bluuebunny/crossref_metadata_2025 huggingface dataset:
XII
Authors: Conrad Joseph
Published: June 2023

On returning to the Heyst bungalow, rapid as if on wings, Ricardo found Lena waiting for him. She was dressed in black; and at once his uplifting exultation was replaced by an awed and quivering patience before her white face, before the immobility of...
XIII
Authors: Conrad Joseph
Published: June 2023

Mr. jones, after firing his shot over Heyst’s shoulder, had thought it proper to dodge away. Like the spectre he was, he had noiselessly vanished from the verandah. Heyst stumbled into the room and looked around. All the objects in there—the books, the gleam...
XIV
Authors: Conrad Joseph
Published: June 2023

“Yes, Excellency,” said Davidson in his placid voice; “there are more dead in this affair—more white people, I mean—than have been killed in many of the battles of the last Achin war.”*

Davidson was talking with an Excellency, because what was alluded to in...
The Game and the Nation—Act First
Authors: Wister Owen
Published: June 2023

There can be no doubt of this:—

All America is divided into two classes,—the quality and the equality. The latter will always recognize the former when mistaken for it. Both will be with us until our women bear nothing but kings.

It was through the...
The Judge Ignores Particulars
Authors: Wister Owen
Published: June 2023

“Do you often have these visitations?” Ogden inquired of Judge Henry. Our host was giving us whiskey in his office, and Dr. MacBride, while we smoked apart from the ladies, had repaired to his quarters in the foreman’s house previous to...
Word to Bennington
Authors: Wister Owen
Published: June 2023

They kept their secret for a while, or at least they had that special joy of believing that no one in all the world but themselves knew this that had happened to them. But I think that there was one person who...
At Dunbarton
Authors: Wister Owen
Published: June 2023

For their first bridal camp he chose an island. Long weeks before-hand he had thought of this place, and set his heart upon it. Once established in his mind, the thought became a picture that he saw waking and sleeping. He had stopped at...
Chapter Seven
Authors: London Jack
Published: June 2023

AT last, after three days of variable winds, we have caught the northeast trades. I came on deck, after a good night’s rest in spite of my poor knee, to find the Ghost foaming along, wing-and-wing, and every sail drawing except the jibs,...
Chapter Eleven
Authors: London Jack
Published: June 2023

THE Ghost has attained the southernmost point of the arc she is describing across the Pacific, and is already beginning to edge away to the west and north toward some lone island, it is rumored, where she will fill her water-casks before proceeding...
Chapter Seventeen
Authors: London Jack
Published: June 2023

STRANGE to say, in spite of the general foreboding, nothing of especial moment happened on the Ghost. We ran on to the north and west till we raised the coast of Japan and picked up with the great seal herd. Coming from no...
Chapter Twenty-Three
Authors: London Jack
Published: June 2023

BRAVE winds, blowing fair, swiftly drove the Ghost northward into the seal herd. We encountered it well up to the forty-fourth parallel,* in a raw and stormy sea across which the wind harried the fog-banks in eternal flight. For days at...
Chapter Twenty-Nine
Authors: London Jack
Published: June 2023

“FOOL!” I cried aloud in my vexation.

I had unloaded the boat and carried its contents high up on the beach, where I had set about making a camp. There was driftwood, though not much, on the beach, and the sight of a coffee tin...
Chapter Thirty-One
Authors: London Jack
Published: June 2023

IT will smell,” I said, “but it will keep in the heat and keep out the rain and snow.”

We were surveying the completed sealskin roof.

“It is clumsy, but it will serve the purpose, and that is the main thing,” I went on, yearning...
Chapter Thirty-Three
Authors: London Jack
Published: June 2023

WE waited all day for Wolf Larsen to come ashore. It was an intolerable period of anxiety. Each moment one or the other of us cast expectant glances toward the Ghost. But he did not come. He did not even appear on deck....

“Perhaps...
Chapter Thirty-Four
Authors: London Jack
Published: June 2023

IT’S too bad the Ghost has lost her masts. Why, we could sail away in her. Don’t you think we could, Humphrey?”

I sprang excitedly to my feet.

“I wonder, I wonder,” I repeated, pacing up and down.

