Knowing how switchgrass (Panicum virgatum L.) responds and adapts to phosphorus (P)-limitation will aid efforts to optimize P-efficiency in this species for sustainable biomass production. This integrative study investigated the impacts of mild, moderate, and severe P-stress on genome transcription and whole-plant metabolism, physiology and development in an unprecedented way for this species. P-limitation reduced overall plant growth, increased root/shoot ratio, increased root branching at moderate P-stress, and decreased root diameter with increased density and length of root hairs at severe P-stress. RNA-seq analysis revealed thousands of genes that were differentially expressed under moderate and severe P-stress in roots and/or shoots compared to P-replete plants, with many stress-induced genes involved in transcriptional and other forms of regulation, primary and secondary metabolism, transport, and other processes involved in P-acquisition and homeostasis. Amongst the latter were multiple miRNA399 genes and putative targets of these. Metabolite profiling showed that levels of most sugars and sugar alcohols decreased with increasing P stress, while organic and amino acids increased under mild and moderate P-stress in shoots and roots, although this trend reversed under severe P-stress, especially in shoots.

The practices of head and neck surgical oncologists must evolve to meet the unprecedented needs placed on our healthcare system by the Coronavirus Disease 2019 (COVID-19) pandemic. Guidelines are emerging to help guide the provision of head and neck cancer care, though in practice, it can be challenging to operationalize such recommendations. Head and neck surgeons at Wuhan University faced significant challenges in providing care for their patients. Similar challenges were faced by the University of Toronto during the severe acute respiratory syndrome (SARS) pandemic in 2003. Herein, we outline our combined experience and key practical considerations for maintaining an oncology service in the midst of a pandemic.

Background: COVID-19 pandemic has strained human and material resources around the world. Practices in surgical oncology had to change in response to these resource limitations, triaging based on acuity, expected oncologic outcomes, availability of supportive resources, and safety of healthcare personnel. Methods: The MD Anderson Head and Neck Surgery Treatment Guidelines Consortium devised the following to provide guidance on triaging Head and Neck cancer (HNC) surgeries based on multidisciplinary consensus. HNC subsites considered included aerodigestive tract mucosa, sinonasal, salivary, endocrine, cutaneous, and ocular. Recommendations: Each subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred. Conclusion: These guidelines are intended to help clinicians caring for HNC patients appropriately allocate resources during a healthcare crisis, such as the COVID-19 pandemic. We continue to advocate for individual consideration of cases in a multidisciplinary fashion based on individual patient circumstances and resource availability.

AUTHORSVelda Ling Yu Chow MD, MS, Jimmy Yu Wai Chan MD, MS, PhD, Valerie Wai Yee Ho MD, George Chung Ching Lee MD, BDS, Melody Man Kuen Wong MD, Stanley Thian Sze Wong BSc, PhD, Wei Gao, BSc, MSc, PhDCORRESPONDING AUTHORVelda Ling Yu Chow MD, MSDivision of Head and Neck SurgeryDepartment of SurgeryUniversity of Hong Kong Li Ka Shing Faculty of MedicineQueen Mary HospitalADDRESS FOR CORRESPONDANCE AND REPRINTDivision of Head and Neck SurgeryDepartment of SurgeryUniversity of Hong Kong Li Ka Shing Faculty of MedicineQueen Mary Hospital102 Pokfulam Road,Hong Kong SAR, ChinaTelephone: +852 2255 2208Fax: +852 2819 3780E-mail: vlychow@gmail.com

