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Primary metabolism in cyanobacteria is built on the Calvin-Benson-Bassham (CBB) cycle, oxidative pentose phosphate (OPP) pathway, Embden-Meyerhof-Parnas (EMP) pathway, and the tricarboxylic acid (TCA) cycle. Phosphoketolase (Xpk), commonly found in cyanobacteria, is an enzyme that is linked to all these pathways. However, little is known about its physiological role. Here, we show that most of the cyanobacterial Xpk surveyed are inhibited by ATP, and both copies of Xpk in nitrogen-fixing Cyanothece ATCC51142 are further activated by ADP, suggesting their role in energy regulation. Moreover, Xpk in Synechococcus elongatus PCC7942 and Cyanothece ATCC51142 show that their expressions are dusk-peaked, suggesting their roles in dark conditions. Finally, we find that Xpk in S. elongatus PCC7942 is responsible for survival using ATP produced from the glycogen-to-acetate pathway under dark, anaerobic condition. Interestingly, under this condition, xpk deletion causes glucose secretion in response to osmotic shock such as NaHCO3, KHCO3 and NaCl as part of incomplete glycogen degradation. These findings unveiled the role of this widespread enzyme and open the possibility for enhanced glucose secretion from cyanobacteria.

The fatherhood scholarship has made much theoretical progress over the past decades, yet existing models and concepts continue to draw primarily on WEIRD-centric assumptions. This review uses demographically sizeable, culturally significant, yet understudied and under-theorized Chinese fathers as an example to reveal the limitations of applying WEIRD-centric perspectives in studying fathering and fatherhood. Specifically, existing models and concepts of fathering and fatherhood, with anemphasis on father involvement, especially in rough-and-tumble play, are predicatedon the assumptionsof nuclear family and western hegemonic masculinity. The Chinese cultural tradition, in contrast, endorses a literatus masculinity and emphasizes the family lineage, therebyencouraging fathers’ educational involvement and inviting grandparental care. These cultural traditions intersect with unfolding social developments in contemporaryChinese societies to shape fathering ideals and practices. A full, routine inclusion of non-WEIRD fathers, such as Chinese fathers, promises tobenefit the scholarship on fathering and fatherhood as a whole.

Background and objectives Cryotherapy for melanocytic lesions is often accompanied by collateral damage to the surrounding skin, resulting in skin necrosis and scarring. Adipocytes, like melanocytes, are neural crest-derived cells. Adipocytes have been shown to be more sensitive to cold exposure than their neighboring cells of ectodermal origin, such as epidermal keratinocytes. Such differential sensitivity to cold exposure has led to the development of novel treatment modalities, like cryolipolysis, to selectively target a cell type while sparing neighboring cells. Study design/materials and methods In this study, we investigated the roles of controlled skin freezing, tissue temperature, and exposure time in inducing selective loss of melanocytes and skin depigmentation in swines. Results The results of our study demonstrated that contact cooling of the skin surface causes selective loss of epidermal melanocytes when the tissue temperature reaches -7.5°C or cooler with an exposure time of 10 minutes or longer, leading to partial skin depigmentation in swine skin. Longer exposures combined with colder temperature exposure led to more complete depigmentation in the treated skin surface. Conclusion Cold-sensitivity of melanocytes can be harnessed to selectively remove melanocytes while sparing surrounding keratinocytes. The results from this study demonstrated that improved clinical treatments specifically targeting melanocytic lesions is possible using skin cooling to achieve tissue temperatures capable of inducing selective loss of melanocytes without skin necrosis or scarring. Additional studies are needed to optimize the treatment conditions to prolong the selective removal of melanocytes. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Alloys with ultra-high strength and sufficient ductility are highly desired for modern engineering applications but difficult to develop. Here we report that, by a careful controlling alloy composition, thermomechanical process, and microstructural feature, a Co-Cr-Ni-based medium-entropy alloy (MEA) with a dual heterogeneous structure of both matrix and precipitates can be designed to provide an ultra-high tensile strength of 2.2 GPa and uniform elongation of 13% at ambient temperature, properties that are much improved over their counterparts without the heterogeneous structure. Electron microscopy characterizations reveal that the dual heterogeneous structures are composed of a heterogeneous matrix with both coarse grains (10∼30 μm) and ultra-fine grains (0.5∼2 μm), together with heterogeneous L12-structured nanoprecipitates ranging from several to hundreds of nanometers. The heterogeneous L12 nanoprecipitates are fully coherent with the matrix, minimizing the elastic misfit strain of interfaces, relieving the stress concentration during deformation, and playing an active role in enhanced ductility., Improving both strength and ductility simultaneously in structural metals and alloys remains a challenge. Here, the authors design a heterogeneous structure in a Co-Cr-Ni alloy that results in ultrahigh strength and significant uniform elongation.

