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Dwi Agustian,1 Insi Farisa Desy Arya,1 Qorinah Estiningtyas Sakilah Adnani,1 Guswan Wiwaha,1 Muhammad Hasan Bashari,2 Windi Nurdiawan,3 Ria Bandiara,4 Wijana Hasansulama,5 Afiat Berbudi,2 Gaga Irawan Nugraha,2 Wiryawan Permadi,3 Ruswana Anwar,3 Irvan Afriandi,1 Arief Kartasasmita,6 Yudi Mulyana Hidayat,3 Tri Hanggono Achmad,2 John Norcini7 1Department of Public Health, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 2Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 3Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 4Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 5Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 6Department of Ophthalmology, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 7Department of Psychiatry, SUNY Upstate Medical University, Philadelphia, PA, USACorrespondence: Dwi Agustian, Department of Public Health, Faculty of Medicine, Universitas Padjadjaran, Jl. Prof. Eyckman No. 38, Bandung, West Java, 40161, Indonesia, Email dwi.agustian@unpad.ac.idAbstract: Although the field of medicine has made significant progress in recent decades, low and middle-income countries continue to face significant difficulties in addressing the unprecedented obstacles to improving health. Medical schools should play a critical role in driving health services reform and take on a new leadership role in strengthening the health system. This paper discusses a conceptual framework and outlines the Academic Health Systems (AHS) agenda in Indonesia. A comprehensive analysis was conducted on the existing literature and frameworks regarding AHS, applying the system thinking method, which engages stakeholders actively. The findings and interpretations from interviews, focus groups, and collaborative workshops were consolidated and a set of proposed frameworks, fundamental principles, and a route for enhancing the health system in Indonesia were put forward. Our recommendations include transformative learning, community engagement, and translational research as pillar principles of AHS program. These recommendations have the potential to be modified and implemented in other low- and middle-income countries.Keywords: academic health system, medical education, Indonesia, health system reform, health services transformation

Sri Yunita,1,* Qorinah Estiningtyas Sakilah Adnani,2 Yenni Zuhairini,2 Meita Dhamayanti,3 Nur Syifa Rahmatika,4,5 Ruswana Anwar,6 Mohammad Ghozali7,* 1Master of Midwifery Program, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 2Departement of Public Health, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 3Department of Child Health, Hasan Sadikin Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 4Master of Biomedical Sciences Program, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 5Faculty of Medicine, Universitas Halu Oleo, Kendari, Southeast Sulawesi, Indonesia; 6Department of Obstetrics and Gynecology, Hasan Sadikin Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 7Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Jatinangor, West Java, Indonesia*These authors contributed equally to this workCorrespondence: Mohammad Ghozali, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Jalan Raya Bandung-Sumedang Km. 21, Jatinangor, West Java, 45363, Indonesia, Tel +6281320359090, Fax +62 (022) 7795595, Email moh.ghozali@unpad.ac.idAbstract: To reduce anemia rates, it is crucial to gain a deeper understanding of anemia and its associated factors. It is essential for teenagers who are going through a period of rapid growth to promptly address anemia since untreated anemia can negatively impact their reproductive health. This literature review investigated the relationship between nutritional and anthropometric status indicators, body composition, and prevalence of anemia in teenage girls. Studies were selected based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. A comprehensive search across multiple databases (PubMed= 409, ScienceDirect= 3153, Scopus= 4, Sage Journals= 358) and manual citation of five articles yielded 3929 articles, of which 630 were excluded for irrelevance, one was inaccessible, and nine articles were included in the study after assessing their eligibility. The review’s findings suggest that indicators such as Body Mass Index (BMI) and Mid-Upper Arm Circumference (MUAC) are indicated as initial assessments to screen the nutritional status of adolescent females and estimate their risk of anemia. Only one article has specifically discussed the connection between fat mass and anemia in terms of body composition. The need for studies on anthropometry and body composition-related anemia underscores the need to broaden investigations to gain a more nuanced understanding of this subject.Keywords: anthropometry, body composition, female adolescents, anemia