Kimberley L Kiong MBBS 1 , Theresa Guo MD 1 , Christopher MKL Yao MD 1 , Neil D Gross MD 1 , Matthew M Hanasono MD 2 , Renata Ferrarotto, MD 3 , David I Rosenthal MD 4 , Jeffrey N Myers MD 1 , Ehab Y Hanna MD1, Stephen Y Lai MD 1 1 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States 2 Department of Plastics and Reconstructive Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States 3Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. 4Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Corresponding author: Stephen Y Lai, MD PhD Professor Patient Safety Quality Officer The University of Texas MD Anderson Cancer Center Department of Head and Neck Surgery Division of Surgery 1515 Holcombe Blvd, Unit 1445 Houston, TX 77030  sylai@mdanderson.org  This work did not receive any grant support and has not been presented at any meeting Running title: Changing Head & Neck surgical practice during COVID-19 Keywords : Otolaryngology, Oncology, SARS-CoV2 Abstract: Background: The COVID-19 pandemic has changed healthcare, challenged by resource constraints and fears of transmission. We report the surgical practice pattern changes in a Head and Neck Surgery department of a tertiary cancer care center and discuss the issues surrounding multidisciplinary care during the pandemic. Methods: We report data regarding outpatient visits, multidisciplinary treatment planning conference, surgical caseload, and modifications of oncologic therapy during this pandemic and compared this data to the same interval last year. Results: We found a 46.7% decrease in outpatient visits and a 46.8% decrease in surgical caseload, compared to 2019. We discuss the factors involved in the decision-making process and perioperative considerations. Conclusions: Surgical practice patterns in head and neck oncologic surgery will continue to change with the evolving pandemic. Despite constraints, we strive to prioritize and balance the oncologic and safety needs of patients with head and neck cancer in the face of COVID-19. IntroductionThe rapid spread of the novel coronavirus 2019 (COVID-19) has disrupted healthcare systems globally. Some of the biggest challenges include shortage of hospital beds, healthcare workers and personal protective equipment (PPE). Given these constraints, there has been a simultaneous push for a reduction in elective clinical practice, to further reduce transmission and conserve resources 1.Cancer care is generally not considered elective and decision making about when to initiate or delay treatment during the pandemic has raised complex ethical and resource utilization issues. Yet amidst the pandemic, patients continue to develop and seek treatment for cancer. Head and neck cancers (HNC) can challenge essential functions such as eating, speaking and breathing. Tumor doubling time ranges between 15 to 99 days 2,3 and delaying treatment decreases survival and contributes to adverse outcomes 4,5. As such, there are recommendations for prompt initiation of treatment of HNC after diagnosis and to reduce the total treatment package time6,7. In an effort to limit the potential adverse effects of delaying cancer treatment during this pandemic, an increasing number of oncology guidelines have been developed, both general and specific to HNC 8,9.At the University of Texas MD Anderson Cancer Center (MDACC), our Head and Neck surgical practice has gradually changed as a result of evolving internal and external guidelines (Table 1). Harris County, Texas reported its first COVID-19 case on March 5th, 2020. Since then, the number of cases has been steadily rising with the current incidence at 35 per 100,000 residents in Texas 10. At the institutional level, MDACC has taken many pre-emptive actions and policy changes in response to the growing pandemic (Table 1).The institutional policies described have served to limit hospital attendances in anticipation of a surge in COVID-19 cases in the region. The number of new patients visits to the institution have decreased from 782/week in the first week of March to 207/week in the last week of March (-73.5%) while systemic treatment appointments, indicative of patients already in the process of treatment, have remained fairly stable (3864 to 3288 visits, -14.9%). As a downstream effect, the number of diagnostic imaging visits has decreased from 9616 to 3971 (first and last weeks of March respectively, -58.7%). Surgeries within the institution have shown a more drastic decrease, from 463 to 149 cases per week (-67.8%). Current institutional census at the time of writing (April 7th, 2020) shows 55% general bed occupancy and 35% ICU occupancy. The numbers will continue to change in response to the development of COVID-19 within the region, as we have not yet reached the peak of infection. Predictive models have suggested that the peak in COVID-19 cases will occur at the end of April11 and there are institutional plans on standby to repurpose physical facilities and the workforce to shift focus from oncology care to COVID-19 treatment if needed.In the context of the developing pandemic and tightening institutional guidelines, we seek to understand the early impact of the COVID-19 pandemic on head & neck oncologic surgery practices. We performed a review of outpatient clinic and surgical caseload within the MDACC Head and Neck Surgery department during the pandemic and compared this to the same time period in the preceding year, along with the deviations in management of patients due to COVID-19.

