Добірка наукової літератури з теми "General Unknown Screening"

SummaryAtrial fibrillation (AF) is associated with a significantly increased stroke risk which is highly preventable with appropriate oral anticoagulant therapy (OAC). However, AF may be asymptomatic and unrecognised prior to stroke. We aimed to determine if single time-point screening for AF could identify sufficient numbers with previously undiagnosed AF, to be effective for stroke prevention. This is a systematic review of clinical trials, by searching electronic medical databases, reference lists and grey literature. Studies were included if they evaluated a general ambulant adult population, using electrocardiography or pulse palpation to identify AF. We identified 30 individual studies (n=122,571, mean age 64 years, 54% male) in nine countries. Participants were recruited either from general practitioner and outpatient clinics (12 studies) or population screening/community advertisements (18 studies). Prevalence of AF across all studies was 2.3% (95% CI, 2.2–2.4%), increasing to 4.4% (CI, 4.1–4.6%) in those ≥65 years (16 studies, n= 27,884). Overall incidence of previously unknown AF (14 studies, n=67,772) was 1.0% (CI, 0.89–1.04%), increasing to 1.4% (CI, 1.2–1.6%) in those ≥65 years (8 studies, n= 18,189) in whom screening setting did not influence incidence identified. Of those with previously unknown AF, 67% were at high risk of stroke. Screening can identify 1.4% of the population ≥65 years with previously undiagnosed AF. Many of those identified would be eligible for, and benefit from OAC to prevent stroke. Given this incidence, community AF screening strategies in at risk older age groups could potentially reduce the overall health burden associated with AF.

Introduzione: L’applicazione delle tecniche di spettrometria di massa ha contribuito significativamente allo sviluppo della ricerca incognita di composti di rilevanza farmaco-tossicologica (PTRC). In particolare, l’approccio library search ha consentito lo sviluppo di efficaci metodi identificativi basati sul confronto automatizzato di uno spettro incognito con gli spettri contenuti in una banca dati di riferimento. Tuttavia questo approccio trova il suo limite più significativo nelle dimensioni ridotte delle banche dati di riferimento, quanto meno nel caso della LC-MS, per la quale i database disponibili generalmente non superano il migliaio di composti. La spettrometria di massa ad alta risoluzione (HRMS) consente l’identificazione della formula bruta di un composto (MF) attraverso la determinazione della massa accurata e del pattern isotopico. Tuttavia, l’identificazione di una sostanza incognita a partire dalla MF richiede strumenti addizionali quali: (a) un database in grado di associare ad ogni MF il nome dei relativi composti, e (b) una strategia per discriminare composti caratterizzati da identica MF. Scopo: Valutare le potenzialità di un nuovo approccio di tipo “metabolomico” e di tipo chemiometrico nel discriminare tra composti con uguale MF. Metodi: Campioni di urine, sangue e capelli sono stati sottoposti a screening mediante ESI-MSTOF (in modalità positiva) in abbinamento sia alla elettroforesi capillare, sia alla LC in fase inversa. I picchi incogniti (massa accurata del relativo ione pseudomolecolare) sono stati ricercati all’interno di un database di PTRC (comprendente ca. 50.500 composti e metaboliti di fase I e II), costruito a partire da PubChem Compound. Al fine di discriminare sostanze con identica MF, è stato valutato un nuovo tipo di approccio “metabolomico” basato sulla tecnica “mass shift”. A partire dal valore di massa accurata di un composto ignoto, sono stati calcolati i difetti/incrementi di massa riferiti a biotrasformazioni prestabilite (demetilazione, idrossilazione, glucuronazione, ecc.) e successivamente i corrispondenti cromatogrammi sono stati estratti dalla corrente ionica totale (TIC) così da verificare la presenza di picchi riferibili a metaboliti. L’uso del software E-Dragon (Talete srl, Milano) ha permesso di calcolare automaticamente il numero dei diversi gruppi funzionali (N,O,S-metili, ossidrili, acetili, ecc.) presenti nella struttura di ciascun composto contenuto nella lista dei candidati. Successivamente la presenza di metaboliti nel TIC è stata confrontata con i dati forniti da E-Dragon così da poter escludere tutte le strutture non compatibili con le biotrasformazioni osservate (es: perdita di un metile da una struttura che non presenta metili, glucuronazione di una molecola priva di siti suscettibili a reazioni di coniugazione). Un’ulteriore analisi è stata eseguita con un nuovo approccio di tipo chemiometrico mediante l’applicazione di un modello matematico capace di correlare il tempo di ritenzione relativo di un composto incognito con alcuni parametri chimico-fisici (tra cui il coefficiente di ripartizione ottanolo/acqua), stimati a partire dalla struttura molecolare di ogni candidato. Risultati: La procedura è stata applicata a 121 composti, tra cui droghe (es. cocaina, oppiacei, MDMA), anticonvulsivanti (es. gabapentina, carbamazepina), benzodiazepine (es. flurazepam), antidepressivi (es. citalopram, trazodone, fluoxetina, amitriptilina, venlafaxina), fenotiazine (es. clorpromazina, promazina, periciazina), antipsicotici (es. amisulpride), antistaminici (es. cetirizina), beta-bloccanti (es. bisoprololo), antiretrovirali (es. emtricitabina, tenofovir) inibitore dell’acetilcolinesterasi (es. rivastigmina), antagonisti dei recettori H2 dell’istamina (es. ranitidina), e i loro metaboliti di fase I. La lunghezza media della lista di candidati (MLL) è risultata pari a 6.71 ± 4.66 (mediana 6, range 1-28) prima dell’applicazione dell’approccio “metabolomico” qui descritto e pari a 3.94 ± 3.07 (mediana 3, range 1-17) dopo. Per i dati in RPLC-TOF, la MLL è stata ridotta da 6.02 ± 3.49 (mediana 6, range 2-21) a 3.42 ± 3.03 (mediana 3, range 1-17) dopo l’applicazione dell’approccio “metabolomico” e a 3.09 ± 2.03 (mediana 2, range 1-9) dopo l’applicazione dell’approccio chemiometrico. L’applicazione combinata dei due approcci ha permesso un’ulteriore riduzione delle MLL a 2.14 ± 1.63 (mediana 2, range 1-9). Conclusioni: La HRMS applicata alla ricerca generica di PTRC offre la possibilità di ampliare significativamente il numero di composti identificabili rispetto ad altri approcci di screening. L’applicazione combinata degli approcci qui descritti ha permesso di ridurre significativamente la lista di composti candidati isobari.
Introduction: The screening for Pharmaco/Toxicologically Relevant Compounds (PTRC) in biosamples has benefited a lot from MS techniques. The so-called library search approach has enabled the development of effective identification methods based on comparison of unknown and reference spectra. However, a downside of this approach is the limited number of reference mass spectra, particularly in the case of LC-MS where in-house/commercial databases typically include not more than one thousand compounds. High resolution MS (HRMS) enables the identification of a molecular formula (MF) through the accurate measurement of mass and isotopic pattern. However, the identification of an unknown compound starting from MF requires additional tools: (a) a database associating MFs to compound names, and (b) a way to discriminate between isomers. Aims: To evaluate the ability of combined novel “metabolomic”/chemometric approach to reduce the list of candidate isomers. Methods: Urine/blood/hair samples collected from real positive cases were submitted to a screening procedure using ESI-MSTOF (positive ion mode) combined with either capillary electrophoresis or reversed phase LC (RPLC). Detected peaks were searched against a PTRC database (ca. 50.500 compounds and phase I and II metabolites) consisting of a subset of PubChem Compound. In order to discriminate between compounds with identical MF first a filter based on a “metabolomic” approach was applied. Starting from the mass of the unknown compound, defects/increments corresponding to pre-defined biotransformations (e.g. demethylation, hydroxylation, glucuronidation, etc.) were calculated and the corresponding mass chromatograms were extracted from the total ion current (TIC) in order to search for metabolite peaks. For each candidate in the retrieved list, the number of different functional groups in the molecule (N,O,S-methyls, hydroxyls, acetyls, etc.) was automatedly calculated using E-Dragon software (Talete srl, Milan, Italy). Then, the presence of metabolites in the TIC was matched with functional groups data in order to exclude candidates whose structure was not compatible with observed biotransformations (e.g. loss of methyl from a structure not bearing methyls, glucuronidation on a structure not bearing any site susceptible to conjugation). A further filter was then applied based on a mathematic model correlating RPLC relative retention time (ISTD nalorphine) with a number of parameters estimated for each candidate compound starting from the Simplified Molecular Input Line Entry Specification (SMILES), including the predicted octanol/water partition coefficient (LogP). Results: The procedure was tested on 121 compounds detected in real positive samples, including drugs of abuse (e.g. cocaine, opiates, MDMA), anticonvulsants (e.g. gabapentin, carbamazepine), benzodiazepines (e.g. flurazepam), antidepressants (e.g. citalopram, trazodone, fluoxetine, amitriptyline, venlafaxine), phenothiazines (e.g. chlorpromazine, promazine, pericyazine), antipsychotics (e.g. amisulpride), antihistamines (e.g. cetirizine), beta-blocker (e.g. bisoprolol), anti-retroviral agents (e.g. emtricitabine, tenofovir), acetyl-cholinesterase inhibitors (e.g. rivastigmine), histamine H2-receptor antagonists (e.g. ranitidine), and their phase I metabolites. Overall, the mean list length (MLL) of compounds was 6.71 ± 4.66 (median 6, range 1-28) before the application of the metabolomic approach and was shortened to 3.94 ± 3.07 (median 3, range 1-17) after. For RPLC-HRMS data the MLL was shorted from 6.02 ± 3.49 (median 6, range 2-21) to 3.42 ± 3.03 (median 3, range 1-17) after the metabolomic filter and to 3.09 ± 2.03 (median 2, range 1-9) after the chemometric approach. The application of both filters allowed a reduction of the MLL to 2.14 ± 1.63 (median 2, range 1-9). Conclusion: HRMS allows a much broader search for PTRC than other screening approaches. The combined metabolomic/chemometric approach significantly reduces the list of candidate isomers.

