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Abstract As large areas of the Mississippi River Delta (MRD) of the USA disappear into the sea, present-day communities and cultural resources are lost. While the land loss may be readily quantified, describing the impact of cultural losses is less straightforward because cultural elements are frequently less tangible and difficult to map, identify, and categorize. The elision of cultural components of landscapes and ecosystems is evident in restoration practices and policies, although numerous scholars have identified the interlinked processes of culture and ecology as critical to rebuilding healthy and resilient environments. We define and measure cultural-ecosystem resilience (CER) in the Mississippi River Delta through analyses of Indigenous oral histories, mound-building practices and settlement patterns, and the persistence and reuse of archaeological sites. CER describes a system containing resilient properties embedded in human-natural settings including river deltas that may manifest in oral cultural traditions, architecture, and the selection of habitable environments. Our interdisciplinary approach demonstrates the role of human-modified landscapes in generating resilience for past and present coastal communities and highlights the importance of consulting records of historic and modern Indigenous traditions in shaping sustainable landscape-management strategies. Results show that archaeological earthen and shell mounds made by Native American Gulf Coast and MRD communities have been persistent features that endured for centuries and are sited in regions of high multicultural value within the dynamic delta. Yet, we document the rapid 20th-century loss of mounds due to coastal erosion, industry, and other human land-use practices. Present-day and future coastal land loss endangers what remains of these keystone features and thus lowers the resilience of modern Mississippi River Delta communities.

Background: Mast cells are found at all levels of dermis, grouped around blood vessels, nerves and appendages. An increase in the mast cell number has been reported in various cutaneous diseases. Mast cells respond to diverse range of stimuli like neuronal impulses, allergens, antigens, hormones, cytokines from T cells and keratinocytes and thus play a role in manifestation of dermatological disorders. The objective was to study mast cell density in various subsets of Hansen’s disease and analyse whether the distribution and density vary amongst the subsets. Methods: A total of 60 skin biopsies diagnosed as leprosy were included in this study. 10 control slides were also studied for mast cell density and distribution. Histopathological diagnosis was made on the biopsy and mast cell density and distribution was assessed on toluidine blue stained sections and compared with those of controls. Results: All the subsets of Hansen’s disease studied showed an increase in the number of mast cells. The highest mean mast cell count was noted in lepromatous leprosy (66/mm2), followed by erythema nodosum leprosum (42.6/mm2) and borderline lepromatous leprosy (40.8/mm2). The mean mast cell count showed progressive increase over the immunological spectrum of tuberculoid leprosy to lepromatous leprosy. The mast cells showed spindle and ovoid morphology in all the lesions (active) while round morphology was seen in controls. Conclusion: Tissue mast cell number, distribution and morphology vary depending on the degree of activation in different leprosy lesions. This may have a bearing on the diagnosis and management.

The recent cases of COVID-19 have brought the prospect of and requirement for point-of-care diagnostic devices into the limelight. Despite all the advances in point-of-care devices, there is still a huge requirement for a rapid, accurate, easy-to-use, low-cost, field-deployable and miniaturized PCR assay device to amplify and detect genetic material. This work aims to develop an Internet-of-Things automated, integrated, miniaturized and cost-effective microfluidic continuous flow-based PCR device capable of on-site detection. As a proof of application, the 594-bp GAPDH gene was successfully amplified and detected on a single system. The presented mini thermal platform with an integrated microfluidic device has the potential to be used for the detection of several infectious diseases.

Abstract Aliovalent substitution of the B component in ABX 3 metal halides has often been proposed to modify the band gap and thus the photovoltaic properties, but details about the resulting structure have remained largely unknown. Here, we examine these effects in Bi-substituted CsSnBr3. Powder X-ray diffraction (XRD) and solid-state 119Sn, 133Cs and 209Bi nuclear magnetic resonance (NMR) spectroscopy were carried out to infer how Bi substitution changes the structure of these compounds. The cubic perovskite structure is preserved upon Bi-substitution, but with disorder in the B site occurring at the atomic level. Bi atoms are randomly distributed as they substitute for Sn atoms with no evidence of Bi segregation. The absorption edge in the optical spectra shifts from 1.8 to 1.2 eV upon Bi-substitution, maintaining a direct band gap according to electronic structure calculations. It is shown that Bi-substitution improves resistance to degradation by inhibiting the oxidation of Sn.

