Impact of MidMed, a general practitioner-led modified comprehensive geriatric assessment for patients with frailty.

INTRODUCTION: the identification and management of frailty occurs mostly in primary care. Several different models of care exist. This study aimed to assess the impact of a new General Practitioner (GP)-led modified Comprehensive Geriatric Assessment (CGA) on service delivery, healthcare utilisation and patient outcomes. METHOD: patients with moderate-severe frailty (electronic Frailty Index score > 0.24) in Newbattle Medical Practice, Scotland, were eligible for a novel intervention (MidMed) in which an additional GP performed a modified CGA and was directly accessible for appointments. The recruits to the intervention (MidMed) group were compared with those waiting to be enrolled (non-MidMed). Outcomes included unscheduled hospital admissions, primary care consultations, continuity of care (Usual Provider of Care (UPC) index), outpatient attendances and mortality. Adjusted rate ratios (aRR), for MidMed compared to non-MidMed, were estimated using regression models adjusting for demographics and healthcare utilisation histories. RESULTS: 510 patients were included: 290 MidMed (mean(SD) age 80.1(7.6)years; 59.6% female) and 220 non-MidMed (75.4(8.6)years; 57.7% female). Median follow-up was 396 days. aRR(95%CI) was 0.46(0.30-0.71) for >1 admission, 0.62(0.41-0.95) >1 Emergency Department (ED) attendance and 1.52(1.30-1.75) for use of primary care, with no difference in outpatient appointments or mortality. Continuity of care was better for the MidMed group (MidMed UPC 0.77(SD 0.19), non-MidMed 0.41(0.18), P < 0.001). CONCLUSION: this GP-led service for frail patients was associated with lower risk of hospital readmission/ED reattendance, greater use of primary care and improved continuity of care. More detailed evaluation of novel primary care frailty services, over longer time-periods, including robust randomised controlled trials, are needed.

Total Synthesis and Prediction of Ulodione Natural Products Guided by DFT Calculations.

A biomimetic synthetic strategy has resulted in a two-step total synthesis of (±)-ulodione A and the prediction of two potential natural products, (±)-ulodiones C and D. This work was guided by computational investigations into the selectivity of a proposed biosynthetic Diels-Alder dimerization, which was then utilized in the chemical synthesis. This work highlights how biosynthetic considerations can both guide the design of efficient synthetic strategies and lead to the anticipation of new natural products.

Focal Gain Control of Thalamic Visual Receptive Fields by Layer 6 Corticothalamic Feedback.

The projections between the thalamus and primary visual cortex (V1) are a key reciprocal neural circuit, relaying retinal signals to cortical layers 4 & 6 while being simultaneously regulated by massive layer 6 corticothalamic feedback. Effectively dissecting the influence of this corticothalamic feedback circuit in higher mammals remains a challenge for vision research. By pharmacologically increasing the focal gain of visually driven layer 6 responses of cat V1 in a controlled fashion, we examined the effects of such focal cortical changes on the response amplitudes and spatial structure of the receptive fields (RFs) of individual dorsal lateral geniculate nucleus (dLGN) cells. We found that enhancing visually driven cortical feedback could facilitate or suppress the overall responses of dLGN cells, and such an effect was linked to the orientation preference of the cortical neuron. Related to these selective retinotopic gain changes, enhanced feedback induced the RFs of dLGN cells to expand, contract or shift their spatial focus. Our results provide further evidence for a functional mechanism through which the cortex can selectively gate visual information flow from the thalamus back to the visual cortex.

Figure-ground modulation in awake primate thalamus.

Figure-ground discrimination refers to the perception of an object, the figure, against a nondescript background. Neural mechanisms of figure-ground detection have been associated with feedback interactions between higher centers and primary visual cortex and have been held to index the effect of global analysis on local feature encoding. Here, in recordings from visual thalamus of alert primates, we demonstrate a robust enhancement of neuronal firing when the figure, as opposed to the ground, component of a motion-defined figure-ground stimulus is located over the receptive field. In this paradigm, visual stimulation of the receptive field and its near environs is identical across both conditions, suggesting the response enhancement reflects higher integrative mechanisms. It thus appears that cortical activity generating the higher-order percept of the figure is simultaneously reentered into the lowest level that is anatomically possible (the thalamus), so that the signature of the evolving representation of the figure is imprinted on the input driving it in an iterative process.