Maud’s eyes were shining with anticipation as...
Chapter Thirty-Five
Authors: London Jack
Published: June 2023

NEXT day, the mast-steps clear and everything in readiness, we started to get the two topmasts aboard. The maintopmast was over thirty feet in length, the foretopmast nearly thirty, and it was of these that I intended making the shears. It was puzzling work. Fastening...
Chapter Thirty-Eight
Authors: London Jack
Published: June 2023

“I THINK my left side is going,” Wolf Larsen wrote, the morning after his attempt to fire the ship. “The numbness is growing. I can hardly move my hand. You will have to speak louder. The last lines are going down.”

“Are you in pain?”...
I
Authors: Saunders Max
Published: June 2023

This is the saddest story I have ever heard. We had known the Ashburnhams for nine seasons of the town of Nauheim* with an extreme intimacy—or, rather, with an acquaintanceship as loose and easy and yet as close as a good glove’s with...
Tarquin of Cheapside
Authors: Bryer Jackson R.
Published: June 2023

Running footsteps — light, soft-soled shoes made of curious leathery cloth brought from Ceylon setting the pace; thick flowing boots, two pairs, dark blue and gilt, reflecting the moonlight in blunt gleams and splotches, following a stone’s throw behind.

Soft Shoes flashes through a patch of moonlight,...
The Lees of Happiness
Authors: Bryer Jackson R.
Published: June 2023

If you should look through the files of old magazines for the first years of the present century you would find, sandwiched in between the stories of Richard Harding Davis and Frank Norris* and others long since dead, the work of one...
The Confusions of Young Törless
Authors: Mitchell Mike , Robertson Ritchie
Published: June 2023

As soon as we put something into words, in a strange way we devalue it. We think we have dived to the bottom of the abyss, and when we return to the surface the drop of water glistening on our pale fingertips no longer resembles...
Exploring the Evolvability of Plant Specialized Metabolism: Uniqueness Out Of Uniformity and Uniqueness Behind Uniformity
Authors: Ono Eiichiro , Murata Jun
Published: June 2023

The huge structural diversity exhibited by plant specialized metabolites has primarily been considered to result from the catalytic specificity of their biosynthetic enzymes. Accordingly, enzyme gene multiplication and functional differentiation through spontaneous mutations have been established as the molecular mechanisms that drive metabolic evolution. Nevertheless, how plants have assembled and maintained such metabolic enzyme genes and the typical clusters that are observed in plant genomes, as well as why identical specialized metabolites often exist in phylogenetically remote lineages, is currently only poorly explained by a concept known as convergent evolution. Here, we compile recent knowledge on the co-presence of metabolic modules that are common in the plant kingdom but have evolved under specific historical and contextual constraints defined by the physicochemical properties of each plant specialized metabolite and the genetic presets of the biosynthetic genes. Furthermore, we discuss a common manner to generate uncommon metabolites (uniqueness out of uniformity) and an uncommon manner to generate common metabolites (uniqueness behind uniformity). This review describes the emerging aspects of the evolvability of plant specialized metabolism that underlie the vast structural diversity of plant specialized metabolites in nature.
DR REDDY’S LABORATORIES (UK) LTD v WARNER-LAMBERT CO LLC
Authors:   Patents Court
Published: June 2023

H1 Patents — European patents — Pharmaceuticals — Multi-party litigation — Interim injunctions and interim undertakings — Cross-undertakings in damages — Threats — Relevant patent claims held invalid — Assessment of damages — Preliminary issues — Counterfactual assumptions
Describing the landscape of integrated clinical educational programs for PAs and NPs
Authors: Polansky Maura N. , Gillum J. Barton , Rooney Maxwell S. , Messing Jonathan
Published: June 2023

Purpose:

Postgraduate clinical training (PCT) has been available to PAs since the 1970s and to NPs since at least 2007. Some programs now enroll PAs and NPs. Although this new training model appears to be expanding, little data about integrated PA/NP programs are available.

Methods:

This study examined the PA/NP PCT landscape in the United States. Programs were identified from membership rosters of the Association of Postgraduate Physician Assistant Programs and the Association of Post Graduate APRN Programs. Data (program name, sponsoring institution, location, specialty, accreditation status) were identified from programs' websites.

Results:

We identified 106 programs at 42 sponsoring institutions. Various specialties, most commonly in emergency medicine, critical care, and surgery, were represented. Few were accredited.