Acute appendicitis is common abdominal condition in our day to day surgical practice. Classical features include periumbilical pain that migrates to the right iliac fossa, anorexia, fever, and tenderness and guarding in the right iliac fossa. However, in our present study, three atypical presentation of acute appendicitis is demonstrated in clinical practice. These three cases do not have classical features of murphy’s triad, that is, nausea, vomiting, fever, and cardinal sign of positive Mcburney’s tenderness. Our three atypical cases are: (1) A 38 year old obese male patient who presented with features of umbilical inflammation with serous discharge due to presence of acute inflamed appendix in pre-existing small umbilical hernial sac. (2) A 49-year-old male medicine seller presented right sided scrotal pain with same sided inguino-scrotal swelling for short duration due to presence of inflamed swollen tip of appendix at bottom of right hemi-scrotum in pre-existing inguinal hernia. (3) A 81-years-male gentleman presented with anorexia, weakness, abdominal fullness, and bilateral pedal edema. He did not have pain abdomen, fever, and right iliac fossa tenderness. Imaging modalities confirmed the acute appendicitis in three cases. Diagnosis of appendicitis in absence of typical features is to be made from pre-occupied knowledge and with help of imaging studies.

Abstract Replication Protein A (RPA), a heterotrimeric complex consisting of RPA1, 2, and 3 subunits, is a single-stranded DNA (ssDNA)-binding protein that is critically involved in replication, checkpoint regulation and DNA repair. Here we have evaluated RPA in 776 pure ductal carcinomas in situ (DCIS), 239 DCIS that co-exist with invasive breast cancer (IBC), 50 normal breast tissue and 4221 IBC. Transcriptomic [METABRIC cohort (n = 1980)] and genomic [TCGA cohort (n = 1090)] evaluations were completed. Preclinically, RPA deficient cells were tested for cisplatin sensitivity and Olaparib induced synthetic lethality. Low RPA linked to aggressive DCIS, aggressive IBC, and shorter survival outcomes. At the transcriptomic level, low RPA tumours overexpress pseudogene/lncRNA as well as genes involved in chemical carcinogenesis, and drug metabolism. Low RPA remains linked with poor outcome. RPA deficient cells are sensitive to cisplatin and Olaparib induced synthetic lethality. We conclude that RPA directed precision oncology strategy is feasible in breast cancers.

Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with essential roles during G1/S transition. The clinicopathological significance of CDK2 in ductal carcinomas in situ (DCIS) and early-stage invasive breast cancers (BCs) remains largely unknown. Here, we evaluated CDK2’s protein expression in 479 BC samples and 216 DCIS specimens. Analysis of CDK2 transcripts was completed in the METABRIC cohort (n = 1980) and TCGA cohort (n = 1090), respectively. A high nuclear CDK2 protein expression was significantly associated with aggressive phenotypes, including a high tumour grade, lymph vascular invasion, a poor Nottingham prognostic index (all p-values < 0.0001), and shorter survival (p = 0.006), especially in luminal BC (p = 0.009). In p53-mutant BC, high nuclear CDK2 remained linked with worse survival (p = 0.01). In DCIS, high nuclear/low cytoplasmic co-expression showed significant association with a high tumour grade (p = 0.043), triple-negative and HER2-enriched molecular subtypes (p = 0.01), Comedo necrosis (p = 0.024), negative ER status (p = 0.004), negative PR status (p < 0.0001), and a high proliferation index (p < 0.0001). Tumours with high CDK2 transcripts were more likely to have higher expressions of genes involved in the cell cycle, homologous recombination, and p53 signaling. We provide compelling evidence that high CDK2 is a feature of aggressive breast cancers. The clinical evaluation of CDK2 inhibitors in early-stage BC patients will have a clinical impact.