Many models of multiaxial fatigue limit under the bending and torsion loading have been reported in literature. In this paper, an attempt is made to extend the multiaxial fatigue limit models to finite fatigue life. Further these empirical models together with uniaxial S-N equations, including the axial S-N equation and torsion S-N equation, are used to perform multiaxial fatigue life assessment. By using a large number of experimental data of fatigue life reported in literature, an accuracy of these empirical models has been checked.

Flora Yan, BA1; Shaun A. Nguyen, MD11: Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina.Word Count: 1,260Conflicts of Interest: None to DiscloseCorresponding Author:Flora YanDepartment of Otolaryngology – Head and Neck Surgery135 Rutledge Avenue, MSC 550, Charleston, SC 29425843-792-8299yanf@musc.eduAbstractSince first identified in December of 2019, COVID-19 has disseminated from Wuhan, China rapidly across the globe. 5-8% of these COVID-19 patients are estimated to become critically ill and will require ICU admission. Predictors of severe/critical ill COVID-19 disease may include increasing age, smoking status, immunosuppression and chronic conditions such as cardiovascular disease, diabetes, hypertension and also cancer. In this brief correspondence, we first describe the outcomes of critically ill patients with and without cancer and extrapolate these findings to the head and neck cancer population.Dear Dr. Hanna,Since first identified in December of 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has disseminated from Wuhan, China rapidly across the globe. On March 11th, 2020 the World Health Organization deemed Coronavirus Disease 2019 (COVID-19) a worldwide pandemic, with the global community in a state of emergency.1 As of April 10th, 2020, 1.6 million COVID-19 cases have been reported worldwide.2 Case-fatality rate have ranged from 2% to 7%.3 Clinically, COVID-19 is initially characterized by a constellation of non-specific symptoms such as cough, fever, and dyspnea. However, this can escalate quickly, with the median time from symptom onset to severe hypoxemia necessitating ICU admission seen to be from 7 to 12 days.4-6 It is clear certain populations such as patients with coexisting conditions, older age, an immunocompromised state and a smoking history are at a high risk for severe disease as well as poor outcomes.7 Head and neck cancer patients are placed in a vulnerable state and may equally be of high-risk to the consequences of COVID-19, given their immunosuppressed state from cancer and corresponding treatment as well as high prevalence of the aforementioned risk factors. In this correspondence, we aim to discuss sequelae of severe COVID-19 disease, in addition to describing head and neck cancer patients as a high-risk population.The majority of COVID-19 cases are of mild severity, however 5-8%5,8 of COVID-19 patients may become critically ill, experiencing respiratory failure, septic shock and/or multi-organ failure. This necessitates admission into the intensive care unit (ICU). Two-thirds of these critically ill patients have met criteria for acute respiratory distress syndrome (ARDS) and require advanced respiratory support. The acute severity and rapid progression of COVID-19 is illustrated with over 63% requiring invasive mechanical ventilation in the first 24 hours of admission.9 Mortality of COVID-19 patients in the ICU has been estimated to be 50%7,10. Of these, patients of older age > 70 years old and with severe comorbidities were seen to have mortality rates of 68 and 59%, respectively.9 As defined by the Center for Disease Control’s weekly morbidity and mortality report regarding COVID-19, these comorbidities may include diabetes mellitus, chronic lung disease, cardiovascular disease, chronic renal disease, and other chronic disease, of which a history of cancer falls under.11ARDS secondary to COVID-19 requires time on mechanical ventilation than is usually required. Bhatraju et al.7 reports a median of 10 days of time on mechanical ventilation before COVID-19 patients were extubated. This is in comparison to 3 to 8 days seen on average for non-COVID related indications for mechanical ventilation.12 Even then, most patients are unable to wean off mechanical ventilation, as seen by a tragically high mortality rate of COVID-19 patients on mechanical ventilation (Table 1) . The Intensive Care National Audit & Research Centre (ICNARC) demonstrated a 67.3% mortality rate of patients receiving advanced (i.e. non-invasive or invasive ventilation, tracheostomy or extracorporeal respiratory support) respiratory support.9 Studies from China examining critically ill COVID-19 patients placed on mechanical ventilation have reported mortality rates of 81% to 97%.4,5 A Seattle-based analysis of critically ill patients on mechanical ventilation saw a comparatively lower mortality rate of 50%, however at the time of this study 3 were still on mechanical ventilation without recovery from COVID-19.7 These extraordinary high mortality rates of patients on mechanical ventilation, ranging from 50% to 97%, may reveal that full intensive care support and life-sustaining therapies still cannot overcome the poor prognosis of certain high-risk populations afflicted by COVID-19. Deterioration despite mechanical ventilation may be confounded by multi-organ system failure. Those who fail mechanical ventilation may be placed on extracorporeal membrane oxygen (ECMO) therapy as end of the line care, however this is often accessible in most hospital systems. In fact, even with substantial cases of critically ill COVID-19 patients, ECMO therapy use has ranged from 6 to 12%.4,5As patients with cancer, especially those in active treatment or in the acute post-treatment phase, are in a particularly immunosuppressed conditions, elucidation of the course of