Luthfi Rahman, Ruswana Anwar, Zulvayanti Zulvayanti, Kevin Dominique Tjandraprawira Department of Obstetrics and Gynecology, Hasan Sadikin General Hospital/ Universitas Padjadjaran, Bandung, IndonesiaCorrespondence: Ruswana Anwar, Email ruswana.anwar@unpad.ac.idIntroduction: Abdominal pain is a diagnostic problem that requires immediate care and treatment for surgeons and gynecologists. The causes of abdominal pain in women of childbearing age range from benign and temporary to potentially life threatening. Rare etiologies such as spontaneous ruptured endometrioma are often not included in the radar of diagnosis due to their rarity and non-specific signs and symptoms in the patient. This case report aimed to show a resemblance between the clinical symptoms of acute abdomen in diffuse peritonitis due to hollow viscus perforation and spontaneous ruptured endometrioma.Case Description: A 42-year-old woman presented to our hospital with abdominal pain. She had a history of fever for two weeks. She came from a tropical rural area where typhoid fever is common. She was advised to undergo emergency laparotomy because of the suspicion of diffuse peritonitis due to a hollow viscus perforation due to typhoid infection. Because of acute abdominal pain, a vertical incision was made to explore her abdominal cavity, and chocolate-like fluid and ovarian cysts were found during surgery. The diagnosis was changed to diffuse peritonitis due to spontaneous rupture of the endometrioma bilaterally.Conclusion: This case suggests that the exact diagnosis and cause of abdominal pain varies. As the current gold standard for endometrioma is laparoscopy, surgeons must prepare a collaborative approach to the cause of the disease.Plain Language Summary: Abdominal pain is common and often requires prompt medical care. In women, it can have various causes, including rare ones, such as spontaneous ruptured endometrioma, which can be difficult to diagnose owing to its rarity and vague symptoms. We describe the case of a 42-year-old woman with abdominal pain and fever, initially suspected to have diffuse peritonitis due to typhoid infection. However, surgery revealed a ruptured endometrioma, highlighting the challenge of accurately diagnosing such conditions. This case emphasizes the need to consider the diverse diagnoses of abdominal pain and the importance of collaborative approaches among medical professionals to ensure accurate diagnosis and treatment.Keywords: case report, chocolate cyst, endometrioma, spontaneous rupture endometrioma

Luthfi Rahman, Kania Praharsini, Aditiyo Januajie, Ruswana Anwar Department of Obstetrics and Gynecology, Hasan Sadikin General Hospital-Padjadjaran University, Bandung, IndonesiaCorrespondence: Luthfi Rahman, Tel +6282239844701, Email luthfirahmanp@yahoo.comPurpose: Uterine rupture is a rare obstetrical and surgical emergency but is often associated with a catastrophic obstetric complication. Traditionally, unscarred uteri without risk factors are considered immune to rupture and information about its risk factors is only few due to its rarity. Complementary and alternative medicine is commonly used in pregnant woman in southeast Asian countries such as Indonesia, however information regarding its toxicity due to irrational use is few. This case report presents a G2P1A0 35-year-old woman with acute abdomen with spontaneous unscarred uterine rupture > 15 cm after continuously consuming herbal water made of Kacip Fatimah leaves in boiling water.Case Description: A 35-year-old pregnant woman was referred to hospital due to abdominal discomfort 3 hours before admission due to suspicion of intrauterine fetal death. She drank the extracted herbal water to help her when the labor comes, which was made from boiled water with rumput Fatimah from her neighbor’s house. Then, she was diagnosed with G2P1A0 parturient aterm latent phase; acute abdomen due to suspicion of placentae abruption dd/ ruptur uteri; and Intrauterine Fetal Death. Exploratory laparotomy was decided due to acute abdominal pain, and during the procedure the operator decided to do subtotal hysterectomy on the patient. The operator found her uterine was already ruptured, approximately 15– 18 cm and the placentae was located outside of the uterus.Conclusion: This case suggest that rational usage of herbal medicine must be implemented to avoid unwanted complication.Keywords: case report, herbal medicine, spontaneous uterine rupture, abdominal pain, unscarred uterus

The series of newer salicylate derivatives incorporating nitroxy functionality were synthesized and evaluated for their potential effect in gastrointestinal (GI) related toxicity produced by aspirin. The synthesized compounds (5a-j) were subjected to %NO (nitric oxide) release study, in-vitro anti-inflammatory potential, % inhibition of carrageenan-induced paw edema and the obtained results were validated by in-silico studies including molecular docking, MD simulations and in-silico ADME (absorption, distribution, metabolism, and elimination) calculations. Compounds 5a (20.86 %) and 5g (18.20 %) displayed the highest percentage of NO release in all the tested compounds. Similarly, 5a and 5h were found to have (77.11 % and 79.53 %) &(78.56 % and 66.10 %) inhibition in carrageenan induced paw edema in animal mode which were relatively higher than ibuprofen (standard used). The obtained results were validated by molecular docking and MD simulations studies. The molecular docking study of 5a and 5h revealed that docking scores were also obtained in very close proximity of −8.35, −9.67 and −8.48 for ibuprofen, 5g and 5h respectively. In MD simulations studies, the calculated lower RMSD (root mean square deviation) values 2.8 Å and 5.6 Å for 5g and 5h, respectively indicated the stability of ligand-protein complexes. Similarly lower RSMF (root mean square fluctuation) values indicated the molecules remained in the active pocket throughout the entire MD simulations run. Further, in-silico ADME calculations were determined and all compounds obey the Lipinski’s rule of five and it was predicted that these molecules would be orally active without any serious toxic effect.