Cyclin-dependent kinases (CDK2, CDK4, CDK6), cyclin D1, cyclin E1 and phosphorylated retinoblastoma (pRB1) are key regulators of the G1/S cell cycle checkpoint and may influence platinum response in ovarian cancers. CDK2/4/6 inhibitors are emerging targets in ovarian cancer therapeutics. In the current study, we evaluated the prognostic and predictive significance of the CDK2/4/6–cyclin D1/E1–pRB1 axis in clinical ovarian cancers (OC). The CDK2/4/6, cyclin D1/E1 and RB1/pRB1 protein expression were investigated in 300 ovarian cancers and correlated with clinicopathological parameters and patient outcomes. CDK2/4/6, cyclin D1/E1 and RB1 mRNA expression were evaluated in the publicly available ovarian TCGA dataset. We observed nuclear and cytoplasmic staining for CDK2/4/6, cyclins D1/E1 and RB1/pRB1 in OCs with varying percentages. Increased nuclear CDK2 and nuclear cyclin E1 expression was linked with poor progression-free survival (PFS) and a shorter overall survival (OS). Nuclear CDK6 was associated with poor OS. The cytoplasmic expression of CDK4, cyclin D1 and cyclin E1 also has predictive and/or prognostic significance in OCs. In the multivariate analysis, nuclear cyclin E1 was an independent predictor of poor PFS. Tumours with high nuclear cyclin E1/high nuclear CDK2 have a worse PFS and OS. Detailed bioinformatics in the TCGA cohort showed a positive correlation between cyclin E1 and CDK2. We also showed that cyclin-E1-overexpressing tumours are enriched for genes involved in insulin signalling and release. Our data not only identified the prognostic/predictive significance of these key cell cycle regulators but also demonstrate the importance of sub-cellular localisation. CDK2 targeting in cyclin-E1-amplified OCs could be a rational approach.

Introduction: Odontogenic cysts are characterized by a pathological cavity either completely or partially covered with epithelial tissue. These cysts are one of the most common osseous -destructive lesions affecting the jaws. The aim of the present study was to determine the relative prevalence of odontogenic cysts and to identify the clinicopathological characteristics. Methodology: A retrospective observational study was conducted on 1011 histopathological reports from January 2008 to December 2012. Patients with radicular cysts, dentigerous cysts, odontogenic keratocysts, lateral periodontal cysts and glandular odontogenic cysts were further analyzed. The following variables were recorded: age, gender, clinical characteristics of the lesions such as size, location and association with impacted teeth and a descriptive analysis of the study variables was carried out. Results: Among 1011 biopsy reports analyzed, 131 cases of odontogenic cysts (13%) were diagnosed. The age of patients ranged from 10 to 85 years. The gender distribution showed a male predilection (n=81; 62%), compared to females (n=50; 38%). The lesion size ranged from 3-130 mm; with a mean size of 18 mm. The mandible (n=74; 56%) was more commonly involved than the maxilla (n=57; 44%). The majority of cysts were detected in the posterior mandible followed by the anterior maxilla. Impacted teeth most commonly associated with odontogenic cysts was lower third molar, followed by upper canine. Conclusion: Radicular cysts, dentigerous cysts and odontogenic keratocysts were the most common cystic lesions, accounting for 88.9% of all odontogenic cysts, with radicular cysts being most common.

The HIV-1 protease is one of several common key targets of combination drug therapies for human immunodeficiency virus infection and acquired immunodeficiency syndrome. During the progression of the disease, some individual patients acquire drug resistance due to mutational hotspots on the viral proteins targeted by combination drug therapies. It has recently been discovered that drug-resistant mutations accumulate on the “flap region” of the HIV-1 protease, which is a critical dynamic region involved in nonspecific polypeptide binding during invasion and infection of the host cell. In this study, we utilize machine learning-assisted comparative molecular dynamics, conducted at single amino acid site resolution, to investigate the dynamic changes that occur during functional dimerization and drug binding of wild-type and common drug-resistant versions of the main protease. We also use a multiagent machine learning model to identify conserved dynamics of the HIV-1 main protease that are preserved across simian and feline protease orthologs. We find that a key conserved functional site in the flap region, a solvent-exposed isoleucine (Ile50) that controls flap dynamics is functionally targeted by drug resistance mutations, leading to amplified molecular dynamics affecting the functional ability of the flap region to hold the drugs. We conclude that better long-term patient outcomes may be achieved by designing drugs that target protease regions that are less dependent upon single sites with large functional binding effects.

