Optimising Multi-stakeholder Practices in Patient Engagement: A Gap Analysis to Enable Focused Evolution of Patient Engagement in the Development and Lifecycle Management of Medicines.

BACKGROUND: The PARADIGM consortium aimed to make patient engagement in the development and lifecycle management of medicines easier and more effective for all, with the development of new tools that fulfil robustly defined gaps where engagement is suboptimal. AIMS: To generate an inventory of gaps in patient engagement practices and process from existing global examples. METHODS: A large set of criteria for effective patient engagement previously defined via a multi-stakeholder Delphi method, were mapped under fourteen overarching themes. A gap analysis was then performed by twenty-seven reviewers against the resulting forty-six mapped criteria, on a sample of seventy initiatives from global databases. RESULTS: An inventory of gaps was identified including contextual information as to why the gaps exist. Our work identified general patterns where patient engagement was suboptimal-defined as; fragmented reporting and dissemination of patient engagement activities, and the fundamental principles defined in frameworks or guidance being poorly adhered to in actual practice. Specific gaps were identified for sixteen criteria. Additionally, it was also common to observe primary aspects of a process were addressed for a given criteria (i.e. training for roles and responsibilities) but a secondary context element was lacking (i.e. making training material accessible/understandable/meaningful to all participants). CONCLUSION: The results show that the evolution towards meaningful and systematic patient engagement is occurring, yet more importantly they provide clear directional insights to help enhance collaborative practices and co-design solutions. This targeted impact to catalyse a needs-oriented health system that integrates patient engagement at its core is essential.

Acute and chronic effects of hot water immersion on inflammation and metabolism in sedentary, overweight adults.

Regular exercise-induced acute inflammatory responses are suggested to improve the inflammatory profile and insulin sensitivity. As body temperature elevations partly mediate this response, passive heating might be a viable tool to improve the inflammatory profile. This study investigated the acute and chronic effects of hot water immersion on inflammatory and metabolic markers. Ten sedentary, overweight men [body mass index (BMI): 31.0 ± 4.2 kg/m2, mean ± SD] were immersed in water set at 39°C for 1 h (HWI) or rested for 1 h at ambient temperature (AMB). Venous blood was obtained before the session, immediately postsession, and 2 h postsession for assessment of monocyte intracellular heat shock protein-72 (iHsp72) and plasma concentrations of extracellular Hsp72 (eHsp72), interleukin-6 (IL-6), fasting glucose, insulin, and nitrite. Thereafter, participants underwent a 2-wk intervention period, consisting of 10 hot water immersion sessions (INT). Eight BMI-matched participants (BMI: 30.0 ± 2.5 kg/m2) were included as control (CON). Plasma IL-6 and nitrite concentrations were higher immediately following HWI compared with AMB (IL-6 P < 0.001, HWI: 1.37 ± 0.94 to 2.51 ± 1.49 pg/ml; nitrite P = 0.04, HWI: 271 ± 52 to 391 ± 72 nM), whereas iHsp72 expression was unchanged ( P = 0.57). In contrast to resting iHsp72 expression ( P = 0.59), fasting glucose ( P = 0.04; INT: 4.44 ± 0.93 to 3.98 ± 0.98 mmol/l), insulin ( P = 0.04; INT: 68.1 ± 44.6 to 55.0 ± 29.9 pmol/l), and eHsp72 ( P = 0.03; INT: 17 ± 41% reduction) concentrations were lowered after INT compared with CON. HWI induced an acute inflammatory response and increased nitric oxide bioavailability. The reductions in fasting glucose and insulin concentrations following the chronic intervention suggest that hot water immersion may serve as a tool to improve glucose metabolism. NEW & NOTEWORTHY A single hot water immersion (HWI) session induces an acute increase in plasma interleukin-6 and nitrite concentrations but does not acutely elevate heat shock protein-72 expression in monocytes [intracellular Hsp72 (iHsp72)]. A chronic HWI intervention reduces fasting glucose and insulin concentrations in the absence of changes in resting iHsp72. Therefore, HWI shows potential as a strategy to combat chronic low-grade inflammation and improve glucose metabolism in individuals without the physical capacity to do so using exercise.

