Bosutinib is approved as first line therapy for treatment of chronic phase CML and also in patients who are either resistant or intolerant to previous TKI. We present a 59 year old male who was intolerant to 2 TKI but showed excellent hematological and major molecular response to Bosutinib.

So, we could answer the question “What did God promise Abraham?” by giving a brief response: God promised Abraham a land (Gen. 12:1);a nation (Gen. 22:17-18); anda blessing to the world (Gen. 17:6).The answer would be correct but incomplete. Indeed, the tripartite answer is technically true but contextually deficient. The aim of this article is not only to answer the question in its most reduced format, but to do so within the larger biblical context. That context of God’s plan of salvation enriches and strengthens the answer to the question, "What did God promise Abraham?"We will answer the question by examining the framework for the Abrahamic Covenant (and all the covenants in the Bible) in the Word of God.A Framework for the Abrahamic CovenantThe answer to the question must begin with the larger worldview that is at work throughout the entire Bible. That worldview, or paradigm of faith, is grounded in pre-Creation covenant between the Triune God, proclaimed at Creation, promised at the Fall, and, consequently, worked out in space and time from the Fall to the coming of Jesus Christ, and, from His life lived for us and his death for our sins, to the Second Coming, the Final Judgement, and a New Heaven and New Earth. The terms of the Covenant are, thus, extended to all who will call on the name of the Lord.This cosmic paradigm of God’s promises—His covenant to restore Eden by His own righteousness and His own sacrifice—is the scarlet thread of Scripture.The Scarlet Thread of ScriptureThe Holy Bible is one sweeping epic that extends from eternity past to eternity future. That the single story of Creation, Fall, Redemption, and Consummation is communicated by men called by God and filled with the Holy Spirit, in 66 books, with near forty authors, and thousands of years, is a phenomenal testimony to Scripture’s self-evidence of its inerrancy and infallibility. The celebrated English Puritan poet and public intellectual, John Milton (1608-1674), divided the entire plan of salvation revealed in Scripture into two titles: "Paradise Lost (1667)," and "Paradise Regained (1671)." One could hardly imagine any greater and more brilliant observation of the entire story of Scripture. However, the division of the plan of God by those two titles (and Milton’s remarkable theological treatise in free verse) is only surpassed by the eponymous division the Church has assigned the Old Covenant and the New Covenant, i.e., the Old Testament and the New Testament. Since the title of this article is, "What did God Promise Abraham?" one may be justified in asking, "Pray tell me, what does your introductory statement on the larger message of Scripture have to do with the more single-minded story of God's promises to Abraham? I quite understand your possible frustration. However, I would respond that my introduction about the unity of the entire Bible with its notable division—whether John Milton's epic titles or the Churches familiar designations—has everything to do with the title of this piece. For every leaf in the book of life is sewn together by a single scarlet thread: the covenant promises of God. That promise of God in Genesis 3:15 is the divinely revealed anchor agreement, or "covenant," from which all the other covenants find their meaning, including the Abrahamic Covenant. After the act of disobedience by Adam and Eve, the One God in Three Persons announces both a curse and a promise of redemption in what has been called "the first evangel.”The First Gospel“And I will put enmity between you and the woman, and between your seed and her Seed; He shall bruise your head, and you shall bruise His heel” (Genesis 3:15).There is much to say about this one passage: God's message is directed to Satan who instigated the Fall; and to woman, who first ate of the forbidden fruit, and a reference to the “seed of the woman”—an enigmatic phrase at its biological essence – combined with the promise of a Redeemer, born of woman without reference to the male, who crushes the head of Satan. This Redeemer’s mission of salvation—of humanity and all Creation—is realized at the deadly price of a viperous wound. Yet, we must leave this passage as it is, except to say that this is, indeed, the fountainhead from which we will discover the unconstrained response to the question, "What did God promise Abraham?"The Covenant of Works and the Covenant of GraceMankind was created and placed into a conditional relationship with God that is rightly called, "The Covenant of Works." In this holy arrangement, Almighty God requires perfect obedience and undivided loyalty. He is God, after all. In return, the Lord offers life and life eternal. The penalty for breaking God’s law—a veritable cosmic rebellion—is death. Mercifully, death is not (necessarily) immediate, but is, by this stage, a “monster inside me,” to borrow the title of a popular real-life show about larva, snails, and man-eating crustaceans lodged in parts of the human body. Its not a very pleasant mental image, I admit. Neither is death from the inside out. Nevertheless, our loving heavenly Father proclaims another way: what theologians call "The Covenant of Grace." By the way, these covenant phrases are not theological archetypes forced upon the Scriptures, but, are, rather, clear concepts derived directly from the Holy Text. In this God• Initiated arrangement, born out of Adam and Eve’s disobedience, and the Lord’s plan to enjoy fellowship with His Creation, God promises to do for them (us) what they (we) could not do for themselves (ourselves). God will keep the law perfectly. He will take the punishment for sin. Like our first parents, we are each born into a covenant of works. Yet, none of us can maintain complete obedience to God. Those who believe they can work their way to God are foolishly wagering that their own supposed holiness can provide a perfection of life that the Lord requires. The assume the punishment for our sins. The tragic end of such delusional spiritual bravado will be death and hell. God provides what we are incapable of doing (and being): we are invited to come to the Lord and to plead for his forgiveness and to receive the gift of his grace.So, this is the framework through which we access the truth of the Abrahamic Covenant and, in doing so, answer the question, “What did God promise Abraham?”The Abrahamic CovenantFirstly, the Abrahamic covenant is but one of several covenants in the Bible. These promises—flowing from that one great Promise in Genesis 3:15—are progressive revelations of God’s intent. The single. most important book on the centrality of covenants in Scripture, divine promises, if you prefer, is the, now, classic work of Dr. O. Palmer Robertson: Christ of the Covenants (1980).  “The primary covenants in Scripture are those made with Noah, Abraham, Moses, David, and the new covenant [The Lord Jesus at Communion]. In addition, strong evidence favors viewing the original creation relationship between God and man, as well as the first bond established by God with man after the fall, as covenantal.”    \cite{robertson1980}Secondly, whilst the Abrahamic Covenant is but one of (at least) seven divine promises from God to Mankind, the Abrahamic covenant is remarkable. It is remarkable in its disclosure of how God will move from an otherwise insignificant band of Semitic peoples, to a land in turmoil, to a nation, to a spiritual realization of the covenant that will bring forth the Messiah, and descendants of Abraham that include the entire world. It is remarkable in that the covenant begins with a grand vision, is, first, realized in a small nation, small piece of land, and a loss of that land because of sin. Thus, some have conceived of the Abrahamic Covenant’s as an hourglass. It goes from the large vision to a tiny dot on the earth and, through Jesus, to the ends of the earth. The covenant was never to be limited to merely a piece of ground, or to one nation. How did Isaiah put it? “He says: ‘It is too light a thing that you should be my servant to raise up the tribes of Jacob and to bring back the preserved of Israel; I will make you as a light for the nations, that my salvation may reach to the end of the earth.’”God’s Promises to AbrahamUsing an expository statement for each covenantal promise to Abraham, as contributed by Rev. Charles Haynes, Jr., here are the covenantal promises of God to Abram (he was not yet Abraham):• I will show you where to go.• I will make you into a great nation.• I will bless you.• I will make your name great.• I will make you a blessing to others.• I will bless those who bless you.• I will curse those who curse you.• I will bless all the people on earth through you. The New Covenant InterpretationThe Abrahamic Covenant was about God separating out a man, Abraham, and his wife, Sarah—a new Adam and Eve, with the supernatural manifestation of birth from sterility, as miraculous as creating the world is six days—and bringing them to a land. The covenant was about God’s sovereign selection of a man and wife to bring forth a line that would bring forth a Messiah who would bless the world.Indeed, except for a small dot of light in Israel, and not all of Israel believing, God brought forth the promise to Abraham (and to the other Covenants): our Lord and Savior Jesus Christ. Those who believed did so against the backdrop of Roman occupation, religious corruption, and the constant threat of persecution. Surely many wondered whether the sared covenant to Abraham would be ever be realized. Yet, the faithful ones, like Simeon, like Anna, clung to the promise of God:“Behold, the days are coming, declares the Lord, when I will make a new covenant with the house of Israel and the house of Judah, not like the covenant that I made with their fathers on the day when I took them by the hand to bring them out of the land of Egypt, my covenant that they broke,… For this is the covenant that I will make with the house of Israel after those days, declares the Lord: I will put my law within them, and I will write it on their hearts. And I will be their God, and they shall be my people. And no longer shall each one teach his neighbor and each his brother, saying, ‘Know the Lord,’ for they shall all know me, from the least of them to the greatest, declares the Lord. For I will forgive their iniquity, and I will remember their sin no more” (Jeremiah 31:31-34 ESV).Jesus proclaimed that covenant fulfillment when he became the life-giving signs of salvation at the Last Supper: “And he took bread, and when he had given thanks, he broke it and gave it to them, saying, "This is my body, which is given for you. Do this in remembrance of me." And likewise, the cup after they had eaten, saying, "This cup that is poured out for you is the new covenant in my blood” (Luke 22:19-20).Who are Abraham’s Children?The Apostle Paul, who would always pray for the ethnic children on Abraham, declared: “Know then that it is those of faith who are the sons of Abraham. 8 And the Scripture, foreseeing that God would justify the Gentiles by faith, preached the gospel beforehand to Abraham, saying, “In you shall all the nations be blessed.” 9 So then, those who are of faith are blessed along with Abraham, the man of faith” (Galatians 3:7-9);  “If you are Christ’s, then you are Abraham’s offspring, heirs according to promise” (Galatians 3:29).When God made His covenant with Abraham, He inaugurated a physical line through Isaac, the son of Sarah and Abraham. This was done so that the origin was spiritual, miraculous, and incapable of being traced to anything of merely Man. The Abraham Covenant, which at first seemed global, and eternal, seemed to become quite narrow (remember the hourglass illustration), until the birth of our Lord Jesus Christ. Through His life, death, resurrection, and ascension, and present rule from heaven, the hourglass widened. By our Savior’s ascension, the Gospel began to spread. By the time of the death of the last Apostle to die, John in Ephesus, the Gospel of Jesus Christ had gone from Europe to India, from Africa to Asia. The Gospel is a centrifugal force. The family of God is growing as billions of human beings have become the children of Abraham. They are from every tribe, tongue, and nation. The Old Covenant is fulfilled in Jesus. The New Covenant is underway.What did God promise Abraham? If you will trust in Jesus Christ, the greater Son of Abraham, who became the living Mediator of the Covenant of Grace—He lived the life you could not; and He died the death that should have been yours—you will become the living answer to the promise. For you will be not just a child of Abraham. You will be a child of God.BibliographyClarence L. Haynes, Jr. 2021. “5 Things to Know about God’s Promise to Abraham.” Crosswalk.Com. April 9, 2021. https://www.crosswalk.com/faith/bible-study/things-to-know-about-gods-promise-to-abraham.html.Milton, John. 2012. Paradise Regained, Samson Agonistes, and the Complete Shorter Poems. Modern Library.Milton, John, and Judith Boss. 1997. Paradise Lost (1667). RS Bear.Robertson, O. Palmer. 1980. The Christ of the Covenants. Baker Book House.“Westminster Confession of Faith: The 1647 Edition.” 2013. July 13, 2013. http://www.covenantofgrace.com/westminster_confession.htm. 

