bluuebunny/crossref_metadata_2025 huggingface dataset:
The Tanino Synthesis of (-)-Glycinoeclepin A
Authors: Taber Douglass F.
Published: November 2020

(-)-Glycinoeclepin A 3 is effective at pg/mL concentrations as a hatch-stimulating agent for the soybean cyst nematode. Approaching the synthesis of 3, Keiji Tanino of Hokkaido University envisioned (Chemistry Lett. 2010, 39, 835) the convergent coupling of the allylic tosylate 2 with the bridgehead anion 1. The assembly of the fragment 2 was particularly challenging, because the synthesis would require not just the establishment of the two adjacent cyclic quaternary centers but also control of the relative configuration on the sidechain. The preparation of 1 began with the prochiral diketone 3. Enantioselective reduction of the mono enol ether 4 set the absolute configuration of 5. Iodination followed by cyclization then completed the assembly of 1. The construction of the bicyclic tosylate 2 began with m-methyl anisole 7. Following the Rubottom procedure, Birch reduction followed by mild hydrolysis gave the ketone 8. Epoxidation followed by β-elimination delivered the racemic 9, which was exposed to lipase to give, after seven days, the residual alcohol in 40% yield and high ee. The sidechain nitrile was prepared from the diol 12. Homologation gave the nitrile 14, which was equilibrated to the more stable enol ether 15. The two cyclic quaternary centers of 3 were set in a single step by the conjugate addition of the anion of 16 to the crystalline enone 11. Mild hydrolysis of 17 gave the keto aldehyde, which underwent aldol condensation to give the enone 18. The hydroboration of 19 followed by coupling of the intermediate organoborane with 20 delivered 21 with 94:6 relative diastereocontrol. Formylation of the enone 22 followed by triflation and reduction then led to 2. Altough the ketone 1 could be deprotonated with LDA, the only product observed, even at –78°C, was the derived aldol dimer. The metalated dimethylhydrazone 25, in contrast, coupled smoothly with 2 to give, after hydrolyis, the desired adduct 26. Pd-mediated carboxylation of the enol triflate followed by selective oxidative cleavage and hydrolysis then completed the synthesis of (-)-glycinoecleptin A 3.
The Boger Synthesis of (+)-Complestatin
Authors: Taber Douglass F.
Published: November 2020

(+)-Complestatin 3 shows promising activity against HIV infectivity. Dale L. Boger of Scripps/La Jolla described (J. Am. Chem. Soc. 2010, 132, 7776) an elegant multicomponent assembly of 3, the key step of which was the atropisomer-selective intramolecular Larock cyclization of 1 to 2. The preparation of 1 began with the protected phenethylamine 5, prepared by Sharpless asymmetric aminohydroxylation of the styrene 4. Conversion of 5 to the areneboronic acid followed by coupling with 6 delivered 7. Acylation led to 8, with the stage set for nitro-assisted addition-elimination, to form the first bis-aryl ether of 3. The product was a mixture of atropisomers, subsequently symmetrized to 9 by removal of the nitro group. Acylation of 9 led to 1. The role of the silyl group on the alkyne of 1 was to direct the regioselectivity of the intramolecular Larock indole synthesis. Again, two atropisomers were possible from the cyclization. Earlier model studies had suggested some preference for one over the other. As it turned out, in this case the desired atropisomer was the only one observed. It is particularly striking that the coupling was efficient even in the presence of the readily reduced and unprotected chlorophenols. The modular nature of this route to (+)-complestatin 3 will make it possible to prepare a variety of analogues. As long as only the substituents on the periphery are changed, the atropisomer selectivity in the Larock cyclization should be maintained.
The Target Product Profile and Its Uses
Authors: Tansey Michael
Published: November 2020

The decision that a new chemical entity (NCE) is a serious candidate for development entails a financial commitment that is the most important one that a pharmaceutical or biotech company can make. The next most important set of decisions is concerned with making sure that development is aimed at a rational and focused set of objectives. Ending up "somewhere else" usually means failure. The two most important activities to ensure ending up in the right place are • preparing the Target Product Profile (TPP); • managing the disparity between results and expectations: the gap analysis. Since just about every development plan has a TPP, there would seem to be nothing new to say, so why devote most of a chapter to this subject? The answer is that the ways in which TPPs are prepared and the formats in which they appear vary enormously. Few seem to be the result of an exhaustive process and, as with most planning and preparatory activities, the process is just as important as the outcome. The objective is to provide a concise, structured basis for designing a development plan that (if successfully implemented) will lead to an uncomplicated approval process and to the desired labeling and data sheets in all markets. The TPP is a summary of requirements for an optimal but realistic profile of the product. • It precisely defines the expectations for the compound, with an explanation for these expectations, so that if they are not fulfilled, a rational analysis of the continuing viability of the compound can be carried out. • It is well-researched and detailed, including competitor and commercial information, and anticipates the environment at the planned date of launch. • Although written when there is little information about the drug in question, it is based on a solid foundation of objective data and not on outlandish or wishful thinking. • It is a relatively fixed document and should only be amended when changes are based on factors that could not have been foreseen when the TPP was originally drafted, such as the introduction of a new class of drugs for the same indication or a change in the standard of care.
Distilling the Essence of the Protocol: The Protocol Synopsis
Authors: Tansey Michael
Published: November 2020