Conclusions:

PA/NP PCT is now common, with about half of the programs accepting PAs and NPs. These programs represent a unique form of interprofessional education involving full integration of two professions in the same program and are worthy of further investigation.
Patient Perspectives and Quality of Life after Breast Reconstruction and the Impact of Subsequent Revisions
Authors: Kandi Lyndsay A. , Hammond Jacob B. , Nadone Haley , Kosiorek Heidi E. , Rebecca Alanna M. , Casey William J. , Reece Edward M. , Cronin Patricia A. , Pockaj Barbara A.
Published: June 2023

Background:

There is limited research on the impact of revisional surgery after breast reconstruction on patient experience and postoperative quality of life (QoL).

Methods:

Patients undergoing mastectomy with immediate implant-based or autologous free-flap breast reconstruction from 2008 to 2020 were reviewed. These patients were categorized by revisions (0–1, 2–3, and 4+) and surveyed on QoL metrics using BREAST-Q and Was It Worth It? (WIWI) questionnaires. BREAST-Q QoL, satisfaction, and WIWI metrics between revision groups were evaluated.

Results:

Among 252 patients, a total of 150 patients (60%) underwent zero to one revisions, 72 patients (28%) underwent two to three revisions, and 30 patients (12%) underwent four or more revisions. Median follow-up was 6 years (range, 1–11 years). BREAST-Q satisfaction among patients with four or more revisions was significantly lower (P = 0.03), while core QoL domains (chest physical, psychosocial, and sexual well-being) did not significantly differ. Analysis of unplanned reoperations due to complications and breast satisfaction showed no significant difference in QoL scores between groups (P = 0.08). Regarding WIWI QoL metrics, four or more revisions were associated with a higher rate of worse QoL (P = 0.035) and worse overall experience (P = 0.001). Most patients in all revision groups felt it was worthwhile to undergo breast reconstruction (86%), would choose breast reconstruction again (83%), and would recommend breast reconstruction to others (79%).

Conclusions:

Overall, a majority of patients undergoing revisions after breast reconstruction still have a worthwhile experience. Although reoperations after breast reconstruction do not significantly impact long-term BREAST-Q QoL domains, patients undergoing four or more revisions have significantly lower breast satisfaction, worse QoL, and a postoperative experience worse than expected.
European Society of Hypertension recommendations for the validation of cuffless blood pressure measuring devices: European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability
Authors: Stergiou George S. , Avolio Alberto P. , Palatini Paolo , Kyriakoulis Konstantinos G. , Schutte Aletta E. , Mieke Stephan , Kollias Anastasios , Parati Gianfranco , Asmar Roland , Pantazis Nikos , Stamoulopoulos Achilleas , Asayama Kei , Castiglioni Paolo , De La Sierra Alejandro , Hahn Jin-Oh , Kario Kazuomi , McManus Richard J. , Myers Martin , Ohkubo Takayoshi , Shroff Sanjeev G. , Tan Isabella , Wang Jiguang , Zhang Yuanting , Kreutz Reinhold , O’Brien Eoin , Mukkamala Ramakrishna
Published: June 2023

Background:

There is intense effort to develop cuffless blood pressure (BP) measuring devices, and several are already on the market claiming that they provide accurate measurements. These devices are heterogeneous in measurement principle, intended use, functions, and calibration, and have special accuracy issues requiring different validation than classic cuff BP monitors. To date, there are no generally accepted protocols for their validation to ensure adequate accuracy for clinical use.

Objective:

This statement by the European Society of Hypertension (ESH) Working Group on BP Monitoring and Cardiovascular Variability recommends procedures for validating intermittent cuffless BP devices (providing measurements every >30 sec and usually 30–60 min, or upon user initiation), which are most common.

Validation procedures:

Six validation tests are defined for evaluating different aspects of intermittent cuffless devices: static test (absolute BP accuracy); device position test (hydrostatic pressure effect robustness); treatment test (BP decrease accuracy); awake/asleep test (BP change accuracy); exercise test (BP increase accuracy); and recalibration test (cuff calibration stability over time). Not all these tests are required for a given device. The necessary tests depend on whether the device requires individual user calibration, measures automatically or manually, and takes measurements in more than one position.