The effect of treatment with selective serotonin reuptake inhibitors in comparison to placebo in the progression of dementia: a systematic review and meta-analysis.

BACKGROUND: selective serotonin reuptake inhibitors (SSRIs) may affect the neurodegenerative process of dementia, enhancing cognition. This systematic review aims to determine whether SSRIs influence cognitive performance, mood and function in people with any type of dementia. METHOD: randomised placebo-controlled studies of SSRIs in people with dementia, which recorded cognitive outcomes, were identified in ALOIS (ALzheimer's and cOgnitive Improvement Studies register) in April 2013 and updated in January 2015. Data were extracted on cognition, agitation, mood, activities of daily living (ADLs) and adverse events. End of treatment statistics were calculated. RESULTS: twelve studies met inclusion criteria (1,174 participants), of which seven studies (710 participants) provided data for meta-analysis on cognition. There was no difference in MMSE score at end of treatment; mean difference (MD) was 0.28 (95% CI -0.83 to 1.39) (six studies, 470 participants). For change in MMSE scores, there was a small improvement; MD was 0.53 (95%CI -0.07 to 1.14) (three studies, 352 participants). The remaining studies showed no improvement in cognition. There was no statistically significant benefit of SSRIs on mood (four studies, 317 participants); standard mean difference (SMD) -0.10 (95% CI -0.39 to 0.2), agitation (three studies, 189 participants); SMD -0.01(95% CI -0.86 to 0.83), or ADLs at end of treatment (four studies, 336 participants); SMD -0.15(95% CI -0.45 to 0.15). There was no difference in mortality between the two groups. Study quality was mixed with concerns over incomplete data. CONCLUSION: a small number of relatively low-powered studies showed no benefit or harm from SSRIs in terms of cognition, mood, agitation or ADLs. Large, methodologically robust studies are needed.

Stereoretentive enantioconvergent reactions.

Enantioconvergent reactions are pre-eminent in contemporary asymmetric synthesis as they convert both enantiomers of a racemic starting material into a single enantioenriched product, thus avoiding the maximum 50% yield associated with resolutions. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate's stereochemical information, thus limiting the potential substrate scope to molecules that contain labile stereogenic units. Here we present an alternative approach to enantioconvergent reactions that can proceed with full retention of the racemic substrate's configuration. This uniquely stereo-economic approach is possible if the two enantiomers of a racemic starting material are joined together to form one enantiomer of a non-meso product. Experimental validation of this concept is presented using two distinct strategies: (1) a direct asymmetric coupling approach, and (2) a multicomponent approach, which exhibits statistical amplification of enantiopurity. Thus, the established dogma that enantioconvergent reactions require substrates that contain labile stereogenic units is shown to be incorrect.

Differential feedback modulation of center and surround mechanisms in parvocellular cells in the visual thalamus.

Many cells in both the central visual system and other sensory systems exhibit a center surround organization in their receptive field, where the response to a centrally placed stimulus is modified when a surrounding area is also stimulated. This can follow from laterally directed connections in the local circuit at the level of the cell in question but could also involve more complex interactions. In the lateral geniculate nucleus (LGN), the cells relaying the retinal input display a concentric, center surround organization that in part follows from the similar organization characterizing the retinal cells providing their input. However, local thalamic inhibitory interneurons also play a role, and as we examine here, feedback from the visual cortex too. Here, we show in the primate (macaque) that spatially organized cortical feedback provides a clear and differential influence serving to enhance both responses to stimulation within the center of the receptive field and the ability of the nonclassical surround mechanism to attenuate this. In short, both center and surround mechanisms are influenced by the feedback. This dynamically sharpens the spatial focus of the receptive field and introduces nonlinearities from the cortical mechanism into the LGN.