The main objective is to get the preparatory phase of the trial, especially protocol feasibility, up and running as rapidly and efficiently as possible. The protocol synopsis is the most important document for ensuring a successful trial. It comprises all the elements essential for planning and carrying out a clinical trial, and is quicker to write, easier to read, less likely to have inconsistencies, and much easier to modify than a full protocol. A protocol synopsis is usually between five and seven pages long, whereas a typical protocol can run from 60 pages (rarely fewer) to 100 pages (sometimes more). The synopsis is therefore the ideal document to use for all the early preparatory activities, as the full protocol adds no value for planning and operational purposes. A fairly typical protocol synopsis template is shown in the appendix at the end of this chapter. The first step is to get an approved draft protocol synopsis. This version of the synopsis should be as complete as possible in every respect, except for those changes that will need to be made as a result of feasibility testing. It is, in effect, the penultimate version of the core of the final protocol. It should go through as many iterations as needed until it reaches the stage at which it can be approved, pending feasibility. At this stage, all aspects relating to the objectives, design, endpoints, investigations, lab tests, and treatment and procedural schedules should be final; otherwise, doing feasibility is a waste of time. This chapter describes how to get to the approved draft protocol synopsis. There are then two more steps that will be described in detail in the following chapters. The second step is the approved protocol synopsis. The draft synopsis has been amended as needed to ensure optimal feasibility without diminishing the validity of the study and has been approved. At this stage, the protocol is, in effect, locked and ready to be implemented.
What about the Customer? The Patient’s Dilemma
Authors: Tansey Michael
Published: November 2020

Apparently no one was listening to Sir William. In a study carried out 80 years after Osler’s exhortation, physicians interrupted patients, on average, after 18 seconds (H. Beckman and R. Frankel, 1984). It is common to take for granted the very people who are essential for our continued paid employment and the success of our endeavors, namely our customers. For example, some airline staff refer to passengers as “self-loading freight” or SLF (www. pprune.org), which, though mildly amusing and certainly accurate, is hardly indicative of a warm and friendly service-focused attitude. Attitudes in the pharmaceutical business are no different. Throughout the development and marketing cycles, the emphasis is primarily on satisfying intermediaries such as regulators, opinion leaders, prescribers, and insurers. Important though these intermediaries may be, they are not the customers. Patients are the sole customers. Only patients pay for their drugs (whether directly or through insurance or taxation) and only patients consume pharmaceutical products and experience the benefits and adverse effects. Only patients decide whether or not to continue taking a drug. Put simply, if there were no patients, there would be no pharmaceutical industry. Sir William Osler was talking in the context of clinical history taking and examination, but his comment applies more broadly. Over the past 10 to 15 years, there has been slowly increasing recognition that there are virtually no aspects of development, registration, and commercialization of a drug in which listening to the patient does not improve the outcome. Guidance issued by the FDA (Guidance for Industry, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, U.S. Department of Health and Human Services, Food and Drug Administration, December 2009) has gone a long way in helping to redirect and focus the industry. The implications are broad and go beyond the traditional areas of patient input such as quality of life measures and can significantly influence trial design, approval, labeling, and reimbursement.
Symptoms, Related Brain Regions, and Diagnosis
Authors: Ahlskog J. Eric
Published: November 2020

As a prelude to the treatment chapters that follow, we need to define and describe the types of problems and symptoms encountered in DLB and PDD. The clinical picture can be quite varied: problems encountered by one person may be quite different from those encountered by another person, and symptoms that are problematic in one individual may be minimal in another. In these disorders, the Lewy neurodegenerative process potentially affects certain nervous system regions but spares others. Affected areas include thinking and memory circuits, as well as movement (motor) function and the autonomic nervous system, which regulates primary functions such as bladder, bowel, and blood pressure control. Many other brain regions, by contrast, are spared or minimally involved, such as vision and sensation. The brain and spinal cord constitute the central nervous system. The interface between the brain and spinal cord is by way of the brain stem, as shown in Figure 4.1. Thought, memory, and reasoning are primarily organized in the thick layers of cortex overlying lower brain levels. Volitional movements, such as writing, throwing, or kicking, also emanate from the cortex and integrate with circuits just below, including those in the basal ganglia, shown in Figure 4.2. The basal ganglia includes the striatum, globus pallidus, subthalamic nucleus, and substantia nigra, as illustrated in Figure 4.2. Movement information is integrated and modulated in these basal ganglia nuclei and then transmitted down the brain stem to the spinal cord. At spinal cord levels the correct sequence of muscle activation that has been programmed is accomplished. Activated nerves from appropriate regions of the spinal cord relay the signals to the proper muscles. Sensory information from the periphery (limbs) travels in the opposite direction. How are these signals transmitted? Brain cells called neurons have long, wire-like extensions that interface with other neurons, effectively making up circuits that are slightly similar to computer circuits; this is illustrated in Figure 4.3. At the end of these wire-like extensions are tiny enlargements (terminals) that contain specific biological chemicals called neurotransmitters. Neurotransmitters are released when the electrical signal travels down that neuron to the end of that wire-like process.
Bladder Problems
Authors: Ahlskog J. Eric
Published: November 2020