We investigate the segmental dynamics and ion transport in two chemically distinct polymer electrolytes, poly(2-cyanoethyl acrylate) (PCEA) and poly(ethylene oxide) (PEO), and their mixtures with lithium bis(trifluoromethane)sulfonimide (LiTFSI) salt. Quasi-elastic neutron scattering experiments reveal slow dynamics in PCEA/LiTFSI relative to that in PEO/LiTFSI, translating to monomeric friction coefficients that are orders of magnitude different. In spite of the enhanced salt dissociation in PCEA due to the presence of polar groups, ion transport is largely dominated by the effect of increased monomeric friction in the pure polymer. Conductivity in these systems is quantified through a simple expression combining salt dissociation, the monomeric friction in the pure polymer, and the effect of added salt on the monomeric friction.

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.

Objective: To determine the clinical course of critically ill, SARS-CoV-2 positive pregnant women and to critically analyze the circumstances which led to their mortality. Methods: A retrospective review of case records examined to analyze the clinical condition with which critically ill SARS-CoV-2 positive pregnant patients were admitted, the in-patient management protocol followed and subsequent clinical course which led to their deaths. Results: There were a total number of 13 maternal deaths which were directly attributed to COVID-19 pneumonia during the study period. Many of these patients had reported with poor oxygen saturation at the time of admission. Oxygen therapy, plasma therapy, antiviral drugs and immunomodulators were administered as part of in -patient management protocol. Conclusion: There is an urgent need of dedicated COVID care facilities for pregnant women. Maternal mortality has always been a matter of concern during any pandemic. Specific needs of pregnant women during this pandemic require urgent attention.

Abstract Influenza B virus (IBV) strains are one of the components of seasonal influenza vaccines in both trivalent and quadrivalent formulations. The vast majority of these vaccines are produced in embryonated chickens’ eggs. While optimized backbones for vaccine production in eggs exist and are in use for influenza A viruses, no such backbones exist for IBVs, resulting in unpredictable production yields. To generate an optimal vaccine seed virus backbone, we have compiled a panel of 71 IBV strains from 1940 to present day, representing the known temporal and genetic variability of IBV circulating in humans. This panel contains strains from the B/Victoria/2/87-like lineage, B/Yamagata/16/88-like lineage and the ancestral lineage that preceded their split to provide a diverse set that would help to identify a suitable backbone which can be used in combination with hemagglutinin (HA) and neuraminidase (NA) glycoproteins from any IBV strain to be incorporated into the seasonal vaccine. We have characterized and ranked the growth profiles of the 71 IBV strains and the best performing strains were used for co-infection of eggs, followed by serial passaging to select for high-growth reassortant viruses. After serial passaging, we selected 10 clonal isolates based on their growth profiles assessed by hemagglutination and plaque-forming units. We then generated reverse genetics systems for the three clones that performed best in growth curves. The selected backbones were then used to generate different reassortant viruses with HA/NA combinations from high and low titer yielding wild type IBV. When the growth profiles of the recombinant reassortant viruses were tested, the low titer yielding HA/NA viruses with the selected backbones yielded higher titers similar to those from high titer yielding HA/NA combinations. The use of these IBV backbones with improved replication in eggs might increase yields for the influenza B virus components of seasonal influenza virus vaccines.