Effects of cortical feedback on the spatial properties of relay cells in the lateral geniculate nucleus.

Feedback connections to early-level sensory neurons have been shown to affect many characteristics of their neural response. Because selectivity for stimulus size is a fundamental property of visual neurons, we examined the summation tuning and discretely mapped receptive field (RF) properties of cells in the lateral geniculate nucleus (LGN) both with and without feedback from visual cortex. Using extracellular recording in halothane-anesthetized cats, we used small luminance probes displaced in Cartesian coordinates to measure discrete response area, and optimal sinusoidal gratings of varying diameter to estimate preferred optimal summation size and level of center-surround antagonism. In conditions where most cortical feedback was pharmacologically removed, discretely mapped RF response areas showed an overall significant enlargement for the population compared with control conditions. A switch to increased levels of burst firing, spatially displaced from the RF center, suggested this was mediated by changes in excitatory-inhibitory balance across visual space. With the use of coextensive stimulation, there were overall highly significant increases in the optimal summation size and reduction of surround antagonism with removal of cortical feedback in the LGN. When fitted with a difference-of-Gaussian (DOG) model, changes in the center size, center amplitude, and surround amplitude parameters were most significantly related to the removal of cortical feedback. In summary, corticothalamic innervation of the visual thalamus can modify spatial summation properties in LGN relay cells, an effect most parsimoniously explained by changes in the excitatory-inhibitory balance.

GP-led adapted comprehensive geriatric assessment for frail older people: a multi-methods evaluation of the 'Living Well Assessment' quality improvement project in Scotland.

BACKGROUND: Evidence to support comprehensive geriatric assessment (CGA) in primary care for frail older people is limited. AIM: To evaluate a GP-led adapted CGA quality improvement project. DESIGN & SETTING: Multi-methods evaluation in a large practice in Midlothian in Scotland. METHOD: The intervention was conducted by 10 GPs in a practice of approximately 11 000 patients, initially in the patient's home, and then remotely (by telephone or video consultation) during the COVID-19 pandemic. Evaluation included a patient questionnaire, and qualitative interviews with GPs delivering the Living Well Assessment (LWA), analysed by thematic analysis. RESULTS: A total of 165/220 (75%) patients responded to the survey, of which 86% reported a 'very good experience' of the LWA. The method of delivery did not significantly influence this although most (58%) stated a preference for face-to-face consultation. For the 31% who preferred remote LWA, most (23%) preferred telephone to video consultation (8%). Problems in remote consultations related to technical issues (video), poor vision (video), or deafness (telephone or video). GPs felt that home-based LWAs had real benefits but switching to remote during the pandemic had proven feasible. Concerns included potential increase in GP workload owing to the LWA and whether it was an efficient use of GPs' time. CONCLUSION: GP-led adapted CGA was feasible in a large practice, even during the pandemic, and highly valued by frail patients. Questions regarding efficient use of GPs' time, effectiveness in terms of important patient outcomes and impact, and cost-effectiveness, requires further investigation in a larger study.

Unified total synthesis of the brevianamide alkaloids enabled by chemical investigations into their biosynthesis.

The bicyclo[2.2.2]diazaoctane alkaloids are a vast group of natural products which have been the focus of attention from the scientific community for several decades. This interest stems from their broad range of biological activities, their diverse biosynthetic origins, and their topologically complex structures, which combined make them enticing targets for chemical synthesis. In this article, full details of our synthetic studies into the chemical feasibility of a proposed network of biosynthetic pathways towards the brevianamide family of bicyclo[2.2.2]diazaoctane alkaloids are disclosed. Insights into issues of reactivity and selectivity in the biosynthesis of these structures have aided the development of a unified biomimetic synthetic strategy, which has resulted in the total synthesis of all known bicyclo[2.2.2]diazaoctane brevianamides and the anticipation of an as-yet-undiscovered congener.

Presymptomatic diagnosis of postoperative infection and sepsis using gene expression signatures.