Conclusion:

The validation of cuffless BP devices is complex and needs to be tailored according to their functions and calibration. These ESH recommendations present specific, clinically meaningful, and pragmatic validation procedures for different types of intermittent cuffless devices to ensure that only accurate devices will be used in the evaluation and management of hypertension.
Is Transcatheter Aortic Valve Implantation Effective in Improving Quality of Life?
Authors: Pollock Meg , Hutchinson Alison M. , Ockerby Cherene , Driscoll Andrea
Published: June 2023

Background

Aortic stenosis (AS) without surgical intervention is associated with morbidity and mortality and is the most common valvular disease in the western world. Transcatheter aortic valve implantation (TAVI) is a minimally invasive surgical option that has become a common treatment for people unable to undergo open aortic valve replacement; despite the increase in TAVI offerings in the last decade, patient quality of life (QoL) outcomes postoperatively are poorly understood.

Objective

The aim of this review was to determine whether TAVI is effective in improving QoL.

Method

A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted, and the protocol was registered on PROSPERO (CRD42019122753). MEDLINE, CINAHL, EMBASE, and PsycINFO were searched for studies published between 2008 and 2021. Search terms included “transcatheter aortic valve replacement” and “quality of life” and their synonyms. Included studies were evaluated, dependent on study design, using either the Risk of Bias-2 or the Newcastle-Ottawa Scale. Seventy studies were included in the review.

Results

Authors of the studies used a wide variety of QoL assessment instruments and follow-up durations; authors of most studies identified an improvement in QoL, and a small number identified a decline in QoL or no change from baseline.

Conclusion

Although authors of the vast majority of studies identified an improvement in QoL, there was very little consistency in instrument choice or follow-up duration; this made analysis and comparison difficult. A consistent approach to measuring QoL for patients who undergo TAVI is needed to enable comparison of outcomes. A richer, more nuanced understanding of QoL outcomes after TAVI could help clinicians support patient decision making and evaluate outcomes.
Understanding Dying Concerns in Parents With Advanced Cancer With Dependent Children for Their Coparent
Authors: Caparso Cinzia , Noble Emma , McCoy MaryAnne , Vallerand April , Benkert Ramona
Published: June 2023

Parents with advanced cancer and their dependent children experience high psychological distress, decreased quality of life, and decreased family functioning due to cancer-related concerns. Dying concerns are defined as fluctuating thoughts or feelings that are conscious or unconscious about an anticipated and approaching death that is attributed to a palliative/terminal diagnosis. This study used Gadamer's phenomenological approach to gain a shared understanding of the perspectives of the parents with advanced cancer about dying concerns, family life before and after advanced cancer diagnosis, and family resources to manage the crisis of advanced cancer for the coparent. The sample consisted of 4 patients from a Midwestern cancer hospital. Data were collected through 2 virtual semistructured interviews and were qualitatively analyzed using the hermeneutic rule and the theoretical concepts from McCubbin and McCubbin's Family Resiliency Model. Four major themes emerged: “Uncertainty in End-of-Life Decisions,” “Effectless Communication,” “Parental Skepticism,” and “Psychological Well-being.” The results showed that parents with advanced cancer have concerns for their coparent outside their parental role. Understanding dying concerns from all family members may increase nurse-initiated communication to improve family outcomes.
Activity Monitoring in Parkinson Disease: A Qualitative Study of Implementation Determinants
Authors: Fowler King Bridget , MacDonald Jillian , Stoff Laura , Nettnin Ella , Jayaraman Arun , Goldman Jennifer G. , Rafferty Miriam
Published: June 2023

Background and Purpose:

There is interest in incorporating digital health technology in routine practice. We integrate multiple stakeholder perspectives to describe implementation determinants (barriers and facilitators) regarding digital health technology use to facilitate exercise behavior change for people with Parkinson disease in outpatient physical therapy.

Methods:

The purposeful sample included people with Parkinson disease (n = 13), outpatient physical therapists (n = 12), and advanced technology stakeholders including researchers and reimbursement specialists (n = 13). Semistructured interviews were used to elicit implementation determinants related to using digital health technology for activity monitoring and exercise behavior change. Deductive codes based on the Consolidated Framework for Implementation Research were used to describe implementation determinants.

Results:

Key implementation determinants were similar across stakeholder groups. Essential characteristics of digital health technology included design quality and packaging, adaptability, complexity, and cost. Implementation of digital health technology by physical therapists and people with Parkinson disease was influenced by their knowledge, attitudes, and varied confidence levels in using digital health technology. Inner setting organizational determinants included available resources and access to knowledge/information. Process determinants included device interoperability with medical record systems and workflow integration. Outer setting barriers included lack of external policies, regulations, and collaboration with device companies.