Merkel cell carcinoma (MCC) is a rare malignant cutaneous neuroendocrine tumour affecting mainly elderly patients and is more common in the West than in Asia. It is associated with Merkel cell polyomavirus (MCPyV), immunosuppression, and ultraviolet light. In this study, we retrospectively investigated the first series of MCC from Taiwan and identified 19 cases from three tertiary centres. All patients were males with a median age of 67.5. Twelve (63%) cases occurred in the extremities, with one unique case presenting initially as nodal metastasis of unknown primary. Immunohistochemically, the great majority of tumours expressed CK20 (89%), synaptophysin (89%), and INSM1 (84%), with none positive for TTF1. Eleven (58%) cases were positive for MCPyV by immunohistochemistry (clone CM2B4). All patients were treated with excision, including four with additional radiotherapy and one with radiotherapy and chemotherapy. Nodal status and treatment modalities significantly affected survival. The median survival time of MCPyV-positive cases was much longer than the negative cases (median 40 vs. 10 months). In summary, we presented the first report on the clinicopathological features of MCC in Taiwan, with 58% cases associated with MCPyV. The prognosis of patients with MCPyV-positive tumours was better than those negative for MCPyV.

Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the cell nucleus, but where KSHV episomal genomes are tethered and the mechanisms underlying KSHV lytic reactivation are unclear. Here, we study the nuclear microenvironment of KSHV episomes and show that the KSHV latency-lytic replication switch is regulated via viral long non-coding (lnc)RNA-CHD4 (chromodomain helicase DNA binding protein 4) interaction. KSHV episomes localize with a CHD4 complex, ChAHP, at epigenetically active genomic regions and tethers frequently near centromeric regions of host chromosomes. The ChAHP complex also occupies the 5’-region of a highly-inducible lncRNAs and terminal repeats of KSHV genome with latency-associated nuclear antigen (LANA). Viral lncRNA binding competes with CHD4 DNA binding, and KSHV reactivation is accompanied by the detachment of KSHV episomes from host chromosome docking sites We propose a model in which elevated lncRNA expression determines the KSHV latency-lytic decision by regulating LANA/ChAHP DNA binding at inducible viral enhancers.

Significance Many ecological processes, such as births, deaths, invasions, or predation, are largely stochastic in nature. Nevertheless, the dynamics occurring in ecosystems following a major change, such as regrowth of a forest after a fire, often follow regular temporal patterns, a phenomenon called ecological succession. We observed similar succession in simple microbial communities consisting of algae and ciliates colonizing a new environment and studied it by measuring dozens of replicates over a period of several days. Abundances, which were initially highly variable across replicates, rapidly converged to similar trajectories, a phenomenon called homeorhesis. These experiments show that fundamental phenomena in ecology, such as succession and homeorhesis, can be observed and quantitatively studied in the laboratory with simple synthetic ecosystems., The dynamics of ecological change following a major perturbation, known as succession, are influenced by random processes. Direct quantitation of the degree of contingency in succession requires chronological study of replicate ecosystems. We previously found that population dynamics in carefully controlled, replicated synthetic microbial ecosystems were strongly deterministic over several months. Here, we present simplified, two-species microbial ecosystems consisting of algae and ciliates, imaged in toto at single-cell resolution with fluorescence microscopy over a period of 1 to 2 weeks. To directly study succession in these ecosystems, we deliberately varied the initial cell abundances over replicates and quantified the ensuing dynamics. The distribution of abundance trajectories rapidly converged to a nearly deterministic path, with small fluctuations, despite variations in initial conditions, environmental perturbations, and intrinsic noise, indicative of homeorhesis. Homeorhesis was also observed for certain phenotypic variables, such as partitioning of the ciliates into distinct size classes and clumping of the algae. Although the mechanism of homeorhesis observed in these synthetic ecosystems remains to be elucidated, it is clear that it must emerge from the ways each species controls its own internal states, with respect to a diverse set of environmental conditions and ecological interactions.