Die Systematische Toxikologische Analyse (STA) stellt auf Grund der großen Vielfalt und der ständigen Zunahme an toxikologisch relevanten Substanzen eine der größten Herausforderungen in der chemischen Analyse dar. In der vorliegenden Arbeit wurde daher die Eignung der Flüssigchromatographie in Kombination mit der Hybrid-Quadrupol-Flugzeitmassenspektrometrie (LC-QTOF-MS) für diesen Zweck untersucht. Dazu wurden eine Datenbank mit über 7360 und eine CID-Spektrenbibliothek mit mehr als 2720 toxikologisch relevanten Substanzen erstellt und geeignete Probenvorbereitungsmethoden entwickelt. Die Erprobung der Methoden erfolgte an dotierten Blut- und Haarproben. Hierbei zeigte sich, dass die Analyse im Auto-MS/MS-Modus (Messzyklen von MS- und MS/MS-Spektren) eine Identifizierung basischer Substanzen mittels CID-Spektren zwischen 0,5 und 2 ng/ml im Blut ermöglichte. Die Nachweisgrenzen der für 24 Wirkstoffe validierten Methode in Haaren lagen bei 3 bis 15 pg/mg. Die Eignung der LC-QTOF-MS zur STA von Haarproben wurde an 30 Drogentodesfällen und 60 Todesfällen mit bekannter chronischer Medikamenteneinnahme zu Lebzeiten sowie an 77 Blutproben nachgewiesen. Für die Suche nach Metaboliten wurde ein Metaboliten-Tool entwickelt. In der praktischen Anwendung auf Datenfiles von Blut- und Haarproben erwies sich das Tool als wertvolles Hilfsmittel zur Identifizierung unbekannter Peaks und zur Bestätigung von Suchergebnissen in der Datenbank. Zur automatischen Konzentrationsabschätzung identifizierter Substanzen wurde ein Tool „Estimate Concentration“ geschaffen. Die Überprüfung des Verfahrens an realen Blut- und Haarproben durch Vergleich mit HPLC-DAD- und GC-MS-Ergebnissen wies eine gute Übereinstimmung der Konzentrationen auf. Insgesamt zeigten die Untersuchungen, dass die LC-QTOF-MS zurzeit die am besten geeignete Methode für die STA darstellt. Auch bei einem erst später aufkommenden Verdacht kann eine gezielte Suche in dem bereits gemessenen Datenfile durchgeführt werden.