COVID-19 in this patient population is paramount. Liang et al.13 describe a cohort of 18 cancer patients (1 [6%] of which with head and neck cancer) having a higher risk of mechanical ventilation or death (39% vs. 8%), compared to non-cancer patients. Cancer patients also more rapidly deteriorated, with a median time to a critical event taking 13 days as opposed to 43 days in non-cancer patients.Multiple other studies have described cancer patients with COVID-19. Desai et al.14 performed a meta-analysis of 11 studies describing clinical courses of COVID-19 cases and found a 2% prevalence of cancer in patients with COVID-19. Desai et al.14also discovered higher risk of severe events for patients recently treated with chemotherapy or surgery in the past 30 days, over non-cancer COVID-19 patients (75% vs. 43%).Zhang et al.15 revealed clinical characteristics of 28 COVID-19 infected cancer patients in Wuhan China, of which 3 (11%) had head and neck cancer. Of this cohort, 10 (36%) of patients required mechanical ventilation and 8 (29%) patients died. If assumed these 8 were on maximum respiratory therapy previous to death, a mortality rate of 80% can be extrapolated and is in line to mortality rates of critically ill non-cancer patients; this, however, is not explicitly validated in the study. Notably, stage IV disease was associated with higher rates of severe events (ICU admission, mechanical ventilation, or death) than stage I-III disease (70% vs 44%). Zhang et al.15 also revealed patients recently treated with chemotherapy, radiation therapy, and/or immunotherapy in the past 14 days had a 4-times increased odds of developing a severe event than those who received any treatment > 14 days.From this we can observe that 1) prevalence of cancer, active or in remission, in COVID-19 patients is higher than in the general population; 2) COVID-19 patients with cancer may deteriorate more rapidly than non-cancer patients 3) active treatment of cancer may be associated with increased risk of severe COVID-19 sequelae than in patients not undergoing treatment; and 4) critically ill COVID-19 patients who have cancer may more likely develop end-stage respiratory failure or death than non-cancer critically ill patients, barring presence of other chronic illnesses. It is difficult to ascertain how cancer patients in remission may far in comparison to the general population, however it is clear patients undergoing active treatment may present as a high-risk population for severe illness following COVID-19 infection. These observations are limited on data provided by retrospective studies of small sample sizes, and thus must be interpreted with caution.Cancer patients present as a high-risk population for COVID-19 development as well as poorer outcomes. Head and neck cancer patients in particularly may be susceptible to the deleterious effects of not only the viral pathogenesis of COVID-19 itself, but also the long-term psychosocial sequelae of intensive critical care, advanced respiratory treatment and other life-saving measures, all amidst a quarantined environment for a patient population characterized as having twice the suicide risk rate of other cancer patients. Given such high death rates of non-cancer patients on mechanical ventilation, the additive vulnerability from head and neck cancer may make severe or critical ill COVID-19 development quite fatal for our patients. Thus, more attention and perhaps additional testing for patients currently undergoing treatment may be warranted. As described in modified head and neck cancer treatment algorithms16, treatment only for advanced head and neck cancers should proceed with full precautions (i.e. COVID testing, PPE) and any possible methods to reduce nosocomial COVID-19 infection is warranted. We hope this correspondence provides insight in the high-risk of head and neck cancer patients for critical illness following COVID-19 infection.Works Cited1. World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19—11 March 2020. 2020; https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020.2. Worldometer. COVID-19 coronavirus pandemic. https://www.worldometers.info/coronavirus/. Accessed April 10th, 2020.3. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy.JAMA. 2020.4. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062.5. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020.6. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet.2020;395(10223):507-513.7. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid-19 in Critically Ill Patients in the Seattle Region — Case Series. New England Journal of Medicine. 2020.8. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242.9. ICNARC COVID-19 Study Case Mix Programme Database. ICNARC report on COVID-19 in critica care. 2020; https://www.icnarc.org/About/Latest-News/2020/04/04/Report-On-2249-Patients-Critically-Ill-With-Covid-19.10. Guan W-j, Ni Z-y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. New England Journal of Medicine. 2020.11. CDC COVID-19 Response Team. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020.Morbidity and Mortality Weekly Report. April 3, 2020.12. Seneff MG, Zimmerman JE, Knaus WA, Wagner DP, Draper EA. Predicting the duration of mechanical ventilation. The importance of disease and patient characteristics. Chest. 1996;110(2):469-479.13. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol.2020;21(3):335-337.14. Desai A, Sachdeva S, Parekh T, Desai R. COVID-19 and Cancer: Lessons From a Pooled Meta-Analysis. JCO Global Oncology.2020(6):557-559.15. Zhang L, Zhu F, Xie L, et al. Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China. Ann Oncol. 2020.16. Day AT, Sher DJ, Lee RC, et al. Head and neck oncology during the COVID-19 pandemic: Reconsidering traditional treatment paradigms in light of new surgical and other multilevel risks. Oral Oncol.2020:104684.