Ag50Cu50 films were deposited on glass substrates by a sputtering system. Effects of accumulated energy on nanoparticle formation in pulse-laser dewetting of AgCu films were investigated. The results showed that the properties of the dewetted films were found to be dependent on the magnitude of the energy accumulated in the film. For a low energy accumulation, the two distinct nanoparticles had rice-shaped/Ag60Cu40 and hemispherical/Ag80Cu20. Moreover, the absorption spectra contained two peaks at 700 nm and 500 nm, respectively. By contrast, for a high energy accumulation, the nanoparticles had a consistent composition of Ag60Cu40, a mean diameter of 100 nm and a peak absorption wavelength of 550 nm. Overall, the results suggest that a higher Ag content of the induced nanoparticles causes a blue shift of the absorption spectrum, while a smaller particle size induces a red shift.

During the last half century, immigration from Asian countries to Canada and the United States has increased dramatically. Thus, researchers need to better understand the complexities of Asian families in the respective countries. Although Canada and the U.S. share the world’s longest undefended border as well as some similarities in their respective histories, the two societies differ in many significant ways. Thus, the purpose of the chapter is to explore Asian families in Canada and the United States. Specifically, we first discuss the conceptualization of the term “Asian” and how countries have defined and operationalized the ethnic term. A brief historical account is also provided, along with a discussion about the issues of labeling individuals. Next, we focus on the immigration policies and demographics of Asian immigrants in the respective countries, bringing some attention to the similarities and differences between them. We further examine the top three largest Asian groups, Chinese, Indian, and Filipino/a immigrants to illustrate the uniqueness of the various ethnic groups.

To gain greater insights into contemporary Chinese immigrant families in North America, it is imperative to understand the history of Chinese societies. This chapter provides an overview of the immigration history of Chinese families to Canada and the United States and the intracultural diversity in major Chinese societies (Mainland China, Taiwan, and Hong Kong) that have influenced these families in their native countries and abroad. We then explore how their acculturation pathways have impacted their family relationships, parenting practices and beliefs. Next, we describe the traditional values regarding family, interpersonal relations, and gender roles that have influenced Chinese families, and how some of the recent social changes have influenced contemporary immigrant and non-immigrant Chinese families’ family lives. We conclude with some practical implications for the mental health and other helping professions to better assist Chinese immigrants to deal with mental health issues and overcome barriers of seeking professional assistance.

As of 2020, Asian immigrants constitute Canada’s leading group of immigrants as well as the second largest group in the United States. Migration from Asia’s 48 countries and three special territories to the New World has helped to transform both Canada and the United States into multicultural nations in which West and East are meeting each other in creative, challenging, and historically unprecedented ways. This volume will provide the reader with a better appreciation of how diverse Asian traditions can be. Thus, the purpose of the chapters is to portray and analyze Asian American and Asian Canadian immigrant families in an integrated yet nuanced fashion, while paying special attention to their mental health and well-being.

