In their study, Ohbe et al. investigated the association between resource-rich intensive care units (ICUs) and patient mortality using large-scale Japanese inpatient database (Diagnosis Procedure Combination inpatient database). They found that resource-rich ICUs were associated with lower ICU mortality. The authors should be admired for elucidating the importance of structural factors in outcomes in a critically ill population wherein outcome-improving interventions are quite limited.I recently read the study by Ohbe et al.(2). The factors that could affect the outcome, including the dependency on intensivists(3), multidisciplinary care with multiple physicians and healthcare providers, patient volumes, or all of these, should be further elucidated.The results, however, should be read with some caution, as suggested by the authors in their discussion of the study limitations. Whether resource richness in ICU itself had a direct impact on outcomes remains unclear. Rich ICUs are probably located in larger, academic hospitals with a higher number of ICU beds. A previous study published by the same group has suggested a volume-outcome relationship specifically in hospitals with a higher ICU-to-hospital bed ratioWhere should the hospital administrators or the policymakers focus next? It is probably based on the findings in this study that resource-rich ICUs improve health; however, this raises the question of how we could achieve “common prosperity.” Should resource-rich ICUs that provide better health outcomes become prevalent throughout the country? Alternatively, should critically ill patients be centralized in more resource-rich ICUs? In fact, the proportion of resource-rich ICUs increased from 7% in 2014 to 34% in 2019, and the number of board-certified intensivists has doubled since 2014 [Data from the Japanese Society of Intensive Care Medicine]. The provision of additional evidence to guide policymakers in modifying ICU system design remains necessary in Japan.“To get rich is glorious.” -Deng XiaopingNonehttps://jp.edanz.com/ac) for editing a draft of this manuscript.We thank John Holmes, MSc, from Edanz (The author solely contributed all of the work for the manuscript.


Graphene and its derivatives have lately been the subject of increased attention for different environmental applications of membrane technology such as water treatment and air filtration, exploiting their antimicrobial and antiviral activity. They are interesting candidates as membrane materials for their outstanding mechanical and chemical stability and for their thin two-dimensional (2D) nanostructure with potential pore engineering for advanced separation. All these applications have evolved and diversified from discovery to today, and now graphene and graphene derivatives also offer fascinating opportunities for the fight against infective diseases such as COVID-19 thanks to their antimicrobial and antiviral properties. This paper presents an overview of graphene-based 2D materials, their preparation and use as membrane material for applications in water treatment and in respiratory protection devices. The COVID-19 pandemic was the defining global health crisis of our time—a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . This tyInfectious diseases caused by viruses threaten the health of both humans and animals, but often, viral diseases can be alleviated or even eradicated by vaccination . In the Graphene (G) is a carbon sheet one atom thick and made up of condensed six membered rings. It is a two-dimensional allotrope of carbon, separated from graphite for the first time in 2004 by A. Geim and K. Novoselov who were awarded the 2010 Nobel Prize in physics for this discovery . Single-Graphene-based materials are widely applied in green energy such as fuel cell, solar cell, lithium-ion batteries (LIBs), supercapacitor, dye-sensitized solar cells (DSSC), photocatalysis and photo-electrochemical cells for hydrogen evolution via water splitting . ReducedGraphene oxide and its derivatives, such as others nanoscale materials, have been widely explored for their antimicrobial properties due to their high surface-to-volume ratios and unique chemical and physical properties ,25. On tThis review, after an initial overview on application of graphene-based membrane for water purification, focuses on the antibacterial and antiviral activity of graphene-based materials and the possibility of using graphene-based membrane for reusable and recyclable masks.Graphite is a 3D material that is organized and built up by millions of graphene layers. Graphene (G), being one-atom thick layer of extended sp2 carbons, represents the limit of the thinnest possible 2D conductive surface, exhibiting very fast electron mobility and high charge carrier density . Until nOther derivatives of graphite are graphene oxide (GO), reduced graphene oxide (rGO), N-doped G (NG), graphene quantum dots (GQDs) etc. . One of 4 is used for graphite oxidation in the presence of H2SO4, NaNO3, and H2O2. The second is the Brodie method that is performed by adding potassium chlorate to slurry of graphite in fuming nitric acid ..65]. The membranes present a composite structure with 2D layered GO supported on macroporus PAI C,D. The Moreover, new PVDF-GO mixed matrix membranes were also developed using DMSO as non-hazardous solvent, in place of traditional substances of very high concern (SVHC), in a combined vapour- and liquid-induced phase separation process in which water in vapour or liquid form works as a non-solvent for the polymer inducing its precipitation. The protocol developed did not include any chemical additive generally used as pore former  in phase separation process for the production of porous membranes . The preContamination of water with bacteria, protozoans and viruses is a serious problem because water acts as a carrier for infectious pathogens that spread harmful diseases . The literature available regarding the separation of viruses from the water mostly denotes the use of polymeric membranes depending on their pore size . In factQu et al. reported that COVID-19 can survive in stool samples for 4 days and that this virus has been positively detected in stool samples of infected patients . In otheMembranes for water purification and water desalination are being used more and more to address global challenges of pollution and scarcity of water . Highly E. coli and creates strong interactions between itself and lipid molecules in bacteria [Some authors reported that the antibacterial ability of graphene can be increased when doped with metal nanoparticles , becausebacteria . Escherichia coli  and Staphylococcus aureus  [E. coli using recycled graphene oxide–iron oxide–silver nanocomposites [Magnetic graphene-based nanocomposites are used as an antibacterial agent for water purification ,86. Bothositive) . These cositive) . The larmposites . Other sThe growing antibacterial resistance spectrum of bacterial infections required the development of novel and efficient antibacterial agents. Biocidal nanomaterial is usually used in the science field to improve medical devices’ wastewater treatment, food packaging, synthetic textiles and dentistry . The increased attraction towards graphene and graphene derivatives such as graphene oxide and reduced graphene oxide is determined by the bactericidal activity of G on several Gram-negative and -positive bacteria . G is onEscherichia coli investigating its antimicrobial mechanism [Escherichia coli than against Staphylococcus aureus because of the absence of any additional outer membrane in the case of S. aureus. E. coli was more damaged by the GO coatings than S. aureus, probably for the oxidative stress from GO [Sometimes authors reported different behavior of graphene derivatives in terms of antibacterial effect. Liu et al. compared the antibacterial activity of graphite (G), graphite oxide (GtO), graphene oxide (GO), and reduced graphene oxide (rGO) toward a bacterial model such as echanism . The autechanism . Other sechanism . De Fariechanism . These oechanism . Many auechanism ,99. The echanism . For exa from GO . Investigating the interactions of GO with Gram-positive and Gram-negative bacteria, often the antimicrobial effects of GO are concentration and time dependent. The main structural difference between these two types of bacteria is that Gram positive bacteria have a thick peptidoglycan layer and no outer lipid membrane, while Gram