PURPOSE: Early accurate diagnosis of infection ± organ dysfunction (sepsis) remains a major challenge in clinical practice. Utilizing effective biomarkers to identify infection and impending organ dysfunction before the onset of clinical signs and symptoms would enable earlier investigation and intervention. To our knowledge, no prior study has specifically examined the possibility of pre-symptomatic detection of sepsis. METHODS: Blood samples and clinical/laboratory data were collected daily from 4385 patients undergoing elective surgery. An adjudication panel identified 154 patients with definite postoperative infection, of whom 98 developed sepsis. Transcriptomic profiling and subsequent RT-qPCR were undertaken on sequential blood samples taken postoperatively from these patients in the three days prior to the onset of symptoms. Comparison was made against postoperative day-, age-, sex- and procedure- matched patients who had an uncomplicated recovery (n =151) or postoperative inflammation without infection (n =148). RESULTS: Specific gene signatures optimized to predict infection or sepsis in the three days prior to clinical presentation were identified in initial discovery cohorts. Subsequent classification using machine learning with cross-validation with separate patient cohorts and their matched controls gave high Area Under the Receiver Operator Curve (AUC) values. These allowed discrimination of infection from uncomplicated recovery (AUC 0.871), infectious from non-infectious systemic inflammation (0.897), sepsis from other postoperative presentations (0.843), and sepsis from uncomplicated infection (0.703). CONCLUSION: Host biomarker signatures may be able to identify postoperative infection or sepsis up to three days in advance of clinical recognition. If validated in future studies, these signatures offer potential diagnostic utility for postoperative management of deteriorating or high-risk surgical patients and, potentially, other patient populations.

The definition of daytime and nighttime influences the interpretation of ABPM in children.

To test if an arbitrary definition of day and night periods that differs to patient-reported awake and sleep periods leads to inaccuracies in interpretation of ambulatory blood pressure monitoring (ABPM). A single-center, retrospective review was performed comparing three different methods to classify day and night periods following a single 24-h ABPM: method A: Patient's record during monitoring; method B: 7:00 am to 11:00 pm day and 11:00 pm to 7:00 am night; method C: 8:00 am to 8:00 pm day and midnight to 6:00 am night. We included 149 studies in 149 children with a mean ± SD age of 13.0 ± 3.4 years. Reported sleep duration was 9.2 ± 1.3 h. Significant differences resulted between three methods for the means of several ambulatory BP parameters including indexed BP values during day, BP load, and nocturnal dipping status. During monitoring [median (range)], 7.5% (0.0-27.5%) readings were misclassified using method B and 0.0% (0.0-20.0%) using method C (p < 0.0001). This misclassification resulted in change of hypertension status for 11.4% (17/149) patients using method B and 9.4% (14/149) patients using method C (p = 0.70). Misclassification of measurements during ABPM can introduce significant errors in its interpretation. The clinical impact of these findings needs further evaluation in larger prospective studies.

Functional alignment of feedback effects from visual cortex to thalamus.

Following from the classical work of Hubel and Wiesel, it has been recognized that the orientation and the on- and off-zones of receptive fields of layer 4 simple cells in the visual cortex are linked to the spatial alignment and properties of the cells in the visual thalamus that relay the retinal input. Here we present evidence showing that the orientation and the on- and off-zones of receptive fields of layer 6 simple cells in cat visual cortex that provide feedback to the thalamus are similarly linked to the alignment and properties of the receptive fields of the thalamic cells they contact. However, the pattern of influence linked to on- and off-zones is phase-reversed. This has important functional implications.

Always returning: feedback and sensory processing in visual cortex and thalamus.

Feedback projections are an integral part of the mammalian visual system. Although it is tempting to relegate them to a subsidiary role in visual processing, because their supposed latency and lag might appear to be unfavourable for an involvement in fast processing, this is a dangerous simplification. Certainly for the world in motion, feedback from higher motion areas can influence the transfer of ascending input when, or even before, the input arrives. Here, we consider the circuit formed by layer 6 feedback cells in the visual cortex and how this straddles the retinothalamic and thalamocortical transfer of visual input. We discuss its links to feedback from the cortical motion area MT (V5), and suggest that motion perception involves a dynamic interplay between MT, V1 and the thalamus. This review is part of the TINS special issue on The Neural Substrates of Cognition.