Due to the large variety and the steady increase of toxicologically relevant substances, systematic toxicological analysis (STA) is one of the most difficult tasks in analytical chemistry and, therefore, a steady topic of research and methodical improvement. For this reason, the suitability of liquid chromatography in combination with hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) for STA was investigated. For this purpose, a database of more than 7360 and a CID spectra library of more than 2720 toxicologically relevant substances and suitable methods for sample preparation were developed. The application was evaluated at spiked blood and hair samples. It was found that the analysis in Auto-MS/MS mode (alternating measurement cycles of MS and MS/MS spectra) allowed substance identification in blood using CID spectra between 0.5 and 2 ng/ml for basic substances. The detection limits of the validated method in hair ranged from 3 to 15 pg/mg for 24 drugs. The suitability of LC-QTOF-MS for STA was tested for hair samples from 30 drug-related death cases and from 60 death cases with known chronic medication as well as for 77 blood samples. For the search of metabolites, a metabolite tool was developed. In the practical application to data files from blood and hair samples, the tool proved to be very helpful for identification of unknown peaks and for confirmation of results obtained only from the database without CID spectra. A tool "Estimate Concentration" was created for automatic estimation of concentrations of identified substances. The application to real blood and hair samples and the comparison of the concentrations with results from HPLC-DAD and GC-MS showed good agreement. Overall, these investigations showed that LC-QTOF-MS is currently the most favorable method for STA. Because of the comprehensive registration of all substances in a sample, the data files can be checked for the presence of certain poisons even later without new measurements.

Sudden cardiac death (SCD) is still one of the leading causes of cardiovascular death in the developed countries. The incidence of out-of-hospital cardiac arrest in Europe varies from 67 to 170 per 100,000 population. The chain of survival will be described in detailed steps. We are going to summarize the treatment options for sudden cardiac arrest from recognition of SCD to resuscitation and post cardiac arrest care. The role of awereness and Automated External Defibrillator and Public Access Defibrillation (AED-PAD) programs will be discussed in brief. SCD is one of the most common causes of death among athletes. Sport can trigger SCD in individuals who already have unknown form of heart disease. Our aim was to detail the underlying causes of SCD in athletes and to identify the possible screening techniques. Existing disease (e.g., myocardial hypertrophy, fibrosis) can be seen as a substrate, and sport as a trigger can cause arrhythmias, increased catecholamine release, acidosis, and dehydration. We will highlight the importance of sports medicine and periodic examination in screening for these conditions. Depending on the etiology, this may include exercise ECG, Holter monitor, CT, MR, echocardiography, and coronagraphy. We are going to conclude the new recommendations for COVID-19 post-infection care for athletes.

While healthy volunteers are concerned about the risks of studies, they are often much more vocal about the economic risk of not qualifying for studies. This chapter examines how being disqualified from studies through screen failures heightens their sense of risk as they attempt to earn income through clinical trials. It also considers how the screening process itself profoundly influences their health behaviors even outside of their study participation, including maintaining a healthy weight, eating nutritious food, consuming vitamins and supplements, and abstaining from deleterious substances, such as alcohol, tobacco, and illicit drugs. These actions on the part of healthy volunteers, which contribute to their model organism status, indicate that Phase I participation could counterintuitively improve their general health even as they expose themselves to the unknown risks of investigational drugs.

An unprecedented outbreak of unknown aetiology pneumonia occurred in Wuhan of Hubei, China, in December 2019. The WHO reported a novel coronavirus causative agent outbreak with limited evidence of COVID-19. SARS-CoV-2 embodies the ssRNA genome containing 29891 nucleotides to encode 9860 amino acids and shows different types of mutations, such as D614G. The epidemic of this virus officially declared an emergency of International Concern by the WHO in January 2020. In the first week of April 2021, a new strain of coronavirus named N-440 was reported in Chandigarh, India. The number of cases of laboratory-confirmed coronavirus has risen at an unprecedented pace worldwide, with more than 132,573,231 cases currently confirmed, including 2,876,411 deaths as of April 06th 2021. The lack of funding to survive the epidemic of this virus, coupled with the concern of overloaded healthcare systems, has driven a lot of countries into a partial/total lockout situation. This epidemic has caused chaos, and a rapid therapy of the disease would be a therapeutic medication with experience of use in patients to overcome the current pandemic. In the recent global emergency, researchers, clinicians and public health care experts around the world continue to search for emerging technologies to help tackle the pandemic of this virus. In this chapter, we rely on numerous reputable sources to provide a detailed analysis of all the main pandemic relevant aspects. This research illustrates not only the immediate safety effects connected with the COVID-19 epidemic but also its impact on the global socioeconomy, education, social life and employment. Artificial Intelligence (AI) plays a significant supporting capacity in countering COVID-19 and may prompt arrangements quicker than we can, in any case, achieve in different zones and applications. With technological developments in AI combined with improved computing capacity, the repurposing of AI-enhanced medications may be useful in the cases of this virus. Artificial intelligence has gotten one of those advances which can undoubtedly distin- guish the transmission of this virus; exceptionally hazardous victims are recognized and are significant for constant control of that contamination. Artificial intelligence could genuinely assist us in battling against this infection through network testing, clinical administrations and advice on controlling diseases. This chapter addresses recent applications of AI in fighting the pandemics of this virus, e.g., monitoring of the epidemic, forecast of hazards, screening and diagnosis, improvement of medical treatment, fake news breaks, strengthening lockdowns, preventing cyber-attacks and finally, effective online education. This chapter will provide a clear definition and general understanding of the field of this virus pandemic and the role of AI to readers and researchers.