Abstract Background Recurrent Aphthous Stomatitis (RAS) is painful oral ulceration frequently treated with topical steroids. There is limited published evidence for the efficacy of any treatment for RAS and there remains a need for longitudinal randomised clinical trials to evaluate and compare the effectiveness of different therapies in the management of RAS. The aim of the current project was to assess the efficacy of betamethasone mouthwash and colchicine tablets, individually and combined, for the treatment of RAS, and to establish the optimum treatment period necessary for a significant reduction in the disease severity. Methodology A randomised, prospective, parallel-group clinical trial was conducted over one year, to compare the efficacy of three therapies in RAS. One hundred and six patients were randomized into three groups; 35 received betamethasone mouthwash, 35 had colchicine tablets and 36 received both therapies. The response was evaluated quantitatively every 3 months for 1 year, using the Ulcer Severity Score (USS). Results For all three treatment regimes, the mean USS decreased by about 30% in the first 3 months (p

Context: Systematic biopsies are additionally recommended to maximize the diagnostic performance of the magnetic resonance imaging (MRI) diagnostic pathway for men with suspected prostate cancer (PCa) and positive scans. To reduce unnecessary systematic biopsies (SBx), MRI-directed approaches comprising targeted plus regional biopsy (TBx + RBx) are being investigated. Objective: To systematically evaluate the diagnostic performance of MRI-directed TBx + RBx approaches in comparison to MRI-directed TBx alone and TBx + SBx approaches. Evidence acquisition: The MEDLINE and Embase databases were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses process. Identified reports were critically appraised according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. Detection of grade group (GG) ≥2 PCa was the endpoint of interest. Fixed-effect meta-analyses were conducted to characterize summary effect sizes and quantify heterogeneity. Only MRI-positive men were included. Evidence synthesis: A total of eight studies were included for analysis. Among a cumulative total of 2603 men with suspected PCa, the GG ≥2 PCa detection rate did not significantly differ between MRI-directed TBx + RBx and TBx + SBx approaches (risk ratio [RR] 0.95, 95% confidence interval [CI] 0.90–1.01; p = 0.09). The TBx + RBx results were obtained using significantly fewer biopsy cores and avoiding contralateral SBx altogether. By contrast, there was significant difference in GG ≥2 PCa detection between MRI-directed TBx + RBx and TBx approaches (RR 1.18, 95% CI 1.10–1.25; p

Semicarbazide-sensitive amine oxidase (SSAO) is both a soluble- and membrane-bound transmembrane protein expressed in the vascular endothelial and in smooth muscle cells. In vascular endothelial cells, SSAO contributes to the development of atherosclerosis by mediating a leukocyte adhesion cascade; however, its contributory role in the development of atherosclerosis in VSMCs has not yet been fully explored. This study investigates SSAO enzymatic activity in VSMCs using methylamine and aminoacetone as model substrates. The study also addresses the mechanism by which SSAO catalytic activity causes vascular damage, and further evaluates the contribution of SSAO in oxidative stress formation in the vascular wall. SSAO demonstrated higher affinity for aminoacetone when compared to methylamine (Km = 12.08 µM vs. 65.35 µM). Aminoacetone- and methylamine-induced VSMCs death at concentrations of 50 & 1000 µM, and their cytotoxic effect, was reversed with 100 µM of the irreversible SSAO inhibitor MDL72527, which completely abolished cell death. Cytotoxic effects were also observed after 24 h of exposure to formaldehyde, methylglyoxal and H2O2. Enhanced cytotoxicity was detected after the simultaneous addition of formaldehyde and H2O2, as well as methylglyoxal and H2O2. The highest ROS production was observed in aminoacetone- and benzylamine-treated cells. MDL72527 abolished ROS in benzylamine-, methylamine- and aminoacetone-treated cells (**** p < 0.0001), while βAPN demonstrated inhibitory potential only in benzylamine-treated cells (* p < 0.05). Treatment with benzylamine, methylamine and aminoacetone reduced the total GSH levels (**** p < 0.0001); the addition of MDL72527 and βAPN failed to reverse this effect. Overall, a cytotoxic consequence of SSAO catalytic activity was observed in cultured VSMCs where SSAO was identified as a key mediator in ROS formation. These findings could potentially associate SSAO activity with the early developing stages of atherosclerosis through oxidative stress formation and vascular damage.

