesis of SV cells was assessed by the expression of adipogenic markers and Oil Red-O staining, while mitogenesis was evaluated by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium dromide) test, phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB; AKT). Based on histological analysis, Wagyu had larger adipocytes compared with Angus. At the tissue level, protein expression of peroxisome proliferator-activated receptor γ (PPARG) in Wagyu was much lower compared with that of Angus. Similarly, a lower mRNA expression of PPARG was found in Wagyu SV cells. No significant difference was observed for the zinc finger protein 423 (ZNF423) expression between Wagyu and Angus. As assessed by Oil Red-O staining, Wagyu SV cells possessed a notable trend of lower adipogenic capability. Interestingly, higher mitogenic ability was discovered in Wagyu SV cells, which was associated with an elevated phosphorylation of ERK1/2. There was no difference in AKT phosphorylation of SV cells between Wagyu and Angus. Moreover, exogenous fibroblast growth factor 2 (FGF2) enhanced mitogenesis and ERK1/2 phosphorylation of SV cells to a greater degree in Angus compared with that in Wagyu. Expression of transforming growth factor ß 3 (TGFB3) and bone morphogenetic protein 2 (BMP2) in Wagyu SV cells was lower than that of Angus, providing potential clues for breed differences on proliferation of SV cells in these two cattle breeds. The results of this study suggest that subcutaneous adipose-derived SV cells of Wagyu possess a lower trend of adipogenesis but higher mitogenesis compared with those of Angus.

Test of an intervention to improve knowledge of women with intellectual disabilities about cervical and breast cancer screening.

BACKGROUND: There is a critical need for evidence-based health education interventions for women with intellectual disabilities (IDs) to promote receipt of preventive health screenings. Previous research has established Women Be Healthy, an 8-week classroom-style intervention designed to teach women with IDs about breast and cervical cancer screenings, as a promising practice. However, additional research is needed to determine how to further improve screening-related knowledge gains. This study aimed to test a modified version of Women Be Healthy, Women Be Healthy 2, and compare its effectiveness in increasing knowledge gains to the original intervention. METHOD: Women living in the community across one state in the United States were randomly assigned to a treatment (n = 98), delayed treatment, (n = 35), or no intervention group (n = 65). Women in the treatment group received Women Be Healthy, and women in the delayed treatment group received the modified Women Be Healthy 2. Baseline and post-intervention interviews were conducted to measure knowledge of cervical and breast cancer screening. Knowledge scores were compared across groups. RESULTS: Among the nine knowledge items measured, one breast knowledge measure and one cervical knowledge measure showed statistically significant group differences; marginally significant differences were observed for two other knowledge measures. After adjusting for covariates, women who received Women Be Healthy 2 had increased knowledge overall compared with the women receiving no intervention. CONCLUSION: Women Be Healthy 2 is promising, but additional efforts appear necessary to increase the knowledge women with IDs have about cervical and breast cancer screening.

Mechanism of killing of spores of Bacillus anthracis in a high-temperature gas environment, and analysis of DNA damage generated by various decontamination treatments of spores of Bacillus anthracis, Bacillus subtilis and Bacillus thuringiensis.

AIMS: To determine how hydrated Bacillus anthracis spores are killed in a high-temperature gas environment (HTGE), and how spores of several Bacillus species including B. anthracis are killed by UV radiation, dry heat, wet heat and desiccation. METHODS AND RESULTS: Hydrated B. anthracis spores were HTGE treated at c. 220°C for 50 ms, and the treated spores were tested for germination, mutagenesis, rupture and loss of dipicolinic acid. Spores of this and other Bacillus species were also examined for mutagenesis by UV, wet and dry heat and desiccation. There was no rupture of HTGE-treated B. anthracis spores killed 90-99·9%, no mutagenesis, and release of DPA and loss of germination were much slower than spore killing. However, killing of spores of B. anthracis, Bacillus thuringiensis and Bacillus subtilis by UV radiation or dry heat, but not wet heat in water or ethanol, was accompanied by mutagenesis. CONCLUSIONS: It appears likely that HTGE treatment kills B. anthracis spores by damage to spore core proteins. In addition, various killing regimens inactivate spores of a number of Bacillus species by the same mechanisms. SIGNIFICANCE AND IMPACT OF THE STUDY: This work indicates how hydrated spores treated in a HTGE such as might be used to destroy biological warfare agent stocks are killed. The work also indicates that mechanisms whereby different agents kill spores are similar with spores of different Bacillus species.