Background: Tonsilloliths/tonsillitis are calcifications that can be found in the lymphoid tissues of the posterior nasopharyngeal wall and the palatine tonsil. The majority of tonsilloliths are tiny, asymptomatic, and are typically discovered by accident during routine dental radiography. Objective: To assess the prevalence and characteristics of tonsilloliths in digital panoramic radiographs. Materials and Methods: The study population showed the presence of tonsilloliths in 400 out of 1000 digital panoramic radiographs screened. Results: Gender distribution of tonsillitis showed 66.5% female and 33.5% male patients. The age range was between 21-69 years with 41–50 years showing a maximum of 25% tonsilloliths. They were found unilaterally in 236 and bilaterally in 164 subjects. The most common location was in the bottom third of the mandibular body (61%), with more tonsillitis on the right side. Females had 44.4% more tonsilitis present unilaterally. The association of tonsilloliths between different age groups revealed highly significant values for the presence, quantity, and side involvement. Conclusion: Tonsilloliths are a frequent incidental finding in radiographs. They can be more easily found using panoramic radiography.

Background: Severe abdominal pain refractory to opioids significantly affects the quality of life (QoL) in patients with abdominal primary cancer or metastatic disease. A neurolytic celiac plexus block (CPB) would be necessary to alleviate pain and improve QoL until death. Aims: The aim of this retrospective study is to investigate pain relief after a transaortic celiac plexus neurolysis for patients with upper gastrointestinal malignancies. Settings and Design: This retrospective observational study was done in the Pain Department, Shri Siddhivinayak Cancer Hospital, Miraj from January 2005 to January 2015. Materials and Methods: One hundred and twenty-four patients with upper abdominal malignancy received a computed trans-aortic celiac plexus block (TAoCPB) on a day-care basis. The primary outcome was pain as assessed with numerical rating scale ranging from 0 to 10; the secondary outcome measures were morphine consumption per day, QoL, and complications, if any. These were recorded before intervention, on day 1 after the block and at 1 month interval until 6 months. Statistical Analysis Used: Bonferroni correction for multiple comparisons and a P < 0.0167 (0.05/3) was considered to be statistically significant due to 3 co-primary outcomes being measured (visual analog scale [VAS] scores, morphine consumption, and QoL). Results: Up to 4.5 months, the VAS score, daily morphine consumption, and the QoL showed improvement for the duration of the study. Pain gradually increased at 6 months with a deterioration of QoL. Respiratory distress and burning sensation in chest occurred in one patient each. Conclusions: A low-volume TAoCPB is effective and established procedure as a day-care procedure. Although pain relief occurs until 4.5 months, a gradual increase was perceived with a decline of quality of health at 6 months.

Background: A chronic history of exertional dyspnea, dry cough, and fatigue, associated with reticulonodular ground-glass opacity indicates an underlying interstitial lung disease (ILD). Pulmonary alveolar proteinosis (PAP) is a rare cause of ILD, in which there is abnormal accumulation of surfactant material in alveoli, thereby impairing gaseous exchange. In children, PAP is usually due to genetic mutations. We report a child with PAP due to mutation in methionyl-transfer RNA synthetase 1 (MARS) gene. Clinical Description: An 8-year-old boy presented with persistent dry cough, and exercise-induced breathlessness for 2 years of age, associated with failure to gain weight. He had multiple exacerbations in the past, requiring common symptomatic treatment, but with minimal improvement. On presentation to us, the child had tachypnea, hypoxia (oxygen saturation [SpO2]: 85%), and Grade 2 clubbing, with bilateral fine crepitation in bilateral lung fields. Management and Outcome: The child was stabilized by providing oxygen via high-flow nasal cannula. Blood investigations were largely normal. His chest X-ray and computerized tomography (CT) of the chest were suggestive of childhood ILD. A lung biopsy revealed periodic acid–Schiff-positive eosinophilic granular material in the alveolar spaces without any fibrosis, suggesting a diagnosis of PAP. Next-generation sequencing revealed a compound heterozygous mutation of the MARS1 gene resulting in PAP. Parental segregation analysis showed each one to be a carrier of one of the genes. Therapeutic whole-lung lavage (WLL) was carried out, following which symptoms improved markedly. SpO2 increased and the child was able to be weaned off oxygen and discharged. Three years, postdischarge, the child is asymptomatic and thriving well. Conclusions: PAP may be a cause of ILD in a child. Although the etiology can be ascertained by high-resolution CT of the chest and bronchoalveolar lavage, further genetic analysis should also be undertaken in children to identify the exact defect. WLL can provide a good outcome in children with PAP due to MARS mutation.