Abstract Human cancers represent complex structures, which display substantial inter- and intratumor heterogeneity in their genetic expression and phenotypic features. However, cancers usually exhibit characteristic structural, physiologic, and molecular features and display specific biological capabilities named hallmarks. Many of these tumor traits are imageable through different imaging techniques. Imaging is able to spatially map key cancer features and tumor heterogeneity improving tumor diagnosis, characterization, and management. This paper aims to summarize the current and emerging applications of imaging in tumor biology assessment.

Probiotics are used as microbial food supplements for health and well-being. They are thought to have immunomodulatory effects although their exact physiological mechanism of action is not clear. This study investigated the influence of probiotic Lactobacillus rhamnosus GG conditioned media (LGG-CM) on macrophage phagocytosis of non-pathogenic Escherichia coli HfrC. The gentamicin protection assay was used to study the bacterial killing phases of phagocytosis. Macrophages co-incubated with E. coli for an hour allowed them to ingest bacteria and then the rate of E. coli killing was monitored for up to 300 min to determine the killing or digestion of the bacteria by recovering them from the macrophage lysate. We found that the LGG-CM significantly increased the bacterial killing by approximately 6-fold when compared with that of controls. By contrast, this killing process was found to be associated with enhanced free radical production via the activation of NADPH oxidase, stimulated by the LGG conditioned medium. We also found that the conditioned medium had small effect on nitric oxide (NO) generation, albeit to a lesser extent. This work suggests that LGG-CM may play an important role in suppressing the total microbial load within the macrophages and hence, the extent to which pro-inflammatory molecules such as free radicals and NO are generated. The modulation of inflammation-promoting signals by LGG-CM may be beneficial as it modulates bacterial killing, and thereby prevents any collateral damage to host.

Abstract Background and aims Rapid and accurate cancer staging following diagnosis underpins patient management, in particular the identification of distant metastatic disease. Current staging guidelines recommend sequential deployment of various imaging platforms such as computerised tomography (CT) and positron emission tomography (PET) which can be time and resource intensive and onerous for patients. Recent studies demonstrate that whole body magnetic resonance Imaging (WB-MRI) may stage cancer efficiently in a single visit, with potentially greater accuracy than current staging investigations. The Streamline trials aim to evaluate whether WB-MRI increases per patient detection of metastases in non-small cell lung and colorectal cancer compared to standard staging pathways. Methods The Streamline trials are multicentre, non-randomised, single-arm, prospective diagnostic accuracy studies with a novel design to capture patient management decisions during staging pathways. The two trials recruit adult patients with proven or highly suspected new diagnosis of primary colorectal (Streamline C) or non-small cell lung cancer (Streamline L) referred for staging. Patients undergo WB-MRI in addition to standard staging investigations. Strict blinding protocols are enforced for those interpreting the imaging. A first major treatment decision is made by the multi-disciplinary team prior to WB-MRI revelation based on standard staging investigations only, then based on the WB-MRI and any additional tests precipitated by WB-MRI, and finally based on all available test results. The reference standard is derived by a multidisciplinary consensus panel who assess 12 months of follow-up data to adjudicate on the TNM stage at diagnosis. Health psychology assessment of patients’ experiences of the cancer staging pathway will be undertaken via interviews and questionnaires. A cost (effectiveness) analysis of WB-MRI compared to standard staging pathways will be performed. Discussion We describe a novel approach to radiologist and clinician blinding to ascertain the ‘true’ diagnostic accuracy of differing imaging pathways and discuss our approach to assessing the impact of WB-MRI on clinical decision making in real-time. The Streamline trials will compare WB-MRI and standard imaging pathways in the same patients, thereby informing the most accurate and efficient approach to staging. Trial registration Streamline C ISRCTN43958015 (registered 25/7/2012). Streamline L ISRCTN50436483 (registered 31/7/2012).

