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Skin cancer is the most commonly occurring cancer in the USA and Germany, and the fourth most common cancer worldwide. Snail-dependent epithelial-mesenchymal transition (EMT) was shown to initiate and promote skin cancer. Previous studies could show that EMT changes actin cortex regulation and cellular mechanics in epithelial cells of diverse tissue origin. However, in spite of its potentially high significance in the context of skin cancer, the effect of EMT on cellular mechanics, mitotic rounding and proliferation has not been studied in skin epithelial cells so far. In this work we show that TGF-β-induced partial EMT results in a transformation of the mechanical phenotype of skin epithelial cells in a cell-cycle dependent manner. Concomitantly, we looked at EMT-induced changes of cell proliferation. While EMT decreases proliferation in 2D culture, we observed an EMT-induced boost of cellular proliferation when culturing cells as mechanically confined aggregates of skin epithelial cells. This proliferation boost was accompanied by enhanced mitotic rounding and composition changes of the actin cortex. We give evidence that observed EMT-induced changes depend on the EMT-upregulated transcription factor Snail. Overall, our findings indicate that EMT-induced changes of cellular mechanics might play a currently unappreciated role in EMT-induced promotion of skin tumor proliferation.Significance statementThis study describes how epithelial-mesenchymal transition (EMT) alters the actin cytoskeleton, cellular mechanics and proliferation in a benign tumor model of skin epithelial cells. We show that corresponding EMT-induced phenotypes depend on the signalling of the transcription factor Snail. Our findings suggest that EMT-induced changes of cellular mechanics and proliferation might play a currently under-appreciated role in EMT-induced promotion of skin tumors.

Epithelial-mesenchymal transition (EMT) is a key cellular transformation for many physiological and pathological processes ranging from cancer over wound healing to embryogenesis. Changes in cell migration, cell morphology and cellular contractility were identified as hallmarks of EMT. These cellular properties are known to be tightly regulated by the actin cytoskeleton. EMT-induced changes of actin-cytoskeletal regulation were demonstrated by previous reports of cell-cycle-dependent changes of actin cortex mechanics in conjunction with characteristic modifications of cortex-associated f-actin and myosin. However, at the current state, the changes of upstream actomyosin signalling that lead to corresponding mechanical and compositional changes of the cortex are not well understood. In this work, we show in breast epithelial cancer cells MCF-7 that EMT results in characteristic changes of the cortical signalling of Rho-GTPases Rac1, RhoA and RhoC and downstream actin regulators cofilin, mDia1 and Arp2/3. In the light of our findings, we propose that cell-cycle-dependent EMT-induced changes in cortical mechanics rely on two hitherto unappreciated signalling paths - i) a cell-cycle-dependent interaction between Rac1 and RhoC and ii) an inhibitory effect of Arp2/3 activity on cortical association of myosin II.

Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients.

The shaping of epithelial tissues into functional organs often depend on asymmetries in mechanical tension present at the apical and basal sides of cells. Contraction of an actomyosin meshwork underlying the apical side of cells is known to generate apical tension. The basal side of cells is also associated with an actomyosin meshwork, but it is, in addition, connected to a specialized extracellular matrix, the basement membrane. However, how basal tension is generated, and the role of the basement membrane in this process, are not well understood. Here, using atomic force microscopy, we measure mechanical tension in the basal surface of the wing disc epithelium of Drosophila. We find that basal tension depends on both the actomyosin cytoskeleton and the basement membrane, and that it is proportional to lateral surface tension and hydrostatic pressure. Collagen IV turnover and mobility are slow indicating that the basement membrane can store elastic stresses. Our data suggest that elastic stresses in the basement membrane induced by basement membrane stretch are a key factor in the adjustment of basal tension. Hydrostatic pressure and lateral actomyosin contractility are two driving forces by which epithelial cells can maintain this basement membrane stretch.