Urinary problems occur with normal aging. In women they often relate to the changes in female anatomy due to the delivering of babies. With superimposed age-related changes in soft tissues, laxity may result in incontinence (loss of urinary control), especially with coughing, laughing, or straining. In men the opposite symptom tends to occur: urinary hesitancy (inability to evacuate the bladder). This is due to constriction of the bladder outlet by an enlarging prostate; the prostate normally surrounds the urethra, through which urine passes. DLB and PDD are often associated with additional bladder problems. Recall that the autonomic nervous system regulates bladder function and that this system tends to malfunction in Lewy disorders. Hence, reduced bladder control is frequent among those with DLB, PDD, and Parkinson’s disease. This condition is termed neurogenic bladder, which implies that the autonomic nervous system control of bladder reflexes is not working properly. This may manifest as urgency with incontinence or hesitancy. Neurogenic bladder problems require different strategies than those used for treating the simple age-related problems that develop in mid-life and beyond. Moreover, there are certain caveats to treatment once a neurogenic bladder is recognized. The bladder is simply a reservoir that holds urine. It is located in the lower pelvis and is distant from the kidneys. The kidneys essentially filter the circulating blood and make the urine. The urine flows down from the kidneys into the bladder, as shown in Figure 14.1. Normally, as the bladder slowly fills with urine, a reflex is triggered when it is nearly full. This results in conscious awareness of the need to urinate, plus it primes the reflexive tendency of the bladder to contract in order to expel the urinary contents. The bladder is able to contract because of muscles in the bladder walls. Normally, nerves activate these muscles at the appropriate time, which forcefully squeeze the bladder, expelling the urine. Nerve sensors in the bladder wall are activated by bladder filling and transmit this information to the central nervous system, ramping up bladder wall muscle activity.
Depression
Authors: Ahlskog J. Eric
Published: November 2020

A diagnosis of DLB or PDD might make anyone depressed. It may also depress the spouse and family, although that is a topic for a later chapter. There are several reasons for depression in those with DLB or PDD. First, it may be a reaction to the diagnosis. Second, depression may also be a response to the limitations placed on life and activities. Third, it may reflect Lewy neurodegenerative damage within brain regions that mediate affect. Further complicating this issue is the fact that signs of parkinsonism give the appearance of depression (e.g., masked face). Moreover, symptoms that psychiatrists consider to be vegetative signs of depression, such as apathy, are also common primary symptoms of parkinsonian disorders. Depression is a quality-of-life issue that needs attention and appropriate treatment. Recognizing true depression is a crucial starting point and may be difficult in the context of DLB or PDD. Parkinsonian features often make someone appear depressed when clinically they are not. The following are primary symptoms and signs of parkinsonism that may be misinterpreted as evidence of depression: • Loss of facial animation (masking) • Slow to respond (bradykinesia) • Slowed thinking (bradyphrenia) • Apathy and loss of motivation • Poor appetite (sometimes) • Sleep disorder Moreover, declining engagement in sports, gardening, yard work, and other activities, may simply be due to the challenges of parkinsonism rather than to depression. Occasionally, people with DLB or PDD develop pseudobulbar affect, which is characterized by a markedly reduced threshold for crying (or laughing) in response to emotional stimuli. For example, mildly emotional stimuli easily provoke tears, such as a religious hymn or ritual. Similarly, scenes in a movie that might bring a tear to the eye of most people provoke uncontrollable crying. People with this condition report incongruity between what they are feeling and the emotional display. Pseudobulbar affect is important to recognize, as this is a component of the neurologic disorder and is not true depression. Although pseudobulbar affect is not true depression, it may respond to a low dose of certain antidepressants: tricyclics (e.g., nortriptyline, amitriptyline) or an SSRI (e.g., fluoxetine, sertraline); see the discussion below of antidepressant drugs.
Families, Caregivers, and Assistance
Authors: Ahlskog J. Eric
Published: November 2020