We aimed to describe the relationships between the relative fat fraction (%FF), muscle-normalized diffusion-weighted (DW) image signal intensity and water apparent diffusion coefficient (ADC), sex and age for normal bone marrow, in the normal population. Our retrospective cohort consisted of 100 asymptomatic individuals, equally divided by sex and 10-year age groups, who underwent whole-body MRI at 1.5 T for early cancer detection. Semi-automated segmentation of global bone marrow volume was performed using the DW images and the resulting segmentation masks were projected onto the ADC and %FF maps for extraction of parameter values. Differences in the parameter values between sexes at age ranges were assessed using the Mann–Whitney and Kruskal–Wallis tests. The Spearman correlation coefficient r was used to assess the relationship of each imaging parameter with age, and of %FF with ADC and normalized DW signal intensity values. The average %FF of normal bone marrow was 65.6 ± 7.2%, while nSIb50, nSIb900 and ADC were 1.7 ± 0.5, 3.2 ± 0.9 and 422 ± 67 μm2/s, respectively. The bone marrow %FF values increased with age in both sexes (r = 0.63 and r = 0.64, respectively, p < 0.001). Values of nSIb50 and nSIb900 were higher in younger women compared to men of the same age groups (p < 0.017), but this difference decreased with age. In our cohort of asymptomatic individuals, the values of bone marrow relative %FF, normalized DW image signal intensity and ADC indicate higher cellularity in premenopausal women, with increasing bone marrow fat with aging in both sexes.

Using semi-automated software simplifies quantitative analysis of the visible burden of disease on whole-body MRI diffusion-weighted images. To establish the intra- and inter-observer reproducibility of apparent diffusion coefficient (ADC) measures, we retrospectively analyzed data from 20 patients with bone metastases from breast (BCa; n = 10; aged 62.3 ± 14.8) or prostate cancer (PCa; n = 10; aged 67.4 ± 9.0) who had undergone examinations at two timepoints, before and after hormone-therapy. Four independent observers processed all images twice, first segmenting the entire skeleton on diffusion-weighted images, and then isolating bone metastases via ADC histogram thresholding (ADC: 650–1400 µm2/s). Dice Similarity, Bland-Altman method, and Intraclass Correlation Coefficient were used to assess reproducibility. Inter-observer Dice similarity was moderate (0.71) for women with BCa and poor (0.40) for men with PCa. Nonetheless, the limits of agreement of the mean ADC were just ±6% for women with BCa and ±10% for men with PCa (mean ADCs: 941 and 999 µm2/s, respectively). Inter-observer Intraclass Correlation Coefficients of the ADC histogram parameters were consistently greater in women with BCa than in men with PCa. While scope remains for improving consistency of the volume segmented, the observer-dependent variability measured in this study was appropriate to distinguish the clinically meaningful changes of ADC observed in patients responding to therapy, as changes of at least 25% are of interest.

Abnormal metabolism is a key tumor hallmark. Proton magnetic resonance spectroscopy (1H-MRS) allows measurement of metabolite concentration that can be utilized to characterize tumor metabolic changes. 1H-MRS measurements of specific metabolites have been implemented in the clinic. This article performs a systematic review of image acquisition and interpretation of 1H-MRS for cancer evaluation, evaluates its strengths and limitations, and correlates metabolite peaks at 1H-MRS with diagnostic and prognostic parameters of cancer in different tumor types.

The development of new therapeutic options against Clostridioides difficile (C. difficile) infection is a critical public health concern, as the causative bacterium is highly resistant to multiple classes of antibiotics. Antimicrobial host-defense peptides (HDPs) are highly effective at simultaneously modulating the immune system function and directly killing bacteria through membrane disruption and oxidative damage. The copper-binding HDPs piscidin 1 and piscidin 3 have previously shown potent antimicrobial activity against a number of Gram-negative and Gram-positive bacterial species but have never been investigated in an anaerobic environment. Synergy between piscidins and metal ions increases bacterial killing aerobically. Here, we performed growth inhibition and time-kill assays against C. difficile showing that both piscidins suppress proliferation of C. difficile by killing bacterial cells. Microscopy experiments show that the peptides accumulate at sites of membrane curvature. We find that both piscidins are effective against epidemic C. difficile strains that are highly resistant to other stresses. Notably, copper does not enhance piscidin activity against C. difficile. Thus, while antimicrobial activity of piscidin peptides is conserved in aerobic and anaerobic settings, the peptide−copper interaction depends on environmental oxygen to achieve its maximum potency. The development of pharmaceuticals from HDPs such as piscidin will necessitate consideration of oxygen levels in the targeted tissue.