The basement membrane is a specialized extracellular matrix (ECM) that is crucial for the development of epithelial tissues and organs. In Drosophila, the mechanical properties of the basement membrane play an important role in the proper elongation of the developing egg chamber; however, the molecular mechanisms contributing to basement membrane mechanical properties are not fully understood. Here, we systematically analyze the contributions of individual ECM components towards the molecular composition and mechanical properties of the basement membrane underlying the follicle epithelium of Drosophila egg chambers. We find that the Laminin and Collagen IV networks largely persist in the absence of the other components. Moreover, we show that Perlecan and Collagen IV, but not Laminin or Nidogen, contribute greatly towards egg chamber elongation. Similarly, Perlecan and Collagen, but not Laminin or Nidogen, contribute towards the resistance of egg chambers against osmotic stress. Finally, using atomic force microscopy we show that basement membrane stiffness mainly depends on Collagen IV. Our analysis reveals how single ECM components contribute to the mechanical properties of the basement membrane controlling tissue and organ shape.

Mechanosensation of cells is an important prerequisite for cellular function, e.g., in the context of cell migration, tissue organization, and morphogenesis. An important mechanochemical transducer is the actin cytoskeleton. In fact, previous studies have shown that actin cross-linkers such as α-actinin-4 exhibit mechanosensitive properties in their binding dynamics to actin polymers. However, to date, a quantitative analysis of tension-dependent binding dynamics in live cells is lacking. Here, we present a, to our knowledge, new technique that allows us to quantitatively characterize the dependence of cross-linking lifetime of actin cross-linkers on mechanical tension in the actin cortex of live cells. We use an approach that combines parallel plate confinement of round cells, fluorescence recovery after photobleaching, and a mathematical mean-field model of cross-linker binding. We apply our approach to the actin cross-linker α-actinin-4 and show that the cross-linking time of α-actinin-4 homodimers increases approximately twofold within the cellular range of cortical mechanical tension, rendering α-actinin-4 a catch bond in physiological tension ranges.

Das Analkarzinom ist eine seltene Erkrankung, deren Inzidenz derzeit in Deutschland zunimmt. Mehr als 80 % aller Analkarzinome sind mit einer Infektion mit humanem Papillomvirus (HPV) assoziiert. In der Behandlung des metastasierten Analkarzinoms steht die systemische Therapie im Vordergrund. Hier gibt es nur wenige prospektive Studien, die fur die Definition eines therapeutischen Standards herangezogen werden konnen. Als neuer Behandlungsansatz wird derzeit die Effektivitat einer Immuntherapie evaluiert. Es wird eine Ubersicht uber die aktuelle Studienlage zur systemischen Therapie des metastasierten Analkarzinoms gegeben. Dazu erfolgte eine Literaturrecherche zur Evidenz der systemtherapeutischen Optionen des metastasierten Analkarzinoms. Als Erstlinienchemotherapie kann Paclitaxel plus Carboplatin oder die Kombination aus 5‑Fluorouracil (5-FU) und Cisplatin gegeben werden. Die Effektivitat einer Zweitlinienchemotherapie wurde bisher in Studien nicht gepruft, sie kann jedoch abhangig vom initialem Einsatz mit einem Taxan oder einem 5‑FU-basierten Regime durchgefuhrt werden. Erste Daten belegen bei vorbehandelten Patienten die Wirksamkeit einer Immuntherapie mit Nivolumab oder Pembrolizumab. Im Rahmen der immuntherapeutischen Behandlungsansatze gewinnt insbesondere die Assoziation des Analkarzinoms mit der HPV-Infektion an Bedeutung. Eine hohe Relevanz fur die Prognose der Patienten scheint daruber hinaus ein multimodales Therapiekonzept zu haben.

This study investigated university teachers’ characteristics and their influence on teaching practices: Coming from expectancy-value theory, teachers’ personal value of teaching was introduced as a...