Objectives: Pleuropulmonary blastoma (PPB) is a very rare, characteristic and highly aggressive neoplasm occurring in children, most under 6 years of age. We assessed the clinical characteristics, treatment modalities, treatment outcomes, and prognostic factors affecting survival in patients with PPB treated at our institution over a 10-year period to improve the prognosis of PPB. Methods: From November 2008 to November 2019, 31 children (21 boys and 10 girls) with a median age of 30 months (range, 22 days-54 months) were treated at our institution. Here, we describe the patient characteristics, treatment modalities and treatment outcomes. The Kaplan-Meier method was used to estimate the progression free survival probability (PFS) and overall survival (OS). Log-rank test was performed for comparison between groups. Results: 3 children were lost to follow-up and 2 were dead of postoperative complications. Of the 26 patients included in the follow-up, 16 PPB patients displayed tumor-free survival. The 6-month, 1-, 3-, and 5-year PFS were 80.8%, 69.0%, 60.4% and 60.4%, respectively. Accordingly, the 6-month, 1-, 3-, and 5-year OS were 84.6%, 72.7%, 60.1% and 60.1%, respectively. Sex, extent of surgery and chemotherapy/irradiation appeared to affect the survival, while age and pathology type appeared not to do. Conclusions: PPB is an aggressive neoplasm. To improve the prognosis of PPB, we should promote radical resection and improve the auxiliary treatment measures.

Aim: This study aims to assess the admission times, manual detorsion rates and outcomes of the testicular torsion cases during COVID-19 pandemic. Methods: A retrospective analysis of the testicular torsion cases was done through our hospital’s electronic archive. Patients with were distributed into two groups as “COVID-19 era” (between 11th of March 2020 – March 2021) and “pre-COVID-19 era” (between January 2018 and 10th of March 2020). Time between the onset of symptoms and the moment of detorsion was calculated as the duration of ischemia. Two groups were compared in terms of ischemia duration, manual detorsion rates and operational outcomes. Results: No statistically significant differences was detected between groups in terms of ischemia duration, manual detorsion rates and surgical procedure type (all p>0.05). During the COVID-19 pandemic, the number and percentage of manual detorsions have increased, resulting in a numerical decrease in orchiectomies. Conclusions: Conditions caused by COVID-19 may prompt urologists to manual detorsion more to set up safer surgical environment. Moreover, this approach may result in a decrease in orchiectomy rates by saving time and preserving the vascularity of the testis. Further studies with larger samples sizes and meta-analyses may support this concept. Keywords: testicular torsion, COVID-19, manual detorsion, orchiectomy, emergency

This work provides an analytical approach to characterize and determine solutions to a porous medium system of equations with views in applications to invasive-invaded biological dynamics. Firstly, the existence and uniqueness of solutions are proved. Afterwards, profiles of solutions are obtained making use of the selfsimilar structure that permits to show the existence of a diffusive front. The solutions are then studied within the Travelling Waves (TW) domain showing the existence of potential and exponential profiles in the stable connection that converges to the stationary solutions in which the invasive specie predominates. The TW profiles are shown to exist based on the geometry perturbation theory together with an analytical-topological argument in the phase plane. The finding of an exponential decaying rate (related with the advection and diffusion parameters) in the invaded specie TW is not trivial in the non-linear diffusion case and reflects the existence of a TW trajectory governed by the invaded specie runaway (in the direction of the advection) and the diffusion (acting along a finite speed front or support).

Barekot rural municipality of Jajarkot district is an Important Bird Areas (IBAs) in Western Nepal. In recent years, illegal hunting and trapping-related cases have increased in this area. Additionally, a hydropower project with a capacity of 410 MW is being constructed within Barekot. The present study aims to update the preliminary checklist of birds and identify the underlying threats to the bird population in this region. Bird survey was conducted in four monitoring blocks of Barekot during the late winter of 2021. Also, a series of consultation meetings and interviews with the local stakeholders were organized to collect information regarding the extant threats. This study revealed eighty-seven bird species of 10 orders and 34 families. Birds most commonly recorded from the family Muscicapidae and order Passeriformes. Among the total recorded species, two species are listed in the IUCN Red List of Nationally Vulnerable Category. Similarly, five species were listed on CITES Appendix II and one species on CITES Appendix I. Approximately 82% of total bird species were of resident type. Despite a decline in bird diversity, Barekot’s unique geographical location still makes it an important IBA in Nepal. Bird numbers have plummeted due to human intrusion and disturbance, and natural system modifications. Based on our findings, we recommend landscape-level research, on the impacts of hydropower projects, roads, poaching, and impacts of the Covid-19 pandemic. Similarly, future conservation efforts should also emphasize preventing habitat fragmentation and raising public awareness. Keywords: Avian community; Bird checklist; Important Bird Area; Threats

Phase transitions between ordered and disordered states of interactive agents have been recognized as integral to dynamics in a range of economic and social processes. Several theorists in the study of financial markets have directly linked phase transitions between disordered and ordered states of agents to a critical point in the dynamics of market price. To date, phase transitions in the dynamics of price in financial markets have been demonstrated with numerical methods. In an application to a financial market, we propose a multicomponent in which a first component is in bounded rationality and a second component is in behavior that generates herding in financial markets. A transition function defines the relative weight of components. We extend conditions of Onsager (1944) for phase transitions in a 2D Ising model and analytically demonstrate that the proposed model evidences phase transitions. Generalizations of the results to other multi-component models are noted.