Prolactin promotes milk production in mammals. It was characterized as a hormone distinct from growth hormone, which also has lactogenic activity, as recently as 1971. In humans, the predominant prolactin species is a 23 kDa, 199 amino acid polypeptide synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin is produced also by other tissues including decidua, breast, T lymphocytes, and several regions of the brain, where its functions are largely unknown and its gene regulation different from that of the pituitary gene. Pituitary prolactin production is under tonic inhibitory control by hypothalamic dopamine, such that pituitary stalk interruption produces hyperprolactinaemia. The neuropeptides thyrotrophin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP) exert less important stimulatory effects on pituitary prolactin release (1). Following the discovery of prolactin as a separate hormone it became apparent that many apparently functionless ‘chromophobe’ pituitary adenomas were prolactinomas. Indeed, prolactinoma is the commonest type of functioning pituitary tumour diagnosed in humans. There is a marked female preponderance and prolactinoma is relatively rare in men. Several studies have revealed small prolactinomas in approximately 5% of autopsy pituitaries, most of which are undiagnosed during life. From a clinical standpoint, prolactinomas are divided arbitrarily into microprolactinomas (≤10 mm in diameter) and macroprolactinomas (>10 mm). This is a useful distinction which predicts tumour behaviour and indicates appropriate management strategies. Generally, microprolactinomas run a benign course. Some regress spontaneously, most stay unchanged over many years, and very few expand to cause local pressure effects. In contrast, macroprolactinomas may present with pressure symptoms, often increase in size if untreated and rarely disappear. Some clinicians find an intermediate category of meso-prolactinoma useful (10–20 mm in diameter), since this tumour group may have a more favourable treatment outcome than for larger macroprolactinomas. Prolactinomas are usually sporadic tumours. Molecular genetics has shown nearly all to be monoclonal, suggesting that an intrinsic pituitary defect is likely to be responsible for pituitary tumorigenesis (see Chapter 2.3.2). Occasionally, prolactinoma may be part of a multiple endocrine neoplasia syndrome type I, but this occurs too infrequently to justify screening in every patient with a prolactinoma. Mixed growth hormone and prolactin-secreting tumours are well recognized and give rise to acromegaly in association with hyperprolactinaemia. Most contain separate growth hormone and prolactin-secreting cells whereas a minority secrete growth hormone and prolactin from a single population of cells, the mammosomatotroph adenomas. Prolactin-secreting adenomas may produce other hormones such as thyroid-stimulating hormone (TSH) or adrenocorticotropic hormone (ACTH), but such tumours are uncommon. Malignant prolactinomas are also very rare. A few cases have been described which have proved resistant to aggressive treatment with surgery, radiotherapy, and dopamine agonists. In a small proportion, extracranial metastases in liver, lungs, bone, and lymph nodes have been documented. The alkylating agent temozolomide is effective against some aggressive prolactinomas (2).

