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Objectives: The introduction of Personalised Medicine (PM) into healthcare systems could benefit from a clearer understanding of the distinct national and regional frameworks around the world. Recent engagement by international regulators on maximising the use of real-world evidence (RWE) has highlighted the scope for improving the exploitation of the treasure-trove of health data that is currently largely neglected in many countries. The European Alliance for Personalised Medicine (EAPM) led an international study aimed at identifying the current status of conditions., Methods: A literature review examined how far such frameworks exist, with a view to identifying conducive factors - and crucial gaps. This extensive review of key factors across 22 countries and 5 regions revealed a wide variety of attitudes, approaches, provisions and conditions, and permitted the construction of a comprehensive overview of the current status of PM. Based on seven key pillars identified from the literature review and expert panels, the data was quantified, and on the basis of further analysis, an index was developed to allow comparison country by country and region by region., Results: The results show that United States of America is leading according to overall outcome whereas Kenya scored the least in the overall outcome., Conclusions: Still, common approaches exist that could help accelerate take-up of opportunities even in the less prosperous parts of the world., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Abstract Recent research highlights the significant impact of the gut microbiota on health and disease. Thalassemia, a hereditary blood disorder, requires regular blood transfusions, leading to an accumulation of iron in the body. Such changes could potentially alter the intestinal microbiota, thereby increasing the susceptibility of thalassemic patients to infection. In this study, we analyzed the fecal microbiota of 70 non-transfusion-dependent (NTDT) β-thalassemia/HbE patients and 30 healthy controls. Our findings indicate that iron chelation intervention had no detectable effect on the microbiome profile of thalassemic patients. However, the cross-sectional analysis revealed that the bacterial diversity and community structure in patients were significantly less diverse and distinct compared to those of healthy subjects. Using reference frames, we were also able to demonstrate that bacterial taxa that are known to produce short chain fatty acids, from the genera Alistipes, Coprococcus, and Oscillospira, and those from the family Ruminococcaceae, were less prevalent in the patients. In contrast, bacterial taxa associated with an unhealthy gut, including the genus Clostridium and those from the families Fusobacteriaceae, Enterobacteriaceae, and Peptostrptococcaceae, were more prevalent in patients and found to be correlated with higher levels of ferritin. Collectively, these changes in the microbiota could be regarded as markers of raised ferritin levels, and therefore, awareness should be exercised as they could interfere, albeit indirectly, with the treatment of the co-morbidities of thalassemia.

Abstract Background Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. Results Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), β-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29–13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. Conclusion The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Abstract Background Current clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India. Results 903 smMIPs were designed to target exon and exon–intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood. Conclusion We developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.

Background: Ropivacaine is an ammino-amide local anesthetic agent with properties similar to bupivacaine, but its decreased lipophilicity is associated with reduced incidence of central nervous system toxicity and cardiotoxicity. This study evaluated the safety, efficacy, effects on hemodynamics and complications of spinal anesthesia using 0.5% hyperbaric bupivacaine and 0.75% hyperbaric ropivacaine in patients undergoing transurethral resection of the prostate (TURP). Aims and Objectives: The aim was to evaluate the safety, efficacy, hemodynamic stability, and side effects of spinal anesthesia using 0.5% hyperbaric bupivacaine and 0.75% hyperbaric ropivacaine in patients undergoing TURP. Materials and Methods: Sixty adult patients with physical status classes I and II, as determined by the American Society of Anesthesiologists, scheduled to undergo elective transurethral resection of prostate, were randomly allocated to receive either hyperbaric ropivacaine 0.75% 2.8 mL plus fentanyl 15 mcg or hyperbaric bupivacaine 0.5% 2.8 mL plus fentanyl 15 mcg. The parameters, such as demographic characteristics, duration of surgery, onset of sensory and motor blockade, hemodynamic stability, and complications, were compared in both groups. Results: Hyperbaric ropivacaine exhibited significantly slower onset times for sensory and motor blockade compared to hyperbaric bupivacaine. Patients in the ropivacaine group demonstrated better hemodynamic stability and experienced less hypotension compared to those who received bupivacaine. Moreover, the sensory and motor block lasted significantly longer in the bupivacaine group. Conclusion: About 0.75% hyperbaric ropivacaine is a better choice for spinal anesthesia in elderly patients undergoing TURP as compared to 0.5% hyperbaric bupivacaine.

Kidney transplant recipients are at an increased risk of hospitalisation and death from SARS-CoV-2 infection, and standard two-dose vaccination schedules are typically inadequate to generate protective immunity. Gut dysbiosis, which is common among kidney transplant recipients and known to effect systemic immunity, may be a contributing factor to a lack of vaccine immunogenicity in this at-risk cohort. The gut microbiota modulates vaccine responses, with the production of immunomodulatory short-chain fatty acids by bacteria such as Bifidobacterium associated with heightened vaccine responses in both observational and experimental studies. As SCFA-producing populations in the gut microbiota are enhanced by diets rich in non-digestible fibre, dietary supplementation with prebiotic fibre emerges as a potential adjuvant strategy to correct dysbiosis and improve vaccine-induced immunity. In a randomised, double-bind, placebo-controlled trial of 72 kidney transplant recipients, we found dietary supplementation with prebiotic inulin for 4 weeks before and after a third SARS-CoV2 mRNA vaccine to be feasible, tolerable, and safe. Inulin supplementation resulted in an increase in gut Bifidobacterium, as determined by 16S RNA sequencing, but did not increase in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third vaccination. Dietary fibre supplementation is a feasible strategy with the potential to enhance vaccine-induced immunity and warrants further investigation.