Impact of lipoprotein(a) levels and apolipoprotein(a) isoform size on risk of coronary heart disease.

OBJECTIVES: Observational and genetic studies have shown that lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] isoform size are both associated with coronary heart disease (CHD) risk, but the relative independence of these risk factors remains unclear. Clarification of this uncertainty is relevant to the potential of future Lp(a)-lowering therapies for the prevention of CHD. METHODS: Plasma Lp(a) levels and apo(a) isoform size, estimated by the number of kringle IV (KIV) repeats, were measured in 995 patients with CHD and 998 control subjects. The associations between CHD risk and fifths of Lp(a) levels were assessed before and after adjustment for KIV repeats and, conversely, the associations between CHD risk and fifths of KIV repeats were assessed before and after adjustment for Lp(a) levels. RESULTS: Individuals in the top fifth of Lp(a) levels had more than a twofold higher risk of CHD compared with those in the bottom fifth, and this association was materially unaltered after adjustment for KIV repeats [odds ratio (OR) 2.05, 95% confidence interval (CI) 1.38-3.04, P < 0.001]. Furthermore, almost all of the excess risk was restricted to the two-fifths of the population with the highest Lp(a) levels. Individuals in the bottom fifth of KIV repeats had about a twofold higher risk of CHD compared with those in the top fifth, but this association was no longer significant after adjustment for Lp(a) levels (OR 1.13, 95% CI 0.77-1.66, P = 0.94). CONCLUSIONS: The effect of KIV repeats on CHD risk is mediated through their impact on Lp(a) levels, suggesting that absolute levels of Lp(a), rather than apo(a) isoform size, are the main determinant of CHD risk.

Recruitment and consent of women with intellectual disabilities in a randomised control trial of a health promotion intervention.

BACKGROUND: The need for evidence-based health promotion interventions for women with intellectual and developmental disabilities is critical. However, significant barriers impede them from participating in research, including those related to recruitment and obtaining informed consent. METHODS: This study describes a procedure for the recruitment and consent of women with intellectual disabilities into a community-based, multi-site randomised controlled trial. RESULTS: Of 269 women who participated in information sessions, 203 (75%) enrolled in the study. While women with and without legal guardians consented at the same approximate rates (83% and 85%, respectively), those with legal guardians enrolled at significantly lower rates (61%) because of lower rates (74%) of guardian consent. CONCLUSIONS: It is possible to recruit community-dwelling women with intellectual disabilities into randomised controlled trials at relatively high participation rates. Recruiting women who have guardians poses additional challenges for researchers.

SLCO1B1 variants and statin-induced myopathy--a genomewide study.

BACKGROUND: Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications. METHODS: We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants. RESULTS: The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4x10(-9)). SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r(2)=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy. CONCLUSIONS: We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. (Current Controlled Trials number, ISRCTN74348595.)

Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors.

BACKGROUND: Cholesterol lowering with statins reduces the risk of vascular disease, but uncertainty remains as to whether more intensive statin therapy produces worthwhile benefits safely. Blood homocysteine level is an independent marker of vascular risk, but it is unknown whether this association is causal. METHODS AND RESULTS: 12,064 myocardial infarction survivors have been randomized to more versus less intensive cholesterol-lowering treatment using simvastatin 80 mg versus 20 mg daily. Allocation to more intensive treatment has yielded average further low-density lipoprotein cholesterol reductions of 0.5 mmol/L at 2 months and 0.4 mmol/L at 5 years. In addition, using a factorial design, these patients have been randomized to homocysteine lowering with folic acid 2 mg plus vitamin B12 1 mg daily versus matching placebo, yielding an average 3 to 4 mumol/L reduction in homocysteine. After 6 years of median follow-up, the annual overall rate of major vascular events is approximately 3%. Follow-up is scheduled to continue for a median of 7 years. CONCLUSION: SEARCH should provide reliable evidence about the efficacy and safety of prolonged use of more intensive cholesterol-lowering therapy and, separately, of folate-based homocysteine-lowering therapy in a high-risk population.