Elderly head and neck cancer patients are at increased risk of adverse outcomes during and after treatment of head and neck cancer. COVID-19 severity and mortality can be expected to be significantly greater in elderly head and neck cancer patients, given that increased age, comorbidities, and presence of malignancy are known risk factors for disease severity and mortality in COVID-19 patients. Therefore, their management requires multidisciplinary consensus and patient input. A thorough geriatric assessment, which has been shown to be beneficial prior to the COVID-19 pandemic, could be particularly helpful in this patient population with the added dimension of COVID-19 risk. In many cases, prudent treatment plan modification may allow for overall best outcomes. Furthermore, recruitment of social services and, when appropriate, palliative care, may allow for optimal management of these patients.

Authors: Arjun Gurmeet Singh MDS (Oral and Maxillofacial Surgery), MFDS (Glasgow) Department of Head and Neck Oncology  Tata Memorial Center and HBNI Mumbai, India (Email: arjun193@gmail.com) Jayita Deodhar,  MD Department of Palliative Medicine Tata Memorial Center and HBNI Mumbai, India (Email: jukd2000@yahoo.co.uk) Pankaj Chaturvedi, MS, FACS, (Corresponding Author) Department of Head and Neck OncologyTata Memorial Center, Mumbai, India (Email: chaturvedi.pankaj@gmail.com)

Aim: The COVID pandemic is caused by infection with the SARS-CoV-2 virus. The major mutation detected to date in the SARS-CoV-2 viral envelope spike protein, which is responsible for virus attachment to the host and is also the main target for host antibodies, is a mutation of an aspartate (D) at position 614 found frequently in Chinese strains to a glycine (G). We sought to infer health impact of this mutation. Result: Increased case fatality rate correlated strongly with the proportion of viruses bearing G614 on a country by country basis. The amino acid at position 614 occurs at an internal protein interface of the viral spike, and the presence of G at this position was calculated to destabilize a specific conformation of the viral spike, within which the key host receptor binding site is more accessible. Conclusion: These results imply that G614 is a more pathogenic strain of SARS-CoV-2, which may influence vaccine design. The prevalence of this form of the virus should also be included in epidemiologic models predicting the COVID-19 health burden and fatality over time in specific regions. Physicians should be aware of this characteristic of the virus to anticipate the clinical course of infection. What is known about this topic? Nothing is known about the health significance of the D614G SARS-CoV-2 variant. What does this article add? A molecular clue to viral molecular pathogenesis of COVID-19 disease.