Background: Among individuals with vestibular dysfunction, the loss of vestibular sensory information is found to alter cognitive abilities that coordinate spatial and non-spatial information. P300 is an event-related potential commonly used to assess cognitive processing. The aim of the present study was to compare the latency and amplitude of cortical auditory evoked potential and P300 between individuals with vestibular dysfunction and individuals with no vestibular dysfunction. Methods: Forty adults with a mean age of 40.5 ± 13.07 participated in the study. Group I included 20 adults diagnosed with vestibular dysfunction and group II included 20 age-matched adults with no vestibular dysfunction. The P300 was recorded from the electrode site Cz and Pz. It was elicited using pure-tones in odd-ball paradigm. The latency and amplitude of peaks P1, N1, P2, and N2 of the cortical auditory evoked potential and the P300 were measured. Results: Significant amplitude difference was observed in cortical potentials at Cz and Pz. The P300 was present only in 70% of individuals with vestibular dysfunction compared to 100% among individuals with no vestibular dysfunction. The mean amplitude of the P300 was slightly larger in group 1 compared to group 2 and the mean latency of the P300 was similar in both groups. However, the difference in amplitude of the P300 between groups was not statistically significant. Conclusions: Knowing the cognitive function of individuals with vestibular dysfunction enables planning vestibular rehabilitation therapy, which enhances the quality of life in these individuals by improving their vestibular and cognitive functions.

Introduction: The present study brings forward the relationship among HIV/acquired immune deficiency syndrome (AIDS) stigma, perceived social support (PSS), and medical adherence found among HIV/AIDS children. Methodology: A sample of 90 HIV/AIDS-affected children aged 10–18 years from motilal nehru hospital, Allahabad, Uttar Pradesh, India, was selected for the study. Participants were assessed HIV/AIDS stigma, pss, and medical adherence. The tools of descriptive statistics, correlational and regression analysis, and mediation analysis were performed to accomplish the desired objective of the study. Results: Correlational analysis makes it evident that HIV/AIDS stigma is prominently negatively correlated to PSS (r (88) = −0.670, P < 0.01) and medical adherence (r (88) = −0.770, P < 0.01). Taking into consideration hierarchical regression analysis, it was found that the PSS significantly contributed to 33.2% variance in HIV/AIDS stigma and hiv/aids stigma contributed to 55.7% variance in the process of medical adherence. The achieved results of the mediation analyses validate the mediating role of HIV/AIDS stigma in the association between pss and medical adherence (β = 0.20, Confidence interval = 0.003 to 0.057, P = 0.031). Conclusion: These findings contribute to empirical evidence about psychological predictors and the observable consequences of hiv/aids-related stigma.

Abstract The dynamics of human mobility have been known to play a critical role in the spread of infectious diseases like COVID-19. In this paper, we present a simple compact way to model the transmission of infectious disease through transportation networks using widely available aggregate mobility data in the form of a zone-level origin-destination (OD) travel flow matrix. A key feature of our model is that it not only captures the propagation of infection via direct connections between zones (first-order effects) as in most existing studies but also transmission effects that are due to subsequent interactions in the remainder of the system (higher-order effects). We demonstrate the importance of capturing higher-order effects in a simulation study. We then apply our model to study the first wave of COVID-19 infections in (i) Italy, and, (ii) the New York Tri-State area. We use daily data on mobility between Italian provinces (province-level OD data) and between Tri-State Area counties (county-level OD data), and daily reported caseloads at the same geographical levels. Our empirical results indicate substantial predictive power, particularly during the early stages of the outbreak. Our model forecasts at least 85% of the spatial variation in observed weekly COVID-19 cases. Most importantly, our model delivers crucial metrics to identify target areas for intervention.

Summary: Background: The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and the related sub-lineage BA.5. Following resolution of the global BA.5 wave, a diverse grouping of Omicron sub-lineages emerged derived from BA.2, BA.5 and recombinants thereof. Whilst emerging from distinct lineages, all shared similar changes in the Spike glycoprotein affording them an outgrowth advantage through evasion of neutralising antibodies. Methods: Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants in the Australian community at three levels: (i) we tracked over 420,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using sequentially collected IgG pools; (ii) we mapped the antibody response in individuals using blood from stringently curated vaccine and convalescent cohorts. (iii) finally we determine the in vitro efficacy of clinically approved therapies Evusheld and Sotrovimab. Findings: In pooled IgG samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases, we observed increased antibody breadth to variants that were yet to be in circulation. Determination of viral neutralization at the cohort level supported equivalent coverage across prior and emerging variants with isolates BQ.1.1, XBB.1, BR.2.1 and XBF the most evasive. Further, these emerging variants were resistant to Evusheld, whilst increasing neutralization resistance to Sotrovimab was restricted to BQ.1.1 and XBF. We conclude at this current point in time that dominant variants can evade antibodies at levels equivalent to their most evasive lineage counterparts but sustain an entry phenotype that continues to promote an additional outgrowth advantage. In Australia, BR.2.1 and XBF share this phenotype and, in contrast to global variants, are uniquely dominant in this region in the later months of 2022. Interpretation: Whilst the appearance of a diverse range of omicron lineages has led to primary or partial resistance to clinically approved monoclonal antibodies, the maturation of the antibody response across both cohorts and a large donor pools importantly observes increasing breadth in the antibody neutralisation responses over time with a trajectory that covers both current and known emerging variants. Funding: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (SGT, GM & WDR), Medical Research Future Fund Antiviral Development Call grant (WDR), the New South Wales Health COVID-19 Research Grants Round 2 (SGT & FB) and the NSW Vaccine Infection and Immunology Collaborative (VIIM) (ALC). Variant modeling was supported by funding from SciLifeLab's Pandemic Laboratory Preparedness program to B.M. (VC-2022-0028) and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 101003653 (CoroNAb) to B.M.

Introduction: Spinal muscular atrophy (SMA) is a neuro-muscular disorder caused by biallelic variations in Survival Motor Neuron 1 gene (SMN1) located on chromosome 5q13.2. It is the most common hereditary cause of neonatal death. Ethnicity specific studies are desirable for estimating the prevalence of carrier status of this disease in a population. Objectives: To estimate the carrier frequency of SMA among individuals of a reproductive age group in a North Indian cohort. Methods: SMA carrier screening was offered to individuals of a reproductive age group (>18 years) visiting a tertiary care center. Multiplex ligation-dependent probe amplification (MLPA) and quantitative real-time polymerase chain reaction (PCR) were the molecular techniques used to detect the carrier status. Results: A total of 198 individuals without a family history of SMA were screened in this study. The carrier frequency of heterozygous deletion of SMN1 gene in our cohort was found to be 1 in 30 (~3/100). Conclusion: The carrier frequency of SMA is high in our country. The data from the study emphasize the need of a population carrier screening program on SMA in India.