negative bacteria have a thin peptidoglycan layer and have an outer lipid membrane. E. coli strain and human HeLa cells. The typical bacterium Escherichia coli and HeLa cell were used to evaluate the antibacterial activity and cytotoxicity of the ZnO/GO composites, respectively. The antibacterial activity of the ZnO/GO composites is dependent on the content of zinc in the composites. It is mainly due to the synergistic effect of ZnO and GO: the possibility of bacteria contact to zinc was increased as ZnO NPs and released zinc ions from ZnO NPs were enriched on the GO sheets. The intimate contact of the E. coli cells and ZnO NPs on the GO sheets enhanced the permeability of the bacterial membrane and the local free zinc concentration around bacteria. The cell viability loss induced by the composites is dose-related. GO exhibited no viability loss, even at relatively high concentrations (50 μg mL−1), indicating the low toxicity of GO to HeLa cells. Similarly, even when the concentration of ZnO/GO-1 (prepared with mass ratio of ZnO/GO was 3:1) reaches 20 μg mL−1, the cell viability is still over 90%. However, a concentration of ZnO NPs (240 μM) decreased the cell viability to 30%. These results illustrate that the ZnO/GO composites cause much lower cytotoxicity than an equivalent amount of ZnO NPs alone. In another study [E. coli after 12 h. This antibacterial activity was probably caused by the synergy of the physical interactions of graphene with bacterial membranes and the antibacterial properties of ZnO that have the aptitude to photo catalytically generate H2O2 and to penetrate cells and disrupt the bacterial membrane. Furthermore, graphene oxide can be easily modified with silver NPs, obtaining the advantages of the physical properties of GO and the strong antibacterial activity of Ag NPs [P. aeruginosa. De Faria et al. [P. aeruginosa over the concentration range investigated. While the GO–Ag nanocomposite showed an antibacterial activity with a minimum inhibitory concentration ranging from 2.5 to 5.0 μg/mL. Moreover, the results showed a 100% inhibition rate of the adhered P. aeruginosa cells on stainless steel surfaces after exposure to the GO–Ag nanocomposite for one hour. This interesting result showed the possibility of using GO–Ag nanocomposites as antibacterial coatings material to avoid the growth of biofilms in food packaging and medical devices.Wang et al.  studied er study , ZnO/graf Ag NPs . Some rea et al.  reportedLukowiak et al.  reportedThe interaction of G-based nanomaterials with bacterial cells depends on their sheet size, surface area, roughness, hydrophilicity, dispersibility and functionalization . The sepThe interaction of bacteria with GO follows a different mechanism when it is in suspension form or immobilized on a coated surface . The phyThe biocidal strength order of Gr-based nanomaterials dispersions is reported as follows: G hybrid NPs, GO and G B; while Despite virus vaccination being the most widely used method for alleviating or eradicating some diseases, attenuated vaccines are not available for all viral infections . The risIn recent years, graphene oxide derivatives were studied to inhibit some viruses such as herpes simplex virus type-1 (HSV-1) competing with the heparan sulfate in binding HSV-1 . One of the major viral pathogens of the lower respiratory tract of infants is the respiratory syncytial virus (RSV). Yang et al.  demonstrVery few studies have reported on the inhibition of the entry and replication of enveloped DNA virus (herpesvirus) and RNA virus (coronavirus) in their target cells by using graphene-based material . Ye et aYe et al. analyzed the impact of GO charge by observing the antiviral activity of GO conjugated with cationic polymer PDDA or nonionic PVP . The resChen et al.  investigA significant advantage of GO-Ag nanocomposites over free Ag NPs is the increasing biocompatibility of the material and the toxicological effects of reducing associated with metallic nanoparticles due to their immobilization on GO. GO-Ag nanocomposites have a specific surface area, are not corrosive and are highly dispersible in water. An important use of GO sheets is as a supporting and stabilizing agent in preventing the agglomeration of the Ag NPs that showed a spherical-like morphology and an average size of 7.5 nm, which is suitable for antiviral activity ,113,118.The study of graphene-based membrane with antiviral activity is still at a nascent stage. Akhavan et al., fabricated Graphene−tungsten oxide composite thin films with sheetlike surface morphology that were applied in photoinactivation of viruses under visible light irradiation . The virGraphene possesses excellent light-to-heat conversion ability owing to its superior thermal conductivity. Deokar et al. designed a graphene-based photothermal antiviral agent that captures and destroys viruses . They syThe main transmission mode of virus such as COVID-19 is through short-range aerosols and droplets . Micron-For this reason, the use of disposable surgical masks or respirator are common for patients, doctors, and even the people in high-risk areas. The United States Centers for Disease Control and Prevention (CDC) recommends the usage of N95 filtering facepiece respirators (FFR) as personal protective equipment for healthcare professionals . The CDCThe N95 FFR is composed of multiple layers of polypropylene with a meltblown layer that is 100−1000 μm in thickness with polypropylene microfibers’ diameters in the range of ∼1−10 μm . These fThe use of disposable surgical masks is common for patients, doctors, and for all people in highly risky areas . As explIn general, the mechanisms of disinfection or sterilization of bacteria and viruses include protein denaturation , DNA/RNA disruption , and cellular disruption , but these methods can modify the masks’ filtration efficiency . Liao et2 laser scribing  filter-based 3D-printed facial protective equipment [Huang et al. identified the bacteria viability on common face masks and found that the majority of bacteria (90%) remain alive after 8 h . The autquipment . The autquipment . Indeed,quipment . For thiquipment  who carrSeveral efforts have been made by the research communities around the globe to contain and reduce the impact of COVID-19. However, the rapid spread of COVID-19 virus was not easily to reduce, and it remains very important to prevent airborne transmission with a respirator filter obtained by using innovative or existing technologies. Very interesting materials that can be used for this purpose are graphene and graphene oxide. This review, after an initial overview on application of graphene-based membrane for water purification, focuses on the antibacterial and antiviral activity of graphene-based materials and the possibility of using graphene-based membrane for reusable and recyclable masks in order to help researchers to find in graphene materials help to fight dangerous viruses and bacteria.The increased attraction towards Graphene and graphene derivatives such as graphene oxide and reduced graphene oxide is determined by the bactericidal activity of G on several Gram-negative and -positive bacteria. G is one of the most recently developed biocidal nanomaterials for its robustness, mechanical strength, great surface area and resistance to degradation, due to its superior surface-to-volume ratio. The attachment and adherence of G to biological cells is due to their active segments, edges, and surfaces. The interaction of G-based nanomaterials with bacterial cells depends on their sheet size, surface area, roughness, hydrophilicity, dispersibility and functionalization.Very recently the possibility was reported to make reusable masks coated on graphene that can be sterilized under sunlight irradiation where the surface temperature can quickly increase to over 80 °C. Other authors produced a prototype for a customizable/multi-used protective respirator mask in which CuO and GO nanoparticles should inactivate viral particles.The study of graphene-based membrane with antiviral activity is still at a nascent stage that needs further work. Indeed, despite the great interest in the use of graphene to modify the mask filters due to its potential use as antibacterial and virucidal properties, additional research efforts should be direct also to the use of new methodologies to complement the actual standard tests and ensure the security of the filters modified with nanomaterials.