By definition, those with DLB or PDD are cognitively impaired. The degree of cognitive impairment is highly variable; some people remain relatively compensated and stable for years. For others, confusion impairs even the simplest of activities. Unlike Alzheimer’s disease, in which dementia occurs in isolation, DLB and PDD are often associated with other problems: gait and balance dysfunction; impairment of hand dexterity; the bowel, bladder, and blood pressure problems of dysautonomia. The challenges to not only the affected person, but also the spouse or partner and family can be substantial. Caregivers may have many responsibilities, and restructured lives become the rule. These issues are so variable that a one-size-fits-all approach is not realistic. Once DLB or PDD has been diagnosed, it is wise for the spouse, partner, or family to discuss with the affected patient whether revisions in decision-making should be addressed. Occasional people with DLB or PDD have relatively limited cognitive problems, and for these individuals perhaps no major changes in the family business or finances are necessary. However, this issue should still be discussed. Investments, taxes, and bill-paying may need to be switched to another family member or spouse. A family business may need new leadership. In some cases, leadership positions may be retained, but with an advisor who reviews all important decisions. When there is uncertainty, formal cognitive testing may provide important insight. Psychologists typically offer psychometric testing, assessing various aspects of cognition. The interpretation of these findings can be translated into implications for decision-making. One of the most disabling restrictions placed on someone in our society is the removal of driving privileges. Communities are no longer structured where one can simply walk to the store, church, or synagogue. In the setting of DLB or PDD, however, driving restrictions or limitations may be appropriate. At least the possibility should be discussed. Driving may be compromised by both cognitive impairment and parkinsonism. Usually it is the cognitive problems that are the greater threat to the driver and public safety.
Externalizing and Unpacking the Problem:Understanding Symptoms and Suffering
Authors: Hamkins SuEllen
Published: November 2020

Seeing the problem as separate from the person is a stance that informs narrative psychiatry. This stance gives us firm footing in responding to our patients with respect and empathy and frees us to nimbly and creatively work with them to mitigate the unwanted effects of problems in their lives. We don’t blame patients for their problems. Rather, we align with them side-by-side to look out at the problem together and see what can be done about it. What this means is seeing problems as separate from our patients’ identities; that is, as outside of what they value and who they are striving to be. In doing so, we see both the problem and the person more clearly. Externalizing the problem in this way is a therapeutic practice that is one of our most powerful narrative interventions. It shifts the psychological landscape in which we are working. Patients often experience their problems as all encompassing. By externalizing the problem, it becomes circumscribed and we can more easily unpack it: characterize it, determine its boundaries, discover how it is impinging on a person’s life, expose the ways in which it operates, and discern what supports it and what weakens it. Separating the problem from the person makes it easier to see how patients are succeeding in living their lives in ways that they find satisfying and how they have freed themselves from the influence of the problem. We can more easily discover areas of the patient’s life in which the problem is not operating or is powerless, and we can more readily discover strengths and resources that a patient can draw on to overcome the problem. Not seeing problems as integral to who patients are provides immediate relief from negative identity conclusions, which are often piled on top of other unwanted effects of problems. These discoveries are energizing, inspire hope, and point the way toward effective treatment. The practice of externalization was developed by Michael White as a way to objectify problems instead of objectifying people.
Finding Happiness: Rising from Despair and Turning Away from Anxiety
Authors: Hamkins SuEllen
Published: November 2020

“Anxiety is ruining my life,” Addie Markiewicz had said to me at her first appointment at age sixteen. Now, four years later, she entered my office, dropped her backpack on the floor, plopped down comfortably on the couch, picked up one of my blue throw pillows and began fiddling with the zipper. A junior in college, Addie had long, dark hair, blue eyes, fair skin, wholesome good looks, and a dry, at times mischievous sense of humor. In our weekly sessions, she could be alternately reticent and forthcoming. A gifted student with lots of friends, she volunteered at a daycare facility for children with special needs and was a respected and beloved babysitter for several families in the area. She had helped to form an advocacy group at her college for students who were dealing with mental health challenges. She had a loving relationship with her parents, whom she called her “best friends,” and her life had been free of any major trauma; on the contrary, her childhood had been characterized by a loving, supportive family and a close-knit community of which she was a cherished member, many of whom shared her Polish American heritage. For the first three years of our work together, I met with Addie for twenty minutes every week or two and she also met with a psychotherapist. After he moved out of the area, I became her primary psychotherapist, meeting with her weekly for fifty minutes. She had made great strides in overcoming profound despair, an ongoing sense of unreality, severe anxiety, and unwanted compulsive urges that had dogged her since she was twelve, but at times one or more of these problems flared up again, and we were still chipping away at them, working toward a fuller recovery. From our first appointment, she had identified a problem of feeling an overwhelming urge to spend hours and hours on her homework until it was flawless, accompanied by a keen anxiety lest there were any mistakes.
Long-Term Pain Management and Health Care Resource Use Among an Employed Population in Japan with Knee Osteoarthritis Combined with Low Back Pain
Authors: Ueda Kaname , Takura Tomoyuki , Fujikoshi Shinji , Meyers Juliana , Nagar Saurabh P , Enomoto Hiroyuki
Published: November 2020

Objective

Assess long-term comorbidity burden and pain management patterns among working-age patients with knee osteoarthritis (KOA) only without low back pain (LBP) (KOA-noLBP) and patients with KOA plus LBP (KOA+LBP) in Japan.