Immune tissue associated with the major histocompatibility complex (MHC) is widely present in vertebrates highly polymorphic gene cluster. However, available published data about how amphibians MHCI genes react to pathogen infections are very few. The present study reports MHCI molecule in Rana dybowskii, and its differential expression in immunologically relevant tissues post-infection with lipopolysaccharide (LPS). The results showed that cDNA sequence of MHCIα contained 1047bp nucleotides encoding putative 348 amino acids. The phylogenetic analysis exhibited its evolutionary conservation within amphibians and formed a different clade with vertebrates. Morover, quantitative reverse transcription PCR analyses demonstrated that the MHCI gene was transcribed in the seven tested tissues, and analysis of immunologically relevant tissues of MHCI gene from the infected Rana dybowskii exhibited differential transcriptional activities. The expression of MHCI in the heart, liver, spleen, lung, kidneys, skin and muscular reached peak levels at 72, 24, 48, 12, 12, 12 and 72h post-infection(hpi), respectively. These findings indicate that MHCI is an indispensable part of the immune system. This is one of the first studies to investigate MHCIα in Rana dybowskii and can provide the foundation for further study of the immune function of MHC molecules in anti-infection.

Understanding the scaling between leaf size and leafing intensity is crucial for comprehending theories about light interception and leaf carbon uptake and adjustments in life history strategies. To test whether have the broad scope predictions between leaf size variation and leafing intensity on first year stem in evergreens and deciduous. A comprehensive data set of minimum (Mmin) and maximum (Mmax) leaf mass and total leaf number in twig was compiled, as well as data for the stem volume and mass. The datasets provide measurements of 123 woody species in subtropical mountain forests. Standardized major axis (SMA) analysis was used to determine the effects of the variation in leaf size (i.e., Mmin to Mmax) and the effects of different functional groups on the trade-off between leaf size and leafing intensity, i.e., the leafing intensity based on stem volume (LIV) and stem mass (LIM). Leaf size plasticity variation did not differ between evergreen and deciduous functional groups, but Mmin scaled as the 1.19 power of Mmax. Across the 123 species, the scaling exponents of the pooled data ranged between -1.14 to -0.96 for Mmin and Mmax vs. the leafing intensity based on stem volume (LIV) and from -1.24 to -1.04 for Mmin and Mmax vs. the leafing intensity based on stem mass (LIM). Across the subtropical woody species examined in this study, the results show the scaling relationship between leaf mass and leafing intensity is constrained to be ≤ -1.0. More importantly, the scopes in twig leaf size and the leafing intensity correlate with the biomass allocation to minimum and maximum leaf mass, and not sensitive to plant functional groups in subtropical mountain forests.

Aims: Proton pump inhibitors (PPIs) were primarily approved for short term use (2 to 8 weeks). However, PPI use continues to expand. Widely believed to be safe, we reviewed emerging evidence on increased mortality with PPI long-term use. Methods: We searched MEDLINE, Embase and Cochrane Central for evidence from systematic reviews (SR) and primary studies reporting all-cause mortality in adults treated with a PPI for any indication (duration > 12 weeks) compared to patients without PPI treatment (no use, placebo or H2RA use). Data was synthesized, analysed, critically examined and interpreted herein. Results: From 1304 articles, one systematic review (SR) was identified that reported on all-cause mortality. The SR pooled 3 observational studies with data to 1 year: odds ratio, 95% confidence interval (CI) 1.53-1.84. A randomized controlled trial (RCT), the COMPASS (Cardiovascular Outcomes for People Using Anticoagulant Strategies) RCT with data to 3 years: hazard ratio (HR) 1.03, 95% CI 0.92-1.15. The US Veterans Affairs cohort study using a large national dataset with data to 10 years; HR 1.17, 95% CI (1.10-1.24), (NNH) 22. The most common causes of death were from cardiovascular and chronic kidney diseases, with an excess death of 15 and 4 per 1000 patients, respectively over 10-year period. Conclusions: Harms arising from real world medication use are best evaluated using a pharmacovigilance ‘convergence of proof’ approach using data from a variety of sources and varied study designs. Careful appraisal of the totality of available evidence leads to the conclusion that long-term PPI utilization increases mortality