Personalised approaches to the management of all solid tumours are increasing rapidly, along with wider accessibility for clinicians. Advances in tumour characterisation and targeted therapies have placed triple-negative breast cancers (TNBC) at the forefront of this approach. TNBC is a highly heterogeneous disease with various histopathological features and is driven by distinct molecular alterations. The ability to tailor individualised and effective treatments for each patient is of particular importance in this group due to the high risk of distant recurrence and death. The mainstay of treatment across all subtypes of TNBC has historically been cytotoxic chemotherapy, which is often associated with off-target tissue toxicity and drug resistance. Neoadjuvant chemotherapy is commonly used as it allows close monitoring of early treatment response and provides valuable prognostic information. Patients who achieve a complete pathological response after neoadjuvant chemotherapy are known to have significantly improved long-term outcomes. Conversely, poor responders face a higher risk of relapse and death. The identification of those subgroups that are more likely to benefit from breakthroughs in the personalised approach is a challenge of the current era where several targeted therapies are available. This review presents an overview of contemporary practice, and promising future trends in the management of early TNBC. Platinum chemotherapy, DNA damage response (DDR) inhibitors, immune checkpoint inhibitors, inhibitors of the PI3K-AKT-mTOR, and androgen receptor (AR) pathways are some of the increasingly studied therapies which will be reviewed. We will also discuss the growing evidence for less-developed agents and predictive biomarkers that are likely to contribute to the forthcoming advances in this field. Finally, we will propose a framework for the personalised management of TNBC based upon the integration of clinico-pathological and molecular features to ensure that long-term outcomes are optimised. Breast cancer (BC) is the most common cancer affecting women and is the leading cause of cancer-related death in women worldwide . Triple-This review provides an overview of contemporary practice in the treatment of early-stage TNBC and highlights promising future directions. We will discuss the growing evidence for newer therapies predicted to contribute to forthcoming advances in this field, and propose a framework for the personalisedmanagement of TNBC based upon the integration of clinical and molecular features.in situ hybridisation. TNBC is disproportionately seen in younger women, as well as in Hispanic and African American populations (TNBC is characterised by the absence of oestrogen (ER) and progesterone (PR) receptor expression, in addition to the absence of HER2 amplification as measured by immunohistochemistry or fluorescence ulations . Diseaseulations . Metastaulations .TNBC is a heterogeneous disease with significant inter- and intra-tumour heterogeneity –8. MultiThe current clinical definition of TNBC encompasses multiple histological subtypes. Approximately 85% of TNBCs are morphologically defined as invasive carcinoma of no special type (IC-NST). The remaining TNBCs are less common tumours of a special type, which are collectively associated with a poor prognosis . IndividNumerous efforts to build upon the molecular classification of TNBCs have been proposed Table 2.Breast cancers can be classified into six intrinsic molecular subtypes by gene expression (GE) profiling , 24 as fBRCA1, and dysregulation of MYC and RB1 pathways  when considering all subtypes of breast cancer, although not consistently for the TNBC cohort when viewed in isolation. Claudin-low tumours are associated with lower pathological complete response (pCR) rates compared to basal-like subtypes . In a suin vivo  subtype displays activation of pathways involved in epithelial–mesenchymal transition (EMT), cellular differentiation, and growth pathways. Luminal androgen receptor (LAR) tumours are characterised by high expression of androgen receptor (AR) and downstream AR targets, and enrichment of pathways involved in steroid synthesis, porphyrin metabolism, and androgen/oestrogen metabolism  . In a reBurstein and colleagues applied non-negative matrix factorisation clustering to identify four distinct TNBC subtypes characterised by key molecular features and prognosis: LAR, mesenchymal, basal-like immunosuppressed (BLIS), and basal-like immune-activated (BLIA). BLIS and BLIA had the best and worst clinical outcomes, respectively. LAR and mesenchymal subtypes revealed significant overlap with Lehmman’s classification. Burstein’s subtypes based on immune signalling  revealed a combination of BL1 and BL2 subtypes .Liu et al. developed a classification system based on the transcriptome profiles of both messenger RNAs and long non-coding RNAs to divide TNBC into four distinct clusters. Cluster A: immunomodulatory subtype, Cluster B: luminal androgen receptor subtype (LAR), Cluster C: mesenchymal-like subtype, and Cluster D: basal-like and immune-suppressed (BLIS) subtype. No significant difference in prognosis was found between the four subtypes. Tumours classified as the BLIS subtype experienced poorer relapse-free survival (RFS) compared with all other subtypes , 32. FurCombining GE and DNA copy number analysis within the METABRIC dataset further expanded the taxonomy of breast cancer . Eleven Prado-Vasquez et al. developed a probabilistic graphical model to classify the cellular components of tumours into four groups based on the ‘stem cell hypothesis,’ defined based on the grade of development of the cells from which they derived luminal (LAR), basal, claudin-high (CLDN-high), and claudin-low (CLDN-low). The sparse k-means method was used to define high or low immune activity and to classify the tumour as immune metanode positive or negative. Immune metanode activity was prognostic overall, and particularly in the luminal group defined by the cellular classification and TNBC type4-LAR .Combining molecular knowledge with patient management is an increasingly accepted technique across tumour types. In early TNBC, lack of reproducibility and the absence of a unified approach have led to the continuous use of unselected clinical strategies that remain insufficient. Stable commonalities among the classification methods of molecular subtyping in TNBC suggest the presence of clear biological groups suitable for personalised therapeutic interventions. For instance, luminal-like and mesenchymal tumours are consistently identified across the methods with decent overlap and reproducible outcome data. Moreover, most methods include a measurement of the interaction between tumours and the immune response, highlighting the importance of considering this element as a key component of the TNBC taxonomy. Overall, these efforts provide the basis for understand how the molecular complexity of TNBC influences outcomes. Considering the treatment response due to dynamic network interaction, rather than focusing on individual static components, is likely to have more predictive power. But even with reproducible and reliable classification, delivering this in a clinical timeframe suitable for neoadjuvant therapy decision-making remains a challenge.–TNBC is characterised by the absence of ER, PR and HER2 expression and is associated with high early response rates to treatment and poor prognosis.–TNBC is a heterogeneous disease with a high level of inter and intra tumour heterogeneity.