Background: Kawasaki disease is a pediatric, systemic, vasculitic disorder. Its exact etiology is still unknown. Genetic polymorphisms are being investigated as susceptibility factor for this disorder. These are likely to vary among different populations. Aim: To investigate the association of single nucleotide polymorphism (SNP) rs113420705 of CASP3 in Kawasaki disease (KD) from North India. Settings and Design: Observational, case–control study. Methods: Polymerase chain reaction and bidirectional Sanger sequencing was used for determining genotypes of SNP rs113420705 in 45 cases of KD and 50 healthy age- and sex-matched controls. Allele and genotype frequencies were assessed and compared between the groups. Results: Among 45 cases, 32 had TT (71.1%), 13 had CT (28.9%) and none had CC genotype of SNP rs113420705. No significant differences in allele, genotype, or carrier frequencies of rs113420705 were found between the two groups. A comparison was also made between subgroups of KD with coronary abnormality (7 children; 15.5%) and KD with normal coronaries (38 children; 84.4%). The C allele was significantly overexpressed in KD with coronary abnormality group (P = 0.005). However, no difference was noted in the genotype frequencies. Conclusion: CT genotype of rs113420705 of CASP3 showed a trend to significance with the occurrence of KD in children in North India. However, we could not establish any association between minor allele C and susceptibility to KD. C allele appeared to be over expressed in children with KD with coronary abnormalities. Larger studies will help us to reach conclusive evidence applicable to all ethnicities.

Background: Vestibular dysfunction is known to affect cognitive abilities related to the processing of spatial and non-spatial information. P300 is an event-related potential (ERP) used to assess cognitive function. Studies have shown abnormalities in P300 in individuals with vestibular hypofunction. However, the literature shows equivocal findings for P300 in individuals with vestibular dysfunction. The aim of present study was to compare the latency and amplitude of cortical auditory evoked potential and P300 between individuals with vestibular dysfunction and individuals with no vestibular dysfunction. Methods: Forty adults with a mean age of 40.5 years participated in the study. Group I included 20 adults diagnosed with vestibular dysfunction and group II included 20 age-matched adults with no vestibular dysfunction. The P300 was recorded using pure-tones in an odd-ball paradigm, from electrode sites Cz and Pz. The latency and amplitude of peaks P1, N1, P2, N2 P300, and N4 were measured. Results: The results showed no significant difference in the latency and amplitude of peaks P1, N1, P2, and N2 of the cortical auditory potentials between groups. The P300 was absent in approximately 30% of individuals with vestibular dysfunction meanwhile, it was present in all individuals in group II. The mean latency and amplitude of the P300 and latency of N4 were not significantly different between the groups. However, a significant difference was observed in N4 amplitude between groups at both electrode sites. And, no correlation was observed between the DHI score and the P300 parameters in group I. Conclusions: the P300 was absent in a greater number of individuals with vestibular dysfunction, suggesting cognitive impairment. However, when the P300 was present the peak latency and amplitude showed no significant difference in both groups.

Summary: Background: Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. The introduction of global vaccine programs has contributed to lower COVID-19 hospitalisation and mortality rates, particularly in developed countries. In late 2021, Omicron BA.1 emerged, with substantially altered genetic differences and clinical effects from other variants of concern. Shortly after dominating global spread in early 2022, BA.1 was supplanted by the genetically distinct Omicron lineage BA.2. A sub-lineage of BA.2, designated BA.5, presently has an outgrowth advantage over BA.2 and other BA.2 sub-lineages. Here we study the neutralisation of Omicron BA.1, BA.2 and BA.5 and pre-Omicron variants using a range of vaccine and convalescent sera and therapeutic monoclonal antibodies using a live virus neutralisation assay. Using primary nasopharyngeal swabs, we also tested the relative fitness of BA.5 compared to pre-Omicron and Omicron viral lineages in their ability to use the ACE2-TMPRSS2 pathway. Methods: Using low passage clinical isolates of Clade A.2.2, Beta, Delta, BA.1, BA.2 and BA.5, we determined humoral neutralisation in vitro in vaccinated and convalescent cohorts, using concentrated human IgG pooled from thousands of plasma donors, and licensed monoclonal antibody therapies. We then determined infectivity to particle ratios in primary nasopharyngeal samples and expanded low passage isolates in a genetically engineered ACE2/TMPRSS2 cell line in the presence and absence of the TMPRSS2 inhibitor Nafamostat. Findings: Peak responses to 3 doses of BNT162b2 vaccine were associated with a 9-fold reduction in neutralisation for Omicron lineages BA.1, BA.2 and BA.5. Concentrated pooled human IgG from convalescent and vaccinated donors and BNT162b2 vaccination with BA.1 breakthrough infections were associated with greater breadth of neutralisation, although the potency was still reduced 7-fold across all Omicron lineages. Testing of clinical grade antibodies revealed a 14.3-fold reduction using Evusheld and 16.8-fold reduction using Sotrovimab for the BA.5. Whilst the infectivity of BA.1 and BA.2 was attenuated in ACE2/TMPRSS2 entry, BA.5 was observed to be equivalent to that of an early 2020 circulating clade and had greater sensitivity to the TMPRSS2 inhibitor Nafamostat. Interpretation: Observations support all Omicron variants to significantly escape neutralising antibodies across a range of vaccination and/or convalescent responses. Potency of therapeutic monoclonal antibodies is also reduced and differs across Omicron lineages. The key difference of BA.5 from other Omicron sub-variants is the reversion in tropism back to using the well-known ACE2-TMPRSS2 pathway, utilised efficiently by pre-Omicron lineages. Monitoring if these changes influence transmission and/or disease severity will be key for ongoing tracking and management of Omicron waves globally. Funding: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (ST, GM & WDR), MRF2001684 (ADK and ST) and Medical Research Future Fund Antiviral Development Call grant (WDR), Medical Research Future Fund COVID-19 grant (MRFF2001684, ADK & SGT) and the New South Wales Health COVID-19 Research Grants Round 2 (SGT).