Methods

Retrospective claims data analyses were conducted on data from the Japan Medical Data Center (JMDC) database. Adult patients (≥40 years) with a diagnosis of knee osteoarthritis (KOA) (January 1, 2011–December 31, 2012) and 5 years of follow-up were evaluated. The first claim with a KOA diagnosis defined the index date. Longitudinal pain management patterns were assessed in both cohorts.

Results

Overall, 1,828 patients met study criteria (717 with KOA-noLBP; 1,111 with KOA+LBP). The mean age of patients with KOA-noLBP was 52.1 years, and that of patients with KOA+LBP was 53.1 years, with more females in the KOA+LBP cohort (49.4% vs. 55.0%). Regardless of cohort, >90% of patients received pharmacological intervention during the 5-year follow-up period. The most common regimen first received was either topical or oral nonsteroidal anti-inflammatory drugs. A higher mean number of pharmaceutical treatments were received by patients in the KOA+LBP cohort (3.6) than by patients in the KOA-noLBP cohort (2.7) during the follow-up period. Regardless of cohort, most of the direct medical cost was derived from medication.

Conclusion

This study demonstrates that a greater proportion of the JMDC population of working individuals with KOA were comorbid with LBP and received pain-related treatment in the long-term perspective relative to patients with KOA without LBP. Appropriate pain management for both KOA and LBP would be key for effective resource utilization in an aging society facing socioeconomic burdens
Citizen Policing in Chinese Societies: A Preliminary Comparative Study on the Models of Citizens’ Participation in Policing in China, Hong Kong, and Taiwan
Authors: Lin Leo S F
Published: November 2020

This article aims to conduct a preliminary comparative study on different models of citizens’ participation in Chinese societies. In examining citizen policing in Chinese societies, this article covers the major geographical locations in China, Hong Kong, and Taiwan. By using thematic analysis, this article has identified three main themes to assess volunteer policing in three Chinese societies, which all connect to the concepts of institutions and social capital: institutional development, institutional impact, and Guanxi as a common socio-cultural challenge. The role of citizens in law enforcement work is contextualized in the different forms of governments in these three societies. In China, there is a lack of legislature at the central level to regulate auxiliary police forces. The local governments developed various forms of auxiliary police systems monitored by public security authorities. Hong Kong, due to its former status as a British colony, has developed a well-established model of the modern auxiliary police system. In Taiwan, the auxiliary police system was influenced by both Chinese institutional development and the Japanese colony; however, a lack of detailed legislature at the local level is found, which has impacted the implementation of volunteer policing. Despite the difference, three of them all have faced the common challenges affected by Guanxi, which is the rudimentary dynamic in personalized social networks of power and is a crucial system of beliefs in Chinese culture. The author concludes that the institutional factors and Guanxi are important determinants of successful implementation of volunteer policing in three Chinese societies.
Screening rate and influential factors of lung cancer with low-dose computed tomography in Asian population: a systematic review and meta-analysis
Authors: Huang Jinxin , Yue Na , Wu Jingwei , Shi Naiyang , Wang Qiang , Cui Tingting , Zheng Mengyun , Sun Siqing , Jin Hui
Published: November 2020

Background

There are currently no studies synthesizing the screening rate and influential factors of low-dose computed tomography (LDCT)-screened lung cancer in Asian population.

Methods

A systematic review was conducted, using both English and Chinese language databases on March, 2019. The pooled screening rate and estimated odds ratios (ORs) of influential factors were analyzed using random effects models. Subgroup and meta-regression analyses were also employed to explore the heterogeneity.

Results

The pooled LDCT lung cancer screening rate was 1.12% (95% confidence interval (CI): 0.94%, 1.32%), and increased with age. Adenocarcinoma and stage I lung cancer had higher screening rates. Analysis of influential factors in the general population showed that female and elder age (≥50 years) were significantly influencing LDCT lung cancer screening rate (for female, OR = 1.32, 95% CI: 1.15–1.52; for adults ≥ 50 years, OR = 1.94, 95% CI: 1.52–2.49). Meta-regression analysis indicated that the heterogeneity maybe significantly correlated with the sample size, risk population and source of population.

Conclusions

Unlike European and American populations, female and adults > 50 years rather than smoking adults were positively associated with screening rate in Asian populations. It is important to further study the benefits of lung cancer screening with LDCT in Asian populations.
Serum IgG2 antibody multi-composition in systemic lupus erythematosus and in lupus nephritis (Part 2): prospective study
Authors: Bruschi Maurizio , Moroni Gabriella , Sinico Renato Alberto , Franceschini Franco , Fredi Micaela , Vaglio Augusto , Cavagna Lorenzo , Petretto Andrea , Pratesi Federico , Migliorini Paola , Locatelli Francesco , Pazzola Giulia , Pesce Giampaola , Bagnasco Marcello , Manfredi Angelo , Ramirez Giuseppe A , Esposito Pasquale , Murdaca Giuseppe , Negrini Simone , Cipriani Leda , Trezzi Barbara , Emmi Giacomo , Cavazzana Ilaria , Binda Valentina , d’Alessandro Matteo , Fenaroli Paride , Pisani Isabella , Garibotto Giacomo , Montecucco Carlomaurizio , Santoro Domenico , Scolari Francesco , Volpi Stefano , Mosca Marta , Tincani Angela , Candiano Giovanni , Prunotto Marco , Verrina Enrico , Angeletti Andrea , Ravelli Angelo , Ghiggeri Gian Marco
Published: November 2020

Objectives

Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes.