Quantitative whole-body diffusion-weighted MRI (WB-DWI) is now possible using semi-automatic segmentation techniques. The method enables whole-body estimates of global Apparent Diffusion Coefficient (gADC) and total Diffusion Volume (tDV), both of which have demonstrated considerable utility for assessing treatment response in patients with bone metastases from primary prostate and breast cancers. Here we investigate the agreement (inter-observer repeatability) between two radiologists in their definition of Volumes Of Interest (VOIs) and subsequent assessment of tDV and gADC on an exploratory patient cohort of nine. Furthermore, each radiologist was asked to repeat his or her measurements on the same patient data sets one month later to identify the intra-observer repeatability of the technique. Using a Markov Chain Monte Carlo (MCMC) estimation method provided full posterior probabilities of repeatability measures along with maximum a-posteriori values and 95% confidence intervals. Our estimates of the inter-observer Intraclass Correlation Coefficient (ICCinter) for log-tDV and median gADC were 1.00 (0.97-1.00) and 0.99 (0.89-0.99) respectively, indicating excellent observer agreement for these metrics. Mean gADC values were found to have ICCinter = 0.97 (0.81-0.99) indicating a slight sensitivity to outliers in the derived distributions of gADC. Of the higher order gADC statistics, skewness was demonstrated to have good inter-user agreement with ICCinter = 0.99 (0.86-1.00), whereas gADC variance and kurtosis performed relatively poorly: 0.89 (0.39-0.97) and 0.96 (0.69-0.99) respectively. Estimates of intra-observer repeatability (ICCintra) demonstrated similar results: 0.99 (0.95-1.00) for log-tDV, 0.98 (0.89-0.99) and 0.97 (0.83-0.99) for median and mean gADC respectively, 0.64 (0.25-0.88) for gADC variance, 0.85 (0.57-0.95) for gADC skewness and 0.85 (0.57-0.95) for gADC kurtosis. Further investigation of two anomalous patient cases revealed that a very small proportion of voxels with outlying gADC values lead to instability in higher order gADC statistics. We therefore conclude that estimates of median/mean gADC and tumour volume demonstrate excellent inter- and intra-observer repeatability whilst higher order statistics of gADC should be used with caution when ascribing significance to clinical changes.

On May 3, 2008, a National Cancer Institute (NCI)-sponsored open consensus conference was held in Toronto, Ontario, Canada, during the 2008 International Society for Magnetic Resonance in Medicine Meeting. Approximately 100 experts and stakeholders summarized the current understanding of diffusion-weighted magnetic resonance imaging (DW-MRI) and reached consensus on the use of DW-MRI as a cancer imaging biomarker. DW-MRI should be tested as an imaging biomarker in the context of well-defined clinical trials, by adding DW-MRI to existing NCI-sponsored trials, particularly those with tissue sampling or survival indicators. Where possible, DW-MRI measurements should be compared with histologic indices including cellularity and tissue response. There is a need for tissue equivalent diffusivity phantoms; meanwhile, simple fluid-filled phantoms should be used. Monoexponential assessments of apparent diffusion coefficient values should use two b values (> 100 and between 500 and 1000 mm2/sec depending on the application). Free breathing with multiple acquisitions is superior to complex gating techniques. Baseline patient reproducibility studies should be part of study designs. Both region of interest and histogram analysis of apparent diffusion coefficient measurements should be obtained. Standards for measurement, analysis, and display are needed. Annotated data from validation studies (along with outcome measures) should be made publicly available. Magnetic resonance imaging vendors should be engaged in this process. The NCI should establish a task force of experts (physicists, radiologists, and oncologists) to plan, organize technical aspects, and conduct pilot trials. The American College of Radiology Imaging Network infrastructure may be suitable for these purposes. There is an extraordinary opportunity for DW-MRI to evolve into a clinically valuable imaging tool, potentially important for drug development.