Objective: This study aimed to determine the duration of hospital admission of the panic diagnosed patients in surgical pathology, examine the factors that may influence hospital admission time, and identify the impact of the COVID-19 pandemic on hospital admission time. Methods: The panic diagnosed patients in surgical pathology between January 2018 and January 2021 were determined. These patients' demographic, clinical, and critical diagnostic form data were documented. The duration of hospital admission of patients during and pre-COVID-19 pandemic period was determined. Results: There were 65 panic diagnosed cases in surgical pathology, of which one patient had leukocytoclastic vasculitis, 10 patients had uterine contents without villi or trophoblasts, and 54 patients had unexpected malignancy. The mean time of admission to the hospital of verbally informed and not verbally informed cases were five days and 156 days, respectively, in the pre-COVID-19 group. All cases in the COVID-19 pandemic group were verbally informed about critical diagnosis and the mean time of admission to the hospital was 18 days (1-40). Admission times were on mean about 13 days longer in verbally informed cases in the COVID-19 pandemic group compared to verbally informed cases in the pre-COVID-19 group. Conclusions: We determined a dramatic decrease in the number of panic diagnosed cases in surgical pathology during the COVID-19 pandemic and patients who are verbally informed admitted to the hospital in a shorter time. The integration of panic diagnosis notification systems to health applications and primary responsible family physician's systems may be useful for preventing unwanted delays.

Background: This study aimed to investigate the risk factors for smoking and negative perinatal outcomes among Jordanian women about smoking status. Methods: A case-control study was conducted among singleton full-term pregnant women who gave birth at the main hospital in Jordan in June 2020. They were divided into three groups according to their smoking status (active, passive and non-smokers) and were interviewed using a semi-structured questionnaire, including demographic information, current pregnancy history, perinatal and neonatal outcomes. The study investigated the effect of smoking status on both independent and dependent variables. Results: Our study revealed that low-level maternal education (OR=25.38), unemployed maternal status (OR=2.67), the absence of following up during pregnancy (OR=5.8), smoking husband were risk factors for smoke exposure among pregnant women. The risk for cesarean section was increased in nulliparous smoking women (OR=9.0), those with low family monthly income (OR=7.8), and those who did not get any information about the hazard effect of smoking (OR=4.38), as well as in unemployed passive smoking women (OR=6.25). Parity of more than one has raised the risk of NICU admission inactive smoking women (OR=10.38). This risk was also increased in active and passive women with a lower level of education (OR=186.33 and OR=17.5), respectively, as well as inactive smoking women with low family monthly income (OR=4.11). Conclusions: Appropriate preventive strategies should focus on modifiable risk factors for smoking during pregnancy.

INTRODUCTION: Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory disease. Previous studies confirmed that inflammation plays an important role and red blood cell distribution width (RDW) is related to the activity of IBD. OBJECTIVES: To identify the prognosis value of RDW in the intestinal resection of IBD. PATIENTS AND METHODS: A total of 366 patients were included in this retrospective analysis, diagnosed with IBD between March 2012 and November 2014 in the Sixth Affiliated Hospital of Sun Yat-Sen University. All participants were followed up at least 5years. Patients’ demographic characteristics and laboratory data were obtained from medical record within 24h at first hospitalization. We compared the clinical features in the intestinal resection and non-intestinal resection groups. Kaplan–Meier estimates of the probability of intestinal resection post-admission time were computed, and compared with log-rank test according to stratification of RDW value. RESULTS: There were 93 patients in the intestinal resection group and 273 in the non- intestinal resection group. Significant higher RDW values were detected in the intestinal resection group (P<0.001). RDW was obviously related to indicators such as C-reactive protein (p=0.008). Univariate Cox regression analysis demonstrated that IBD type (Crohn’s disease or ulcerative colitis) (P<0.001), RDW (P<0.001), C-reactive protein (P<0.001) and others were associated with intestinal resection probability. But only RDW [OR: 1.088 (95% CI 1.009-1.173), P=0.03] and IBD type (P=0.001) were independent predictors. CONCLUSIONS: RDW and IBD type were independent predictors of intestinal resection in IBD. KEY WORDS: inflammatory bowel disease, intestinal resection, red blood cell distribution width

Clinical genetic sequencing tests often identify variants of uncertain significance (VUS). One source of data that can help classify the pothogenicity of variants is familial cosegregation analysis. Identifying and genotyping relatives for cosegregation analysis can be time consuming and costly. We propose an algorithm that describes a single measure of expected variant information gain from genotyping a single additional relative in a family. Then we explore the performance of this algorithm by comparing actual recruitment strategies used in 35 families who had pursued cosegregation analysis with synthetic pedigrees of possible testing outcomes if the families had pursued an optimized testing strategy instead. For each actual and synthetic pedigree, we calculated the likelihood ratio of pathogenicity as each successive test was added to the pedigree. We analyzed the differences in cosegregation likelihood ratio over time resulting from actual versus optimized testing approaches. Employing the testing strategy indicated by the algorithm would have led to maximal information more rapidly in 30 of the 35 pedigrees (86%). Many clinical and research laboratories are involved in targeted cosegregation analysis. The algorithm we present can facilitate a data driven approach to optimal relative recruitment and genotyping for cosegregation analysis and more efficient variant classification.