Discussion and Conclusions:

Future implementation interventions should address key determinants, including required processes for how and when physical therapists instruct people with Parkinson disease on digital health technology, organizational readiness, workflow integration, and characteristics of physical therapists and people with Parkinson disease who may have ingrained beliefs regarding their ability and willingness to use digital health technology. Although site-specific barriers should be addressed, digital health technology knowledge translation tools tailored to individuals with varied confidence levels may be generalizable across clinics.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content available at: http://links.lww.com/JNPT/A436).
Psychological distress in patients with cancer at the Kenyatta National Hospital in Nairobi, Kenya, during the COVID-19 pandemic
Authors: Ong'ondi Matilda , Njuguna Irene , Obulumire Ronniey , Munyoro Esther , Okech Violet , Ann Njoroge , Bultz Barry
Published: June 2023

Background:

Psychosocial care for oncology patients is now recognized as a critical aspect of care because it has a positive impact on patient outcomes. Various screening tools have been validated to objectively measure the levels of distress, such as the National Comprehensive Cancer Network distress thermometer. However, there is little evidence of its use in sub-Saharan Africa, where the cancer burden continues to increase. This study sought to evaluate the levels of psychological distress in patients with cancer and the impact of the COVID-19 pandemic.

Methods:

This was a single-center cross-sectional study among patients with a histological diagnosis of cancer attending the hemato-oncology and radio-oncology units at the Kenyatta National Hospital, a referral tertiary center. We used the National Comprehensive Cancer Network Distress Thermometer and Problem Checklist to define psychological distress, fear of COVID-19 scale, and Corona Anxiety Score to determine the level of fear and anxiety caused by COVID-19 given the study happened during the pandemic, and the Eastern Cooperative Oncology Group (ECOG) to assess the performance status.

Results:

Of the 361 patients, the median age was 54 years (interquartile range, 43–63), and most were female (70%). The leading cancer diagnosis was breast cancer (26%), followed by cervical cancer (24%), with most of the patients having advanced disease and 28% having ECOG 3. Most (80%) patients were able to continue with their treatment despite the COVID-19 pandemic; however, 71% had a high level of fear of COVID-19 but minimal anxiety symptoms based on Corona Anxiety Score. The mean distress thermometer score was 2.7 (SD, 2.6), with 30% having a high level of distress (4 or above). ECOG status was the only variable significantly associated with high levels of distress, with the strongest association observed in the highest ECOG status (ECOG 4: OR, 6.8 [95% CI, 2.8–16.6] P < .001). Transportation was the main problem in the practical domain (62%) while fears and worries in the emotional domain (46% and 49%, respectively), and pain (65%) were the main physical problems.

Conclusions:

One-third of patients experienced high levels of distress. These patients reported significant concerns, such as transportation, fears, worry, and pain, in the problem checklist. There is a need to incorporate screening for distress into our patient population to help identify these patients and institute appropriate interventions.
Minimally Invasive Removal of Leukotrichia and Hair Transplantation: A 2-Step Surgery in the Treatment of Stable Follicular Vitiligo
Authors: Zhang Jiarui , Qu Qian , Fan Zhexiang , Guo Yilong , Chen Ruosi , Hu Zhiqi , Miao Yong
Published: June 2023

Background:

Follicular vitiligo is a distinct subtype of vitiligo characterized by the selective destruction of the follicular melanocytic reservoir. Treatment of follicular vitiligo–associated leukotrichia has always been a clinical challenge.

Methods:

Twenty participants (mean age, 29 years) with stable follicular vitiligo were recruited between 2020 and 2021 for 2-stage surgery. In stage 1, an incision around the vitiligo lesion was performed to subcutaneously dissect and scrape the leukotrichia. In stage 2, healthy follicles obtained from the occipital donor site were transplanted into the vitiligo area. Follow-up examinations were conducted for 1 year postoperatively using a camera and dermatoscope to observe the growth rate, color, and surviving number of the transplanted hairs. Patient satisfaction was recorded to evaluate the potential surgical improvement.

Results:

The transplanted hair grew with natural texture, as expected. The average survival rate of the transplanted hair follicles was 93.8%. No recurrence of leukotrichia was observed in the recipient area. No complications were observed, and the postoperative scars in the recipient area were entirely covered by black hair. All patients were satisfied with their resulting appearance.