Heart failure is a common clinical syndrome, often presenting with breathlessness, fatigue and peripheral oedema. It is predominantly a disease of older people. The prevalence is increasing, exceeding 2% of the adult population in developed countries. The pathophysiology of heart failure is complex. A common feature is salt and water retention, possibly triggered by a relative fall in renal perfusion pressure. Common aetiologies include ischaemic heart disease, hypertension, and valvular heart disease. The early diagnosis of heart failure relies on a low threshold of suspicion and screening of people at risk before the onset of obvious symptoms or signs. In patients with suspected heart failure, routine investigation with electrocardiography and blood tests for urea and electrolytes, haemoglobin and BNP/NT-proBNP are recommended. Low plasma concentrations of BNP/NT-proBNP exclude most forms of heart failure. Intermediate or high concentrations should prompt referral for echocardiography to identify possible causes of heart failure and the left ventricular ejection fraction (LVEF). Patients can be classified as reduced (<40%) LVEF (HFrEF), normal (>50%) LVEF (HFnEF), or borderline (40–50%) LVEF (HFbEF). Currently HFbEF and HFnEF are managed similarly by current guidelines. Treatable causes for heart failure (e.g. valvular disease, tachyarrhythmias, thyrotoxicosis, anaemia or hypertension) should be identified and corrected. Patients with heart failure will generally benefit from lifestyle advice (diet, exercise, vaccination). Pharmacological therapy is given to improve symptoms and prognosis. Diuretic therapy is the mainstay for control of congestion and symptoms; it may be life-saving for patients with acute heart failure but its effect on long-term prognosis is unknown. For patients with HFrEF, either angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or, more recently, angiotensin receptor neprilysin inhibitors, combined with β‎-blockers and mineralocorticoid receptor antagonists (triple therapy) provide both symptomatic and prognostic benefit. Ivabridine may be added for those in sinus rhythm where the heart rate remains above 70 bpm. Whether digoxin still has a role in contemporary management is uncertain. Cardiac resynchronization therapy is appropriate for symptomatic patients with HFrEF if they are in sinus rhythm and have a broad QRS (>140 ms). Implantable defibrillators provide additional prognostic benefit in selected patients with an ejection fraction below 35%. For patients with HFnEF, treatments directed at comorbid conditions (e.g. hypertension, atrial fibrillation) and congestion (e.g. diuretics and mineralocorticoid receptor antagonists) are appropriate but there is no robust evidence that any treatment can improve prognosis. Heart transplantation or assist devices may be options for highly selected patients with endstage heart failure; many others may benefit from palliative care services. Effective management of chronic heart failure requires a coordinated multidisciplinary team, including heart failure nurse specialists, primary care physicians, and cardiologists. New treatments have improved the prognosis of heart failure substantially over the past two decades. The annual mortality is now probably less than 5% for patients with HFrEF receiving good contemporary care whose symptoms are stable and controlled. For patients with recurrent or recalcitrant congestion requiring admission to hospital, the prognosis is much worse. In-patient mortality is about 5% for those aged less than 75 years but threefold higher for older patients; mortality in the year after discharge ranges from 20% to 40% depending on age.

Background: Infectious diseases (IDs) account for 8% of deaths annually in Qatar, and therefore, represent a significant challenge for public health. Interestingly, the spread and severity of viral infections vary considerably between individuals and populations. The most recent example is SARS-CoV-2, which ranges from mild/asymptomatic to a severe respiratory syndrome. It has been previously reported that polymorphisms in genes linked to immunity can influence individuals’ responses to infections as observed in tuberculosis, influenza, and HIV; however, studies exploring causal host genetic variants in IDs are still limited and dramatically skewed with regard to population inclusion. In fact, the genetic susceptibility to IDs in the Qatari population is largely unknown. Aim: To perform a comprehensive genetic screening to investigate the presence and frequency of variants previously associated with various infections in the Qatari population. Methods: Whole-genome sequencing was previously performed for 18,000 QBB participants using Illumina HiSeq X Ten1 sequencers. The initial data processing and quality assessment of the raw data has also been performed and variant calling files (VCF) were created. We were granted the access to the VCF files of 6,218 sequenced samples. The genetic variant data was then converted to PLINK file format using PLINK-1.9. Standardized quality-assurance and quality control (QA/QC) methods were followed to generate high quality and confidence on both SNPs and sample levels. The final file used for calculating allele frequency contained 6,047 subjects. Additionally, list of infections-related SNPs that were previously reported in the literature and deposited in GWAS catalog was extracted and used to calculate and compare the allelic frequency in the Qatari genomes compared to other populations. Results: The frequency of infections-related SNPs in the Qatari population was significantly lower for most infections. Most variants (78%) showed negative fold change in the Qatari genomes. Only 22% of all variants were more prevalent in Qatari population compared to others. The most significant differences were observed in genes related to TB and HIV (200-940 and 160-710 fold change, respectively). Conclusion: This study reports a lower susceptibility of the Qatari population to IDs in general. Nonetheless, this might also indicate the presence of unknown Qatari-unique variants and hence, highlights the need for further investigation in future GWAS.