Objectives The aim of this study was to compare patient reported pain scores and analgesia requirements between endoscopic and microscopic ear surgery. Design Prospective cohort study Setting Secondary care setting from June 2017 to December 2020. Participants Patients undergoing ear surgery performed by a single surgeon. Main outcome measures The primary outcome measure was patient reported pain as recorded by a visual analogue scale (VAS) at days 1,2,3 and 7 post-operatively. Secondary outcome measure was post-operative analgesia requirement. Results Overall, forty-nine patients encompassing 65.3 % (32/49) endoscopic and 34.7% (17/49) microscopic procedures were audited. Endoscopic procedures have statistically significant lower VAS pain threshold outcomes when compared against the microscopic procedures on post- operative day one (endoscopic group median VAS 1.5 [0.00;11.5] mm versus microscopic group median VAS 27.0 [15.0;65.0] mm); to day seven (endoscopic group median VAS 0.5 [0.00;2.75] mm versus microscopic group median VAS 9.00 [2.00;52.0] mm).  Requirement for analgesia was greater in the microscopic group at day one compared to the endoscopic group (64.5 %, 20/31 endoscopic group vs. 100 %, 17/17 microscopic; p= 0.004). Conclusion Endoscopic ear surgery is less painful and requires less analgesia in the initial post-operative period than microscopic surgery in this cohort. The overall results of this study are useful for pre-operative patient counselling and pain management in the clinical setting. Given the differing applications of microscopic and endoscopic ear surgery, further research is required to study the influence of bone removal, type of operation, and incision type on pain after ear surgery.

Background: The impact of tinnitus on significant others (SOs) is largely unknown. Objectives: The study aims included investigating third-party disability in a sample of SOs of individuals with tinnitus and to investigate factors associated with third-party disability. Design: The study used a cross-sectional survey design. Setting: The study was undertaken online Participants: Individuals with tinnitus together with their SOs completed questionnaires online. Outcome measures: The SO sample completed the newly developed Consequences of Tinnitus on Significant Others Questionnaire (CTSOQ). Individuals with tinnitus completed standardized self-reported outcome measures for tinnitus severity, anxiety, depression, insomnia, hearing related quality of life, tinnitus cognitions, hearing disability and hyperacusis to identify any associations between these scores and those of the significant others. Results: A total of 194 pairs of individuals with tinnitus and their SOs that participated, with a mean age of 57 and 56 years, respectively. The CTSOQ showed that 37 (19%) of SOs had mild impact, 58 (29%) had significant impact, and 101 (52%) had severe impact. The clinical variables of tinnitus severity, anxiety and hyperacusis in individuals with tinnitus were the best predictors of the impact of tinnitus on SOs. Conclusions: This study indicates that SOs of individuals with tinnitus may experience third-party disability. The effect of the individual’s tinnitus on SOs may be greater when the individual with tinnitus has greater tinnitus severity, anxiety and hyperacusis. Ways of mitigating these effects should be prioritized such as involving them in the tinnitus management process.

