Infant and preschool attachment, continuity and relationship to caregiving sensitivity: findings from a new population-based Australian cohort.

BACKGROUND: Here, we report new prevalence and temporal stability data for child attachment and parental caregiving behaviour, from infancy (1 year) to preschool (4 years). METHODS: Attachment (SSP) and caregiving data (MBQS) were from observations of parents and their infants and preschoolers, who represent the third generation of participants within an Australian longitudinal cohort. RESULTS: At 1 year (n = 314 dyads) and at 4 years (n = 368 dyads), proportions assessed secure were 59% and 71%, respectively. Proportions assessed avoidant were 15% and 11%; ambivalent 9% and 6%, and disorganised 17% and 12%, at 1 and 4 years. Continuity of attachment pattern was highest for the infant secure group. Of dyads initially classified disorganised in infancy, 36% remained so at the preschool assessment. Attachment and caregiving continuities across the infancy-preschool period were highest for the stable secure attachment group and lowest for the stable insecure attachment group. Loss of secure attachment to mother by age 4 years correlated with decreased maternal caregiving sensitivity, and acquisition of secure status by age 4 was associated with increased maternal sensitivity. We found no difference in caregiving sensitivity scores for mothers and fathers for female and male preschool children. CONCLUSIONS: The contemporary infant and preschool attachment proportions we report here closely mirror the patterns of those reported in prior decades, with an inclination towards secure base relationships. Our findings alert practitioners anew to the responsiveness of early attachment status to change in caregiving responsiveness and support ongoing investment in early identification of disorganised attachment.

Assessing the effectiveness and implementation of a universal classroom-based set of educator practices to improve preschool children's social-emotional outcomes: Protocol for a cluster randomized controlled type 2 hybrid trial in Singapore.

BACKGROUND: Providing high-quality early childhood care and education is understood as key to maximizing children's potential to succeed later in life, as it stimulates young children's development of skills and competencies needed to promote optimal outcomes and success later in life. Despite the government's efforts to support the early childhood sector, educators in Singapore continue to report difficulties in implementing practices in classrooms that promote children's social, emotional, and cognitive development. To enhance educators' skills in these domains, we developed the Enhancing And Supporting Early development to better children's Lives (EASEL) Approach, a set of universal, educator-delivered practices for use with 3-6-year-old children in early childhood settings to improve social, emotional, behavioral, and executive functioning (SEB+EF) outcomes. METHODS: This study will evaluate the effectiveness and implementation of the EASEL Approach in improving early childhood educators' teaching practices and, in turn, children's SEB+EF outcomes. We will conduct a cluster randomized controlled trial with a type 2 hybrid effectiveness-implementation study in 16 childcare centers. The EPIS (Explore, Prepare, Implement, Sustain) Framework will be used to inform the implementation of the EASEL Approach. Implementation strategies include training, educator self-assessments, practice-based coaching, and data monitoring. Our primary outcome is educators' teaching practices. Secondary outcomes include educators' adoption of the EASEL Approach in everyday practice, the acceptability and feasibility of the EASEL Approach, and children's SEB+EF outcomes. Quantitative and qualitative data will be collected at baseline, six months, and after implementation. CONCLUSION: Findings from this study will provide significant evidence on the effectiveness of the EASEL Approach in improving educators' teaching practices and its impact on children's SEB+EF outcomes and the implementation of the EASEL Approach in early childhood classrooms in Singapore. TRIAL REGISTRATION: This study was prospectively registered on ClinicalTrials.gov, Identifier: NCT05445947 on 6th July 2022.

Exploring Perinatal Indicators of Infant Social-Emotional Development: A Review of the Replicated Evidence.

The importance of infant social-emotional development for outcomes across the lifecourse has been amply demonstrated. Despite this, most screening measures of social-emotional development are designed for children 18 months of age and over, with a clear gap in earlier infancy. No systematic review has yet harvested the evidence for candidate indicators in the perinatal window. This paper examines modifiable risk and protective factors for two seminal early markers of social-emotional development: attachment security and behavioral regulation mid-infancy. We searched meta-analytic and longitudinal studies of developmental relationships between modifiable exposures in the perinatal window (pregnancy to 10 months postpartum) and attachment and behavioral regulation status measured between 12 and 18 months. Six electronic databases were used: ERIC, PsycINFO, Medline Complete, Informit, Embase, and Scopus. Twelve meta-analytic reviews and 38 original studies found replicated evidence for 12 indicators across infant, caregiving, and contextual domains predictive of infant behavioral regulation and attachment status between 12 and 18 months. Key among these were caregiving responsiveness, maternal mental health, couple relationship, and SES as a contextual factor. Perinatal factors most proximal to the infant had the strongest associations with social-emotional status. Beyond very low birthweight and medical risk, evidence for infant-specific factors was weaker. Risk and protective relationships were related but not always inverse. Findings from this review have the potential to inform the development of reliable tools for early screening of infant social-emotional development for application in primary care and population health contexts.