Methods

Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques.

Results

LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months.

Conclusions

Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN.

Trial registration

The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).
Neutrophil extracellular traps mediate joint hyperalgesia induced by immune inflammation
Authors: Schneider Ayda Henriques , Machado Caio Cavalcante , Veras Flávio Protásio , Maganin Alexandre Gomes de Macedo , de Souza Flávio Falcão Lima , Barroso Lívia Corrêa , de Oliveira Renê Donizeti Ribeiro , Alves-Filho José Carlos , Cunha Thiago Mattar , Fukada Sandra Yasuyo , Louzada-Júnior Paulo , da Silva Tarcília Aparecida , Cunha Fernando Queiroz
Published: November 2020

Objective

To evaluate the role of neutrophil extracellular traps (NETs) in the genesis of joint hyperalgesia using an experimental model of arthritis and transpose the findings to clinical investigation.

Methods

C57BL/6 mice were subjected to antigen-induced arthritis (AIA) and treated with Pulmozyme (PLZ) to degrade NETs or Cl-amidine to inhibit NET production. Oedema formation, the histopathological score and mechanical hyperalgesia were evaluated. NETs were injected intra-articularly in wild type (WT), Tlr4−/−, Tlr9−/−, Tnfr1−/− and Il1r−/− mice, and the levels of cytokines and Cox2 expression were quantified. NETs were also quantified from human neutrophils isolated from RA patients and individual controls.

Results

AIA mice had increased NET concentration in joints, accompanied by increased Padi4 gene expression in the joint cells. Treatment of AIA mice with a peptidyl arginine deiminase 4 inhibitor or with PLZ inhibited the joint hyperalgesia. Moreover, the injection of NETs into joints of naïve animals generated a dose-dependent reduction of mechanical threshold, an increase of articular oedema, inflammatory cytokine production and cyclooxygenase-2 expression. In mice deficient for Tnfr1, Il1r, Tlr4 and Tlr9, joint hyperalgesia induced by NETs was prevented. Last, we found that neutrophils from RA patients were more likely to release NETs, and the increase in synovial fluid NET concentration correlated with an increase in joint pain.

Conclusion

The findings indicate that NETs cause hyperalgesia possibly through Toll-like receptor (TLR)-4 and TLR-9. These data support the idea that NETs contribute to articular pain, and this pathway can be an alternative target for the treatment of pain in RA.
SUBOPTIMAL MODULATION OF RADIATION DOSE IN THE COMPUTED TOMOGRAPHY COMPONENT OF WHOLE-BODY POSITRON EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY
Authors: Inoue Yusuke , Adachi Mizuho , Shimizu Hirokazu , Nagahara Kazunori , Itoh Hiroyasu , Takano Makoto , Jinguji Koji
Published: November 2020

Radiation exposure in computed tomography (CT) is automatically modulated by automatic exposure control (AEC) mainly based on scout images. To simulate the whole-body positron emission tomography/CT, CT images of a phantom were obtained using the posteroanterior scout image alone (PA scout) or the posteroanterior and lateral images (PA + Lat scout). Old and new versions of the AEC software were compared. Using the old version of the software and the PA scout, a markedly high dose at the top of the head was observed, which varied depending on the position of the phantom. This issue was resolved in the new version of the software. Radiation dose in the shoulder region was much higher using the PA scout than using the PA + Lat scout, even with the new version of the software. AEC may cause unreasonably high radiation exposure locally, and the appropriateness of the dose modulation pattern should be examined at each facility.
NEUTRON AND GAMMA ALBEDO EVALUATION AT AN IRRADIATION FACILITY
Authors: Ciolini Riccardo , Marini Andrea , Giusti Valerio , d’Errico Francesco
Published: November 2020

The irradiation facility of the University of Pisa (UNIPI) is a neutron and gamma irradiation facility of the University of Pisa used for calibration purposes and to evaluate detectors and dosemeters for mixed neutron and gamma fields. The facility consists of a fairly large room (5.0 × 7.8 × 2.5 m3) with concrete walls and roof designed to minimise radiation scattering. Sealed neutron and gamma radionuclide sources are stored in the facility for calibration and test purposes. In order to perform accurate response measurements, this study applied a methodology of general validity to assess the neutron and gamma room scatter contributions (albedo) to the fluence and to the ambient dose equivalent rates. The assessment was done for the standard irradiation points of the facility, using detailed Monte Carlo simulations and considering several source-to-wall and source-to-detector distances.
Posterior medial frontal cortex and threat-enhanced religious belief: a replication and extension
Authors: Holbrook Colin , Iacoboni Marco , Gordon Chelsea , Proksch Shannon , Balasubramaniam Ramesh
Published: November 2020