Background Australia is a multi-cultural society with increasing rates of people from culturally and linguistically diverse (CALD) backgrounds. On average, CALD groups have higher rates of tobacco use, lower participation in cancer screening programs, and poorer health outcomes than the general Australian population. Lower cancer screening and smoking cessation rates are due to differing cultural norms, health-related attitudes, and beliefs, and language barriers. Interventions can help address these potential barriers and increase tobacco cessation and cancer screening rates among CALD groups. Cancer Council NSW (CCNSW) aims to reduce the impact of cancer and improve cancer outcomes for priority populations including CALD communities. In line with this objective, CCNSW commissioned this rapid review of interventions implemented in Australia and comparable countries. Review questions This review aimed to address the following specific questions: Question 1 (Q1): What smoking cessation interventions have been proven effective in reducing or preventing smoking among culturally and linguistically diverse communities? Question 2 (Q2): What screening interventions have proven effective in increasing participation in population cancer screening programs among culturally and linguistically diverse populations? This review focused on Chinese-, Vietnamese- and Arabic-speaking people as they are the largest CALD groups in Australia and have high rates of tobacco use and poor screening adherence in NSW. Summary of methods An extensive search of peer-reviewed and grey literature published between January 2013-March 2022 identified 19 eligible studies for inclusion in the Q1 review and 49 studies for the Q2 review. The National Health and Medical Research Council (NHMRC) Levels of Evidence and Joanna Briggs Institute’s (JBI) Critical Appraisal Tools were used to assess the robustness and quality of the included studies, respectively. Key findings Findings are reported by components of an intervention overall and for each CALD group. By understanding the effectiveness of individual components, results will demonstrate key building blocks of an effective intervention. Question 1: What smoking cessation interventions have been proven effective in reducing or preventing smoking among culturally and linguistically diverse communities? Thirteen of the 19 studies were Level IV (L4) evidence, four were Level III (L3), one was Level II (L2), none were L1 (highest level of evidence) and one study’s evidence level was unable to be determined. The quality of included studies varied. Fifteen tobacco cessation intervention components were included, with most interventions involving at least three components (range 2-6). Written information (14 studies), and education sessions (10 studies) were the most common components included in an intervention. Eight of the 15 intervention components explored had promising evidence for use with Chinese-speaking participants (written information, education sessions, visual information, counselling, involving a family member or friend, nicotine replacement therapy, branded merchandise, and mobile messaging). Another two components (media campaign and telephone follow-up) had evidence aggregated across CALD groups (i.e., results for Chinese-speaking participants were combined with other CALD group(s)). No intervention component was deemed of sufficient evidence for use with Vietnamese-speaking participants and four intervention components had aggregated evidence (written information, education sessions, counselling, nicotine replacement therapy). Counselling was the only intervention component to have promising evidence for use with Arabic-speaking participants and one had mixed evidence (written information). Question 2: What screening interventions have proven effective in increasing participation in population cancer screening programs among culturally and linguistically diverse populations? Two of the 49 studies were Level I (L1) evidence, 13 L2, seven L3, 25 L4 and two studies’ level of evidence was unable to be determined. Eighteen intervention components were assessed with most interventions involving 3-4 components (range 1-6). Education sessions (32 studies), written information (23 studies) and patient navigation (10 studies) were the most common components. Seven of the 18 cancer screening intervention components had promising evidence to support their use with Vietnamese-speaking participants (education sessions, written information, patient navigation, visual information, peer/community health worker, counselling, and peer experience). The component, opportunity to be screened (e.g. mailed or handed a bowel screening test), had aggregated evidence regarding its use with Vietnamese-speaking participants. Seven intervention components (education session, written information, visual information, peer/community health worker, opportunity to be screened, counselling, and branded merchandise) also had promising evidence to support their use with Chinese-speaking participants whilst two components had mixed (patient navigation) or aggregated (media campaign) evidence. One intervention component for use with Arabic-speaking participants had promising evidence to support its use (opportunity to be screened) and eight intervention components had mixed or aggregated support (education sessions, written information, patient navigation, visual information, peer/community health worker, peer experience, media campaign, and anatomical models). Gaps in the evidence There were four noteworthy gaps in the evidence: 1. No systematic review was captured for Q1, and only two studies were randomised controlled trials. Much of the evidence is therefore based on lower level study designs, with risk of bias. 2. Many studies provided inadequate detail regarding their intervention design which impacts both the quality appraisal and how mixed finding results can be interpreted. 3. Several intervention components were found to have supportive evidence available only at the aggregate level. Further research is warranted to determine the interventions effectiveness with the individual CALD participant group only. 4. The evidence regarding the effectiveness of certain intervention components were either unknown (no studies) or insufficient (only one study) across CALD groups. This was the predominately the case for Arabic-speaking participants for both Q1 and Q2, and for Vietnamese-speaking participants for Q1. Further research is therefore warranted. Applicability Most of the intervention components included in this review are applicable for use in the Australian context, and NSW specifically. However, intervention components assessed as having insufficient, mixed, or no evidence require further research. Cancer screening and tobacco cessation interventions targeting Chinese-speaking participants were more common and therefore showed more evidence of effectiveness for the intervention components explored. There was support for cancer screening intervention components targeting Vietnamese-speaking participants but not for tobacco cessation interventions. There were few interventions implemented for Arabic-speaking participants that addressed tobacco cessation and screening adherence. Much of the evidence for Vietnamese and Arabic-speaking participants was further limited by studies co-recruiting multiple CALD groups and reporting aggregate results. Conclusion There is sound evidence for use of a range of intervention components to address tobacco cessation and cancer screening adherence among Chinese-speaking populations, and cancer screening adherence among Vietnamese-speaking populations. Evidence is lacking regarding the effectiveness of tobacco cessation interventions with Vietnamese- and Arabic-speaking participants, and cancer screening interventions for Arabic-speaking participants. More research is required to determine whether components considered effective for use in one CALD group are applicable to other CALD populations.