AbstractNano-junctions between the endoplasmic reticulum and the cytoplasmic surfaces of the plasma membrane and other organelles shape the spatiotemporal features of biological Ca2+ signals. Herein we propose that 2D Ca2+ exchange-diffusion on the negatively charged phospholipid surface lining the nano-junctions participates in guiding Ca2+ from its source (channel or carrier) to its target (transport protein or enzyme). Evidence provided by in vitro Ca2+ flux experiments using an artificial phospholipid membrane is presented in support of the above  proposed concept, and results from stochastic simulations of Ca2+ trajectories within nano-junctions are discussed to substantiate its possible requirements. Finally, we analyze recent literature on Ca2+ lipid interactions, which suggest that 2D interfacial Ca2+ diffusion may represent an important mechanism of signal transduction in other biological systems characterized by high phospholipid surface-to-aqueous volume ratios.IntroductionAll rapid functions in the body are selectively regulated by the universal biological messenger: ionic calcium (Ca2+). For this single ionic messenger to harmoniously control such a great range of biological mechanisms, it is crucial that its signals are delivered with pinpoint precision and millisecond  timing. The endoplasmic reticulum (ER) is the main organelle that orchestrates  this essential spatiotemporal precision of Ca2+ signalling via numerous different close contact sites or nano-junctions (NJ) with the plasma membrane (PM), mitochondria, lysosomes and other organelles \cite{23339179}. NJs have been defined as cytoplasmic sub-compartments where membranes of different organelles appose each other within the nano-metre scale. Typically the limiting membranes are separated by 20 nm or less and the specialized signalling function has been shown to fail at separation distances greater than 50 nm \cite{15541459,17418403,Pritchard2019}. The main function of the NJs in cells is to precisely localize the Ca2+ signals to specific Ca2+ sensors positioned within organellar membrane or PM domains, while bypassing the bulk cytoplasm. For example, refilling of the sarcoplasmic reticulum (SR) of vascular smooth muscle cells, in order to maintain asynchronous [Ca2+]cyt oscillations, is achieved by coupling Ca2+ entry via Ca2+-influx-mode NCX (rNCX) to SERCA at PM-SR NJs, thus bypassing the bulk cytoplasm \cite{Lee2002}. Employing stochastic particle simulator modelling software and using known NCX and SERCA turnover rates and surface densities, it was possible to generate a computational model of this cellular signalling process, which demonstrated that the rate of Ca2+ entry via rNCX/SERCA was indeed sufficient for replacing the Ca2+ released by periodic opening and closing of IP3Rs during the activation of asynchronous cytoplasmic Ca2+ waves that stimulate contraction \cite{17418403}. However, to generate plausible predictions by our computational model, it was necessary to implement a Ca2+ target size on SERCA of approximately 20 nm2, which is 2500 times larger than the area occupied by the dehydrated Ca2+ with a diameter of 1 Å. Assuming that short range local electrostatic forces of attraction between the fixed negatively charged binding sites on the SERCA macromolecule and the positively charged Ca2+ would increase the effective target size to an area several times larger than the size of the non-hydrated Ca2+, it would still be orders of magnitude smaller than 20 nm2. Therefore, in order to achieve effective functional transfer of Ca2+ from NCX on the PM to SERCA on the SR, it appears that an additional, as yet ignored, mechanism is operative to support the linkage between Ca2+ signalling elements (sources and sinks) within NJs, besides the proximity of the PM and SR in these regions. To this end, all available computational modelling data prompt us to conclude that, by itself, a 3D random walk of the Ca2+ between their sources and sinks on the two closely apposing membrane surfaces may be insufficient for efficient NJ Ca2+signalling. We thus propose that, in addition, 2D exchange diffusion of Ca2+ on the targeted surface of the NJ has the potential to increase the efficiency of Ca2+ reaching its target.BackgroundIt is well established that Ca2+ can move rapidly through negatively charged solid lattices, such as fluorapatite, by the process of exchange diffusion \cite{Jay_2011}. An analogous model, featuring negatively charged phospholipids (PLs), has been described some time ago \cite{TOBIAS1962,5723329,5803390}. This experimental model consists of a millipore filter impregnated with a mixture of phospholipids of animal origin, separating two aqueous phases and exhibits properties that are highly relevant to the topic of Ca2+ movements through narrow aqueous passages lined by PLs. Its salient feature is that it supports net transfer of Ca2+ through relatively long PL lined pores at a much faster rate than would be possible for free diffusion within the limited adjoining aqueous phase. The mechanism that was presented to explain Ca2+ transport through this solid ion exchange membrane involves the association of Ca2+ with a negatively charged phosphate or carboxyl group of the PL surface on the cis-side of the membrane, followed by transfer of Ca2+ within a 2-dimensional matrix of similar sites, constituted by the pore-lining PL layers, and a final step of dissociation of Ca2+ from the negatively charged PL head groups on the trans-side of the membrane. The rate of this PL-mediated transport of radioactive labeled Ca2+ through the membrane was decreased by removal of Ca2+ from the buffered solution on the trans-side of the membrane. Paradoxically, further removal of remaining Ca2+ from the trans-solution by the addition of the soluble, but non-permeant chelator EDTA, increased the rate of PL-mediated net Ca2+ transport across the PL lined millipore filter by more than one order of magnitude. The mechanism proposed to explain the latter observation is that dissociation of Ca2+ from PL head groups on the trans-side of the membrane is rate-limiting and addition of a freely diffusible, impermeant Ca2+ binding site on EDTA, to the trans-side of the flux chamber facilitates the dissociation of PL bound Ca2+. Once the Ca2+ transported from the cis-side of the flux chamber has been chelated by EDTA, which is dissolved in a large volume of buffered solution on the trans-side, it cannot rebind to the PL membrane, but is replaced by the next Ca2+arriving from the cis-side.  In this model system, electro-neutrality is preserved by the movement of Mg2+ and monovalent cations in the opposite direction. The mechanism envisioned for the transfer of Ca2+ from the PL membrane to EDTA involves an intermediary step of partial dissociation from the negative PL site and simultaneous association with a carboxyl group of EDTA. We propose herein, that a similar mechanism is involved in the transfer of Ca2+ bound to PL head-groups of the membranes lining the NJ to its biological target site on the Ca2+-receptor protein.Model DescriptionWhen we compare the artificial PL-mediated Ca2+ transport in the model described above with biological PL-lined nano-spaces some striking parallels become obvious. For example, rod outer segments of the bovine eye feature a 15-nm wide cytoplasmic phase between the intercalated discs, which stretch for several microns \cite{McLaughlin1981}. The lipid bilayers lining this narrow space contain 45% phosphatidylethanolamine, 36% phosphatidylcholine and 16% phosphatidylserine, calculated as percent of the total PL. At physiological pH, phosphatidylcholine and phosphatidylethanolamine are zwitterions and phosphatidylserine has one net negative charge \cite{McLaughlin1981}. In this example, it was calculated that of the Ca2+ released during stimulation, 90% to 99% was bound to the PL-head groups of membranes Iining the nano-spaces between the intercalated discs, which is similar to the high ratio of bound/free Ca2+ in the above model membrane. Although historically it has been accepted that such binding slows diffusion, due to a drastic decrease in freely diffusible Ca2+ in the aqueous phase, it is also possible that the PL-bound Ca2+ within the water-PL membrane interface of the nano-space continues its trajectory by the mechanism of 2D Ca2+ exchange diffusion. We therefore propose that the mechanism of 2D Ca2+/Mg2+, K+ exchange diffusion at the aqueous/phospholipid interfaces of NJs facilitates targeting of Ca2+ receptors located on organellar membranes and the inner PM.Returning to the example of NCX-mediated SR refilling in vascular smooth muscle, we propose that Ca2+ enters the NJ via the reverse mode of NCX located in the junctional domain of the PM. It will then perform a 3D random walk and when it hits the negatively charged PL membrane boundary of the junctional nano-space proceeds along the lipid-water interface by a series of steps of reversible binding to negatively charged oxygen molecules for some variable time before being released back into the aqueous phase to resume its 3D random walk. After a number of such cycles the Ca2+ is envisioned to hit the ER membrane surface in the proximity of its target protein, in this case SERCA, which will then be reached more effectively by 2D surface exchange diffusion than would be expected if it depended solely on 3D diffusion in the aqueous phase.