–Multiple TNBC classifications that split TNBC tumours based on unique molecular features have been described but have yet to be incorporated into routine clinical practice.BRCA (gBRCA) carriers following results of the OlympiA trial is expected to reshape clinical practice  meta-analysis of 32,000 patients. This resulted in a ~50% reduction in 2-year recurrence and a 20–25% decrease in BC . ChemothAnthracyclines target cell proliferation pathways by interacting with DNA gyrase and leading to DNA double-strand breaks (DSBs). The ABC trials proved that the addition of an anthracycline to taxane and cyclophosphamide improved patient outcomes, with the greatest benefit in high-risk patients, those with lymph node involvement or hormone-negative disease . More reAnthracycline-free chemotherapy regimens are considered when cardiotoxicity is a concern, and routine use of such regimens for treatment de-escalation is an area of increasing interest  see Ta.Taxanes inhibit cell division by stabilising microtubules, preventing depolymerisation, spindle formation, and progression through the cell cycle. Paclitaxel and docetaxel are regularly used to treat early-stage TNBC. An EBCTCG meta-analysis showed that the addition of taxane to anthracycline resulted in a proportional reduction in mortality rates of 15–20% . The EurThere are several novel alternatives to traditional taxanes under investigation. Nab-paclitaxel is a solvent-free albumin-bound nanoparticle formulation of paclitaxel. It potentially enables higher intra-tumoural taxane concentrations, better efficacy, and improved tolerability. The GeparSepto  and ETNAEpothilones are promising alternatives to taxanes in development. These novel potent microtubule stabilisers can bypass common resistance mechanisms seen with taxanes, such as drug efflux pumps and β-tubulin. In the early setting, the phase 3 TITAN trial has shown similar efficacy and reduced rates of peripheral neuropathy, dose modifications, and discontinuation with Ixabepilone comparised with paclitaxel .gBRCA-associated TNBC. Carboplatin is increasingly used in neoadjuvant regimens, improving both pCR and long-term outcomes (DNA Damage Response (DDR).The clinical activity of platinum agents has been significantly associated with a DDR vulnerability in both sporadic and outcomes . Please 2 and standard anthracycline-taxane adjuvant chemotherapy (ACT) established a significant 5-year disease free survival (DFS) benefit  classifies tumour response to chemotherapy using a numeric score based on four characteristics of surgical outcome: primary tumour bed dimensions; cellularity fraction of invasive cancer; size of largest metastasis; and number of positive lymph nodes . Four prLiquid biopsies for circulating tumour DNA (ctDNA) measurement are a promising dynamic approach to assess residual disease and predict treatment response in real-time . FragmenBRCA carriers.Patients with residual disease after surgery are often considered for further systemic therapy. Current treatment options in this setting following NACT include capecitabine and poly ADP-ribose polymerase inhibitors (PARPi) for gThe Create-X trial demonstrated that six to eight cycles of capecitabine improved 5-year DFS and OS compared to no further therapy, especially in the TNBC cohort . In contBRCA1/2 mutations (3-year iDFS of 85.9% for olaparib vs 77.1% for placebo)  . A 32% rBRCA carriers with high-risk TNBC. A direct comparison between adjuvant olaparib and capecitabine is unavailable. The theoretical advantage for olaparib use includes targeting a known tumour susceptibility in a selected population, leading to an improved response and improved tolerability compared to standard cytotoxics. Interestingly, a phase 2 trial that assessed the value of molecularly targeted postneoadjuvant treatment vs choice of clinician in TNBC patients with residual disease did not demonstrate the superiority of this approach  was closed early as neither cisplatin nor carboplatin was able to demonstrate non-inferiority or superiority over capecitabine, and toxicity rates were higher .via base excision repair. PARP1 is also a critical early event for DNA DSB repair activation and regulation of resection (Poly ADP-ribose polymerase (PARP) activity is crucial for maintaining the correct fork speed and fidelity of DNA synthesis. PARP1 is involved in the response to single-strand DNA (ssDNA) damage and maintains genome integrity esection . PARP inesection . In tumoesection .BRCA mutations who have received prior chemotherapy (BRCA mutations and sporadic (non-BRCA) TNBC in the early setting.Robust evidence now supports the efficacy of single-agent PARPi in BC patients with gotherapy , 108. A gBRCA1/2 or germline PALB2 mutations. A numerical enrichment of somatic HR mutations and BRCA1 methylation in the responding group suggests favourable activity of olaparib here. Other trials in the neoadjuvant setting combine olaparib with chemotherapy. GeparOLA included patients with HER2-negative BC and HRD, received paclitaxel with olaparib or carboplatin followed by epirubicin and cyclophosphamide  is being investigated as monotherapy in chemotherapy-resistant TNBC as part of a pre-surgical window of opportunity and post-surgical biomarker study , reviewing the change in mean proliferation index between baseline and post-treatment. PARTNERING is a phase 2 sub-study for the PARTNER trial that offers durvalumab along with AZD6738 to patients with evidence of residual disease after completion of NACT and before surgery. WEE 1 inhibitors have not yet been reviewed in the early TNBC setting.BRCA carriers.−There is strong evidence to support the addition of platinum agents to NACT to improve patient outcomes, especially in high-risk and g−Improvements in pCR and EFS rates with platinum chemotherapy combinations need to be balanced against additive chemotherapy toxicities.−PARP inhibition causes replication stress, induces ssDNA breaks and affects the normal regulation of p53 and its downstream effectors.BRCA mutations who have no prior chemotherapy exposure.−Encouraging evidence supports the efficacy of single agent PARPi in BC patients with g−The group of patients with TNBC most likely to benefit from PARP inhibition in the neoadjuvant setting is yet to be established.BRCA carriers with high-risk HER2 negative disease following neoadjuvant or adjuvant chemotherapy.−Olaparib improves DFS in gBRCA and somatic BRCA mutations for response to platinum and PARPi has been validated in large clinical trials that included patients with ovarian and metastatic BC   , gBRCA mboplatin .BRCA1/2 mutation carriers with the TNBC subtype in the I-SPY 2 trial were significantly more likely to achieve a pCR than non-BRCA TNBC (predicted pCR of 75% vs. 29%) , particularly in the TNBC subgroup .vs. 29%)  and a grignature . SubgrouA status . HoweverA status  gBRCA muBRCA1 promoter methylation were associated with olaparib and its overall response (OR) of 88.9% , exploratory analysis revealed no difference between treatment arms if somatic or germline BRCA1/2 mutations were detected  in the HR pathways and/or of 88.9% . Althougdetected .).Several attempts to simplify and systematically identify common molecular changes associated with defective HR have been published. The evaluation of DNA damage repair-related genes by either gene expression or by the presence of mutations has shown a positive association with response. Confirmation of the predictive value of these individual efforts has not always been accomplished given the underlying heterogeneity of some of these variations Table 7BRCA1/2 mutations has been tested in TNBC treated with platinum, and used to aid patient selection in PARPi trials  . A highecarriers .BRCA status as an independent predictive biomarker among the TNBC population in the neoadjuvant setting is unclear.−The role of −Overall, alterations in DNA damage repair-related genes by either gene expression or presence of mutations has shown a positive association with response to NACT and/or PARPi.BRCA1/BRCA2 deficiency or a `BRCA-ness status` have shown a trend to positive association with response to platinum chemotherapy. However, these results are signature specific and should be considered preliminary. Data from randomised clinical trials that prospectively assess the value of these biomarkers is awaited.−Mutational signatures predictive of −Higher TMB has been observed in BC tumours that harbour DDR gene mutations. Correlation with response to platinum agents is not yet established.Although BC is largely considered an immune-quiescent cancer type , increasTumours evade detection and eradication by the immune system through the dysregulation of pathways controlled by immune checkpoints. Immunotherapy harnesses the immune system of the patient to target malignant cells using immune checkpoint inhibitors (ICI), chimeric antigen receptor T cells, or cancer vaccines. ICIs release the immune system from tumour-induced inhibitory signals, allowing an effective anti-tumour response. They include monoclonal antibodies (mAbs) against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1).Pembrolizumab is the most well-established and successful anti-PD-1 ICI in operable TNBC. The addition of pembrolizumab to NACT has shown increases in pCR rates across several RCTs, including the KEYNOTE-173 and I-SPY 2 trials , 137. ThKEYNOTE-522 evaluated neoadjuvant pembrolizumab along with carboplatin/paclitaxel and anthracycline-based NACT, and then adjuvantly as monotherapy, in high-risk early TNBC. The pCR rate improved by 7.5% (95% CI: 1.6 to 13.4%) with the addition of pembrolizumab, and after a median follow-up of 39.1 months, 36-month EFS improved from 77 to 85% . OS data remains immature at the time of analysis . High-riAtezolizumab, durvalumab, and avelumab are the most established anti-PD-L1 ICIrs being investigated in operable TNBC, although results from trials have been inconsistent. The pCR rate improved from 41 to 58% with the addition of atezolizumab to anthracycline/taxane-based chemotherapy in Impassion031 . SecondaGeparNUEVO assessed Durvalumab in addition to anthracycline/taxane-based NACT. This showed a non-significant 9% improvement in pCR rate. Improvements in 3-year iDFS and 3-year OS were also seen, though this trial was not powered to definitively assess long-term survival differences. An underpowered subgroup analysis showed a particular benefit in patients who received durvalumab alone for two weeks prior to NACT, suggesting immunological interactions with priming in this window phase , 143. WhThe use of ICIs in TNBC is an area of active research, although it is at an early stage, and long-term outcome data remain immature for the majority of the neoadjuvant trials. Concern regarding the use of pCR as a primary endpoint upon which to grant regulatory approval for neoadjuvant pembrolizumab was cited by the FDA, and long-term survival data is of particular interest . There iCancer vaccines use tumour associated antigens to stimulate CD4+ and CD8+ T cells, inducing the immune system of the patient to target cancer cells that were previously successfully evading immune suppression. They have yet to show success in late-stage clinical trials or to receive regulatory approval for TNBC. Clinical trials evaluating cancer vaccines in non-metastatic TNBCs are listed in −Immunotherapy is of particular interest in TNBC due to the higher degree of immune activation seen in comparison to other BC types.−TNBC is a heterogeneous disease that exhibits various degrees of immunogenicity.−Several early stage BC trials have established PD-1 and PD-L1 ICIs as a promising treatment option in combination with chemotherapy.−Pembrolizumab has been granted FDA approval in the neoadjuvant setting for high-risk early-stage TNBC in combination with chemotherapy and to continue as monotherapy in the adjuvant setting (KEYNOTE-522).PD-L1 expression is higher in TNBCs compared with non-TNBCs  and quanHigh tumour mutational burden precipitates enhanced immunogenicity by increasing the number of tumour antigenic peptides or neoantigens that can be recognised by T cells . Based oDue to limited data availability and differences among TMB quantification methods, the role of mutational load as an independent predictive biomarker of ICI response is yet to be defined in TNBC. In the GeparNUEVO trial, TMB was higher in patients with pCR (median 1.87 versus 1.39 mut/MB), and both continuous TMB and the immune GE profile independently predicted pCR . In compBoth intra-tumoural TILs (iTILS) and stromal TILs (sTILs) have prognostic and predictive roles for treating early TNBC and have also been evaluated in this setting as biomarkers of immunotherapy response. In the GeparNUEVO trial , sTILs bGE immune signatures have been extensively used to describe profiles of immune infiltration and immune cell types that impact on the prognosis of many tumour types, including TNBC –163. FewPembrolizumab monotherapy received FDA approval in 2017 for treating advanced mismatch repair deficient solid tumours . Althoug–Response to ICIs appears to be independent of PD-L1 status in early TNBC.–High TMB has been correlated with an increased likelihood of response to ICI, particularly in tumours where CD8+ T-cell levels are positively correlated with neoantigen load.–The role of mutational load as an independent predictive biomarker of ICI response is yet to be defined in TNBC.–Increased TILs are associated with a more favourable response to NACT and long-term outcomes.–Modest positive association of GE immune signatures with ICI response has been reported.–The interaction between TMB and GE immune signatures has been shown to be a promising independent predictor of pCR.–The dynamics of immune activation after treatment are strongly associated with long term outcome, independently of response rate.–Tumours with defects in the mismatch repair pathways are known to have highly upregulated expression of multiple immune checkpoints and increased sensitivity to ICI.via PIK3CA mutations (~9–18%), loss of PTEN (~35%), or INPP4B (~30%), and amplification of PIK3CA (~43%). The frequency of PI3K/AKT/mTOR pathway activation and its spectrum varies by TNBC subtype  for anthracycline refractory TNBC with PIK3CA or PTEN alterations, with exploratory objectives to assess biomarkers of response and resistance to alpelisib and nab-paclitaxel combination.AR expression is found in approximately 10–35% of TNBCs as detected by immunohistochemistry , 176. ThThere is a paucity of data for drugs targeting the AR pathway in the early TNBC setting. Enzalutamide has been trialled as monotherapy , and aloApproximately 35% of TNBCs as defined by immunohistochemistry could be classified as HER2-low . SomaticHER2 or EGFR , it rose to 63% ((OR 37%)   and Tras(OR 37%)  now requVEGF promotes angiogenesis, invasion, and increases vascular permeability and is an essential element in TNBC formation, progression, and metastasis. VEGF-A expression is higher in TNBC compared with other BC subtypes . Basal BC with elevated MET and FGFR1 signatures is associated with poor relapse-free survival .EGFR dysregulation is frequently reported in TNBC  among all solid tumours  that includes both sporadic TNBC and BRCA-associated tumours will help elucidate the value of gBRCA mutations in predicting the response to the addition of PARPi to platinum-based chemotherapy  continues to be a challenge. Robust evidence supports the association between RCB score and long-term outcome in patients twho have received NACT . ConversSeveral molecular predictors of response that incorporate various ‘omic’ data to aid clinical decisions have been developed. Limited clinical impact has been derived due to lack of reproducibility, lengthy timeline of results, and expense. The real-time delivery of genomic and transcriptomic results will facilitate the implementation of adaptive trial designs and permit the investigation of novel and existing biomarkers. There are multiple pan-cancer studies assessing the implementation of genomics and transcriptomics into clinical care, for example, the UK 100,000 Genomes Project , the DutThe ultimate aim is that every patient diagnosed with early-stage TNBC has a bespoke treatment pathway developed that fits their TNBC. The individualised use of preclinical models such as patient-derived organoids or xenografts , and theIn conclusion, advances in tumour characterisation, real-time biomarker/genomic testing, trial design, and drug development provide the foundation for an era of precision treatment in early TNBC. The development of complex strategies that integrate multi-modal data to derive individualised care plans, should consider the holistic needs of each patient to achieve a truly personalised approach.KP, LD, RL, and JA each contributed to the design, literature review, writing, and editing of the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.We would like to thank and acknowledge our funders, the Cancer Research UK (CRUK) ; Addenbrookes Charitable Trust (98100) and the Mark Foundation for Cancer Research (RDZD/174). This research was also supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.The authors want to thank the CRUK Precision Breast Cancer Institute, Cambridge and the Cambridge Cancer Trials Centre Womens’ Team for their support for our work in Triple Negative Breast Cancer. We also acknowledge the CRUK Cambridge Centre for its core support. We would like to thank the patients, families and carers who inspire us to work on TNBC.