This field study compares the effectiveness of teacher-guided and student-activating teaching methods. Expert observations of 80 university courses were combined with self-report data from 1713 students attending the courses. Controlling for students’ initial interest on the individual level and for course format, homework, and initial interest on the course level, two-level path analyses with the amount of teacher-guided and student-activating methods as predictors, and students’ final interest, subjective learning achievement, and perceived development of academic competencies as criteria – all mediated by the students’ cognitive involvement – revealed opposing effects of the two methods. Teacher-guided methods were associated with an increase in students’ cognitive involvement, interest, learning achievement, and development of academic competencies, whereas student-activating methods tended to show negative effects.

BackgroundPrimary tumor location (left vs. right) has prognostic and predictive impact on the therapeutic management of metastatic colorectal cancer (mCRC) in particular in the context of anti-epithelial growth factor receptor (anti-EGFR) antibodies. This analysis evaluates the relevance of exact segment-by-segment tumor location in patients with metastatic colorectal cancer on outcome and efficacy of anti-EGFR-antibodies.MethodsThis is a retrospective, pooled analysis of five randomized clinical trials (FIRE-1, CIOX, FIRE-3, XELAVIRI and VOLFI) treating metastatic colorectal cancer patients in a first-line setting, published between 2011-2019. Each trial was a multicentre, phase 2 or phase 3 trial in which patients with untreated metastatic colorectal cancer received chemotherapy regimens with or without monoclonal antibodies (anti-VEGF, anti-EGFR). Eligible were patients with histologically confirmed metastatic colorectal cancer in good performance status who were at least 18 years old. Individual data of 1809 patients with available exact primary tumor location were included into this analysis. Prognostic and predictive effects of primary tumor location were evaluated in uni- and multivariate analyses using the Kaplan Meier method, log rank tests, Cox regressions and logistic regressionsResults Exact primary tumor location is an important determinant of overall survival (OS) in mCRC patients (PConclusions Primary tumor location of metastatic colorectal cancer affects prognosis. Anti-EGFR efficacy increases continuously from proximal to distal segments of the colorectum in metastatic colorectal cancer patients with RAS/BRAF wild-type and BRAF mutant tumors. Therefore, patients with BRAF mutant tumors of the distal segments may benefit from first-line Anti-EGFR-based therapy.Trial registrationFIRE1 trial registration ID n/aCIOX trial registration ID NCT00254137FIRE3 trial registration ID NCT00433927XELAVIRI trial registration ID NCT01249638VOLFI trial registration ID NCT01328171

The actin cortex is a key structure for cellular mechanics and cellular migration. Accordingly, cancer cells were shown to change their actin cytoskeleton and their mechanical properties in correlation with different degrees of malignancy and metastatic potential. Epithelial-mesenchymal transition (EMT) is a cellular transformation associated with cancer progression and malignancy. To date, a detailed study of the effects of EMT on the frequency-dependent viscoelastic mechanics of the actin cortex is still lacking. In this work, we have used an established atomic force microscope-based method of cell confinement to quantify the rheology of the actin cortex of human breast, lung, and prostate epithelial cells before and after EMT in a frequency range of 0.02–2 Hz. Interestingly, we find for all cell lines opposite EMT-induced changes in interphase and mitosis; whereas the actin cortex softens upon EMT in interphase, the cortex stiffens in mitosis. Our rheological data can be accounted for by a rheological model with a characteristic timescale of slowest relaxation. In conclusion, our study discloses a consistent rheological trend induced by EMT in human cells of diverse tissue origin, reflecting major structural changes of the actin cytoskeleton upon EMT.

Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients.