Biosecurity and biocontainment in alpaca operations.

Biosecurity on South American camelid operations involves both external and internal measures to prevent the introduction and spread of disease. External biosecurity involves practices and techniques directed at the prevention of entry of new diseases into a group of animals. Internal biosecurity or biocontainment, involves practices and techniques that are directed at the prevention or spread of disease within an existing group of animals. External biosecurity is particularly important in North America camelid operations due to the extensive movement of animals for breeding or show purposes. Internal biosecurity typically involves this the prevention and treatment of failure of passive transfer, maintenance of proper nutrition and housing, and the implementation of an appropriate vaccination program for endemic or relevant diseases. Attention to appropriate cleaning and disinfection procedures related to housing, feeding, and treatment equipment is important for the maintenance of both internal and external biosecurity practices. This paper discusses various risk factors associated with the control of infectious disease in the context of external and internal biosecurity measures in camelids operations.

Age-related innate immune response in calves to Babesia bovis involves IL-12 induction and IL-10 modulation.

There is a strong innate immunity in calves to infection with Babesia bovis. Interleukin (IL)-12 and IL-10 have been shown in vitro to be important immunoregulatory cytokines. Here we demonstrate in vivo that the protective innate response in young calves to infection with virulent B. bovis involves the early appearance of IL-12 and interferon-gamma (IFN-gamma) transcripts in the spleen. In contrast, IL-12 and IFN-gamma mRNA expression in the spleens of adult cattle that succumbed to the infection was delayed and depressed and occurred within the context of IL-10 expression. Also in contrast with calves, there was no detectable antibody response before death in adults. A vigorous CD8+ T-cell expansion occurred in the spleens of both calves and adults.

IL-4 and IL-10 inhibition of IFN-gamma- and TNF-alpha-dependent nitric oxide production from bovine mononuclear phagocytes exposed to Babesia bovis merozoites.

The requirement for IFN-gamma and/or TNF-alpha as co-stimulants with Babesia bovis merozoites for nitric oxide (NO) production was examined, as well as the regulatory role of IL-4 and IL-10. Purified B. bovis merozoites did not induce the production of NO in undifferentiated monocytes without addition of exogenous IFN-gamma and TNF-alpha unless the monocytes taken ex vivo were producing TNF-alpha endogenously. Under the latter condition, the NO production resulting from merozoite stimulation remained IFN-gamma-dependent. There was no evidence for endogenous synthesis of TNF-alpha in monocyte-derived macrophages (MDM), and merozoites alone were incapable of inducing TNF-alpha mRNA in MDM. However, while merozoites plus IFN-gamma induced TNF-alpha mRNA expression in MDM, NO was not produced. Both IL-4 and IL-10 inhibited expression of iNOS and production of NO in merozoite-stimulated monocytes.

Bovine neonatal immunology.

The majority of early, in utero immune development occurs independent of antigen exposure. Only later during development can a fetus respond to antigens, and even then the response depends on the stage of fetal development and the nature of the antigen. At birth, the neonate is rapidly exposed to large numbers of potential pathogens. Although immunocompetent, the neonate is immunonaive and dependent on passively acquired maternal immunoglobulins, immune cells, and other substances from colostrum for protection. Neonates that suffer failure of passive transfer of maternal immunoglobulins may be at increased risk for disease; however, many other factors interact in conjunction with the level of passively acquired immunoglobulin to determine the occurrence of disease. These include, but are not limited to, management, environment, hygiene, infection pressure, virulence of organisms, and antibody specificity. In addition to immunoglobulins, colostrum contains large numbers of immune cells and cytokines. It is thought that the primary role for the cellular component of colostrum is to interact with the development of local immunity and to modulate active immunization of the neonatal intestine. In particular, T lymphocytes are thought to transfer immune functions and secrete cytokines. Although most of the major cytokines have been identified in colostrum and milk, their biologic effects on the neonate have yet to be determined.