Radical new possibilities of improved treatment of cancer are on offer from an advanced medical technology already demonstrating its significance: next-generation sequencing (NGS). This refined testing provides unprecedentedly precise diagnoses and permits the use of focused and highly personalized treatments. However, across regions globally, many cancer patients will continue to be denied the benefits of NGS as long as some of the yawning gaps in its implementation remain unattended. The challenges at the regional and national levels are linked because putting the solutions into effect is highly dependent on cooperation between regional- and national-level cooperation, which could be hindered by shortfalls in interpretation or understanding. The aim of the paper was to define and explore the necessary conditions for NGS and make recommendations for effective implementation based on extensive exchanges with policy makers and stakeholders. As a result, the European Alliance for Personalised Medicine (EAPM) developed a maturity framework structured around demand-side and supply-side issues to enable interested stakeholders in different countries to self-evaluate according to a common matrix. A questionnaire was designed to identify the current status of NGS implementation, and it was submitted to different experts in different institutions globally. This revealed significant variability in the different aspects of NGS uptake. Within different regions globally, to ensure those conditions are right, this can be improved by linking efforts made at the national level, where patients have needs and where care is delivered, and at the global level, where major policy initiatives in the health field are underway or in preparation, many of which offer direct or indirect pathways for building those conditions. In addition, in a period when consensus is still incomplete and catching up is needed at a political level to ensure rational allocation of resources—even within individual countries—to enable the best ways to make the necessary provisions for NGS, a key recommendation is to examine where closer links between national and regional actions could complement, support, and mutually reinforce efforts to improve the situation for patients.

BackgroundA diagnosis of cancer is associated with significant physical, psychological and financial burden. Including costs of cancer is an important component of shared decision making. Doctors bear a responsibility towards educating patients about the financial aspects of care. Multiple organisations have advocated for price transparency and implementing Informed Financial Consent in the clinic. However, few studies have evaluated the perspectives of oncologists on the current state of this discussion.AimsThe aim of this study is to determine the views and perspectives of medical oncologists regarding communication of costs and financial burden in patients with cancer.MethodsWe conducted a prospective cross-sectional online survey via REDCap. The survey was distributed to medical oncologists and advanced trainees currently registered with Medical Oncology Group of Australia (MOGA). Data was collected using the online survey comprising socio-demographic characteristics, discussion of costs and financial burden, and facilitators and barriers to these discussions.Results547 members of MOGA were invited to participate in the study, and 106 of 547 MOGA members (19%) completed the survey. Most oncologists (66%) felt that it was their responsibility to discuss costs of care, however a majority of oncologists (59.3%) reported discussing costs with less than half of their patients. Only 25% of oncologists discussed financial concerns with more than half of their patients, and most oncologists were unfamiliar with cancer-related financial burden. Most Oncologists with greater clinical experience and those working in private practice were more likely to discuss costs with a majority of their patients.ConclusionsCertain characteristics of medical oncologists and their practices were associated with reported prevalence of discussing costs of care and financial burden with their patients. In the context of rising costs of cancer care, interventions targeting modifiable factors such as raising oncologist awareness of costs of care and financial burden, screening for financial toxicity and availability of costs information in an easily accessible manner, may help increase the frequency of patient-doctor discussions about costs of care, contributing to informed decision-making and higher-quality cancer care.

Tackling cancer is a major challenge right on the global level. Europe is only the tip of an iceberg of cancer around the world. Prosperous developed countries share the same problems besetting Europe–and the countries and regions with fewer resources and less propitious conditions are in many cases struggling often heroically against a growing tide of disease. This paper offers a view on these geographically wider, but essentially similar, challenges, and on the prospects for and barriers to better results in this ceaseless battle. A series of panels have been organized by the European Alliance for Personalised Medicine (EAPM) to identify different aspects of cancer care around the globe. There is significant diversity in key issues such as NGS, RWE, molecular diagnostics, and reimbursement in different regions. In all, it leads to disparities in access and diagnostics, patients’ engagement, and efforts for a better understanding of cancer.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus-cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)-confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of "high responders" maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design.

Introduction The primary aim of the National Institute of Health Research-funded global health research group, Warwick-India-Canada (WIC), is to reduce the burden of psychotic disorders in India. India has a large pool of undetected and untreated patients with psychosis and a treatment gap exceeding 75%. Evidence-based packages of care have been piloted, but delivery of treatments still remains a challenge. Even when patients access treatment, there is minimal to no continuity of care. The overarching ambition of WIC programme is to improve patient outcomes through (1) developing culturally tailored clinical interventions, (2) early identification and timely treatment of individuals with mental illness and (3) improving access to care by exploiting the potential of digital technologies.Methods and analysis This multicentre, multicomponent research programme, comprising five work packages and two cross-cutting themes, is being conducted at two sites in India: Schizophrenia Research Foundation, Chennai (South India) and All India Institute of Medical Sciences, New Delhi (North India). WIC will (1) develop and evaluate evidence-informed interventions for early and first-episode psychosis; (2) determine pathways of care for early psychosis; (3) investigate the efficacy and cost-effectiveness of community care models, including digital and mobile technologies; (4) develop strategies to reduce the burden of mental illnesses among youth; (5) assess the economic burden of psychosis on patients and their carers; and (6) determine the feasibility of an early intervention in psychosis programme in India.Ethics and dissemination This study was approved by the University of Warwick’s Biomedical and Scientific Research Ethics Committee (reference: REGO-2018-2208), Coventry, UK and research ethics committees of all participating organisations. Research findings will be disseminated through peer-reviewed scientific publications, presentations at learnt societies and visual media.