Mothers' Experience of Intimate Partner Violence and Subsequent Offspring Attachment Security Ages 1-5 Years: A Meta-Analysis.

Attachment status in early childhood is a key yet modifiable contributor to the development of social-emotional competence. The security and organization of the infant-mother attachment bond is particularly susceptible to stressors in the caregiving environment. While the impacts of normative interparental conflict on infant attachment are increasingly understood, the potentially unique place of intimate partner violence (IPV) in this pathway has been under-researched. This study surveyed all empirical work in this area, including unpublished literature (k = 6, N = 3,394), to examine meta-analytic associations between maternal experiences of IPV and offspring attachment security (ages 1-5 years) measured at least 6 months post-IPV exposure. Mothers' reports of IPV from pregnancy onward were inversely associated with offspring attachment security, r = -.23, CI [-0.42, -0.04], p = .02. Sample risk characteristics (e.g., clinical vs. community) moderated this association; child's age at attachment measurement and method of assessing child attachment (e.g., observational, representational, parent report) also moderated at a trend level. Implications for early screening, intervention, and future research are discussed.

Early childhood attachment stability and change: a meta-analysis.

Examining degrees of stability in attachment throughout early childhood is important for understanding developmental pathways and for informing intervention. Updating and building upon all prior meta-analyses, this study aimed to determine levels of stability in all forms of attachment classifications across early childhood. Attachment stability was assessed between three developmental epochs within early childhood: infancy, toddlerhood, and preschool/early school. To ensure data homogeneity, only studies that assessed attachment with methods based on the strange situation procedure were included. Results indicate moderate levels of stability at both the four-way (secure, avoidant, resistant, and disorganised; κ = 0.23) and secure/insecure (r = 0.28) levels of assessment. Meta-regression analysis indicated security to be the most stable attachment organisation. This study also found evidence for publication bias, highlighting a preference for the publication of significant findings.

Re-examination of the Family Law Detection of Overall Risk Screen (FL-DOORS): Establishing fitness for purpose.

Conflicted parental separation is associated with escalating risks to wellbeing and safety for all family members. The Family Law DOORS (FL-DOORS, Detection Of Overall Risk Screen) is a three-part framework designed to assist frontline workers to identify, evaluate, and respond to these risks in separated families. The FL-DOORS system includes a 10-domain parent self-report screening measure, covering child and parent wellbeing, cultural and social risks, and safety risks experienced by and initiated by each parent. A first validation study of this screen was conducted with the first 660 separated parents to complete the measure at a frontline community agency, and found robust psychometric properties (McIntosh, Wells, & Lee, 2016). This paper presents a revalidation study of FL-DOORS screening measure with a new cohort of 5,429 separated parents, including 1,642 pairs. Our aim was to evaluate whether FL-DOORS was fit for the purpose of indicating a range of safety and wellbeing risks in separated families. We repeated internal scale reliability and concurrent and external criterion validity analyses. Original subscales were largely confirmed, and validity analyses were extended through a Multi-Trait Multi-Method (MTMM) approach. In this second larger cohort, the FL-DOORS screen was again found fit-for-purpose as an indicator of domestic violence and wellbeing risks in separated families. (PsycINFO Database Record

Couple relationship quality and offspring attachment security: a systematic review with meta-analysis.

This paper provides a meta-analytic examination of strength and direction of association between parents' couple relationship quality and early childhood attachment security (5 years and under). A comprehensive search of four EBSCOhost databases, Informit, Web of Science, and grey literature yielded 24 studies meeting eligibility criteria. Heterogeneity of the couple quality construct and measurement was marked. To disaggregate potentially differentially acting factors, we grouped homogeneous studies, creating two predictor variables defined as "positive dyadic adjustment" and "inter-parental conflict". Associations of each construct with offspring attachment security were examined in two separate meta-analyses. Inter-parental conflict was inversely associated (8 studies, k = 17, r = -0.28, CI = [-0.39 to -0.18]), and dyadic adjustment was not associated with offspring attachment security (5 studies, k = 12, r = 0.14, CI = [-0.03 to 0.32]). The study supports finer distinctions of couple relationship constructs and measurement in developmental research, assessment, and intervention.

Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3).

A high-throughput screen against Aurora A kinase revealed several promising submicromolar pyrimidine-aniline leads. The bioactive conformation found by docking these leads into the Aurora A ATP-binding site had a semicircular shape. Macrocycle formation was proposed to achieve novelty and selectivity via ring-closing metathesis of a diene precursor. The nature of the optimal linker and its size was directed by docking. In a kinase panel screen, selected macrocycles were active on other kinase targets, mainly FLT3, JAK2, and CDKs. These compounds then became leads in a CDK/FLT3/JAK2 inhibitor project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. Interaction with this residue explains the observed selectivity. The Asp86 residue is conserved in most CDKs, resulting in potent pan-CDK inhibition by these compounds. Optimized macrocycles generally have good DMPK properties, and are efficacious in mouse models of cancer. Compound 5 (SB1317/TG02), a pan-CDK/FLT3/JAK2 inhibitor, was selected for preclinical development, and is now in phase 1 clinical trials.

Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3).

Macrocycles from our Aurora project were screened in a kinase panel and were found to be active on other kinase targets, mainly JAKs, FLT3 and CDKs. Subsequently these compounds became leads in our JAK2 project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. This residue is conserved in most CDKs resulting in potent pan CDK inhibition. One of the main project objectives was to achieve JAK2 potency with 100-fold selectivity against CDKs. Macrocycles with an ether linker have potent JAK2 activity with the ether oxygen forming a hydrogen bond to Ser936. A hydrogen bond to the equivalent residues of JAK3 and most CDKs cannot be formed resulting in good selectivity for JAK2 over JAK3 and CDKs. Further optimization of the macrocyclic linker and side chain increased JAK2 and FLT3 activity as well as improving DMPK properties. The selective JAK2/FLT3 inhibitor 11 (Pacritinib, SB1518) has successfully finished phase 2 clinical trials for myelofibrosis and lymphoma. Another selective JAK2/FLT3 inhibitor, 33 (SB1578), has entered phase 1 clinical development for the non-oncology indication rheumatoid arthritis.

Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis.

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.

Natural history and predictors of faster glomerular filtration rate decline in a referred population of older patients with type 2 diabetes mellitus.

AIM: To study the natural history and predictors of faster glomerular filtration rate (GFR) decline in a referred population of older patients (aged ≥ 65 years) with type 2 diabetes mellitus. METHODS: A retrospective medical record analysis in an outpatient diabetes clinic for older patients. Baseline characteristics and blood pressure readings for each clinic visit were recorded. All laboratory results were downloaded from the central database of the pathology laboratory. Annual rate of GFR decline was calculated by linear regression analysis as the slope per year for each individual. Patients were then divided into 2 groups on either side of the mean GFR decline. Group 1 had a slower GFR decline (below the mean value) and group 2 had a faster GFR decline (above the mean value). Five variables were investigated as predictors of faster decline in GFR: cardiovascular disease (CVD), hypertension, diabetes control, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and albuminuria. RESULTS: The study included 100 patients with a mean age of 69.5 (standard deviation [SD], 3.9) years on referral, and 54 patients were men. The mean duration of study was 14.4 (SD, 2.0) years. A total of 3908 GFR results were downloaded during the study. The mean annual rate of GFR decline was 1.5 (SD, 1.2) mL/min/1.73 m2. Glomerular filtration rate values were comparable in both groups on first referral. Mean annual rate of GFR decline was 2.6 (SD, 0.9) mL/min/1.73 m2 in group 2 compared with 0.7 (SD, 0.5) mL/min/1.73 m2 (P < 0.001) in group 1. Development of CVD was the only independent predictor of faster renal function decline (odds ratio, 2.9; 95% CI, 1.1-7.6; P = 0.03). CONCLUSION: Cardiovascular disease is an independent risk factor for faster decline in GFR in older patients with type 2 diabetes mellitus.

Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma.

Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.

Synthesis and evaluation of alkenyl indazoles as selective Aurora kinase inhibitors.

A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays.

The epidemic challenge of chronic kidney disease in older patients.