Immigrant Chinese fathers remain severely under-researched despite their sizable and growing presence in host countries around the world and the recent progress in research on immigrant and ethnic minority fathers. In this chapter, we review the major themes and methods used in existing studies involving immigrant Chinese fathers and explore reasons behind immigrant Chinese fathers’ low visibility in the fatherhood scholarship. While the demographic under-representation of immigrant Chinese families may be a possible reason, stereotypical assumptions about immigrant or ethnic minority fathers and particularly Chinese men may have contributed to the neglect of immigrant Chinese fathers. Specifically, these stereotypical assumptions include that immigrant Chinese fathers are well-integrated immigrants who successfully fulfill essential paternal responsibilities of co-residence and provision, as typically defined by the white mainstream fatherhood ideal. A focus on immigrant Chinese fathers would considerably enrich the fatherhood scholarship, especially when the fathers’ parenting experiences, beliefs, practices, and influences are examined through a critical ecological approach.

In drug development, nonclinical safety assessment is pivotal for human risk assessment and support of clinical development. Selecting the relevant/appropriate animal species for toxicity testing increases the likelihood of detecting potential effects in humans, and although recent regulatory guidelines state the need to justify or disqualify animal species for toxicity testing, individual companies have developed decision-processes most appropriate for their molecules, experience and 3Rs policies. These generally revolve around similarity of metabolic profiles between toxicology species/humans and relevant pharmacological activity in at least one species for New Chemical Entities (NCEs), whilst for large molecules (biologics) the key aspect is similarity/ presence of the intended human target epitope. To explore current industry practice, a questionnaire was developed to capture relevant information around process, documentation and tools/factors used for species selection. Collated results from 14 companies (Contract Research Organisations and pharmaceutical companies) are presented, along with some case-examples or over-riding principles from individual companies. As the process and justification of species selection is expected to be a topic for continued emphasis, this information could be adapted towards a harmonized approach or best practice for industry consideration.

Immigrants account for 22% of the Canadian population, including 34% of youth under 25. According to Bronfenbrenner’s ecological framework, context plays an important role in the adaptation of immigrants. Specifically, the microsystems that impact immigrant youth include their parents, peers, schools, and communities. The youth interact with these systems directly and these systems also interact with one another to form the mesosystem. The role of the mesosystem in the identity and belonging of Russian-speaking immigrant youth is the focus of the current study. The experiences of these invisible immigrants are of interest because they may not integrate with white mainstream Canadians, yet they may also not fit in with their visible minority immigrant peers. Using constructivist grounded theory methodology, semi-structured interviews were conducted with 24 first- and second-generation Russian-speaking immigrant youth (15–19 years of age). Results indicated that parents played an important indirect role in creating and maintaining the other microsystems through their choices of neighborhoods to live in, schools, activities, etc. In turn, these ethnic/cultural enclaves that most of the youth lived in provided a protective mechanism for their identity and belonging and consequently fostered their relationships with both their parents and peers. Implications for research and practice are discussed.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington&rsquo, s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington&rsquo, s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.

Follicular lymphoma (FL) is usually a nodal lymphoma expressing CD10, rarely with leukaemic presentation (FL-LP).We searched for FL-LP in our institution from 2000 to 2018 and characterised the neoplastic cells by flow cytometry, immunohistochemistry and fluorescence in situ hybridization. Thirteen (6.1%) of 212 FL cases were FL-LP, all de novo neoplasms. The leukaemic cells were small in 12 cases and large in one. All had concurrent FL, mostly (92%; 12/13) low-grade. The single case with large leukaemic cells had a concurrent primary splenic low-grade FL and a double-hit large B-cell lymphoma in the marrow.CD10 was expressed in the leukaemic cells in 38% (5/13) cases by flow cytometry and in 77% (10/13) cases in tumours (p= 0.0471). IGH/BCL2 reciprocal translocation was identified in 85% (11/13) cases. Most patients were treated with chemotherapy. In a median follow-up time of 36 months, nine patients were in complete remission. The 2- and 5-year survival rates were at 100% and 83%, respectively. In this study, we characterised a series of de novo FL-LP in Taiwan. All patients had concurrent nodal and/or tissue tumours, which might suggest that these patients seek medical help too late.The lower CD10 expression rate by flow cytometry than by immunohistochemistry might be due to different epitopes for these assays. Alternatively, loss of CD10 expression might play a role in the pathogenesis of leukaemic change. The clinical course of FL-LP could be aggressive, but a significant proportion of the patients obtained complete remission with chemotherapy.