Background: Surgical lung biopsy (SLB) or video-assisted thoracic surgery (VATS) has been the traditional gold standard modality for diagnosing paediatric interstitial lung diseases. Cryobiopsy of the lung has recently been shown to be a novel technique with very good sensitivity and specificity in the diagnosis of various interstitial lung disorders in adults. Although there are a few case reports of the same in children, pediatric cryo lung biopsies are rarely performed due to the lack of the necessary equipment and the lack of expertise. Methods: A retrospective single-centre study was conducted with twelve consecutive children with diffuse parenchymal lung disease diagnosed both clinically and on high-resolution computed tomography (HRCT) of the chest which were included in the study between October 2020 and September 2022 to measure the diagnostic yield and safety of the procedure. The site from where cryobiopsy was to be done was chosen after a multidisciplinary meeting with the paediatric radiologist. Results: Twelve children (eight males and four females) were included in the study who underwent a cryobiopsy in the duration of two years. The mean age of the cases involved was 8 years and 3 months. With the youngest and oldest being 12 days and 15 years, respectively, all children underwent cryobiopsy as mentioned above. Diagnostic yield was achieved in 92% of cases. Conclusion: Cryobiopsy is a valuable diagnostic tool in childhood interstitial lung diseases, which offers a less invasive option for obtaining lung tissue samples with a better yield which can aid in accurate diagnosis, a good safety profile and a shorter hospital stay. Our study emphasizes that in trained centres, TBCB is a safe, effective and less invasive way to obtain tissue diagnosis in children with ChILD.

Background: Increasing adolescent obesity, a reason for the onset of adult chronic diseases, has become an important public health priority. Food choices are impacted by the growing availability of processed and pre-packaged meals, the rise in eating out compared to eating at home, low nutrition literacy, and the inability to evaluate calorie and nutrient information. Objective: The objective is to assess the current knowledge, attitude, and practice (KAP) of the adolescents regarding food label information to make healthier food choices, to improve their KAP regarding the same through health education using pictorial representation, and to evaluate the effectiveness of the health education. Materials and Methods: An educational intervention study was performed among 200 adolescent students (13–15 years) in selected schools in Bangalore city. Health education was given using materials like charts, models, and posters in an interactive way. Pre-KAP and post-KAP were assessed using questionnaires. Results: The study comprised 145 (72.5%) girls and 55 (27.5%) boys with the mean age of 14.02 years. Only 102 (51%) were having knowledge that food labels must be read irrespective of health issues or disease. Only 81 (40.5%) calculated the total nutrient intake before taking food items before intervention, which was increased to 147 (73.5%) post intervention. Conclusion: The results of the present study successfully proved that nutritional educational intervention by pictorial representation was feasible and successfully improved the understanding and use of food label information for making healthier food choices among adolescents.

Gastroparesis is defined by delayed gastric emptying in the absence of mechanical obstruction of the stomach. Patients experience symptoms of nausea, vomiting, abdominal pain, fullness, and early satiety. The recognition of the disorder has progressed due to availability of gastric emptying scintigraphy and advancements made in understanding its pathophysiology and treatment options. The clinical presentation and treatment of gastroparesis overlap with a more commonly recognized disorder of gut-brain interaction, functional dyspepsia. Recent studies have reenergized the discussion whether these two are separate entities or perhaps reflect a spectrum of gastroduodenal neuromuscular disorders. The societal guidelines conflict on the utility of gastric emptying scintigraphy in assessment of patients with upper gastrointestinal symptoms. A better appraisal of similarities and differences between gastroparesis and functional dyspepsia will allow targeted treatment for these disorders. This is particularly important as specific pharmacological and endoscopic treatment options are being developed for gastroparesis which are unlikely to be helpful for functional dyspepsia. This review makes the case for considering these disorders in a spectrum where identification of both would most ideally position us toward providing the optimal clinical care.