Research indicates that the posterior medial frontal cortex (pMFC) functions as a ‘neural alarm’ complex broadly involved in registering threats and helping to muster relevant responses. Holbrook and colleagues investigated whether pMFC similarly mediates ideological threat responses, finding that downregulating pMFC via transcranial magnetic stimulation (TMS) caused (i) less avowed religious belief despite being reminded of death and (ii) less group bias despite encountering a sharp critique of the national in-group. While suggestive, these findings were limited by the absence of a non-threat comparison condition and reliance on sham rather than control TMS. Here, in a pre-registered replication and extension, we downregulated pMFC or a control region (MT/V5) and then primed participants with either a reminder of death or a threat-neutral topic. As mentioned previously, participants reminded of death reported less religious belief when pMFC was downregulated. No such effect of pMFC downregulation was observed in the neutral condition, consistent with construing pMFC as monitoring for salient threats (e.g. death) and helping to recruit ideological responses (e.g. enhanced religious belief). However, no effect of downregulating pMFC on group bias was observed, possibly due to reliance on a collegiate in-group framing rather than a national framing as in the prior study.
Co-production of knowledge in transdisciplinary communities of practice: Experiences from food governance in South Africa
Authors: Adelle Camilla , Görgens Tristan , Kroll Florian , Losch Bruno
Published: November 2020

Communities of Practice are sites of social learning for the co-production of knowledge. Building on recent literature on Transdisciplinary Communities of Practice, this article reflects on the experiences of an emergent ‘Food Governance Community of Practice’ in South Africa that brings together multiple stakeholders to co-produce knowledge to inform local food policy and governance. Our results show the following lessons for managers and participants engaged in establishing similar ‘third spaces’ for knowledge co-production: 1) make inevitable power asymmetries explicit; 2) the identity of the group should not be built on a particular normative position but emerge from discursive processes and 3) create a balance between supporting peripheral learning and maintaining the specialist cutting edge discussions needed for co-production. Furthermore, the most beneficial legacy of a Community of Practice may not be the outputs in terms of the co-produced knowledge but the development of a cohesive group of stakeholders with a new shared way of knowing.
Lipocalin-type prostaglandin D synthase levels increase in patients with narcolepsy and idiopathic hypersomnia
Authors: Wang Peipei , Li Qinghua , Dong Xiaosong , An Haiyan , Li Jing , Zhao Long , Yan Han , Aritake Kosuke , Huang Zhili , Strohl Kingman P , Urade Yoshihiro , Zhang Jun , Han Fang
Published: November 2020

Study Objectives

Excessive daytime sleepiness (EDS) is a frequent cause for consultation and a defining symptom of narcolepsy and idiopathic hypersomnia (IH). The associated mechanisms remain unclear. Lipocalin-type prostaglandin D synthase (LPGDS) is a plausible sleep-inducing candidate. This study is to compare cerebral spinal fluid (CSF) and serum LPGDS levels in patients group with hypersomnia of central origin, including those with narcolepsy type 1 (NT1) and type 2 (NT2) and IH, to those in healthy controls (Con).

Methods

Serum LPGDS, CSF LPGDS, and CSF hypocretin-1(Hcrt-1) levels were measured by ELISA in 122 narcolepsy patients (106 NT1 and 16 NT2), 27 IH, and 51Con.

Results

LPGDS levels in CSF (p = 0.02) and serum (p < 0.001) were 22%–25% lower in control subjects than in patients with EDS complaints, including NT1, NT2, and IH. In contrast to significant differences in CSF Hcrt-1 levels, CSF L-PGDS levels and serum L-PGDS were comparable among NT1, NT2, and IH (p > 0.05), except for slightly lower serum LPGDS in IH than in NT1 (p = 0.01). Serum L-PGDS correlated modestly and negatively to sleep latency on MSLT (r = −0.227, p = 0.007) in hypersomnia subjects.

Conclusions

As a somnogen-producing enzyme, CSF/serum LPGDS may serve as a new biomarker for EDS of central origin and imply a common pathogenetic association, but would complement rather than replaces orexin markers.
Circular RNAs in Toxicology
Authors: Shao Yueting , Jiang Yiguo
Published: November 2020