Family socialization is integral to the development of well-adjusted children, and parenting by two parents provides important resources. For many families, children are socialized in contexts where their biological fathers are physically absent. Unfortunately, these children are regarded as fatherless in the literature and social commentary. Drawing on semi-structured interviews with 24 Afro-Jamaican fathers in a context with a high prevalence of single female-headed families, the current study explored fathers’ perspectives on fathering presence/absence and their involvement. Thematic analysis from a social constructivist perspective revealed that children’s experiences of being fathered are complex, involving biological and social fathering. Also, fatherlessness was regarded as the opposite of fathering whereby there was a lack of behavioral, affective, cognitive, and spiritual involvement. From fathers’ own childhood experiences and being fathers themselves, they viewed the label as an inaccurate term. Rather, children may more likely experience levels of inadequate fathering or a lack of biological fathering. Moreover, complex factors including relationship dynamics and culture affect father involvement. The present findings highlight the need for policymakers and social activists to advocate for support programs for fathers and incentives to promote fathers’ involvement rather than reinforcing inaccurate labels. Also, professionals working with families should promote social fathering.

Sensitivity and resolution of molecular analysis are often compromised by the use of techniques that measure the ensemble average of large cell populations. Having a research tool to nondestructively identify the KSHV replication stage in an infected cell would not only allow us to effectively isolate cells of interest from cell populations but also enable more precise sample selection for advanced single-cell analysis. We prepared a recombinant KSHV that can report on its replication stage in host cells by differential fluorescence emission. Consistent with previous host gene expression studies, our experiments reveal the highly heterogenic nature of KSHV replication/gene expression at individual cell levels. The utilization of a newly developed reporter-KSHV and initial characterization of KSHV replication in single cells are presented., Molecular mechanisms of Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation have been studied primarily by measuring the total or average activity of an infected cell population, which often consists of a mixture of both nonresponding and reactivating cells that in turn contain KSHVs at various stages of replication. Studies on KSHV gene regulation at the individual cell level would allow us to better understand the basis for this heterogeneity, and new preventive measures could be developed based on findings from nonresponding cells exposed to reactivation stimuli. Here, we generated a recombinant reporter virus, which we named “Rainbow-KSHV,” that encodes three fluorescence-tagged KSHV proteins (mBFP2-ORF6, mCardinal-ORF52, and mCherry-LANA). Rainbow-KSHV replicated similarly to a prototype reporter-KSHV, KSHVr.219, and wild-type BAC16 virus. Live imaging revealed unsynchronized initiation of reactivation and KSHV replication with diverse kinetics between individual cells. Cell fractionation revealed temporal gene regulation, in which early lytic gene expression was terminated in late protein-expressing cells. Finally, isolation of fluorescence-positive cells from nonresponders increased dynamic ranges of downstream experiments 10-fold. Thus, this study demonstrates a tool to examine heterogenic responses of KSHV reactivation for a deeper understanding of KSHV replication. IMPORTANCE Sensitivity and resolution of molecular analysis are often compromised by the use of techniques that measure the ensemble average of large cell populations. Having a research tool to nondestructively identify the KSHV replication stage in an infected cell would not only allow us to effectively isolate cells of interest from cell populations but also enable more precise sample selection for advanced single-cell analysis. We prepared a recombinant KSHV that can report on its replication stage in host cells by differential fluorescence emission. Consistent with previous host gene expression studies, our experiments reveal the highly heterogenic nature of KSHV replication/gene expression at individual cell levels. The utilization of a newly developed reporter-KSHV and initial characterization of KSHV replication in single cells are presented.

At Taiwan Photon Source (TPS), the main liquid-nitrogen (LN2) transfer line of length 600 m for beamline endstations was installed in 2015. It formerly supplied LN2 to maximum 24 beamline endstations. Beamline endstation 13A, of which the aim is advanced and general studies of biological structures and structural kinetics in solution or condensed forms under environmental simulations, from atomic to micrometre scale and time resolution from microsecond to minute, was installed during 2018 and 2019. We designed and self-manufactured one LN2 transfer line according to the requirement of beamline endstation 13A, to supply LN2 into the double-crystal monochromator (DCM), to solve the problem of thermal deformation of the crystal. Otherwise the keep-full device was designed to replace the phase separator of the chiller. In this paper we present the pipeline design, performance testing, keep-full device, pressure reducer, noise reduction and heat-load measurement.