A high-sensitivity electrochemiluminescence-based ELISA for the measurement of the oxidative stress biomarker, 3-nitrotyrosine, in human blood serum and cells.

The generation of 3-nitrotyrosine, within proteins, is a post-translational modification resulting from oxidative or nitrative stress. It has been suggested that this modification could be used as a biomarker for inflammatory diseases. Despite the superiority of mass spectrometry-based determinations of nitrotyrosine, in a high-throughput clinical setting the measurement of nitrotyrosine by an enzyme-linked immunosorbent assay (ELISA) is likely to be more cost-effective. ELISAs offer an alternative means to detect nitrotyrosine, but many commercially available ELISAs are insufficiently sensitive to detect nitrotyrosine in healthy human serum. Here, we report the development, validation and clinical application of a novel electrochemiluminescence-based ELISA for nitrotyrosine which provides superior sensitivity (e.g. a 50-fold increase in sensitivity compared with one of the tested commercial colorimetric ELISAs). This nitrotyrosine ELISA has the following characteristics: a lower limit of quantitation of 0.04 nM nitrated albumin equivalents; intra- and inter-assay coefficients of variation of 6.5% and 11.3%, respectively; a mean recovery of 106 ±â€¯3% and a mean linearity of 0.998 ±â€¯0.001. Far higher nitration levels were measured in normal human blood cell populations when compared to plasma. Mass spectrometry was used to validate the new ELISA method. The analysis of the same set of chemically modified albumin samples using the ELISA method and mass spectrometry showed good agreement for the relative levels of nitration present in each sample. The assay was applied to serum samples from patients undergoing elective surgery which induces the human inflammatory response. Matched samples were collected before and one day after surgery. An increase in nitration was detected following surgery (median (IQR): 0.59 (0.00-1.34) and 0.97 (0.00-1.70) nitrotyrosine (fmol of nitrated albumin equivalents/mg protein) for pre- and post-surgery respectively. The reported assay is suitable for nitrotyrosine determination in patient serum samples, and may also be applicable as a means to determine oxidative stress in primary and cultured cell populations.

Immune Desensitization Allows Pediatric Blood Group Incompatible Kidney Transplantation.

BACKGROUND: Blood group incompatible transplantation (ABOi) in children is rare as pretransplant conditioning remains challenging and concerns persist about the potential increased risk of rejection. METHODS: We describe the results of 11 ABOi pediatric renal transplant recipients in the 2 largest centers in the United Kingdom, sharing the same tailored desensitization protocol. Patients with pretransplant titers of 1 or more in 8 received rituximab 1 month before transplant; tacrolimus and mycophenolate mofetil were started 1 week before surgery. Antibody removal was performed to reduce titers to 1 or less in 8 on the day of the operation. No routine postoperative antibody removal was performed. RESULTS: Death-censored graft survival at last follow-up was 100% in the ABOi and 98% in 50 compatible pediatric transplants. One patient developed grade 2A rejection successfully treated with antithymocyte globulin. Another patient had a titer rise of 2 dilutions treated with 1 immunoadsorption session. There was no histological evidence of rejection in the other 9 patients. One patient developed cytomegalovirus and BK and 2 others EBV and BK viremia. CONCLUSIONS: Tailored desensitization in pediatric blood group incompatible kidney transplantation results in excellent outcomes with graft survival and rejection rates comparable with compatible transplants.

Growth factor receptor interplay and resistance in cancer.