Since the introduction of estimated glomerular filtration rate (GFR), the number of patients with chronic kidney disease (CKD) has considerably increased. This is particularly true for elderly patients as the majority have a low GFR. Chronic kidney disease has a significant impact on a patient's outcome. We have reviewed important aspects of CKD in older patients, with emphasis on diagnosis and management, as well as explored decision-making regarding specialist-care referral and renal replacement therapy.

Structure-based design of Aurora A & B inhibitors.

The Aurora family of serine/threonine kinases are mitotic regulators involved in centrosome duplication, formation of the bipolar mitotic spindle and the alignment of the chromosomes along the spindle. These proteins are frequently overexpressed in tumor cells as compared to normal cells and are therefore potential therapeutic oncology targets. An Aurora A high throughput screen revealed a promising sub-micromolar indazole-benzimidazole lead. Modification of the benzimidazole portion of the lead to a C2 linker with a phenyl ring was proposed to achieve novelty. Docking revealed that a conjugated linker was optimal and the resulting compounds were equipotent with the lead. Further structure-guided optimization of substituents on the 5 & 6 position of the indazole led to single digit nanomolar potency. The homology between the Aurora A & Aurora B kinase domains is 71% but their binding sites only differ at residues 212 & 217 (Aurora A numbering). However interactions with only the latter residue may be used for obtaining selectivity. An analysis of published Aurora A and Aurora B X-ray structures reveals subtle differences in the shape of the binding sites. This was exploited by introduction of appropriately sized substituents in the 4 & 6 position of the indazole leading to Aurora B selective inhibitors. Finally we calculate the conformational energy penalty of the putative bioactive conformation of our inhibitors and show that this property correlates well with the Aurora A binding affinity.

An unusual cause of 'pleuritic' chest pain.

A 77 year old man presented to A&E with sudden onset left sided chest pain. This chest pain was severe enough to wake him up from sleep in the early hours of the morning. The pain was pleuritic in nature and severe enough to require administration of intravenous morphine. He had a past medical history of ischaemic heart disease (1997), pulmonary embolism (1997), and left sided pnuemothorax (1998). Drug history consisted of lansoprazole 30mg od, isosorbide mononitrate 60mg od, nicorandil 10mg bd, aspirin 75mg od, beclomethasone 100 inhaler 1 puff bd, salbutamol 100 inhaler prn and combivent nebuliser qds. He was a retired miner, having worked for 40 years underground. There was also a 20 pack year smoking history although he had stopped for 20 years. He was independent and had a 100 to 200 yard exercise tolerance on the flat. Observations showed respiratory rate of 18, temperature of 36.5 degrees Celsius, BP 133/69, oxygen saturation of 98% on air and a regular pulse of 70 beats per minute. Clinical examination did not reveal any abnormality, with no abdominal or chest wall tenderness.

Delayed discharges due to initiation of warfarin in atrial fibrillation: a prospective audit.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. OBJECTIVE: The goal of this study was to determine whether initiation of warfarin treatment in patients with AF, while in thc hospital, is associated with an increased length of stay. METHODS: This was a prospective audit involving patients with AF newly started on warfarin while in the hospital. It was conducted in 3 acute medical wards (total, 96 beds) of a district general hospital. Patients were reviewed daily regarding the necessity of their hospital stay. Their stay was considered delayed if their original medical condition had resolved and their stay was attributed solely to initiation of warfarin to reach a therapeutic International Normalized Ratio (INR). The Barthel Index score was used to assess patients' activities of daily living. The medical teams treating these patients were unaware of the objective of the study. RESULTS: Over a 6-month period, 23 patients with AF (13 men, 10 women; mean [SD] age, 75.4 [9.2] years) were started on warfarin while in the hospital and thus comprised our study group. Of these 23 patients, 7 (30%) had delayed discharges that were solely attributed to initiation of warfarin. Total length of stay for all patients combined was 217 days; of these, 36 (17%) days were considered delayed discharges. Only 10 (43%) patients were discharged with their INR in the target range of 2 to 3. There was no significant difference between patients who had delayed discharges versus nondelayed discharges in terms of age, sex, number of comorbidities, number of medications, Barthel Index score, reason for admission, mean INR, number of patients achieving target INR on discharge, or main warfarin loading regimens. CONCLUSIONS: Initiation of warfarin in these patients with AF while in the hospital led to increased length of stay. A move toward starting anticoagulation in an outpatient setting could reduce length of hospital stay.