Personalization of oral small molecule anticancer drug doses based on individual patient blood drug levels, also known as therapeutic drug monitoring or TDM, has the potential to significantly improve the effectiveness of treatment by maximizing drug efficacy and minimize toxicity. However, this option has not yet been widely embraced by the oncology community. Some reasons for this include increased logistical complexity of dose individualization, the lack of clinical laboratories that measure small molecule drug concentrations in support of patient care, and the lack of reimbursement of costs. However, the main obstacle may be the lack of studies clearly demonstrating that monitoring of oral small molecule anticancer drug levels actually improves clinical outcomes. Without unequivocal evidence in support of TDM-guided dose individualization, especially demonstration of improved survival with TDM in randomized controlled trials, wide acceptance of this approach by oncologists and reimbursement by insurance companies is unlikely, and patients may continue to suffer as a result of receiving incorrect drug doses. This article reviews the current status of therapeutic drug monitoring of oral small molecule drugs in oncology and intends to provide strategic insights into the design of studies for evaluating the utility of TDM in this clinical context.

Triple energizer (Sanjiao, 三焦) is an extremely important concept in Traditional Chinese Medicine (TCM), which participates in comprehensive Zangfu viscera functions, but its spatial scope and anatomical basis has remained unknown for more than two-thousand years. Combining TCM and modern medicine, we have firstly identified triple energizer anatomical characteristics, and established a new definition of real triple energizer. Triple energizer is the sum of systemic connective tissues. It wraps around and supports the body tissues, viscera and cells, and sustains the basic upright posture of the human body, whose network is essential to human health. New definition reasonably unifies its anatomy and integrated functions. Thus, we have unraveled, for the first time, the medical mystery on the triple energizer of perplexing human beings. In a clear understanding of the basis of triple energizer, we have solved big issue of meridians (Jingluo, 经络). As pericardium belongs to the triple energizer system, not a separate viscus. Pancreas plays the role of Jueyin meridian. The hand Jueyin pancreas and hand Shaoyang triple energizer meridians are a pair of Yin and Yang related meridians involved in the formation of the twelve meridians. These primitive findings will contribute to the progress of human medicine.

IntroductionUpper respiratory tract diseases and colds in the first place (common cold) are considered trivial diseases, which, almost inevitably, are encountered seasonally in winter/cold periods.In most cases, they run benevolently, with self-resolution in five to seven days.However, serious complications may be present, especially in elderly or chronically ill subjects; or there may be viral variants of greater aggression (SARS-CoV; MERS-CoV; SARS-CoV-2)However, even if only considering the most cases, i.e. those with a benevolent course, the social and economic impact is remarkable.

The deployment of artesunate for severe malaria and the artemisinin combination therapies (ACTs) for uncomplicated malaria has been a major advance in antimalarial therapeutics. These drugs have reduced treated mortality, accelerated recovery, and reduced treatment failure rates and transmission from the treated infection. These drugs remain highly effective against falciparum malaria in most malaria endemic areas but significant resistance has emerged in the Greater Mekong subregion of Southeast Asia. Resistance to artemisinin was followed by resistance in the ACT partner drugs, and fit multidrug resistant parasite lineages have now spread widely across the region. ACTs are highly effective against P. vivax and the other malaria species. Recent studies show that radical curative regimens of primaquine (to prevent relapse) can be shortened to seven days, and that the newly introduced single dose tafenoquine is an alternative, although the currently recommended dose is insufficient in Southeast Asia and Oceania. Targeted malaria elimination using focal mass treatments with dihydroartemisinin-piperaquine have proved safe and effective malaria elimination accelerators, but progress overall towards malaria elimination is very slow. Indeed since 2015 overall malaria case numbers globally have risen.