Background: Dengue is a common vector-borne disease in countries like India, where it occurs in specific pockets including many in Maharashtra. During July–August 2018, an outbreak of dengue was suspected in a village of Wardha district, following an increase in the number of fever cases from the village, which demanded an urgent outbreak investigation to be carried out before it progressed into an epidemic/larger outbreak. Objectives: The aim of this study was to find out more cases, source of infection and to recommend necessary actions to control the dengue outbreak. Materials and Methods: This was a cross-sectional epidemiological study, where we used pre-tested, pre-designed epidemiological case sheets obtained from Integrated Disease Surveillance Program (IDSP). A case definition was proposed before beginning the investigation. Line listing, collection of blood samples, distribution of paracetamol tablets to fever cases, and making a spot map were some of the important steps carried out during the investigation. Results: Out of a total of 64 suspected fever cases, 36 cases fulfilled the case definition of dengue, set for the purpose of outbreak investigation. Twenty-three of them got admitted in different hospitals among whom two of them died. Apart from that, four of them were found to be positive for both dengue IgM and NS1 antigen in their blood samples. It was age group of 21–30 years which was mostly affected. Compared to males, the female population suffered more from the illness. House, container, and Breteau index were found to be 0.26, 0.09, and 0.32, respectively. Conclusion: Following the investigation, a detailed report was made, which was shared with the district health authority. The report also contained recommendations for necessary actions to be taken to control this outbreak and to further prevent such outbreaks in future.

Introduction: Cholera, though a preventable and treatable disease, is still regarded as an important public health problem in developing countries including India. Migration, unhygienic living conditions, overcrowding, open field defecation, and ignorance about the spread of disease are the major reasons for the occurrence of cholera in the slum areas. Cholera was detected in the stool sample of a 3-year-old child from a slum area of urban Wardha, which demanded an urgent outbreak investigation to be carried out before it progressed into an epidemic. Materials and Methods: This was a cross-sectional epidemiological study, where we have used pretested, predesigned epidemiological case sheets obtained from IDSP. A case definition was proposed before beginning the investigation. Linelisting, collection of stool and water samples, immediate referral, and treatment of the patients suffering from loose stool and/or vomiting were performed. A detailed epidemiological report was made with recommendations and plan of action that was forwarded to the district health system. Results: In all, 28 suspected cases of cholera were line listed. Among the affected population, more than half of the suspected cases were from the age group of 0–10 years of age. Males were more affected when compared with females. The overall attack rate was 27% and case fatality rate was 0%. There was positive history of travel in the index case. Two of the water samples were found to be unsatisfactory for drinking. Conclusion: The investigation report was soon developed and shared with the district health authorities, and recommendations were given to prevent such outbreaks in future.

Thoracoschisis and gastroschisis are types of ventral body wall defects. Usually thoracoabdominoschisis presents as a continuous defect. Here the authors present the case of autopsy of 18 weeks old fetus with two well-separated ventral body wall defects. Thoracoschisis was a right lateral thoracic wall defect while gastroschisis, a midline infraumblical abdominal wall defect. Through the right lateral thoracic wall parts of two organs appeared to be protruding. On dissection, 8th and 9th ribs with the liver and the lower lobe of the right lung were herniating outside the body. The right lung was haemorrhagic. Various embryological theories on ventral body wall defects have been discussed in view of the present case.

Fibrothecomas are rare sex cord stromal tumours. They usually occur in postmenopausal women and are mostly unilateral. They are usually associated with good prognosis; however, difficulties are encountered in establishing diagnosis. The treatment includes surgical resection. Here, the authors describe a rare case of a bilateral ovarian fibrothecoma in a 20-year-old female who presented with a large pelvic mass. On examination, there was a regular, immobile solid mass extending 30 weeks pregnancy size per abdomen. Pelvic examination revealed a firm nodular mass with minimal mobility and uterus could not be appreciated separately. On ultrasonography, a large solid mass arising from the pelvis superior and to the right of the uterus extending up to right hypochondrium was seen along with few cystic spaces and peripheral vascularity. Computerised tomography demonstrated two large solid cystic abdominopelvic mass lesion with internal solid enhancing areas and calcification of approximately 18 cm on the right side and 14 cm on the left side. The patient underwent exploratory laparotomy. Intra-operatively, the right ovarian mass was found, which was histopathologically confirmed as bilateral ovarian tumour (Bilateral Fibrothecoma).

F-Actin remodeling is important for the spread of HIV via cell–cell contacts; however, the mechanisms by which HIV corrupts the actin cytoskeleton are poorly understood. Through live cell imaging and focused ion beam scanning electron microscopy (FIB-SEM), we observed F-Actin structures that exhibit strong positive curvature to be enriched for HIV buds. Virion proteomics, gene silencing, and viral mutagenesis supported a Cdc42-IQGAP1-Arp2/3 pathway as the primary intersection of HIV budding, membrane curvature and F-Actin regulation. Whilst HIV egress activated the Cdc42-Arp2/3 filopodial pathway, this came at the expense of cell-free viral release. Importantly, release could be rescued by cell–cell contact, provided Cdc42 and IQGAP1 were present. From these observations, we conclude that a proportion out-going HIV has corrupted a central F-Actin node that enables initial coupling of HIV buds to cortical F-Actin to place HIV at the leading cell edge. Whilst this initially prevents particle release, the maturation of cell–cell contacts signals back to this F-Actin node to enable viral release & subsequent infection of the contacting cell.

Context: Prevalence of musculoskeletal disorders (MSDs) is common among farmers as agriculture work is highly physically demanding. India's 54.6% of the population is engaged in agriculture and allied activities. There is a need for accurate measurement and assessment of the impact of musculoskeletal conditions for public health action. Hence, in order to obtain prevalence and health impact of these problems as well as to evoke interest of researchers in this area, this study was conducted. Aim: To study the prevalence and health impact of MSD among farmers. Subjects and Methods: Study settings: Village from Sangli district. Study design: This was a cross-sectional study. Study subjects: Farmers of both sexes. Exclusion criteria: Farmers having history of arthritis or having MSD due to accidents. Sample size and sampling technique: Calculated sample 1150 from randomly selected village. Study tools: (a) Pro forma developed by investigator, (b) Modified Nordic Questionnaire, and (c) Ovako Working Posture Analyzing System. Statistical Analysis Used: Frequencies, percentages, Chi-square test, and binary logistic regression analysis was done with the help of SPSS software. Results: A total of 964 (83.8%) farmers experienced MSD in the last 1 year. Knee was the most commonly affected body part. Weeding with squatting position was most common posture. MSDs were significantly associated with age, addiction, and associated diseases. Binary logistic regression analysis concluded age, weight, height, and body mass index as strong predictors of MSD. Duration of disability as a result of MSD ranged from 1 to 190 days. Mean expenditure on medication was Rs. 3040.82. Conclusions: Prevalence of MSDs in farmers was high. MSDs had affected farmers adversely in terms of long disability days resulting into economic loss in terms of failure to work to earn and expenditure on treatment.