The actin cortex is a key structure for cellular mechanics and cellular migration. Accordingly, cancer cells were shown to change their actin cytoskeleton and their mechanical properties in correlation with different degrees of malignancy and metastatic potential. Epithelial-Mesenchymal transition (EMT) is a cellular transformation associated with cancer progression and malignancy. To date, a detailed study of the effects of EMT on the frequency-dependent viscoelastic mechanics of the actin cortex is still lacking. In this work, we have used an established AFM-based method of cell confinement to quantify the rheology of the actin cortex of human breast, lung and prostate epithelial cells before and after EMT in a frequency range of 0.02 – 2 Hz. Interestingly, we find for all cell lines opposite EMT-induced changes in interphase and mitosis; while the actin cortex softens upon EMT in interphase, the cortex stiffens in mitosis. Our rheological data can be accounted for by a rheological model with a characteristic time scale of slowest relaxation. In conclusion, our study discloses a consistent rheological trend induced by EMT in human cells of diverse tissue origin reflecting major structural changes of the actin cytoskeleton upon EMT.Significance statementThe actin cortex is a key structure for cellular mechanics and cellular migration. Correspondingly, migratory cancer cells were shown to change their mechanical properties to a softer phenotype. EMT is a cellular transformation associated with cancer progression and malignancy. To date, a detailed study of the effects of EMT on the mechanics of the actin cortex is still lacking. In this work, we provide such a study for human breast, lung and prostate epithelial cells in dependence of the cell cycle stage. We observe a softening of the actin cortex in interphase but stiffening in mitosis upon EMT. In conclusion, our study discloses a consistent mechanical trend induced by EMT in human cells of diverse tissue origin.

Mechano-sensation of cells is an important prerequisite for cellular function, e.g. in the context of cell migration, tissue organisation and morphogenesis. An important mechano-chemical-transducer is the actin cytoskeleton. In fact, previous studies have shown that actin cross-linkers, such asα-actinin-4, exhibit mechanosensitive properties in its binding dynamics to actin polymers. However, to date, a quantitative analysis of tension-dependent binding dynamics in live cells is lacking. Here, we present a new technique that allows to quantitatively characterize the dependence of cross-linking lifetime of actin cross-linkers on mechanical tension in the actin cortex of live cells. We use an approach that combines parallel plate confinement of round cells, fluorescence recovery after photo-bleaching, and a mathematical mean-field model of cross-linker binding. We apply our approach to the actin cross-linkerα-actinin-4 and show that the cross-linking time ofα-actinin-4 homodimers increases approximately twofold within the cellular range of cortical mechanical tension renderingα-actinin-4 a catch bond in physiological tension ranges.

A crucial part of recommender systems is to model the user’s preference based on her previous interactions. Different neural networks (e.g., Recurrent Neural Networks), that predict the next item solely based on the sequence of interactions have been successfully applied to sequential recommendation. Recently, BERT4Rec has been proposed, which adapts the BERT architecture based on the Transformer model and training methods used in the Neural Language Modeling community to this task. However, BERT4Rec still only relies on item identifiers to model the user preference, ignoring other sources of information. Therefore, as a first step to include additional information, we propose KeBERT4Rec, a modification of BERT4Rec, which utilizes keyword descriptions of items. We compare two variants for adding keywords to the model on two datasets, a Movielens dataset and a dataset of an online fashion store. First results show that both versions of our model improves the sequential recommending task compared to BERT4Rec.

To advance the discussion on the validity of student evaluations of university teaching, student ratings of two teaching dimensions – student involvement and rapport – were compared with co...

The nervous system is a central regulator of longevity, but how neuronal communication interfaces with ageing pathways is not well understood. Gap junctions are key conduits that allow voltage and metabolic signal transmission across cellular networks, yet it has remained unexplored whether they play a role in regulating ageing and longevity. We show that the innexin genes encoding gap junction subunits inCaenorhabditis eleganshave extensive and diverse impacts on lifespan. Loss of the neural innexinunc-9increases longevity by a third and also strongly benefits healthspan.Unc-9acts specifically in a glutamatergic circuit linked to mechanosensation. Absence ofunc-9depends on a functional touch-sensing machinery to regulate lifespan and alters the age-dependent decline of mechanosensory neurons. The life extension produced by removal ofunc-9requires reactive oxygen species. Our work reveals for the first time that gap junctions are important regulators of ageing and lifespan.