Helium is an expensive consumable in cryogenic facilities and is used widely in space, medical and energy research. At NSRRC, liquid helium is used as a coolant for superconducting magnets and SRF cavities . Minor contaminants such as nitrogen, oxygen, moisture and oil will be picked up when liquid helium circulates in large scale cryogenic systems and such contaminants can crystalize and cause damage to the cold box turbo expanders resulting in system damage and failure . Therefore, a helium purification system is designed as an integral part of the cryogenic system to conserve helium by providing 99.9995% pure helium to the liquefier after eliminating contaminants. The NSRRC helium purification process is based on two principles, the first one being a cryo-sorption device using activated charcoal and a molecular sieve and the other being a cryo-condensation unit using a tubular heat exchanger. The purifier has been designed to purify impure helium with overestimated contaminants of as much as 2.5% nitrogen and 2.5% oxygen with a mass flow rate of 475 nm3/hr and delivering a pressure of 17 bar(a) of impure helium to the purifier, the actual impurity will be much lower than the actual design contaminants. In this paper, calculation and design of the helium purification system and components composed of one double pipe counter flow heat exchanger, one vessel and tube heat exchanger, one pre-cooler and one charcoal vessel will be discussed together with charcoal mass requirement calculations and design of other components. In NSRRC, helium is liquefied and is used as a coolant for the SRF system and for cryogenic undulators. During a cryogenic cycle in the cryogenic system, helium may pick up contaminants such as moisture, oxygen, oil, and nitrogen, which have a higher freezing point than liquid helium and will crystalize. These frozen impurities will then affect plant capacity and operation such as alternating flow characteristics, damaging moving parts like turbines in the cold box causing the overall cooling efficiency to drop. Eliminating the contaminants is therefore very important for the cryogenic system.

Objective Lidocaine acts as a local anesthetic by blocking transmembrane sodium channel permeability, but also induces the synthesis of heat shock proteins and sensitizes cells to hyperthermia. A previous study reported two cases of deep focal skin ulceration at points corresponding to depot local lidocaine injection sites after treatment with non-ablative fractional resurfacing and it was hypothesized that lidocaine had focally sensitized keratinocytes to the thermal damage of laser treatment. The objective of this study was to investigate whether lidocaine potentiates hyperthermia damage to both normal and cancerous skin cells using an in vitro model. Methods Normal skin cell lines (fibroblasts, keratinocytes), skin cancer cell lines (melanoma, basal cell carcinoma), and a mucosal cancer cell line (cervical carcinoma) were exposed to various concentrations of lidocaine (0-0.3%) with or without hyperthermia (37°C, 42°C). Results Compared to normal skin cells, we demonstrate that cancer cell lines show significantly increased cell toxicity when a moderate temperature (42°C) and low lidocaine concentrations (0.1-0.2%) are combined. The toxicity directly correlates with a higher percentage of cells in S-phase (28-57%) in the cancer cell lines compared to normal skin cell lines (13-19%; R-square 0.6752). Conclusion These results suggest that lidocaine potentiates thermal sensitivity of cell cycle active skin cells. The direct correlation between cell toxicity and S-phase cells could be harnessed to selectively treat skin and mucosal cancer cells while sparing the surrounding normal tissue. Additional research pre-clinically and clinically using several different heat sources (e.g., lasers, ultrasound, etc.) and lidocaine concentrations is needed to confirm and optimize these results. Lidocaine-enhanced hyperthermia may provide a non-invasive, alterative treatment option for highly proliferating, superficial skin, and mucosal lesions such as cancer or warts. Lasers Surg. Med. 51:88-94, 2019. © 2018 Wiley Periodicals, Inc.