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Assessment of cellular immune responses in clinical trials that evaluate the immunogenicity of these new generation vaccines is thus of utmost importance. Moreover, studies are needed to examine whether these cross-reactive cellular immune responses can be considered as new or complementary correlates of protection in the evaluation of traditional and next-generation influenza vaccines. An overview of the assays that can be applied to measure cell-mediated immune responses to influenza with their strengths and weaknesses is provided here.Influenza vaccines remain the most effective tools to prevent flu and its complications. Trivalent or quadrivalent inactivated influenza vaccines primarily elicit antibodies towards haemagglutinin and neuraminidase. These vaccines fail to induce high protective efficacy, in particular in older adults and immunocompromised individuals and require annual updates to keep up with evolving influenza strains (antigenic drift). Vaccine efficacy declines when there is a mismatch between its content and circulating strains. Current correlates of protection are merely based on serological parameters determined by haemagglutination inhibition or single radial haemolysis assays. However, there is ample evidence showing that these serological correlates of protection can both over- or underestimate the protective efficacy of influenza vaccines. Next-generation universal influenza vaccines that induce cross-reactive cellular immune responses (CD4 Orthomyxoviridae, a family of enveloped negative-sense single-stranded RNA viruses with a segmented genome. Three genera, influenza A, B and C, cause human respiratory disease of which influenza A and B are clinically most important. The influenza A viruses are further classified into subtypes according to the antigenicity of their major membrane glycoproteins, haemagglutinin (HA) and neuraminidase (NA). Since 1977 influenza A/H1N1 and A/H3N2 have been co-circulating and causing annual epidemics of varying severity  containing 15 µg haemagglutinin (HA) of each of the three selected influenza strains  which are administered intramuscularly. The influenza strains are selected for inclusion in a seasonal vaccine on the basis of predictions made from surveillance data acquired under the coordination of the WHO . However, since there are two influenza B lineages circulating (B/Yamagata and B/Victoria), suboptimal vaccine protection can occur when the predominant circulating influenza B virus strain is from the alternate lineage to the B strain present in the vaccine . The samIn 2003, the first live-attenuated influenza virus vaccine (LAIV) was licensed in the US as an intranasal spray. This vaccine is produced by re-assortment of the selected influenza virus strains with the cold-adapted A/Ann Arbor/6/1960 vaccine strain, which replicates efficiently at 25°C in the nasal passages but not at the higher temperatures deeper in the respiratory tract. This LAIV seems to have the advantage to induce mucosal IgA and more broadly protective immune responses in infants and children compared to inactivated vaccines . HoweverFor many years, the evaluation of vaccine immunogenicity and licensure relied merely on the serological assessment of the immune response using the haemagglutination inhibition (HI) and the single radial haemolysis (SRH) assays. Every year, vaccine manufacturers had to do a small clinical trial involving around 100 participants including 50 subjects aged ≥60 years of whom pre- and post-vaccination serum samples had to be collected. The immunogenicity of the vaccine was then assessed based on three criteria that are shown in + T-cells responding to internal influenza proteins were associated with lower virus shedding and less severe illness  is no longer sufficient to conclude whether a vaccine is protective in a target population , 35. It nfection . First anfection –39.A seroprevalence study of antibodies against influenza viruses  in children of 0 to 7 years of age in the Netherlands showed that all children had acquired antibodies to at least one influenza virus by the age of 6 years while the highest attack rates were observed in children of 2 and 3 years . This shAfter infection, both innate and adaptive immune responses are activated to combat and clear the virus Figure 2+ and CD8+ T-cells change the expression of homing receptors and migrate via several mechanisms to the site of infection. Here, CD8+ T-cells or cytotoxic T-lymphocytes (CTL) contribute to viral clearance by direct lysis of the infected cells via perforins and granzymes or expression of tumor necrosis factor (TNF) ligands (e.g. Fas ligand) of which the receptors (e.g. Fas) are expressed on infected cells. Both mechanisms result in apoptosis of the infected cells after which the cell debris is cleared by phagocytes such as macrophages and neutrophils  and regulatory T-cells (Treg)) which are all characterized by their unique cytokine patterns and functions. Influenza virus infection induces all CD4+ T-cell responses but there is a bias towards a Th1 response. The main function of Th1 cells is to enhance the pro-inflammatory cellular immunity while Th2 cells promote anti-inflammatory immune responses. Polyfunctional T-cells, T-cells with multiple functions such as degranulation of cytotoxic proteins and simultaneous production of multiple cytokines, are functionally superior over single-cytokine producing cells and are important in control of infection  and have diverse T-cell receptor profiles indicating that they can immediately detect and combat different viral influenza strains via different mechanisms  techniques, commonly used for the quantification of antibody concentrations and as such for the assessment of humoral immune responses, can also be applied for measurement of other proteins such as cytokines. Cytokine production by activated immune cells can be quantified in a variety of biological samples such as serum, plasma, bronchoalveolar lavage fluids and cell or tissue culture supernatants. ELISA methods are sensitive, precise and accurate. However, the technique is less often used for the assessment of cellular immunity in clinical studies as it is not able to determine the numbers and type of cells which are producing the cytokines . Standars occurs .via a conjugated secondary detection antibody and a colorimetric reaction - 5-bromo-4-chloro-3’-indolyphosphate p-toluidine (BCIP) or horse-radish peroxidase (HRP)-tetramethylbenzidine (TMB) systems)  , 79. Thesystems) , 82. Thesystems)  and showsystems) . Alternasystems) . For thesystems) .via several cell types of the immune system (e.g. NK-cells)  . These lFlow cytometry allows for the characterization of the functional heterogeneity of T-cell responses as it provides information on both the phenotype and the cytokine production of the of the responding T-cells.Intracellular Cytokine Staining (ICS) enables the detection and quantification of antigen-specific, low frequency, cytokine-secreting cells on a single-cell basis. As in ELISpot, the frequency of activated cells can be expressed as a fraction of the total population. PBMCs are stimulated with a specific antigen and a co-stimulus in the presence of a Golgi inhibitor (e.g. Brefeldin A or monensin) to prevent the secretion of translated cytokines so they remain intracellular in the cytoplasm. After staining of extracellular targets , the cells are fixed and permeabilized in order to permit intracellular staining of different cytokines with anti-cytokine antibodies which are conjugated to different fluorophores. Depending on the cytokine-specific antibody panels used, different T-cell subsets  can be identified . Due to + and CD8+ T-cells. It shows less intra-assay variation, better precision and linearity compared to the ICS and ELISpot assays. It is based on tetramers of synthetic biotinylated MHC Class I (for CD8) and Class II (for CD4) molecules which are conjugated to fluorescently labeled streptavidin molecules. These complexes are loaded with antigen-specific peptides which then bind to the CD4+ or CD8+ T-cells of interest via the T-cell receptor. This approach increases the avidity for epitope specific interactions and has already extensively been used in influenza research  can be used for the detection of activated antigen specific immune cells with minimal bystander activation effects. A variety of these assays have been developed for the detection of antigen specific CD4nd 4-1BB .via different assays. Most in vitro assays make use of the incorporation of a marker molecule in the newly-formed DNA of dividing cells. These marker molecules can be either radio-active compounds or fluorophores that are measured by a scintillation counter or flow cytometer, respectively. The very first proliferation assay was the 3H-thymidine assay in which this radio-active nucleoside is incorporated in the DNA of dividing cells which results in an increasing radio-active signal measured with a scintillation counter. Results are typically reported as a stimulation index in which the counts measured in stimulated cells are divided by those measured in unstimulated control culture. This technique was extensively used in the 80’s and 90’s but was progressively replaced by non-radioactive alternatives such as the 5-bromo-2’-deoxyuridine (BrdU) assay. This assay is based on the antibody-mediated detection of BrdU which is incorporated in the DNA of dividing cells. These antibodies can be either conjugated to a fluorophore and measured by flow cytometry or conjugated to an enzyme (i.e. AP or HRP) and measured by a colorimetric reaction  host  host . All thed method .