A spatial approach to combatting wildlife crime.

Poaching can have devastating impacts on animal and plant numbers, and in many countries has reached crisis levels, with illegal hunters employing increasingly sophisticated techniques. We used data from an 8-year study in Savé Valley Conservancy, Zimbabwe, to show how geographic profiling-a mathematical technique originally developed in criminology and recently applied to animal foraging and epidemiology-can be adapted for use in investigations of wildlife crime. The data set contained information on over 10,000 incidents of illegal hunting and the deaths of 6,454 wild animals. We used a subset of data for which the illegal hunters' identities were known. Our model identified the illegal hunters' home villages based on the spatial locations of the hunting incidences (e.g., snares). Identification of the villages was improved by manipulating the probability surface inside the conservancy to reflect the fact that although the illegal hunters mostly live outside the conservancy, the majority of hunting occurs inside the conservancy (in criminology terms, commuter crime). These results combined with rigorous simulations showed for the first time how geographic profiling can be combined with GIS data and applied to situations with more complex spatial patterns, for example, where landscape heterogeneity means some parts of the study area are less likely to be used (e.g., aquatic areas for terrestrial animals) or where landscape permeability differs (e.g., forest bats tend not to fly over open areas). More broadly, these results show how geographic profiling can be used to target antipoaching interventions more effectively and more efficiently and to develop management strategies and conservation plans in a range of conservation scenarios.

The effect of passive heating on heat shock protein 70 and interleukin-6: A possible treatment tool for metabolic diseases?

Increasing physical activity remains the most widely publicized way of improving health and wellbeing. However, in populations that benefit most from exercise (EX), adherence is often poor and alternatives to EX are important to bring about health improvements. Recent work suggests a role for passive heating (PH) and heat shock proteins (HSP) in improving cardio-metabolic health. The aim of this study was to investigate the expression of HSP70 and interleukin-6 in response to either EX or PH and the subsequent effect on glucose control. Fourteen males volunteered and were categorized lean (BMI 23.5 ± 2.2 kg·m-2) or overweight (29.2 ± 2.7 kg·m-2) and completed 60 minutes of either moderate cycling at a fixed rate of metabolic heat production (EX) or warm water immersion in 40°C water (PH). Extracellular HSP70 increased from baseline in both conditions with no differences between PH (0.98 ± 1.1 ng·mL-1) or EX (0.84 ± 1.0 ng·mL-1, p = 0.814). IL-6 increased following both conditions with a two-fold increase after PH and four-fold after EX. Energy expenditure increased by 61.0 ± 14.4 kcal·h-1 (79%) after PH. Peak glucose concentration after a meal immediately following PH was reduced when compared with EX (6.3 ± 1.4 mmol·L-1 versus 6.8 ± 1.2 mmol·L-1; p < 0.05). There was no difference in 24-hour glucose area under the curve (AUC) between conditions. These data indicate the potential for thermal therapy as an alternative treatment and management strategy for those at risk of developing metabolic disease where adherence, or ability to EX, may be compromised.

Precipitation SELEX: identification of DNA aptamers for calcium phosphate materials synthesis.

DNA aptamers that enhance calcium phosphate mineral formation were identified using a novel precipitation SELEX method. The evolved DNA library was substantially enriched in G nucleotides and in predicted G-quadruplex structures, suggesting their importance in the mechanism of mineralization. This work could readily be extended to provide additional novel DNA aptamers for materials synthesis.

Pricing and reimbursement experiences and insights in the European Union and the United States: Lessons learned to approach adaptive payer pathways.