Conclusion:

Minimally invasive removal of leukotrichia combined with hair transplantation might be an appropriate surgical option for stable follicular vitiligo to create natural and stable pigmented hair.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
The Effects of NAM on the Symmetry of the Face and Maxillary Arch in Babies With Unilateral Cleft
Authors: de Souza Tânia Mara , Batista Sabrina Tailane , de Souza Rodrigo Xavier Silveira , Rezende Sérgio Edriane , Alessi Mariana Sisto , Almeida Tatiana Fernandes Araújo , Frazão Diogo Campos , Pretti Henrique , Freitas Renato da Silva , Macari Soraia
Published: June 2023

The study aimed to evaluate the effect of nasoalveolar molding (NAM) therapy through reverse engineering, or its absence, to obtain symmetry of the face and maxillary arch. Twenty-six babies with unilateral cleft lip and palate received treatment with NAM, and 12 babies with unilateral cleft lip and palate without presurgical orthopedics (control group). Patients were molded and photographed in 2-stages: the first month of life (T1/pre) and after the use of NAM/before the cheiloplasty (T2/post). In the digital models, the analyses performed were arch perimeter, arch length, and labial frenulum angle. The photographs allowed us to analyze nasal width, mouth width, columella angle, and nostril area. The results demonstrated that there was an increase in arch perimeter and arch length in control and NAM groups in the T2 period in comparison to T1. Labial frenulum angle was reduced in the NAM group compared to the NAM-T1 and control-T2 periods. Treatment with NAM yielded a reduction in nasal width in the period of T2 compared with T1. Columella angle was enhanced after NAM use in T2 and, was different from control group. The nostril area was reduced in the NAM group in T2 compared with control group. Nasoalveolar molding therapy reduced the labial frenulum angle, contributing to a reduction in the extension of the cleft. The NAM protocol improved facial symmetry, mainly through nasal effects, whereas the absence of orthopedic therapy yielded a commitment to the face and maxillary arch symmetry.
Do changes in body mass alter white blood cell profiles and immune function in Australian cane toads (
Rhinella marina
)?
Authors: Brown Gregory P. , Hudson Cameron M. , Shine Richard
Published: June 2023

Variation in food resources can result in dramatic fluctuations in the body condition of animals dependent on those resources. Decreases in body mass can disrupt patterns of energy allocation and impose stress, thereby altering immune function. In this study, we investigated links between changes in body mass of captive cane toads (
Rhinella marina
), their circulating white blood cell populations, and their performance in immune assays. Captive toads that lost weight over a three-month period had increased levels of monocytes and heterophils and reduced levels of eosinophils. Basophil and lymphocyte levels were unrelated to changes in mass. Because individuals that lost mass had higher heterophil levels but stable lymphocyte levels, the ratio of these cell types was also higher, partially consistent with a stress response. Phagocytic ability of whole blood was higher in toads that lost mass, owing to increased circulating levels of phagocytic cells. Other measures of immune performance were unrelated to mass change. These results highlight the challenges faced by invasive species as they expand their range into novel environments which may impose substantial seasonal changes in food availability that were not present in the native range. Individuals facing energy restrictions may shift their immune function towards more economical and general avenues of combating pathogens.

This article is part of the theme issue ‘Amphibian immunity: stress, disease and ecoimmunology’.
A perspective into the relationships between amphibian (
Xenopus laevis
) myeloid cell subsets
Authors: Hossainey Muhammad Riadul Haque , Hauser Kelsey A. , Garvey Christina N. , Kalia Namarta , Garvey Juliette M. , Grayfer Leon
Published: June 2023