We describe our semi-automatic segmentation of whole-body diffusion-weighted MRI (WBDWI) using a Markov random field (MRF) model to derive tumor total diffusion volume (tDV) and associated global apparent diffusion coefficient (gADC); and demonstrate the feasibility of using these indices for assessing tumor burden and response to treatment in patients with bone metastases. WBDWI was performed on eleven patients diagnosed with bone metastases from breast and prostate cancers before and after anti-cancer therapies. Semi-automatic segmentation incorporating a MRF model was performed in all patients below the C4 vertebra by an experienced radiologist with over eight years of clinical experience in body DWI. Changes in tDV and gADC distributions were compared with overall response determined by all imaging, tumor markers and clinical findings at serial follow up. The segmentation technique was possible in all patients although erroneous volumes of interest were generated in one patient because of poor fat suppression in the pelvis, requiring manual correction. Responding patients showed a larger increase in gADC (median change = +0.18, range = -0.07 to +0.78 × 10(-3) mm2/s) after treatment compared to non-responding patients (median change = -0.02, range = -0.10 to +0.05 × 10(-3) mm2/s, p = 0.05, Mann-Whitney test), whereas non-responding patients showed a significantly larger increase in tDV (median change = +26%, range = +3 to +284%) compared to responding patients (median change = -50%, range = -85 to +27%, p = 0.02, Mann-Whitney test). Semi-automatic segmentation of WBDWI is feasible for metastatic bone disease in this pilot cohort of 11 patients, and could be used to quantify tumor total diffusion volume and median global ADC for assessing response to treatment.

One of the key challenges for nuclear physics today is to understand from first principles the effective interaction between hadrons with different quark content. First successes have been achieved using techniques that solve the dynamics of quarks and gluons on discrete space-time lattices1,2. Experimentally, the dynamics of the strong interaction have been studied by scattering hadrons off each other. Such scattering experiments are difficult or impossible for unstable hadrons3-6 and so high-quality measurements exist only for hadrons containing up and down quarks7. Here we demonstrate that measuring correlations in the momentum space between hadron pairs8-12 produced in ultrarelativistic proton-proton collisions at the CERN Large Hadron Collider (LHC) provides a precise method with which to obtain the missing information on the interaction dynamics between any pair of unstable hadrons. Specifically, we discuss the case of the interaction of baryons containing strange quarks (hyperons). We demonstrate how, using precision measurements of proton-omega baryon correlations, the effect of the strong interaction for this hadron-hadron pair can be studied with precision similar to, and compared with, predictions from lattice calculations13,14. The large number of hyperons identified in proton-proton collisions at the LHC, together with accurate modelling15 of the small (approximately one femtometre) inter-particle distance and exact predictions for the correlation functions, enables a detailed determination of the short-range part of the nucleon-hyperon interaction.

The measurement of the azimuthal-correlation function of prompt D mesons with charged particles in pp collisions at s=5.02TeV and p–Pb collisions at sNN=5.02TeV with the ALICE detector at the LHC is reported. The D , D +, and D ∗ + mesons, together with their charge conjugates, were reconstructed at midrapidity in the transverse momentum interval 30.3GeV/c and pseudorapidity | η| < 0.8. The properties of the correlation peaks appearing in the near- and away-side regions (for Δ φ≈ 0 and Δ φ≈ π, respectively) were extracted via a fit to the azimuthal correlation functions. The shape of the correlation functions and the near- and away-side peak features are found to be consistent in pp and p–Pb collisions, showing no modifications due to nuclear effects within uncertainties. The results are compared with predictions from Monte Carlo simulations performed with the PYTHIA, POWHEG+PYTHIA, HERWIG, and EPOS 3 event generators.

The measurement of the azimuthal-correlation function of prompt D mesons with charged particles in pp collisions at s=5.02TeV and p–Pb collisions at sNN=5.02TeV with the ALICE detector at the LHC is reported. The D , D +, and D ∗ + mesons, together with their charge conjugates, were reconstructed at midrapidity in the transverse momentum interval 30.3GeV/c and pseudorapidity | η| < 0.8. The properties of the correlation peaks appearing in the near- and away-side regions (for Δ φ≈ 0 and Δ φ≈ π, respectively) were extracted via a fit to the azimuthal correlation functions. The shape of the correlation functions and the near- and away-side peak features are found to be consistent in pp and p–Pb collisions, showing no modifications due to nuclear effects within uncertainties. The results are compared with predictions from Monte Carlo simulations performed with the PYTHIA, POWHEG+PYTHIA, HERWIG, and EPOS 3 event generators.

The study of (anti-)deuteron production in pp collisions has proven to be a powerful tool to investigate the formation mechanism of loosely bound states in high-energy hadronic collisions. In this paper the production of (anti-)deuterons is studied as a function of the charged particle multiplicity in inelastic pp collisions at s=13 TeV using the ALICE experiment. Thanks to the large number of accumulated minimum bias events, it has been possible to measure (anti-)deuteron production in pp collisions up to the same charged particle multiplicity (d Nch/ d η∼ 26) as measured in p–Pb collisions at similar centre-of-mass energies. Within the uncertainties, the deuteron yield in pp collisions resembles the one in p–Pb interactions, suggesting a common formation mechanism behind the production of light nuclei in hadronic interactions. In this context the measurements are compared with the expectations of coalescence and statistical hadronisation models (SHM).