Mashael Algethami,1 Sanat Kulkarni,2 Maaz T Sadiq,3 Hiu KC Tang,4 Juliette Brownlie,1 Jennie N Jeyapalan,1 Nigel P Mongan,1 Emad A Rakha,1 Srinivasan Madhusudan1,4 1Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham, NG7 3RD, UK; 2Department of Medicine, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, B18 7QH, UK; 3Cancer Centre, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Trust, Birmingham, B15 2GW, UK; 4Department of Oncology, Nottingham University Hospitals, Nottingham, NG51PB, UKCorrespondence: Srinivasan Madhusudan, Nottingham Biodiscovery Institute, School of Medicine, University Park, University of Nottingham, Nottingham, NG7 3RD, UK, Tel +44(0)115 823 1850, Fax +44(0)115 823 1849, Email srinivasan.madhusudan@nottingham.ac.ukAbstract: Despite advances in surgery and chemotherapy, the overall outcomes for patients with advanced ovarian cancer remain poor. Although initial response rates to platinum-based chemotherapy is about 60– 80%, most patients will have recurrence and succumb to the disease. However, a DNA repair–directed precision medicine strategy has recently generated real hope in improving survival. The clinical development of PARP inhibitors has transformed lives for many patients with BRCA germline-deficient and/or platinum-sensitive epithelial ovarian cancers. Antiangiogenic agents and intraperitoneal chemotherapy approaches may also improve outcomes in patients. Moreover, evolving immunotherapeutic opportunities could also positively impact patient outcomes. Here we review the current clinical state of PARP inhibitors and other clinically viable targeted approaches in ovarian cancer.Keywords: ovarian cancer, poly-(ADP)-ribose polymerase, PARP, synthetic lethality, platinum chemotherapy

Abstract Background Pain from rib fractures (posterior/lateral/anterior) is associated with significant pulmonary morbidity. Earlier epidural and paravertebral blocks were implemented in the algorithm for multimodal pain management of rib fracture pain. Administration of these blocks are fraught with challenges encountered in intensive care unit (ICU). The erector spinae plane block (ESPB) is a viable alternative in ICU set up. This retrospective study compared continuous thoracic ESPB and continuous thoracic epidural analgesia (TEA) [n=28 versus n=24] for polytrauma patients who sustained unilateral multiple rib fractures (MRFs), i.e., more than 3 admitted in ICU. Demography data were noted and compared. Outcome measures were block efficacy in terms of pain scores, opioid consumption (intravenous fentanyl), technical difficulties, and complications. Results Age, gender, and sides of ribs fractures were comparable in all groups. Pain scores and fentanyl consumption were significantly better in patients who received TEA. Conclusions Though statistically significant analgesic efficacy was observed with continuous TEA for managing pain due to unilateral posterolateral MRFs, the small sample size was a major limitation. Further prospective comparative study including effects on incentive spirometry and effectiveness of chest physiotherapy is warranted. However, continuous ESPB is simple and safe to perform with few theoretical contraindications.

Background: Paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer (MBC) patients. However, with response rates of 21.5–53.7% and significant risk of peripheral neuropathy, there is need for better chemotherapy. Patients and methods: This open-label phase II/III trial randomised HER2-negative MBC patients 1:1 to either 6 cycles of three-weekly cabazitaxel (25 mg/m2), or, weekly paclitaxel (80 mg/m2) over 18 weeks.The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results: 158 patients were recruited. Comparing cabazitaxel to paclitaxel, median PFS was 6.7 vs 5.8 months (HR 0.87; 80%CI 0.70–1.08, P = 0.4). There was no difference in median OS (20.6 vs 18.2 months, HR 1.00; 95%CI 0.69–1.45, P = 0.99), ORR (41.8% vs 36.7%) or TTR (HR 1.09; 95%CI 0.68–1.75, P = 0.7).Grade ≥3 adverse events occurred in 41.8% on cabazitaxel and 46.8% on paclitaxel; the most common being neutropenia (16.5%) and febrile neutropenia (12.7%) cabazitaxel and neutropenia (8.9%) and lung infection (7.6%) paclitaxel. Peripheral neuropathy of any grade occurred in 54.5% paclitaxel vs 16.5% cabazitaxel.Mean EQ-5D-5L single index utility score (+0.05; 95%CI 0.004–0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1–12.3, P = 0.001) were higher in cabazitaxel vs paclitaxel. Conclusions: Three-weekly cabazitaxel in HER2-negative MBC does not significantly improve PFS compared to weekly paclitaxel, although it has a lower risk of peripheral neuropathy with better patient reported QoL outcomes. It is well tolerated and requires fewer hospital visits.