Mechanical properties of cancer cells and their microenvironment contribute to breast cancer progression. While mechanosensing has been extensively studied using two-dimensional (2D) substrates, much less is known about it in a physiologically more relevant 3D context. Here we demonstrate that breast cancer tumor spheroids, growing in 3D polyethylene glycol-heparin hydrogels, are sensitive to their environment stiffness. During tumor spheroid growth, compressive stresses of up to 2 kPa built up, as quantitated using elastic polymer beads as stress sensors. Atomic force microscopy (AFM) revealed that tumor spheroid stiffness increased with hydrogel stiffness. Also, constituent cell stiffness increased in a ROCK- and F-actin-dependent manner. Increased hydrogel stiffness correlated with attenuated tumor spheroid growth, a higher proportion of cells in G0/G1 phase and elevated levels of the cyclin-dependent kinase inhibitor p21. Drug-mediated ROCK inhibition reversed not only cell stiffening upon culture in stiff hydrogels but also increased tumor spheroid growth. Taken together, we reveal here a mechanism by which the growth of a tumor spheroid can be regulated via cytoskeleton rearrangements in response to its mechanoenvironment. Thus, our findings contribute to a better understanding of how cancer cells react to compressive stress when growing under confinement in stiff environments and provide the basis for a more in-depth exploration of the underlying mechanosensory response.

Cell shape changes are vital for many physiological processes such as cell proliferation, cell migration, and morphogenesis. They emerge from an orchestrated interplay of active cellular force generation and passive cellular force response, both crucially influenced by the actin cytoskeleton. To model cellular force response and deformation, cell mechanical models commonly describe the actin cytoskeleton as a contractile isotropic incompressible material. However, in particular at slow frequencies, there is no compelling reason to assume incompressibility because the water content of the cytoskeleton may change. Here, we challenge the assumption of incompressibility by comparing computer simulations of an isotropic actin cortex with tunable Poisson ratio to measured cellular force response. Comparing simulation results and experimental data, we determine the Poisson ratio of the cortex in a frequency-dependent manner. We find that the Poisson ratio of the cortex decreases in the measured frequency regime analogous to trends reported for the Poisson ratio of glassy materials. Our results therefore indicate that actin cortex compression or dilation is possible in response to acting forces at sufficiently fast timescales. This finding has important implications for the parameterization in active gel theories that describe actin cytoskeletal dynamics.

3552 Background: Prognostic biomarkers beside RAS/BRAF status are necessary to identify metastatic colorectal cancer (mCRC) patients who benefit from combined (COMB) versus sequential (SEQ) treatment with fluoropyrimidine, bevacizumab and irinotecan (randomized phase III XELAVIRI trial). Methods: mRNA was extracted from formalin-fixed paraffin embedded (FFPE) tumor tissue of 337 patients, gene expression was measured by the Nanostring PanCancer Progression Panel. Consensus molecular subtypes (CMS) classification was re-derived using a multinomial regression model. Data of Guinney et al. (Nat. Med. 2015. 21:1350-6) and FIRE-3 served as training and validation set. RAS/BRAF MUT were assessed by pyrosequencing. Median overall (OS) and progression free survival (PFS), hazard ratios (HR) and 95% confidence interval (CI) were estimated by Kaplan-Meier method and univariate Cox regression. Results: The multinomial regression model employed in the present analysis correctly predicted CMS labels in 98.3 % of the original Guinney- and 100.0 % of FIRE-3 population. In XELAVIRI, CMS subgroups were predicted as follows: CMS1: n = 62 (18.4 %); CMS2: n = 174 (51.6 %); CMS3: n = 9 (2.7 %); CMS4: n = 92 (27.3 %). A general prognostic impact of CMS was not observed when all patients were analysed. In RAS/BRAF WT mCRC patients, substantial benefit of COMB versus SEQ treatment was shown for OS and PFS in CMS2 and CMS4, but not in CMS1. Conversely, OS was significantly longer for COMB treatment in patients with RAS MUT and CMS1 mCRC, while SEQ treatment was not inferior in RAS MUT and CMS2 or CMS4 subgroups (see TABLE). Additional data for overall response rates, early tumor shrinkage and sidedness might be presented at the meeting. Conclusions: This retrospective analysis of XELAVIRI suggests that CMS may serve as biomarker that predicts response to initially combined versus less intensive sequential chemotherapy in patients with RAS/BRAF WT mCRC.[Table: see text]

Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B‑ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK‑2206 promises meticulous pan‑AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK‑2206 on B‑ALL cell lines and primary samples and investigate potential synergistic effects with BCL‑2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK‑2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK‑2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK‑2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4, 11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK‑2206. Functional assessment of BCL‑2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK‑2206 and venetoclax incubation. In summary, we demonstrate that the pan‑AKT inhibitor MK‑2206 potently blocks B‑ALL cell proliferation and for the first time characterize the synergistic effect of combined MK‑2206 and venetoclax treatment in B‑ALL.

Background Little is known on the performance of the newly introduced health benefit assessment process, AMNOG, in Germany compared to other health technology assessment agencies. Objective We analysed whether decisions of the German Federal Joint Committee (FJC) deviate from decisions of the UK National Institute for Health and Care Excellence (NICE), the Scottish Medicines Consortium (SMC) and the Australian Pharmaceutical Benefits Advisory Committee (PBAC). Methods We analysed decisions made for comparable patient subgroups by the four agencies between 2011 and 2014. First, decisions were compared (a) by their final outcome, i.e. whether a health benefit was identified, and (b) by the agencies’ judgement on comparative effectiveness. Subsequently, we partially explored reasons for differences between HTA agencies. Results From the 192 FJC decisions, we identified 55 that overlapped with NICE, 166 with SMC and 119 with PBAC. FJC agreed with NICE in 40% in final outcome (Cohen’s Kappa = −0.13). Similar results were obtained for FJC and SMC (47.6%, kappa = 0.03) and FJC and PBAC (48.7%, kappa = 0.07). Agreement increased when comparing judgements based on comparative effectiveness only. However, the FJC’s final decision was positive only in 43.6%, 39.2% and 44.5% of the patient subgroups, as opposed to 74.5% (NICE), 68.7% (SMC), and 68.9% (PBAC), respectively. Conclusion We show that the FJC – an agency relatively new in structurally assessing the health benefit of pharmaceuticals – deviates considerably in decisions compared to other HTA agencies. Our study also reveals that the FJC tends to appraise stricter than NICE.

Quality of maternal and newborn care could be improved if health care providers’ knowledge and competencies as well as system level constraints are addressed. However, due to several barriers staff nurses who form the frontline of health care workforce have limited access to enhancing their clinical knowledge and competencies. To address this gap, a new cadre of nurse mentors (NMs) for the public health system were trained by specialists from a teaching hospital in a special 5-week training course. This included 54 hours of theory and 110 hours of practical in clinical obstetric and newborn care, apart from mentoring, quality improvement and health systems issues. The nurse mentors were assigned to support staff nurses in the primary health care centres (PHCs) in eight northern Karnataka districts. Each NM covered 6-8 PHCs monthly for 2 - 3 days and thus a total of 385 PHCs were reached. They received support in the field through supportive supervision visits done by the specialists who had trained them, as well as by refresher training and clinical postings to the district hospitals. This paper presents impact of the training program on change in immediate and long term knowledge and competency scores of nurse mentors. Their baseline knowledge scores changed from 44.3 ± 12.7 to 72.1 ± 13.8 immediately after the training in obstetric and from 18.2 ± 19.1 to 66.4 ± 14.9 in newborn (p p p > 0.05). Skills score soon after training increased from 62.2 ± 13.2 to 69.6 ± 12.5 in obstetric after a 1 year period and from 52.6 ± 9.3; 63.5 ± 14.4 in newborn (p < 0.001) content areas respectively. These findings have implications for those interested in improving quality of maternal and child care through nurse-dependent health delivery systems.