Using the Hierarchies of Evidence Applied to Lifestyle Medicine (HEALM) Approach to Assess the Strength of Evidence on Associations between Dietary Patterns and All-Cause Mortality

Dietary guidelines should be underpinned by high-quality evidence. Quality assessment methods that reflect traditional evidence hierarchies prioritise evidence from randomised controlled trials (RCTs). The Hierarchies of Evidence Applied to Lifestyle Medicine (HEALM) approach is an alternative quality assessment method for research questions that for practical and/or ethical reasons, cannot be answered using RCTs. The aim of this study was to investigate how the HEALM approach could be used to assess the strength of evidence on associations between dietary patterns and all-cause mortality (a research question that is difficult to answer using RCTs). Two data sources were used: an existing systematic review of dietary patterns and all-cause mortality that synthesised evidence from observational studies; and an overview of reviews that was conducted to summarise relevant evidence from mechanistic and intervention studies. A set of four criteria were developed and used in the application of HEALM. Using different datasets in combination, the strength of evidence was rated as ‘Grade B: moderate/suggestive’ or ‘Grade C: insufficient/inconclusive’. HEALM is a novel approach for integrating and assessing the strength of evidence from mechanistic, intervention, and observational studies. Further research is needed to address the practical challenges that were identified in the application of HEALM.     

A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA)

Background Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor.Methods NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity.Results In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype.Conclusions NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT03494816","term_id":"NCT03494816"}}NCT03494816.Subject terms: Surgical oncology, Renal cell carcinoma, Predictive markers     

Environment Symmetry Drives a Multidirectional Code in Rat Retrosplenial Cortex

We investigated how environment symmetry shapes the neural processing of direction by recording directionally tuned retrosplenial neurons in male Lister hooded rats exploring multicompartment environments that had different levels of global rotational symmetry. Our hypothesis built on prior observations of twofold symmetry in the directional tuning curves of rats in a globally twofold-symmetric environment. To test whether environment symmetry was the relevant factor shaping the directional responses, here we deployed the same apparatus (two connected rectangular boxes) plus one with fourfold symmetry (a 2 × 2 array of connected square boxes) and one with onefold symmetry (a circular open-field arena). Consistent with our hypothesis we found many neurons with tuning curve symmetries that mirrored these environment symmetries, having twofold, fourfold, or onefold symmetric tuning, respectively. Some cells expressed this pattern only globally (across the whole environment), maintaining singular tuning curves in each subcompartment. However, others also expressed it locally within each subcompartment. Because multidirectionality has not been reported in naive rats in single environmental compartments, this suggests an experience-dependent effect of global environment symmetry on local firing symmetry. An intermingled population of directional neurons were classic head direction cells with globally referenced directional tuning. These cells were electrophysiologically distinct, with narrower tuning curves and a burstier firing pattern. Thus, retrosplenial directional neurons can simultaneously encode overall head direction and local head direction (relative to compartment layout). Furthermore, they can learn about global environment symmetry and express this locally. This may be important for the encoding of environment structure beyond immediate perceptual reach.SIGNIFICANCE STATEMENT We investigated how environment symmetry shapes the neural code for space by recording directionally tuned neurons from the retrosplenial cortex of rats exploring single- or multicompartment environments having onefold, twofold, or fourfold rotational symmetry. We found that many cells expressed a symmetry in their head direction tuning curves that matched the corresponding global environment symmetry, indicating plasticity of their directional tuning. They were also electrophysiologically distinct from canonical head directional cells. Notably, following exploration of the global space, many multidirectionally tuned neurons encoded global environment symmetry, even in local subcompartments. Our results suggest that multidirectional head direction codes contribute to the cognitive mapping of the complex structure of multicompartmented spaces.     

Pathways for Memory,Cognition and Emotional Context: Hippocampal,Subgenual Area 25, and Amygdalar Axons Show Unique Interactions in the Primate Thalamic Reuniens Nucleus

The reuniens nucleus (RE) is situated at the most ventral position of the midline thalamus. In rats and mice RE is distinguished by bidirectional connections with the hippocampus and medial prefrontal cortex (mPFC) and a role in memory and cognition. In primates, many foundational questions pertaining to RE remain unresolved. We addressed these issues by investigating the composition of the rhesus monkey RE in both sexes by labeling for GABA, a marker of inhibitory neurons, and for the calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR), which label thalamic excitatory neurons that project to cortex. As in rats and mice, the macaque RE was mostly populated by CB and CR neurons, characteristic of matrix-dominant nuclei, and had bidirectional connections with hippocampus and mPFC area 25 (A25). Unlike rodents, we found GABAergic neurons in the monkey RE and a sparser but consistent population of core-associated thalamocortical PV neurons. RE had stronger connections with the basal amygdalar complex than in rats or mice. Amygdalar terminations were enriched with mitochondria and frequently formed successive synapses with the same postsynaptic structures, suggesting an active and robust pathway to RE. Significantly, hippocampal pathways formed multisynaptic complexes that uniquely involved excitatory projection neurons and dendrites of local inhibitory neurons in RE, extending this synaptic principle beyond sensory to high-order thalamic nuclei. Convergent pathways from hippocampus, A25, and amygdala in RE position it to flexibly coordinate activity for memory, cognition, and emotional context, which are disrupted in several psychiatric and neurologic diseases in humans.SIGNIFICANCE STATEMENT The primate RE is a central node for memory and cognition through connections with the hippocampus and mPFC. As in rats or mice, the primate RE is a matrix-dominant thalamic nucleus, suggesting signal traffic to the upper cortical layers. Unlike rats or mice, the primate RE contains inhibitory neurons, synaptic specializations with the hippocampal pathway, and robust connections with the amygdala, suggesting unique adaptations. Convergence of hippocampal, mPFC, and amygdalar pathways in RE may help unravel a circuit basis for binding diverse signals for conscious flexible behaviors and the synthesis of memory with affective significance in primates, whereas disruption of distinct circuit nodes may occur in psychiatric disorders in humans.     

A Summer School for Special Children,September 1991

A summer school for seven children provided a therapeutic environment in which emotional needs could be addressed. This approach led to gains in development and reductions in severe behaviour disturbance. The scheme utilised finance from the health authority and the Mental Health Foundation, staff on short-term contracts and a variety of help from existing resources. The combined effort ensured a crisis-free summer and presented evidence of a way of working that is beneficial to some very disturbed children.