Plant species synthesize a multitude of specialized compounds 10 help ward off pests. and these in turn may well serve as an alternative to synthetic pesticides to reduce environmental damage and health risks to humans. The general goal of this research was to perform a genetic and biochemical dissection of the natural-insecticides methylketone pathway that is specific to the glandular trichomes of the wild species of tomato, Solanumhabrochaites f. glabratum (accession PI126449). Previous study conducted by us have demonstrated that these compounds are synthesized de novo as a derivate pathway of the fatty acid biosynthesis, and that a key enzyme. designated MethylketoneSynthase 1 (MKS 1). catalyzes conversion of the intermediate B-ketoacyl- ACPs to the corresponding Cn-1 methylketones. The approach taken in this proposed project was to use an interspecific F2 population. derived from the cross between the cultivated lV182 and the wild species PIl26449. for three objectives: (i) Analyze the association between allelic status of candidate genes from the fatty acid biosynthesis pathway with the methylketone content in the leaves (ii) Perform bulk segregant analysis of genetic markers along the tomato genome for identifying genomic regions that harbor QTLs for 2TD content (iii) Apply differential gene expression analysis using the isolated glands of bulk segregant for identifying new genes that are involved in the pathway. The genetic mapping in the interspecific F2 population included app. 60 genetic markers, including the candidate genes from the FAS pathway and SSR markers spread evenly across the genome. This initial; screening identified 5 loci associated with MK content including the candidate genes MKS1, ACC and MaCoA:ACP trans. Interesting observation in this genetic analysis was the connection between shape and content of the glands, i.e. the globularity of the four cells, typical to the wild species. was associated with increased MK in the segregating population. In the next step of the research transcriptomic analysis of trichomes from high- and 10w-MK plants was conducted. This analysis identified a new gene, Methy1ketone synthase 2 (MKS2), whose protein product share sequence similarity to the thioesterase super family of hot-dog enzymes. Genetic analysis in the segregating population confirmed its association with MK content, as well as its overexpression in E. coli that led to formation of MK in the media. There are several conclusions drawn from this research project: (i) the genetic control of MK accumulation in the trichomes is composed of biochemical components in the FAS pathway and its vicinity (MKS 1 and MKS2). as well as genetic factors that mediate the morphology of these specialized cells. (ii) the biochemical pathway is now realized different from what was hypothesized before with MKS2 working upstream to I\1KS 1 and serves as the interface between primary (fatty acids) and secondary (MK) metabolism. We are currently testing the possible physical interactions between these two proteins in vitro after the genetic analysis showed clear epistatic interactions. (iii) the regulation of the pathway that lead to specialized metabolism in the wild species is largely mediated by transcription and one of the achievements of this project is that we were able to isolate and verify the specificity of the MKS1 promoter to the trichomes which allows manipulation of the pathways in these cells (currently in progress). The scientific implications of this research project is the advancement in our knowledge of hitherto unknown biochemical pathway in plants and new leads for studying a new family in plants (hot dog thioesterase). The agricultural and biotechnological implication are : (i) generation of new genetic markers that could assist in importing this pathway to cultivated tomato hence enhancing its natural resistance to insecticides, (ii) the discovery of MKS2 adds a new gene for genetic engineering of plants for making new fatty acid derived compounds. This could be assisted with the use of the isolated and verified MKS1 promoter. The results of this research were summarized to a manuscript that was published in Plant Physiology (cover paper). to a chapter in a proceeding book. and one patent was submitted in the US.