Earlier patient access to beneficial therapeutics that addresses unmet need is one of the main requirements of innovation in global healthcare systems already burdened by unsustainable budgets. "Adaptive pathways" encompass earlier cross-stakeholder engagement, regulatory tools, and iterative evidence generation through the life cycle of the medicinal product. A key enabler of earlier patient access is through more flexible and adaptive payer approaches to pricing and reimbursement that reflect the emerging evidence generated.

An assessment of implications of adaptive licensing for pharmaceutical intellectual property and regulatory exclusivity rights in the European Union.

One of the key advantages of adaptive licensing (AL) is to align the licensing of new medicines more closely with patient needs for earlier access to beneficial treatments. From an innovators perspective, "earlier" market access may seem an obvious incentive to gain earlier revenue generation. However, this is offset with an "earlier" start to patent and regulatory protection periods, which, depending on the technology, disease, population, and timing of subsequent asset protection periods, can present a conflict.

Conductive and evaporative precooling lowers mean skin temperature and improves time trial performance in the heat.

Self-paced endurance performance is compromised by moderate-to-high ambient temperatures that are evident in many competitive settings. It has become common place to implement precooling prior to competition in an attempt to alleviate perceived thermal load and performance decline. The present study aimed to investigate precooling incorporating different cooling avenues via either evaporative cooling alone or in combination with conductive cooling on cycling time trial performance. Ten trained male cyclists completed a time trial on three occasions in hot (35 °C) ambient conditions with the cooling garment prepared by (a) immersion in water (COOL, evaporative); (b) immersion in water and frozen (COLD, evaporative and conductive); or (c) no precooling (CONT). COLD improved time trial performance by 5.8% and 2.6% vs CONT and COOL, respectively (both P < 0.05). Power output was 4.5% higher for COLD vs CONT (P < 0.05). Mean skin temperature was lower at the onset of the time trial following COLD compared with COOL and CONT (both P < 0.05) and lasted for the first 20% of the time trial. Thermal sensation was perceived cooler following COOL and COLD. The combination of evaporative and conductive cooling (COLD) had the greatest benefit to performance, which is suggested to be driven by reduced skin temperature following cooling.

Development of an enzymatic pretargeting strategy for dual-modality imaging.

A pretargeted imaging strategy based on the HaloTag dehalogenase enzyme is described. Here, a HaloTag-Trastuzumab conjugate has been used as the primary agent targeting HER2 expression, and three new radiolabelled HaloTag ligands have been used as secondary agents, two of which offer dual-modality (SPECT/optical) imaging capability.

Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model.

BACKGROUND: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown. METHODS: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 µg/kg and maintenance infusion at doses from 10 to 0.6 µg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling. RESULTS: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 µg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 µg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia. CONCLUSIONS: Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.

Interleukin-6 in combination with the interleukin-6 receptor stimulates glucose uptake in resting human skeletal muscle independently of insulin action.

AIM: To examine if the physiological concentrations of both interleukin-6 (IL-6), in combination with IL-6 receptor (IL-6R), are able to stimulate glucose uptake in human skeletal muscle and to identify the associated signalling pathways. METHODS: Skeletal muscle tissue (~60 mg) obtained from healthy female volunteers via muscle biopsy was subjected to incubation in the absence or presence of insulin (60 µU/ml), recombinant human IL-6 (rhIL-6) (4 ng/ml) or a combination of rhIL-6 (4 ng/ml) and rhIL-6R (100 ng/ml) for 30 min, with glucose transport measured for each incubation. Western blot analysis was conducted on key signalling proteins, protein kinase B (PKB/Akt), adenosine monophosphate kinase (AMPK) and mammalian target of rapamycin (mTOR) to gain an early insight into any differing transport mechanisms. RESULTS: Human skeletal muscle exhibited increased glucose uptake with insulin (1.85-fold; p < 0.05) and stimulated phosphorylation of PKB/Akt and AMPK (0.98 ± 0.23 and 1.49 ± 0.13, respectively, phosphorylated: total; p < 0.05). IL-6/IL-6R increased phosphorylation of mTOR (fourfold, p < 0.05) compared to insulin, IL-6 alone and basal control. IL-6 did not stimulate glucose uptake but combined with IL-6R, induced 1.5-fold increase in glucose uptake (p < 0.05) and phosphorylation of AMPK (0.95 ± 0.19; phosphorylated: total, p < 0.05). CONCLUSIONS: IL-6 in combination with IL-6R and not IL-6 alone increased glucose uptake in human skeletal muscle. IL-6/IL-6R-mediated glucose uptake occurred independently of PKB/Akt phosphorylation, showing that IL-6/IL-6R-induced glucose uptake is dependent on a divergent pathway.