Following the 1st release of the “Emerging PV reports” , the best achievements in the performance of emerging photovoltaic devices in diverse emerging photovoltaic research subjects are summarized, as reported in peer-reviewed articles in academic journals since August 2020. Updated graphs, tables and analyses are provided with several performance parameters, e.g. power conversion efficiency, open-circuit voltage, short-circuit current density, fill factor, light utilization efficiency, and stability test energy yield. These parameters are presented as a function of the photovoltaic bandgap energy and the average visible transmittance for each technology and application, and are put into perspective using, e.g., the detailed balance efficiency limit. The 2nd instalment of the“Emerging PV reports” extends the scope towards tandem solar cells and presents the current state of the art in tandem solar cell performance for various material combinations.

Emerging technologies based on the detection of electro-magnetic energy offer promising opportunities for sampling biodiversity. We exploit their potential bye showing here how they can be used in bat point counts - a novel method to sample flying bats - to overcome shortcomings of traditional sampling methods, and to maximise sampling coverage and taxonomic resolution of this elusive taxon with minimal sampling bias. We conducted bat point counts with a sampling rig combining a thermal scope to detect bats, an ultrasound recorder to obtain echolocation calls, and a near-infrared camera to capture bat morphology. We identified bats with the first dedicated identification key combining acoustic and morphological features, and compared bat point counts to the standard bat sampling methods of mist netting and automated ultrasound recording in three oil palm plantation sites in Indonesia, over nine survey nights. Based on rarefaction and extrapolation sampling curves, we show that bat point counts were the most time-efficient and effective method for sampling the oil palm species pool. Point counts sampled species that tend to avoid nets and those that are not echolocating, and thus cannot be detected acoustically. We identified some bat sonotypes with near-infrared imagery, and bat point counts revealed strong sampling biases in previous studies using capture-based methods, suggesting similar biases in other regions might exist. While capture-based methods allow to identify bats with absolute and internal morphometry, and unattended ultrasound recorders can effectively sample echolocating bats, bat point counts are a promising, and potentially competitive new tool for sampling all flying bats without bias and observing their behavior in the wild.

Seafloor characteristics can help in the prediction of fish distribution, which is required for fisheries and conservation management. Despite this, only 5-10% of the world’s seafloor has been mapped at high resolution as it is a time-consuming and expensive process. Multibeam echo-sounders (MBES) can produce high-resolution bathymetry and a broad swath coverage of the seafloor, but require greater financial and technical resources for operation and data analysis than singlebeam echo-sounders (SBES). In contrast, SBES provide comparatively limited spatial coverage, as only a single measurement is made from directly under the vessel. Thus, producing a continuous map requires interpolation to fill gaps between transects. This study assesses the performance of demersal fish species distribution models by comparing those derived from interpolated SBES data with full-coverage MBES distribution models. A Random Forest classifier was used to model the distribution of Abalistes stellatus, Gymnocranius grandoculis, Lagocephalus sceleratus, Loxodon macrorhinus, Pristipomoides multidens and Pristipomoides typus, with depth and depth derivatives (slope, aspect, standard deviation of depth, terrain ruggedness index, mean curvature and topographic position index) as explanatory variables. The results indicated that distribution models for A. stellatus, G. grandoculis, L. sceleratus, and L. macrorhinus performed poorly for MBES and SBES data with Area Under the Receiver Operator Curves (AUC) below 0.7. Consequently, the distribution of these species could not be predicted by seafloor characteristics produced from either echo-sounder type. Distribution models for P. multidens and P. typus performed well for MBES and the SBES data with an AUC above 0.8. Depth was the most important variable explaining the distribution of P. multidens and P. typus in both MBES and SBES models. While further research is needed, this study shows that in resource-limited scenarios, SBES can produce comparable results to MBES for use in demersal fish management and conservation.

Modification of coronally advanced flap (CAF) by tunneling procedure was applied on four cases of gingival recession. Post-operative follow up, at different time breaks recorded full coverage of almost all receded root surfaces. The technique and the clinical outcome of this technique will be demonstrated in this case series report.

Objectives: To report changes in adult hospital admission rates for acute ENT infections following the introduction of Covid-19-related physical interventions such as hand washing, use of face mask and social distancing of 2-metres in the United Kingdom. Design: Retrospective cohort study comparing a one-year period after the introduction of Covid-related physical interventions (2020-21) with a one-year period before this (2019-20). Settings: 3 UK secondary care ENT departments Participants: Adult patients admitted with acute tonsillitis, peritonsillar abscess, epiglottitis, glandular fever, peri-orbital cellulitis, acute otitis media, acute mastoiditis, retropharyngeal abscess and parapharyngeal abscess. Main outcome measures: Number of adult hospital admissions Results: In total there were significantly fewer admissions for ENT infections (n=1073, 57.56%, p<0.001; RR 2.36, 95% CI [2.17, 2.56]) in the 2020-2021 period than in the 2019-2020 period. There were significant reductions in admissions for tonsillitis (64.4%; p<0.001), peritonsillar abscess (60.68%; p<0.001), epiglottitis (66.67%; p<0.001), glandular fever (38.79%; p=0.001), acute otitis media (26.85%; p=0.01) and retropharyngeal and/or parapharyngeal abscesses (45.45%; p=0.04) Conclusion: Our study demonstrates a sizeable reduction in adult admissions for ENT infections since the introduction of Covid-19-related physical interventions. There is evidence to support the use of physical interventions in the prevention of viral transmission of respiratory disease. Preventing ENT infections requiring admission through simple physical interventions could be of great benefit to the quality of life of patients and economical benefit to healthcare systems.