+ cytotoxic T-cells and NK-cells to lyse virus infected cells, a function of the immune system which is important for viral clearance. A wide variety of cytotoxic assays exists and can be classified in different categories such as dye exclusion methods (e.g. Trypan blue), fluorescent DNA binding dye assays (e.g. propidium iodide), metabolic activity assays (e.g. MTT assay) and markers that leak out of dying/dead cells in the supernatant ) ) , 107. Inernatant . While 5his cell . In genehis cell .+ T-cells and NK cells. CD107a is a lysosomal-associated membrane protein (LAMP-1) which is present on the lipid bilayer of lytic granules. Therefore, membrane expression of this protein is a marker for cytotoxic degranulation of cells and it has been demonstrated that this expression (as measured by flow cytometry) is directly correlated to increased cytotoxicity (as measured by a fluorolysometric assay)  , 111. Thc assay) –115. Othc assay) , 117.A more recent approach to study pathogen- or vaccine-induced responses is the measurement of differential gene expression patterns between activated and non-activated immune cells which can be investigated by microarray or more recent next generation sequencing technologies . MeasuriOne of the disadvantages of this bulk sequencing is that the behavior of all cells is averaged within the population and that antigen-specific responses are ‘diluted’ by non-affected cells. A limitation which is not present in single-cell approaches. Single-cell RNA sequencing (scRNA-Seq) is able to characterize gene expression on single-cell level and shows great promise in vaccinology by better understanding host-pathogen interactions . One of Another approach to identify cellular immune responses after vaccination is the analysis of signal transduction pathways. A recently developed mRNA-based method uses JAK-STAT signal pathway activity to quantitatively measure cellular immune responses using microarray data. In this assay, a higher pathway activity is associated with a stronger adaptive immune response. This assay can be used for the analysis of whole blood samples or isolated PBMCs. Activity of the JAK-STAT1/2 pathway is elevated in whole blood samples of influenza infected patients. However, after vaccination with a TIV, no increases in activity are observed which can be explained by the fact that TIV do not elicit a strong cellular immune response . AlternaBesides transcriptomics, other biological systems such as metabolomics, proteomics, lipidomics and glycomics can be employed to investigate influenza vaccine responses .via measurement of antibody titers, but also by using ELISpot which uses plates that are coated with the antigen of interest  on which the antibodies produced by the B-cells bind. This approach is often used for detection of memory B-cells and/or plasmablasts , use of fresh or cryopreserved PBMCs and differences in equipment and reagents. As a result, even baseline ELISpot responses vary greatly between different studies. Therefore, it can be more informative to use fold changes (pre-vaccination vs post-vaccination) rather than absolute ELISpot data to define correlates of protection using the IFN-γ ELISpot assay. These data then need to be generated in the context of human challenge studies or studies where natural influenza infections are monitored . SimilarInitiatives such as FLUCOP aim at developing standardized methods to assess cellular immunity. These may eventually reduce the interlaboratory variation and hereby facilitate the discovery of cellular correlates of protection and the development of cross-protective universal influenza vaccines. One of the main goals of the project was the development of standardized protocols for PBMC preparation and cryopreservation, IFN-γ ELISpot, ICS and data analysis and reporting . SimilarAs of February 2017, the European Medicines Agency’s (EMA) committee for human medicines (CHMP) implemented new guidelines for market authorization of novel influenza vaccines . MeasureSeveral novel or improved influenza vaccines are currently under investigation, such as vaccines formulated with potent adjuvants, vaccines targeting more conserved viral proteins, viral-vectored vaccines and mRNA based vaccines . Better This chapter provides an overview of a selection of clinical trials in which the cellular immunogenicity of novel or improved influenza vaccines has been examined.®). MF59 is approved for use in seasonal flu vaccines (Fluad®) while AF03 was only evaluated in clinical studies of influenza vaccine candidates  of the adjuvanted TIV was observed against influenza A H3N2. CMI was not explored in this study   . Oligometion (®) , 169. Intion (®) . A phaset manner .A second novel influenza vaccine candidate is the Flu-V recombinant vaccine, developed by PepTcell . It contains four synthetic polypeptides that cover regions from the conserved NP, matrix proteins M1 and M2 of both human and animal influenza A and B strains and is administered with a potent Montanide ISA-51 water-in-oil emulsion adjuvant . In the 3H-thymidine lymphoproliferation assay and secretion of IL-2 and IFN-γ by ELISA upon stimulation of PBMC with M-001, different influenza virus strains or T-helper epitope peptides derived from the NP and HA proteins (+ T-cells (ICS) when it was used as a primer for subsequent QIV vaccination (unpublished results) (A third vaccine candidate directed against conserved influenza epitopes was the Multimeric-001 (M-001) vaccine developed by BiondVax Pharmaceutical Ltd. (Israel). M-001 is a synthetic recombinant protein specifically designed to activate both cellular and humoral immunity. It contains 3 repetitions of 9 B- and T-cell epitopes from the HA, M1, and NP viral proteins from both influenza A and B strains. In the initial phase I trial, the M-001 vaccine was shown to induce cellular responses as demonstrated by the proteins . The pharesults) . Howeverresults) .+ and CD8+ T-cells were increased with also an expansion of pre-existing CD8+ T-cells  and EFPIA companies’ in kind contribution.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The NHS Long-Term Plan includes the perinatal mental health objective: by 2023/24 ‘Maternal Mental Health Services’ will be available across the country to provide psychological therapy for those who experience mental health difficulties directly arising from birth trauma and or/perinatal loss. We achieved early implementer status via application to NHS England and, using transformation funding received, ‘Thrive’ was piloted in East Kent. A gap in service provision was identified: some existing primary care services provide intervention for this cohort, however some people remain in psychological distress but do not meet the criteria for specialist perinatal mental health secondary care services; these secondary care services are not commissioned to support those who have experienced perinatal loss. Thrive is co-delivered by a mental health trust and acute healthcare trust; NICE recommended psychological interventions are provided by Psychological Therapists, Specialist Mental Health Midwives and a Peer Support Worker. The aim of this project was to evaluate the effectiveness of the Thrive pilot in reducing PTSD symptomology whilst also collating feedback from patients, their families and healthcare staff across the maternity system, in order to adapt the service offer for full county rollout.40 people who received care from Thrive from 11th January 2021 to 31st December 2021 were included in this evaluation.Data were collected retrospectively at the end of each period of care via:PCL-5: a 20-item self-report measure assessing the 20 DSM-5 symptoms of PTSD.CORE-34: a universal method of establishing well-being and risk.HoNOS : a measure of the health and social functioning of people with severe mental illness.Patient Satisfaction Survey .Clinical outcomes measures (quantitative):100% of patients improved following Thrive intervention: PCL-5 (significant change = a reduction in score by 10–20 points has been met) / CORE-34 .Clinical improvement: HoNOS = 100% of patients improved following Thrive intervention.Evaluation has evidenced the effectiveness of Thrive in successfully treating those with PTSD symptomology arising from their maternity experience. Post-treatment measures indicate that the level of trauma symptomology and the impact of psychological distress on the functioning of patients who have received intervention from Thrive has reduced to a sub-clinical level in all cases.