Abstract Measurement of the field distribution in a multimode applicator of a microwave heating system has been a challenging problem. We report here a simple but comprehensive scheme for its semi‐quantitative estimation under no‐load conditions. It involves the measurement of temperature (T) versus time (t) profiles in a small silicon carbide (SiC) sensor ring positioned at the junction end of a metal‐jacketed microwave‐compatible thermocouple probe arrangement. These heating profiles (T vs. t) were measured using a data acquisition system, keeping the SiC ring at different (x, y, z) positions in the applicator. Using this measurement scheme, the spatial positions with local field minimum as inferred from very high reflected power or those with local field maximum with associated thermal runaway type condition could be well identified. Given the thermal and the dielectric properties of SiC material and the physical dimensions of the sensor ring, a uniform microwave field‐based model with a thermal lumped element type approximation (with no thermal gradient across SiC) was applied for analysis of the T versus t heating profiles. Within this model, the locally effective electric field E could be inferred for low and moderate electric field ranges. While the accuracy of the field estimation is currently limited by the use of the metal‐jacketed thermocouple and other factors, this SiC sensor‐based methodology has the potential to be developed further to be useful in the area of microwave applicator design.

Abstract Gastric cancer has emerged as a key challenge in oncology research as a malignant tumour with advanced stage detection. Apart from surgical management, a pharmacotherapeutic approach to stomach cancer treatment is an appealing option to consider. Andrographolide has been shown to have anticancer and chemosensitizer properties in a variety of solid tumors, including stomach cancer but the exact molecular mechanism is skeptical. In this study, we identified and validated pharmacological mechanism involved in the treatment of GC with integrated approach of network pharmacology and molecular docking. The targets of andrographolide and GC were obtained from databases. The intersected targets between andrographolide and GC-related genes were used to construct protein–protein interaction (PPI) network. Furthermore, mechanism of action of the targets was predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Finally, these results were validated by molecular docking experiments, mRNA and protein expression level. A total of 197 targets were obtained for andrographolide treating GC. Functional enrichment analysis revealed that the target genes were exerted promising therapeutic effects on GC by HIF-1 and PI3K-Akt signaling pathway. The possible mechanism of action is by inactivation of HIF-1 signaling pathway which is dependent on the inhibition of upstream PI3K-AKT pathway. The PPI network identified SRC, AKT1, TP53, STAT3, PIK3CA, MAPK1, MAPK3, VEGFA, JUN and HSP90AA1 as potential hub targets. In addition, these results were further validated with molecular docking experiments. Survival analysis indicated that the expression levels of the hub genes were significantly associated with the clinical prognosis of GC. This study provided a novel approach to reveal the therapeutic mechanisms of andrographolide on GC, making future clinical application of andrographolide in the treatment of GC.

Abstract Earth observation (EO) is undergoing a paradigm shift with the development of cloud‐based analytical platforms supporting EO data collection and access, parallel processing, easier communication of results, and expanded accessibility. As the global community of users and the diversity of applications grow, there is a clear need for expanded educational capacity to leverage these developments and increase the impact of EO research and teaching. Drawing upon extensive conversations between educators, practitioners, and researchers, we propose three pillars that must be prioritized to prepare students, researchers, and professionals to take full advantage of the cloud‐based EO paradigm and guide future growth.