We derive a Bayesian model to forecast the continuation of a cumulative progression of records. We show that the model compares favourably to past least-square prediction models for records in running events. We also check the validity of the model for the case where we have access to the underlying attempts, using data from athletic events in the Olympics.

Rationale, aims and objectives The concept of patient or case complexity is relevant – and widely used – at all levels and stages of mental health service provision, but there have been few methodologically robust attempts to define this term. This study aimed to establish a consensus on factors contributing to patient complexity in adult psychological services using Delphi Methodology. Method Applied psychologists in a single urban/suburban UK National Health Service setting took part in a three-round modified Delphi study. Twenty-eight respondents in round one gave qualitative data on factors they considered when assessing complexity, which was subject to thematic analysis. Twenty-five respondents in round two rated how central/peripheral each theme was to their judgement using Likert scales. In a third round, twenty respondents addressed discrepancies and possible utilities of the emerging framework. Results Thirteen factors contributing to patient/case complexity (Active Severe/Enduring Mental Health, Current Coping/Functioning, Engagement, Forensic History, Iatrogenic Factors, Interpersonal Functioning, Neuro-Cognitive Functioning, Physical Health, Problematic Substance Use, Risk, Severity/Chronicity of Presenting Problems, Systemic and Socio-Economic Factors and Trauma) were identified with a high degree of consensus. All were rated as central to complexity. Conclusions We conclude that applied psychologists do have a shared understanding of complexity and make recommendations for further research validating, developing and applying this empirically derived framework. Keywords: psychological, complexity, definition, operationalising, framework development, clinical judgement

Objective: This study investigated maternal and fetal outcomes following warm water immersion (WWI) and/or waterbirth compared with land birth for women with moderate obstetric risk factors. Design: Prospective cohort study. Setting: Maternity hospital, Australia, 2019-2020 Population: 1665 participants, some with ‘risk factors’ for adverse perinatal outcomes requiring continuous electronic fetal monitoring (CEFM) during labour. Method: Multivariate logistical regressions were used to determine the odds of neonatal and maternal outcome measures between three groups: waterbirth, WWI and land birth Main outcome measures: Neonatal morbidity and mortality, including neonatal unit admission (NNU). Maternal clinical outcome measures, including mode of birth, perineal injury, postpartum haemorrhage, length of labour and morbidity. Results: NNU admissions for a suspected infectious condition were significantly higher in the land birth group (p=0.035). After accounting for labour duration, epidural use, previous birth mode, and labour onset, no significant difference was detected between land births and WWI/water births in the odds of NNU admission (p=0.200). No babies were admitted to NNU with signs of water inhalation or drowning. Women birthing on land had a higher mean blood loss (p=0.036) and were more likely to be febrile (2% v 0%; p=0.007); Obstetric anal sphincter injury was similar between groups. Pharmacological analgesia use was lower in the WB/WWI group (p<0.001). There was 1 cord avulsion in the waterbirth group (0.41%). Mode of birth was similar between groups (p=0.697). Conclusion: Despite moderate obstetric risk factors such as oxytocin administration and induction of labour; maternal and neonatal outcomes were similar between groups.

Thrombotic events are common during COVID-19 infection. Aspirin might be beneficial. Objective: Systematic review and meta-analysis of deaths in users and non-users of aspirin. Data sources: Pubmed Medline, Google scholar, Clinicaltrials.gov, Cochrane, to June 8, 2021, Study selection: Studies providing adjusted or matched evaluation of association of exposure to aspirin and death in COVID-19 patients were included. Data extraction and synthesis: Data were used as published, as Odds ratio, hazard ratio or relative risks and 95% CI from which log(OR) and SE were recalculated. These were entered in an inverse variance odds ratios random-effects model, using RevMan 5.4 (the Cochrane Collaboration). Main outcomes and measure: The prespecified outcome studied was death. Results: Nine studies (8 observational, one interventional) included 14989 patients exposed to aspirin and 15857 unexposed. Overall Odds Ratio of death in aspirin exposed patients in a random effects model was 0.63, 95% confidence interval [0.40-0.99], I2 94%. Using a fixed-effect model did not change much the result (0.76 [0.71-0.81], removing the Recovery trial (OR 0.43 [0.38-0.49], I271%, or the two largest studies (0.66 [0.47-0.93], I2 38%) reduced heterogeneity without materially altering the results. The funnel plot showed no evident publication bias Conclusion: this meta-analysis suggests that the use of aspirin may be associated with a lower risk of death in COVID-19. Considering the results of the Recovery Study, it would appear preferable to continue aspirin in patients who have a non-covid indication, but possibly useless to add it if they don’t.

The main protease of SARS-CoV-2 (called Mpro or 3CLpro) is essential for processing polyproteins encoded by viral RNA. Macromolecules adopt several favored conformations in solution depending on their structure and shape, determining their dynamics and function. Integrated methods combining the lowest-frequency movements obtained by Normal Mode Analysis (NMA), and the faster movements from Molecular Dynamics (MD), and data from biophysical techniques, are necessary to establish the correlation between complex structural dynamics of macromolecules and their function. In this article, we used a hybrid simulation method to sample the conformational space to characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutants, including several mutations that appear in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. Integrated Hybrid methods combining NMA and MD have been useful to study the correlation between the complex structural dynamics of macromolecules and their functioning mechanisms. Here, we applied this hybrid approach to elucidate the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro, considering their flexibility, solvent accessible surface area analyses, global movements, and catalytic dyad distance. Furthermore, some mutants showed significant changes in their structural dynamics and conformation, which could lead to distinct functional properties.