Circular RNAs (circRNAs) are a type of closed, long, non-coding RNAs, which have attracted significant attention in recent years. CircRNAs exhibit unique functions and are characterized by stable expression in various tissues across different species. Because the identification of circRNA in plant viroids in 1976, numerous studies have been conducted to elucidate its generation as well as expression under normal and disease conditions. The rapid development of research focused on the roles of circRNAs as biomarkers in diseases such as cancers has led to increased interests in evaluating the effects of toxicants on the human genetics from a toxicological perspective. Notably, increasing amounts of chemicals are generated in the environment; however, their toxic features and interactions with the human body, particularly from the epigenetic viewpoint, remain largely unknown. Considering the unique features of circRNAs as potential prognostic biomarkers as well as their roles in evaluating health risks following exposure to toxicants, the aim of this review was to assess the latest progress in the research concerning circRNA, to address the role of the circRNA-miRNA-mRNA axis in diseases and processes occurring after exposure to toxic compounds. Another goal was to identify the gaps in understanding the interactions between toxic compounds and circRNAs as potential biomarkers. The review presents general information about circRNA (ie, biogenesis and functions) and provides insights into newly discovered exosome-contained circRNA. The roles of circRNAs as potential biomarkers are also explored. A comprehensive review of the available literature on the role of circRNA in toxicological research (ie, chemical carcinogenesis, respiratory toxicology, neurotoxicology, and other unclassified toxicological categories) is included.
Spatiotemporal Dynamics of ‘Candidatus Liberibacter asiaticus’ Colonization Inside Citrus Plant and Huanglongbing Disease Development
Authors: Pandey Sheo Shankar , Nogales da Costa Vasconcelos Fernanda , Wang Nian
Published: November 2020

‘Candidatus Liberibacter asiaticus’ (CLas), the causal agent of citrus huanglongbing (HLB), colonizes inside the phloem and is naturally transmitted by the Asian citrus psyllid (ACP). Here, we investigated spatiotemporal CLas colonization in different tissues after ACP transmission. Of the nine plants successfully infected via ACP transmission, CLas was detected in the roots of all trees at 75 days postremoval of ACPs (DPR) but in the mature leaf of only one tree; this finding is consistent with the model that CLas moves passively from source to sink tissues. At 75 and 365 DPR, CLas was detected in 11.1 and 43.1% of mature leaves not fed on by ACPs during transmission, respectively, unveiling active movement to the source tissue. The difference in colonization timing of sink and source tissues indicates that CLas is capable of both passive and active movement, with passive movement being dominant. At 225 DPR, leaves fed on by ACPs during the young stage showed the highest ratio of HLB symptomatic leaves and the highest CLas titer, followed by leaves that emerged after ACP removal and mature leaves not fed on by ACPs. Importantly, our data showed that ACPs were unable to transmit CLas via feeding on mature leaves. It is estimated that it takes 3 years at most for CLas to infect the whole tree. Overall, spatiotemporal detection of CLas in different tissues after ACP transmission helps visualize the infection process of CLas in planta and subsequent HLB symptom development and provides evidence showing that young leaves should be the focus of HLB management.
Inflammatory Response and Phenotyping in Severe Acute Respiratory Infection From the Middle East Respiratory Syndrome Coronavirus and Other Etiologies
Authors: Arabi Yaseen M. , Jawdat Dunia , Hajeer Ali H. , Sadat Musharaf , Jose Jesna , Vishwakarma Ramesh K. , Almashaqbeh Walid , Al-Dawood Abdulaziz
Published: November 2020

Objectives:

In this study, we evaluated the inflammatory response in patients with severe acute respiratory infection due to the Middle East respiratory syndrome and non-Middle East respiratory syndrome and assessed the presence of distinct inflammatory subphenotypes using latent class analysis.

Design:

Prospective cohort study.

SETTING:

A tertiary care ICU in Riyadh, Saudi Arabia.

PATIENTS:

Consecutive critically ill patients with laboratory-confirmed Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection.

INTERVENTION:

None.

MEASUREMENTS AND MAIN RESULTS:

We measured cytokines on days 1, 3, 7, and 14 of ICU stay. We included 116 patients (40 with Middle East respiratory syndrome severe acute respiratory infection and 76 with non-Middle East respiratory syndrome severe acute respiratory infection). On ICU day 1, both patients with Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection had higher levels of interleukin-3, interleukin-4, interleukin-6, interleukin-8, interleukin-17A, eotaxin, and epidermal growth factor compared with healthy controls. There were no differences in cytokines over time between patients with Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection. Using day 1 cytokine levels, latent class analysis categorized patients into two subphenotypes: subphenotype 1 (n = 74 [64%]) and subphenotype 2 (n = 42 [36%]); the latter had significantly higher levels of interleukin-1β, interleukin-1ra, interleukin-2, interleukin-6, interleukin-7, interleukin-8, interleukin-10, interleukin-12p70, interleukin-15, interleukin-17A, inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, macrophage inflammatory protein-1β, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, granulocyte-colony stimulating factor, interferon-α, and interferon-γ. Although baseline characteristics were not different between the two subphenotypes, patients in the subphenotype 2 had higher ICU mortality compared with the subphenotype 1 (18/42 [43%] vs 17/74 [23%]; p = 0.03).

Conclusions:

One third of critically ill patients with Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection demonstrated a subphenotype characterized by increased proinflammatory cytokines, consistent with cytokine storm. Further research is needed to examine whether immunomodulators have differential effects based on inflammatory subphenotypes.