Simulating NIRS and MRS measurements during cerebral hypoxia-ischaemia in piglets using a computational model.

We present a group analysis of the changes in cerebral haemodynamics, and the oxidation state of cytochrome-c-oxidase measured using broadband near-infrared spectroscopy (NIRS) and intracellular pH measured by phosphorous ((31)P) magnetic resonance spectroscopy (MRS) during and after cerebral hypoxia-ischaemia (HI) in 15 piglets. We use a previously published computational model of cerebral metabolism in the piglet [1] to integrate these measurements and simulate HI. We successfully simulate changes in cellular metabolism including shifts in intracellular pH observed in the piglet brain during HI. In this process, we optimise physiological parameters in the model identified through sensitivity analysis (such as the rate of glucose metabolism and intracellular lactate concentration), to fit simulated and measured data. The model fits the data reasonably and suggests a 20 % drop in glucose consumption, a ~65 % increase in lactate concentration and ~35 % drop in the cerebral metabolic rate of oxygen (CMRO2) during HI.

Brain mitochondrial oxidative metabolism during and after cerebral hypoxia-ischemia studied by simultaneous phosphorus magnetic-resonance and broadband near-infrared spectroscopy.

BACKGROUND: Multimodal measurements combining broadband near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy ((31)P MRS) assessed associations between changes in the oxidation state of cerebral mitochondrial cytochrome-c-oxidase (Δ[oxCCO]) and (31)P metabolite peak-area ratios during and after transient cerebral hypoxia-ischemia (HI) in the newborn piglet. METHODS: Twenty-four piglets (aged<24 h) underwent transient HI (inspired oxygen fraction 9% and bilateral carotid artery occlusion for ~20 min). Whole-brain (31)P MRS and NIRS data were acquired every minute. Inorganic phosphate (Pi)/epp, phosphocreatine (PCr)/epp, and total nucleotide triphosphate (NTP)/epp were measured by (31)P MRS and were plotted against Δ[oxCCO] during HI and recovery (epp=exchangeable phosphate pool=Pi+PCr+2γ-NTP+ß-NTP). RESULTS: During HI Δ[oxCCO], PCr/epp and NTP/epp declined and Pi/epp increased. Significant correlations were seen between (31)P ratios and Δ[oxCCO]; during HI a threshold point was identified where the relationship between Δ[oxCCO] and both NTP/epp and Pi/epp changed significantly. Outcome at 48 h related to recovery of Δ[oxCCO] and (31)P ratios 1h post-HI (survived: 1-h NTP/epp 0.22 ± 0.02, Δ[oxCCO] -0.29 ± 0.50 µM; died: 1-h NTP/epp 0.10 ± 0.04, Δ[oxCCO] -2.41 ± 1.48 µM). CONCLUSIONS: Both lowered Δ[oxCCO] and NTP/epp 1h post-HI indicated mitochondrial impairment. Animals dying before 48 h had slower recovery of both Δ[oxCCO] and (31)P ratios by 1 h after HI.

Synthesis and bioactivity of nobilamide B.