Introduction: Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder which has a complex pathophysiology including the role of inflammation being recently studied. Aim: To assess the role of mast cells and Intraepithelial Lymphocytes (IELs) in IBS patients by morphometry. Materials and Methods: In this study, 148 cases of IBS using the Rome III criteria and 28 controls were taken. IBS patients were divided into two subgroups of Post Infectious (PI) and Non Post Infectious (NPI) subgroups on the basis of past history of episodes of gastroenteritis. All of them underwent full length colonoscopy and biopsy from the descending colon. Histopathology of these two were compared with special attention to morphometric count of IELs by “pin hole” method and mast cells using toluidine blue highlighting. Results: Biopsies were unremarkable in 23(15.54%) patients, whereas 125 (84.46%) patients were diagnosed as Non Specific Colitis (NSC). The difference in IEL counts and mast cell counts were extremely significant (p

Protective signaling from the leukemia microenvironment leads to leukemia cell persistence, development of resistance, and disease relapse. Here, we demonstrate that fibroblast growth factor 2 (FGF2) from bone marrow stromal cells is secreted in exosomes, which are subsequently endocytosed by leukemia cells, and protect leukemia cells from tyrosine kinase inhibitors (TKIs). Expression of FGF2 and its receptor, FGFR1, are both increased in a subset of stromal cell lines and primary AML stroma; and increased FGF2/FGFR1 signaling is associated with increased exosome secretion. FGFR inhibition (or gene silencing) interrupts stromal autocrine growth and significantly decreases secretion of FGF2-containing exosomes, resulting in less stromal protection of leukemia cells. Likewise, Fgf2 -/- mice transplanted with retroviral BCR-ABL leukemia survive significantly longer than their +/+ counterparts when treated with TKI. Thus, inhibition of FGFR can modulate stromal function, reduce exosome secretion, and may be a therapeutic option to overcome resistance to TKIs.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Introduction: Dilatation of the pupil is essential for eye examinations and procedures, and when the characteristics are known it will help the clinical work flow. Tropicamide-Phenylephrine combination is the most commonly used dilating agent in ophthalmic clinical practice. Aim: To study the pupil dynamics and properties on dilatation with Tropicamide (0.8%) + Phenylephrine (5%) combination drops. Materials and Methods: This was a cross sectional observational study conducted on 132 eyes (right eye) from 132 patients. Baseline measurement of the pupil and pupil dynamics were noted after dilatation with a single drop of TropicamidePhenylephrine (5%). Pupil Diameter was measured with Optical Biometer at every 2 minutes till 44 minutes or till the patient achieved full dilatation. Data was analysed using t-test, MannWhitney U test and ANOVA was used to compare data between groups. Results: The average onset of dilatation in our study population was at 9.02±5.2 minutes (2 to 24 min) from the time of instillation of drops. The mean time taken for full dilatation was 33.02±5.09 minutes (22 to 42 min) with mean amplitude of 2.39±0.68 mm (0.9 to 4.2 mm). The rate of dilatation of the pupil was 0.07±0.022 mm/sec (0.03 to 0.14 mm/min). A 98.4% of patients maximally dilated in an average time of 33.03 minutes. Conclusion: Instillation of a single drop of TropicamidePhenylephrine combination drop was effective and provides adequate dilatation for all ophthalmological clinical situations.

Uncoating of the metastable HIV-1 capsid is a tightly regulated disassembly process required for release of the viral cDNA prior to nuclear import. To understand the intrinsic capsid disassembly pathway and how it can be modulated, we have developed a single-particle fluorescence microscopy method to follow the real-time uncoating kinetics of authentic HIV capsids in vitro immediately after permeabilizing the viral membrane. Opening of the first defect in the lattice is the rate-limiting step of uncoating, which is followed by rapid, catastrophic collapse. The capsid-binding inhibitor PF74 accelerates capsid opening but stabilizes the remaining lattice. In contrast, binding of a polyanion to a conserved arginine cluster in the lattice strongly delays initiation of uncoating but does not prevent subsequent lattice disassembly. Our observations suggest that different stages of uncoating can be controlled independently with the interplay between different capsid-binding regulators likely to determine the overall uncoating kinetics.

BACKGROUND:Mobile application based delivery of psycho-social interventions may help reduce the treatment gap for severe mental illnesses (SMIs) and decrease the burden on caregivers. Apps developed in high income settings show effectiveness, but they suffer from lack of applicability in low resource scenarios due to the difference in technology penetration, affordability, and acceptance. OBJECTIVE:This study aimed to understand health technology usage, perceived needs, and acceptability of app based interventions in patients with SMIs to improve illness management and reduce caregiver burden. METHODS:The study was conducted in inpatient and outpatient settings of a tertiary care center in North India. A cross-sectional survey assessed smartphone and health app usage. Further, three focus group discussions evaluated the needs and apprehensions in using apps in management of SMIs. RESULTS:A total of 176 participants including 88 patients and 88 caregivers completed the survey. Smartphone ownership was similar to the national average (30%) in both caregivers (38.6%) and in patients (31.8%). Although subjects regularly used a third party app, health app usage was very low. Cost, unfamiliarity, and language were significant barriers to adoption. The focus group discussions provided insight into the various apprehensions of caregivers in using and in allowing patients to use smartphones and such apps. Caregivers wanted mobile apps for accessing information regarding services and resources available for people with SMI, and they felt such apps can be helpful if they could automate some of their routine caregiving activities. However, the significant difficulty was perceived in regards to the cost of the device, language of the medium, and unfamiliarity in using technology. Apprehensions that SMI patients might misuse technology, or damage the device were also prevalent. CONCLUSIONS:The study systematically looks into the scope, design considerations and limitations of implementing a mobile technology based intervention for low resource settings. With only one-third of the patients and caregivers having access to smartphones and internet, parallel outreach strategies like IVRS should be actively considered while designing interventions. The difficulty of understanding and searching in a non-native language needs to be addressed. Hand holding of caregivers and frequent encouragement from treating doctors might significantly help in technology adoption and in surmounting the apprehensions related to using technology. To make the solution acceptable and useful to the already over-burdened caregivers, developers need to work closely with patients' family members and follow a ground-up collaborative approach to app development. The scope of delivering mental health services through technology is immense in resource constrained settings like India, provided we, researchers, appreciate and accept the fact that in the varied landscape of a divergent economic, educational, and cultural milieu, a single solution will never suffice for all, and intervention modality matching with end user capacity will be of paramount importance in determining the success of the endeavor.