Aberrant signalling through the epidermal growth factor receptor (EGFR) plays a major role in the progression and maintenance of the malignant phenotype and the receptor is therefore a rational anti-cancer target. A variety of approaches have been developed to specifically target the EGFR which include monoclonal antibodies and small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa). However, the recent clinical experience across a range of cancer types is revealing that despite the anti-EGFR agents demonstrating some anti-tumour activity, there is a high level of de novo and acquired resistance to such treatments and moreover, overexpression of the EGFR is clearly not the sole determinant of response to such therapies. Such adverse phenomena, which serve to limit the overall therapeutic impact of these new agents, implies the existence of a greater complexity involved in the regulation of EGFR signalling than was previously assumed. Indeed, evidence is accumulating which demonstrates that signalling interplay occurs between the EGFR, and the IGF-1 receptor (IGF-1R) and the review will focus on the emerging concept of growth factor pathway switching between these two receptors as a means of influencing the effectiveness of anti-EGFR agents such as gefitinib.

Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy.

Aberrant epidermal growth factor receptor (EGFR) signalling, a key feature of a variety of human malignancies, can drive a range of mechanisms underlying tumour growth and progression, including increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. Anti-EGFR therapies, as monotherapies and in combination with chemotherapy, have proved effective in inhibiting these processes both in the clinical and in the preclinical settings. However, only a small cohort of patients have derived significant benefit from this therapy, with both de novo and acquired resistance to these agents evident in a number of recent studies. If we are to improve the effectiveness of such targeted therapies, then there is an urgent need to understand the resistance mechanisms. Here, we describe both non-genomic and genomic mechanisms of resistance to the selective EGFR tyrosine kinase inhibitor gefitinib (IRESSA), which we have identified initially in an EGFR-positive tamoxifen-resistant MCF-7 breast cancer cell line, but more recently in other EGFR-positive cancer types. Importantly, we show that gefitinib, in common with anti-hormonal agents, is not a passive bystander in the cellular response to drug treatment, but plays an active role in promoting signalling pathways that serve to limit its anti-tumour activity and maintain the cellular cohort from which acquired resistance can ultimately evolve. These findings indicate that inductive signalling is an important determinant of response to EGFR-targeted therapies and deciphering such pathways may provide us with the opportunity to design more effective strategies to combat resistance mechanisms and improve response to initial therapy.

Escherichia coli lacking the AcrAB multidrug efflux pump also lacks nonproteinaceous, PHB-polyphosphate Ca2+ channels in the membrane.

PHB(polyP) complexes bind calcium and form calcium channels in the cytoplasmic membrane in Escherichia coli and are likely to be important in Ca(2+) homeostasis in this organism. E. coli N43, which lacks the AcrA component of a major multidrug resistance pump, was shown to be defective in calcium handling, with an inability to maintain submicromolar levels of free Ca(2+) in the cytoplasm. Therefore, using an N-phenyl-1-napthylamine (NPN)-dependent fluorescence assay, we measured temperature-dependent phase transitions in the membranes of intact cells. These transitions specifically depend on the presence of PHB(Ca(2+)polyP) complexes. PHB(Ca(2+)polyP) channel complexes, particularly in stationary phase cultures, were detected in wild-type strains; however, in contrast, isogenic acrA(-) strains had greatly reduced amounts of the complexes. This indicates that the AcrAB transporter may have a novel, hitherto undetected physiological role, either directly in the membrane assembly of the PHB complexes or the transport of a component of the membrane, which is essential for assembly of the complexes into the membrane. In other experiments, we showed that the particular defective calcium handling detected in N43 was not due to the absence of AcrA but to other unknown factors in this strain.

Nonendocrine pathways and endocrine resistance: observations with antiestrogens and signal transduction inhibitors in combination.

An increasing body of evidence demonstrates that growth factor networks are highly interactive with estrogen receptor signaling in the control of breast cancer growth. As such, tumor responses to antiestrogens are likely to be a composite of the estrogen receptor and growth factor-inhibitory activity of these agents, with alterations/aberrations in growth factor signaling providing a mechanism for the development of antiestrogen resistance. In this light, the current article focuses on illustrating the relationship between growth factor signaling and antiestrogen failure in our in-house tumor models of breast cancer and describing how we are now beginning to successfully target growth factor activity to improve the effects of antiestrogen drugs and to block aggressive disease progression.