An alternative and facile solution/solid-phase approach is reported for the total synthesis of neuroactive peptide, nobilamide B. Z-Dhb was formed in solution via EDC/CuCl induced elimination. The solid-phase synthesis employed HBTU/Oxyma Pure™ coupling using Barlos resin. Synthetic nobilamide B was also found to be neuroactive in primary cultures of dorsal root ganglion (DRG) neurons.

Effect of river sediment on phosphorus chemistry of similarly aged natural and created wetlands in the Atchafalaya Delta, Louisiana, USA.

The goal of wetland creation is to produce an artificial wetland that functions as a natural wetland. Studies comparing created wetlands to similarly aged natural wetlands provide important information about creation techniques and their improvement so as to attain that goal. We hypothesized that differences in sediment phosphorus accretion, deposition, and chemistry between created and natural wetlands in the Atchafalaya Delta, Louisiana, USA were a function of creation technique and natural river processes. Sediment deposition was determined with feldspar marker horizons located in created and natural wetlands belonging to three age classes (<3, 5-10, and 15-20 yr old). Phosphorus fractions were measured in these deposited sediments and in suspended and bedload sediment from the Atchafalaya River. Bedload sediment had significantly lower iron- and aluminum-bound, reductant-soluble, and total phosphorus than suspended sediment due to its high sand percentage. This result indicates that wetlands artificially created in the Atchafalaya Delta using bedload sediment will initially differ from natural wetlands of the same age. Even so, similarities between the mudflat stratum of the <1- to 3-yr-old created wetland and the mudflat stratum of the 15- to 20-yr-old natural wetland support the contention that created wetlands in the Atchafalaya Delta can develop natural characteristics through the deposition of river suspended sediment. Differences between three created wetland strata, the 15- to 20-yr-old willow stratum and the <1- to 3-yr-old willow and mixed marsh strata, and their natural counterparts were linked to design elements of the created wetlands that prevented the direct deposition of the river's suspended sediment.

Virtual simulation in palliative lung radiotherapy.

AIMS: To study the accuracy of tumour-volume localisation in a comparison of conventional and virtual simulation for palliative lung radiotherapy. To assess if three-dimensional tumour outlining is necessary for the virtual simulation process. MATERIALS AND METHODS: Ten consecutive patients with non-small cell lung cancer underwent target localisation for palliative lung radiotherapy using conventional and virtual simulation. The treatment fields were initially marked with a conventional simulator using fluoroscopy, plain X-ray film and available diagnostic imaging. Each patient then had a computed tomography (CT), and these simulated treatment fields were reproduced within the virtual simulation planning system. Two clinicians then independently defined treatment fields using virtual simulation alone. The virtual simulation was achieved without outlining the tumour in three dimensions. The coverage of an 'ideal' CT-defined planning-target volume (PTV) was then calculated for each of the virtually and conventionally simulated fields. In addition, the amount of irradiated normal lung was measured using dose-volume histograms (DVH). Field sizes and differences in tumour volume coverage were compared. RESULTS: There was significantly greater tumour volume coverage using virtual simulation compared with conventional simulation (P < 0.03). This advantage was more pronounced in tumours that were larger and those that were closer to the patient's midline. There was no statistically significant difference in the volume of uninvolved lung irradiated between the two methods. CONCLUSION: In this small sample of patients, we have demonstrated improved tumour volume coverage using virtual simulation, without increasing the volume of uninvolved lung treated. A simple but consistent method of virtual simulation for this patient group is offered as an alternative to both PTV-defined CT simulation and fluoroscopy-based conventional simulation.

Microsatellite instability in germ cell tumors of the testis and ovary.