Background: Friction plays a very crucial role in our daily life and orthodontics is no exception. Various materials possess friction of varying intensity, which ultimately affects tooth movement. Aim: The aim was to compare the frictional resistance (FR) between various bracket types and archwire materials when ligated with low-friction and conventional elastic ligatures so as to obtain best bracket-archwire combination possessing least FR for clinicians in achieving optimal mechanotherapy. Materials and Methods: Study consisted of three types of preadjusted edgewise brackets including ceramic, stainless steel (SS) and self-ligating brackets (0.022" slot, MBT prescription), two types of archwire materials, 0.019 × 0.025" SS and 0.019 × 0.025" Teflon coated (TC) and two types of ligatures including low-friction and conventional elastic ligature. A total of 10 combinations were formed with the above mentioned material. Each combination was tested 10 times on universal testing machine for FR. The data was statistically analyzed using one-way ANOVA and unpaired t-tests. Results: Self-ligating brackets exhibited least FR (2.35 ± 0.15N) followed by metal brackets. Ceramic brackets showed the highest FR (7.32 ± 0.10N). In general, the mean value for TC wire was less than that of SS wire indicating low FR possessed by TC wires. Results also showed that low-friction ligatures produce lower-friction when compared with conventional elastic module (P > 0.05). Conclusion: The study demonstrated that self-ligating brackets with TC wire showed the least FR and ceramic brackets with SS wire when ligated with conventional elastic ligature showed the highest FR.

Protein phosphatase 2A (PP2A) is a ubiquitously expressed Serine-Threonine phosphatase mediating 30-50% of protein phosphatase activity. PP2A functions as a heterotrimeric complex, with the B subunits directing target specificity to regulate the activity of many key pathways that control cellular phenotypes. PP2A-B56α has been shown to play a tumor suppressor role and to negatively control c-MYC stability and activity. Loss of B56α promotes cellular transformation, likely at least in part through its regulation of c-MYC. Here we report generation of a B56α hypomorph mouse with very low B56α expression that we used to study the physiologic activity of the PP2A-B56α phosphatase. The predominant phenotype we observed in mice with B56α deficiency in the whole body was spontaneous skin lesion formation with hyperproliferation of the epidermis, hair follicles and sebaceous glands. Increased levels of c-MYC phosphorylation on Serine62 and c-MYC activity were observed in the skin lesions of the B56αhm/hm mice. B56α deficiency was found to increase the number of skin stem cells, and consistent with this, papilloma initiation was accelerated in a carcinogenesis model. Further analysis of additional tissues revealed increased inflammation in spleen, liver, lung, and intestinal lymph nodes as well as in the skin lesions, resembling elevated extramedullary hematopoiesis phenotypes in the B56αhm/hm mice. We also observed an increase in the clonogenicity of bone marrow stem cells in B56αhm/hm mice. Overall, this model suggests that B56α is important for stem cells to maintain homeostasis and that B56α loss leading to increased activity of important oncogenes, including c-MYC, can result in aberrant cell growth and increased stem cells that can contribute to the initiation of malignancy.

The orbit is a frequent site of metastasis, particularly from the breast, prostate gland and the lung. Carcinoma of the cervix metastasizing to the orbit is rare. We report a 27-year-old woman with Stage II B cervical cancer who presented with progressive painless protrusion of the left eye of one month duration associated with diplopia. Histology of the orbital mass was similar to that of the cervical cancer and reported as squamous cell carcinoma. She received palliative radiation to the left orbit 30 Gy in 10 fractions along with chemotherapy (Paclitaxel and Carboplatin). This resulted in regression of the proptosis. We review published literature of cases of carcinoma of the uterine cervix with metastasis to the orbit.

The Siah1 and Siah2 E3 ubiquitin ligases play an important role in diverse signaling pathways and have been shown to be deregulated in cancer. The human Siah1 and Siah2 isoforms share high sequence similarity but possess contrary roles in cancer, with Siah1 more often acting as a tumor suppressor while Siah2 functions as a proto-oncogene. The different function of Siah1 and Siah2 in cancer is likely due to the ubiquitination of distinct substrates. Hence, we decided to investigate the molecular basis of the substrate specificity, utilizing the well-characterized Siah2 substrate PHD3. Using chimeric and mutational approaches, we identified critical residues in Siah2 that promote substrate specificity. Thus, we have found that four residues in the N-terminal region of the Siah2 substrate binding domain (SBD) (Ser132, His150, Pro155, Tyr163) are critical for substrate specificity. In the C-terminal region of the SBD, a single residue, Leu250, was identified to promote the specific binding of Siah2 SBD to PHD3. Our study may help to overcome the challenges in the identification of Siah2 specific inhibitors.