Some capability dimensions may be more important than others in determining someone’s well-being, and these preferences might be dependent on ill-health experience. This study aimed to explore the relative preference weights of the 16 items of the German language version of the OxCAP-MH  capability instrument and their differences across cohorts with alternative levels of mental ill-health experience.A Best–Worst-Scaling (BWS) survey was conducted in Austria among 1) psychiatric patients , 2)  healthcare experts , and 3) primary care patients with no mental ill-health experience. Relative importance scores for each item of the German OxCAP-MH instrument were calculated using Hierarchical Bayes estimation. Rank analysis and multivariable linear regression analysis with robust standard errors were used to explore the relative importance of the OxCAP-MH items across the three cohorts.Self-determination and Limitation in daily activities were regarded as the most important for all three cohorts. Freedom of expression was rated significantly less important by psychiatric patients than by the other two cohorts, while Having suitable accommodation appeared significantly less important by the expert cohort. There were no further significant differences in the relative preference weights of OxCAP-MH items between the cohorts or according to gender.The study included 158 participants with complete cases and acceptable fit statistic. The relative importance scores for the full cohort ranged from 0.76 to 15.72. Findings of the BWS experiment indicated that the items Our study indicates significant between-item but limited mental ill-health related heterogeneity in the relative preference weights of the different capability items within the OxCAP-MH. The findings support the future development of preference-based value sets elicited from the general population for comparative economic evaluation purposes.The online version contains supplementary material available at 10.1186/s12955-022-02009-6. The assessment of outcomes in health intervention and care related studies requires information not only about the identification and measurement of impacts, but also the consideration of how valuable these impacts are to patients or the general public . OutcomeThe idea of developing value sets for capability instruments has first appeared in 2008, during the development of the OCAP-18 . HoweverThis study aimed to explore the relative preference weights of the 16 items of the German language version of the OxCAP-MH  capability instrument and their differences across cohorts with alternative levels of mental ill-health experience.https://healtheconomics.meduniwien.ac.at/downloads/oxcap-mh/, and the full list of items is included in the Additional file The study was conducted prospectively in Austria using the German language version of the OxCAP-MH capability wellbeing questionnaire. The OxCAP-MH is a 16-item instrument originally developed for capability wellbeing measurement in the mental health context. Items are rated on a 1–5 Likert scale. The total level sum score assumes equal weights between the different items and is converted using the formula: 100 × ),The statistical analysis aimed to estimate weights to the OxCAP-MH items across different cohorts. Sociodemographic characteristics of the respondents were summarised as mean values by cohorts. The weights for the items were calculated by Hierarchical Bayes (HB) estimation using Sawtooth Software’s analysis tool. HB estimation was employed because its calculation is based on individual respondents and consequently enables segmentation by cohorts. Instead of estimating each respondent’s utilities individually, the algorithm estimates how different the respondent’s utilities are from the other respondents in the study . Hence, Finally, multivariable linear regression analyses were conducted to explore the relative adjusted importance of the items across cohorts. The continuous RIS of each item was regressed on binary group indicators, whilst adjusting for gender and cohort. Other demographic variables  were not considered as adjustments as they were main attributes of the cohorts' characteristics. Robust standard errors to account for violations of model assumptions and the implicit correlation of the outcome variables were obtained using the Jackknife method. It means that each participant was omitted in turn, the HB scores were re-estimated and the regressions of the HB scores on the covariates were re-fitted. From the regression coefficients of these 16 (items) The standard errors were calculated as The HB estimation and count analysis were performed in Sawtooth Software, the regression analyses were calculated using R version 4.0.2  and all An indicative preference weight set for the German OxCAP-MH was developed for Austria by a linear transformation of values based on HB estimation across all three cohorts. Since each of the 16 OxCAP-MH items has five levels and the assumption was that they carry proportionately constant weights, i.e. their contribution to the overall preference weight was assumed to be equally distributed. Worst capability levels carried the multiplication factor of 0, best capability levels the multiplication factor of 1, and those in-between the multiplication factors of 0.25, 0.5, 0.75, respectively. Similar to other capability instruments, the proposed indicative preference weight set of the OxCAP-MH instrument is anchored on a scale of 0 (no capability) to 1 (full capability).Initially, 235 people were approached, with response rates of ca. 90% for psychiatric patients, nearly 100% for  healthcare experts, and ca. 70% for primary care attendees. In total, 195 persons agreed to participate, out of whom 159 participants fully completed the BWS questionnaire and was initially included in the analysis as shown in Fig. In a subsequent step, one psychiatric patient had to be excluded because the calculated HB fit statistic was under 0.2, and it was therefore assumed that the responses of this participant were provided by chance. Table Self-determination and Limitation in daily activities. The RIS also suggest that Influencing local decisions and Losing sleep over worry are regarded as the least important items.Figure More detailed information about the Mean Relative Importance Scores and Standard Deviations of OxCAP-MH items calculated by Hierarchical Bayes estimation can be found in the Additional file Table Social networks with Enjoying friendship and support; Likelihood of assault with Likelihood of discrimination; and Likelihood of discrimination with Freedom of expression.Figure The rank orders and observed mean RIS scores for each of the three cohorts revealed that the mean RIS per cohort significantly differs in eight out of the 16 OxCAP-MH items Table . This isFreedom of expression was rated significantly less important by psychiatric patients than by the other two cohorts, given that the adjusted difference in RIS was 3.25 units, which is approximately half of the overall mean RIS for this item. Moreover, Having suitable accommodation appeared significantly less important for the expert cohort than for primary care patients with no mental ill-health experience. The difference for this item between psychiatric patients and experts was even larger in terms of the regression coefficient, but with a larger standard error. There were no further significant differences in the relative preference weights of OxCAP-MH items between the cohorts or according to gender.The regression coefficients with robust standard errors and p-values presented in Table Table This study is the first to explore the relative preference weights of the items of the OxCAP-MH, a capability well-being instrument that was originally developed for outcome measurement in this context, and the impact of mental ill-health experience on these. As opposed to other capability instruments with existing preference weight or value sets such as the ASCOT , ICECAP-Self-determination and Limitation in daily activities, suggesting that these concepts have large spans within the ‘capability space’ covered by the OxCAP-MH. The relatively high importance of these items also demonstrates that respondents placed a much higher emphasis on individual aspects of capabilities than on community-based aspects, including Influencing local decisions, in the Austrian context . Future preference weight set developments should address the issue of preferences related to levels. The indicative preference weight set could be used as current best proxy to calculate individual scores for different capability states in economic evaluations .This study found no evidence that preference weights for the items of the mental health-specific OxCAP-MH capability well-being instrument could not be elicited from alternative population cohorts with differing mental ill-health experience. Interim, the current preference weight set can be seen as the best proxy for calculating individual scores for different capability states as defined by the OxCAP-MH in economic evaluations. Our approach can also serve as an example for other BWS preference elicitation studies for more complex patient-reported outcome measures (PROMs) in order to be used for cost-effectiveness analyses.Additional file 1. Appendix 1: List of OxCAP-MH items, questions and attributes included in the BWS task. Appendix 2: Mean Relative Importance Scores and Standard Deviations of OxCAP-MH domains calculated by hierarchical Bayes estimation. Appendix 3: Sample BWS questionnaire (translated from German). Appendix 4: Mean Relative Importance Scores  by cohort (n=158)