The study of (anti-)deuteron production in pp collisions has proven to be a powerful tool to investigate the formation mechanism of loosely bound states in high-energy hadronic collisions. In this paper the production of (anti-)deuterons is studied as a function of the charged particle multiplicity in inelastic pp collisions at s=13 TeV using the ALICE experiment. Thanks to the large number of accumulated minimum bias events, it has been possible to measure (anti-)deuteron production in pp collisions up to the same charged particle multiplicity (d Nch/ d η∼ 26) as measured in p–Pb collisions at similar centre-of-mass energies. Within the uncertainties, the deuteron yield in pp collisions resembles the one in p–Pb interactions, suggesting a common formation mechanism behind the production of light nuclei in hadronic interactions. In this context the measurements are compared with the expectations of coalescence and statistical hadronisation models (SHM).

The striking similarities that have been observed between high-multiplicity proton-proton (pp) collisions and heavy-ion collisions can be explored through multiplicity-differential measurements of identified hadrons in pp collisions. With these measurements, it is possible to study mechanisms such as collective flow that determine the shapes of hadron transverse momentum (pT) spectra, to search for possible modifications of the yields of short-lived hadronic resonances due to scattering effects in an extended hadron-gas phase, and to investigate different explanations provided by phenomenological models for enhancement of strangeness production with increasing multiplicity. In this paper, these topics are addressed through measurements of the K⁎(892)0 and ϕ(1020) mesons at midrapidity in pp collisions at s= 13 TeV as a function of the charged-particle multiplicity. The results include the pT spectra, pT-integrated yields, mean transverse momenta, and the ratios of the yields of these resonances to those of longer-lived hadrons. Comparisons with results from other collision systems and energies, as well as predictions from phenomenological models, are also discussed.

Experimental results are presented on event-by-event net-proton fluctuation measurements in Pb–Pb collisions at sNN=2.76 TeV, recorded by the ALICE detector at the CERN LHC. These measurements have as their ultimate goal an experimental test of Lattice QCD (LQCD) predictions on second and higher order cumulants of net-baryon distributions to search for critical behavior near the QCD phase boundary. Before confronting them with LQCD predictions, account has to be taken of correlations stemming from baryon number conservation as well as fluctuations of participating nucleons. Both effects influence the experimental measurements and are usually not considered in theoretical calculations. For the first time, it is shown that event-by-event baryon number conservation leads to subtle long-range correlations arising from very early interactions in the collisions.

Experimental results are presented on event-by-event net-proton fluctuation measurements in Pb–Pb collisions at sNN=2.76 TeV, recorded by the ALICE detector at the CERN LHC. These measurements have as their ultimate goal an experimental test of Lattice QCD (LQCD) predictions on second and higher order cumulants of net-baryon distributions to search for critical behavior near the QCD phase boundary. Before confronting them with LQCD predictions, account has to be taken of correlations stemming from baryon number conservation as well as fluctuations of participating nucleons. Both effects influence the experimental measurements and are usually not considered in theoretical calculations. For the first time, it is shown that event-by-event baryon number conservation leads to subtle long-range correlations arising from very early interactions in the collisions.

The production of K∗(892)0 and φ(1020) in pp collisions at s=8 TeV was measured by using Run 1 data collected by the ALICE collaboration at the CERN Large Hadron Collider (LHC). The pT-differential yields d2N/dydpT in the range 0

The striking similarities that have been observed between high-multiplicity proton-proton (pp) collisions and heavy-ion collisions can be explored through multiplicity-differential measurements of identified hadrons in pp collisions. With these measurements, it is possible to study mechanisms such as collective flow that determine the shapes of hadron transverse momentum (pT) spectra, to search for possible modifications of the yields of short-lived hadronic resonances due to scattering effects in an extended hadron-gas phase, and to investigate different explanations provided by phenomenological models for enhancement of strangeness production with increasing multiplicity. In this paper, these topics are addressed through measurements of the K⁎(892)0 and ϕ(1020) mesons at midrapidity in pp collisions at s= 13 TeV as a function of the charged-particle multiplicity. The results include the pT spectra, pT-integrated yields, mean transverse momenta, and the ratios of the yields of these resonances to those of longer-lived hadrons. Comparisons with results from other collision systems and energies, as well as predictions from phenomenological models, are also discussed.