Cancer cachexia is a syndrome of weight loss that results from the selective depletion of skeletal muscle mass and contributes significantly to cancer morbidity and mortality. The driver of skeletal muscle atrophy in cancer cachexia is systemic inflammation arising from both the cancer and cancer treatment. While the importance of tumor derived inflammation is well described, the mechanism by which cytotoxic chemotherapy contributes to cancer cachexia is relatively unexplored. We found that the administration of chemotherapy to mice produces a rapid inflammatory response. This drives activation of the hypothalamic-pituitary-adrenal axis, which increases the circulating level of corticosterone, the predominant endogenous glucocorticoid in rodents. Additionally, chemotherapy administration results in a significant loss of skeletal muscle mass 18 hours after administration with a concurrent induction of genes involved with the ubiquitin proteasome and autophagy lysosome systems. However, in mice lacking glucocorticoid receptor expression in skeletal muscle, chemotherapy-induced muscle atrophy is completely blocked. This demonstrates that cytotoxic chemotherapy elicits significant muscle atrophy driven by the production of endogenous glucocorticoids. Further, it argues that pharmacotherapy targeting the glucocorticoid receptor, given in concert with chemotherapy, is a viable therapeutic strategy in the treatment of cancer cachexia.

Infants and children below five years of age are more prone to develop empyema which results due to unrecognised or improperly treated pneumonia. Bilateral empyema in infants are rarely reported. The present case highlights the importance of early interventions by tube thoracostomies and appropriate antibiotics for better outcome.

BACKGROUND: MMP-13, a zinc dependent protease which catalyses the cleavage of type II collagen, is expressed in osteoarthritis (OA) and rheumatoid arthritis (RA) patients, but not in normal adult tissues. Therefore, the protease has been intensively studied as a target for the inhibition of progression of OA and RA. Recent reports suggest that selective inhibition of MMP-13 may be achieved by targeting the hemopexin (Hpx) domain of the protease, which is critical for substrate specificity. In this study, we applied a cheminformatics-based drug design approach for the identification and characterization of inhibitors targeting the amino acid residues characteristic to Hpx domain of MMP-13; these inhibitors may potentially be employed in the treatment of OA and RA. METHODOLOGY/PRINCIPAL FINDINGS: Sequence-based mutual information analysis revealed five characteristic (completely conserved and unique), putative functional residues of the Hpx domain of MMP-13 (these residues hereafter are referred to as HCR-13(pf)). Binding of a ligand to as many of the HCR-13(pf) is postulated to result in an increased selective inhibition of the Hpx domain of MMP-13. Through the in silico structure-based high-throughput virtual screening (HTVS) method of Glide, against a large public library of 16908 molecules from Maybridge, PubChem and Binding, we identified 25 ligands that interact with at least one of the HCR-13(pf). Assessment of cross-reactivity of the 25 ligands with MMP-1 and MMP-8, members of the collagenase family as MMP-13, returned seven lead molecules that did not bind to any one of the putative functional residues of Hpx domain of MMP-1 and any of the catalytic active site residues of MMP-1 and -8, suggesting that the ligands are not likely to interact with the functional or catalytic residues of other MMPs. Further, in silico analysis of physicochemical and pharmacokinetic parameters based on Lipinski's rule of five and ADMET (absorption, distribution, metabolism, excretion and toxicity) respectively, suggested potential utility of the compounds as drug leads. CONCLUSIONS/SIGNIFICANCE: We have identified seven distinct drug-like molecules binding to the HCR-13(pf) of MMP-13 with no observable cross-reactivity to MMP-1 and MMP-8. These molecules are potential selective inhibitors of MMP-13 that can be experimentally validated and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for OA, RA and other inflammatory disorders. The systematic cheminformatics-based drug design approach applied herein can be used for rational search of other public/commercial combinatorial libraries for more potent molecules, capable of selectively inhibiting the collagenolytic activity of MMP-13.

Resistance to Imatinib Mesylate (IM) is a major problem in Chronic Myelogenous Leukaemia management. Most of the studies about resistance have focused on point mutations on BCR/ABL. However, other types of resistance that do not imply mutations in BCR/ABL have been also described. In the present report we aim to study the role of several MAPK in IM resistance not associate to BCR/ABL mutations. Therefore we used an experimental system of resistant cell lines generated by co-culturing with IM (K562, Lama 84) as well as primary material from resistant and responder patient without BCR/ABL mutations. Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype. However, Erk2, but not Erk1, is critical for the acquired resistance to IM. In fact, Bcr/Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c-Abl part of the chimeric protein. Finally, we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM. In summary our data support the use of therapeutic approaches based on Erk2 inhibition, which could be added to the therapeutic armamentarium to fight CML, especially when IM resistance develops secondary to Erk2 activation.

Since the incidence of symptomatic congenital cytomegalovirus infection is low (~0.05%) and risk factors are not well defined, it is difficult to develop strategies for prevention. The aim of this study was to recognise the utility of specific Immunoglobulin G avidity analysis for distinguishing primary infection from past/recurrent infection. Sera from 50 women with cytomegalovirus specific Immunoglobulin M antibodies without proven seroconversion and infants born to these women were tested for presence of Immunoglobulin M antibodies by commercial enzyme immunoassay. For cytomegalovirus specific immunoglobulin G avidity, sera were measured by commercial kit according to manufacturer's recommendations. Among 50 sera form mothers, 26 showed the presence of Immunoglobulin M antibodies out of which 15 had low avidity antibodies. Out of 50 sera from children, 18 showed the presence of Immunoglobulin M antibodies. Out of these 18 sera from children, 12 were symptomatic, which all showed the presence of low avidity antibodies. The results showed that an avidity index

Protective signaling from the leukemia microenvironment leads to leukemia cell persistence, development of resistance, and disease relapse. Here, we demonstrate that fibroblast growth factor 2 (FGF2) from bone marrow stromal cells is secreted in exosomes, which are subsequently endocytosed by leukemia cells, and protect leukemia cells from tyrosine kinase inhibitors (TKIs). Expression of FGF2 and its receptor, FGFR1, are both increased in a subset of stromal cell lines and primary AML stroma; and increased FGF2/FGFR1 signaling is associated with increased exosome secretion. FGFR inhibition (or gene silencing) interrupts stromal autocrine growth and significantly decreases secretion of FGF2-containing exosomes, resulting in less stromal protection of leukemia cells. Likewise, Fgf2 -/- mice transplanted with retroviral BCR-ABL leukemia survive significantly longer than their +/+ counterparts when treated with TKI. Thus, inhibition of FGFR can modulate stromal function, reduce exosome secretion, and may be a therapeutic option to overcome resistance to TKIs. This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).