Using Andrews’ multi-series generaliazation of Watson’s $_8\phi_7$ transformation, we give a new extension of the (H.2) supercongruence of Van Hamme for primes $p\equiv 3\pmod{4}$, as well as its $q$-analogue. Meanwhile, applying the method of ‘creative microscoping’, recently introduced by the author and Zudilin, we establish some further $q$-supercongruences modulo $\Phi_n(q)^3$, where $\Phi_n(q)$ denotes the $n$-th cyclotomic polynomial in $q$.

The present paper is devoted to study the space identification problem for the elliptic-telegraph differential equation in Hilbert spaces with the self-adjoint positive definite operator. The main theorem on the stability of the space identification problem for the elliptictelegraph differential equation is proved. In applications, theorems on the stability of three source identification problems for one dimensional with nonlocal conditions and multidimensional elliptic-telegraph differential equations are established.

In that paper, firstly we get two additional different non-null space curve evolutions in Minkowski 3-space by considering Landau-Lifshitz (LL-) equation where we identify the spin vector with the binormal vector and the normal vector of these curves, respectively. Then, we obtain some links for constructing the moving non-null space curves by using the integrable LL- equation. Finally, we give as an application, the exact solution of the moving non-null curve evolutions obtained by taking the spin vector the normal vector of the curve and we showed graphically that these solutions are wave solutions.

We prove the existence, multiplicity and nonexistence of positive radial solutions to the following p-Laplacian equations $$ \left \{ \begin{array}{l} -\triangle_p z_1=g_1(|x|,z_1,z_2,a,b) \ \ \text{in} \ \Omega,\\ -\triangle_p z_2=g_2(|x|,z_1,z_2,a,b) \ \ \text{in} \ \Omega,\\ (z_1, z_2) \rightarrow (0,0)\ \ as\ \ |x|\rightarrow \infty,\\ \frac{\partial z_1}{\partial n} =\frac{\partial z_2}{\partial n}= 0\ \ \text{on}\ \ |x|=r_0, \end{array} \right. $$ where $\triangle_p u=\text{div}({|\nabla u|}^{p-2}\nabla u),\ 1r_0>0\}$.

In this paper, an asynchronous periodic sampling consensus method is proposed for second-order continuous-time multi-agent systems with event-triggered mechanism. Stochastic matrix theory is employed successfully to analyze the consensus of the closed-loop multi-agent systems. By appropriately choosing parameters of the proposed consensus control protocol, it is proved that states of all agents can reach consensus and the Zeno behaviour is excluded if the topology graph contains a directed spanning tree. Finally, a numerical simulation example is given to illustrate the advantages of the asynchronous periodic sampling consensus method.

We considered an incompressible fluid-saturated porous layer bounded by two infinite parallel plates. Boussinesq approximation and Darcy’s law are applied. The permeability is assumed to be a linear function of the depth $z$. The linear stability is investigated. The long wavelength expansion method is applied to conduct the weakly nonlinear stability analysis. The evolution equation is derived and analyzed. A uniformly valid periodic solution of the evolution equation is obtained by the application of Poincar\’e-Lindstedt method. Some numerical simulations is presented.

Unsteady flow of Casson fluid past through a vertical channel has been studied by some researchers due to its importance applications in science and technology. Therefore, the main purpose of this paper is to obtain exact solutions for unsteady free convection flows of Casson fluid with effects of magnetohydrodynamics (MHD) past through vertical channel. Dimensional governing equations are converted into dimensionless forms by using appropriate dimensionless variables. Dimensionless parameters are obtained through dimensionless process such as Casson fluid, time, Prandtl number, Grashof number and magnetic field. Laplace transform method is used to solve the dimensionless equations with associated initial and boundary conditions. Solutions for velocity and temperature profiles are obtained. Skin friction and Nusselt number are also calculated. The obtained analytical results for velocity and temperature are plotted graphically to discuss the influence of dimensionless parameters on profiles. It is observed that fluid velocity increases with increases of Grashof number, Gr and time, t whereas it decreases with increases of Casson parameter, γ, magnetic field parameter, M and Prandtl number, Pr. Besides that, it is found that temperature profiles decrease with high value of Prandtl number, Pr while increases with high value of time, t. In order to validate the results, the obtained results in limiting cases are compared with the published results and it is found to be in a mutual agreement.