OBJECTIVES: Widespread replication-type error (RER) is a genetic alteration that has been observed in many different neoplasms and has been associated with defective DNA repair activity. There are conflicting data regarding the role that this type of genetic instability plays in the development and progression of adult germ cell tumors. METHODS: Universal amplification was performed on 104 paired specimens of tumor and constitutional DNA isolated from adult male and female germ cell tumors, in addition to subpopulations of carcinoma in situ (CIS), the precursor of testicular germ cell tumors (TGCTs). Preamplified DNA samples of TGCTs and ovarian germ cell tumors (OGCTs) were assayed for the presence of RER at 78 and 64 microsatellite loci, respectively. RESULTS: RER was observed at a single microsatellite locus in 7 of 24 individual testicular germ cell tumors, including subpopulations of CIS isolated from one of these patients. There was some evidence of RER clustering for microsatellite loci mapping to the short arm of chromosome 12. Genetic instability was more frequent in OGCTs, with widespread RER observed at 38 of 64 microsatellite loci. These alterations were noted in 12 of 36 malignant OGCTs showing RER at 1 or more loci, including 3 OGCTs demonstrating RER at more than 6 separate microsatellite loci. CONCLUSIONS: The pathogenetic significance of genetic instability in germ cell tumors remains uncertain, although the results of this study suggest a lesser role in TGCTs compared to that in OGCTs.

Allelic losses in carcinoma in situ and testicular germ cell tumours of adolescents and adults: evidence suggestive of the linear progression model.

Testicular germ cell tumours (TGCTs) may arise through a process of multi-step carcinogenesis, and loss of heterozygosity (LOH) at specific loci is likely to be an important early event, although this has not been studied in detail. In order to explore the pathogenetic relationships among TGCTs, we investigated the genetic changes in testicular tumours that exhibit a disease continuum through the precursor carcinoma in situ (CIS) to either seminoma (SE) and/or non-seminomatous germ cell tumour (NSGCT). Universal amplification has been performed on 87 TGCT specimens and 36 samples of CIS cells microdissected from single paraffin-embedded tumour sections from 40 patients, including multiple specimens of CIS and TGCT cells of varied histology microdissected from 24 individual patients. Seventy-seven microsatellite markers were used to assay these samples for LOH at candidate regions selected from the literature, mapping to 3q, 5q, 9p, 11p, 11q, 12q, 17p and 18q. Construction of deletion maps for each of these regions identified common sites of deletion at 3q27-q28, 5q31, 5q34-q35, 9p22-p21 and 12q22, which correlate with allelic losses we have also observed in the precursor CIS cells. Evidence for allelic loss at 3q27-q28 was observed in all of the embryonal carcinoma samples analysed. We conclude that inactivation of gene(s) within these regions are likely to be early events in the development and progression of TGCTs. These results also provide molecular evidence in support of the hypothesis that SE is an intermediate stage of development within a single neoplastic pathway of progression from CIS precursor cells to NSGCT.

Molecular genetic analysis of malignant ovarian germ cell tumors.

OBJECTIVE: Relatively little is known about the molecular mechanisms involved in the initiation and progression of ovarian germ cell tumors (OGCTs), in contrast to testicular germ cell tumors (TGCTs) which have been extensively investigated. Ovarian germ cell tumors share many pathological and biological features with TGCTs and it is likely that they share similar molecular genetic alterations, although this has not been studied in detail. The aim of this study was to compare and contrast loss of heterozygosity (LOH) in OGCTs at chromosomal regions that are commonly involved in TGCTs. METHODS: Universal amplification was performed on 35 paired specimens of malignant OGCT and constitutional DNA that had been microdissected from single paraffin-embedded tissue sections in 32 patients. Sixty-two microsatellite markers were used to assess LOH at chromosomal regions mapping to 3q, 5q, 9p, 11p, 11q, 12q, 17p, and 18q as these are commonly involved in testicular germ cell tumors. RESULTS: Assessment of these regions demonstrated common sites of deletion at 3q27-q28 (50%), 5q31 (33%), 5q34-q35 (46%), 9p22-p21 (32%) and 12q22 (53%) in all histological subtypes of OGCT. We and others have previously found these regions to be frequently deleted at early stages of tumor development in TGCTs. CONCLUSIONS: These chromosomal regions may contain tumor suppressor genes that are important in the initiation and progression of both malignant OGCTs and TGCTs.