Macrophage (M
ϕ
)-lineage cells are integral to the immune defences of all vertebrates, including amphibians. Across vertebrates, M
ϕ
differentiation and functionality depend on activation of the colony stimulating factor-1 (CSF1) receptor by CSF1 and interluekin-34 (IL34) cytokines. Our findings to date indicate that amphibian (
Xenopus laevis
) M
ϕ
s differentiated with CSF1 and IL34 are morphologically, transcriptionally and functionally distinct. Notably, mammalian M
ϕ
s share common progenitor population(s) with dendritic cells (DCs), which rely on fms-like tyrosine kinase 3 ligand (FLT3L) for differentiation while
X. laevis
IL34-M
ϕ
s exhibit many features attributed to mammalian DCs. Presently, we compared
X. laevis
CSF1- and IL34-M
ϕ
s with FLT3L-derived
X. laevis
DCs. Our transcriptional and functional analyses indicated that indeed the frog IL34-M
ϕ
s and FLT3L-DCs possessed many commonalities over CSF1-M
ϕ
s, including transcriptional profiles and functional capacities. Compared to
X. laevis
CSF1-M
ϕ
s, the IL34-M
ϕ
s and FLT3L-DCs possess greater surface major histocompatibility complex (MHC) class I, but not MHC class II expression, were better at eliciting mixed leucocyte responses
in vitro
and generating
in vivo
re-exposure immune responses against
Mycobacterium marinum
. Further analyses of non-mammalian myelopoiesis akin to those described here, will grant unique perspectives into the evolutionarily retained and diverged pathways of M
ϕ
and DC functional differentiation.

This article is part of the theme issue ‘Amphibian immunity: stress, disease and ecoimmunology’.
Towards the generation of gnotobiotic larvae as a tool to investigate the influence of the microbiome on the development of the amphibian immune system
Authors: Miller Abigail J. , Gass Jordan , Jo Myung Chul , Bishop Lucas , Petereit Juli , Woodhams Douglas C. , Voyles Jamie
Published: June 2023

The immune equilibrium model suggests that exposure to microbes during early life primes immune responses for pathogen exposure later in life. While recent studies using a range of gnotobiotic (germ-free) model organisms offer support for this theory, we currently lack a tractable model system for investigating the influence of the microbiome on immune system development. Here, we used an amphibian species (
Xenopus laevis
) to investigate the importance of the microbiome in larval development and susceptibility to infectious disease later in life. We found that experimental reductions of the microbiome during embryonic and larval stages effectively reduced microbial richness, diversity and altered community composition in tadpoles prior to metamorphosis. In addition, our antimicrobial treatments resulted in few negative effects on larval development, body condition, or survival to metamorphosis. However, contrary to our predictions, our antimicrobial treatments did not alter susceptibility to the lethal fungal pathogen
Batrachochytrium dendrobatidis
(
Bd
) in the adult life stage. While our treatments to reduce the microbiome during early development did not play a critical role in determining susceptibility to disease caused by
Bd
in
X. laevis
, they nevertheless indicate that developing a gnotobiotic amphibian model system may be highly useful for future immunological investigations.

This article is part of the theme issue ‘Amphibian immunity: stress, disease and ecoimmunology’.
Ontogeny of immunity and potential implications for co-infection
Authors: Ramsay Chloe , Rohr Jason R.
Published: June 2023

Immunity changes through ontogeny and can mediate facilitative and inhibitory interactions among co-infecting parasite species. In amphibians, most immune memory is not carried through metamorphosis, leading to variation in the complexity of immune responses across life stages. To test if the ontogeny of host immunity might drive interactions among co-infecting parasites, we simultaneously exposed Cuban treefrogs (
Osteopilus septentrionalis
) to a fungus (
Batrachochytrium dendrobaditis
, Bd) and a nematode (
Aplectana hamatospicula
) at tadpole, metamorphic and post-metamorphic life stages. We measured metrics of host immunity, host health and parasite abundance. We predicted facilitative interactions between co-infecting parasites as the different immune responses hosts mount to combat these infectious are energetically challenging to mount simultaneously. We found ontogenetic differences in IgY levels and cellular immunity but no evidence that metamorphic frogs were more immunosuppressed than tadpoles. There was also little evidence that these parasites facilitated one another and no evidence that
A. hamatospicula
infection altered host immunity or health. However, Bd, which is known to be immunosuppressive, decreased immunity in metamorphic frogs. This made metamorphic frogs both less resistant and less tolerant of Bd infection than the other life stages. These findings indicate that changes in immunity altered host responses to parasite exposures throughout ontogeny.

This article is part of the theme issue ‘Amphibian immunity: stress, disease and ecoimmunology’.
Evolutionary ecology of host competence after a chytrid outbreak in a naive amphibian community
Authors: Longo Ana V. , Lips Karen R. , Zamudio Kelly R.
Published: June 2023

Naive multi-host communities include species that may differentially maintain, transmit and amplify novel pathogens; therefore, we expect species to fill distinct roles during infectious disease emergence. Characterizing these roles in wildlife communities is challenging because most disease emergence events are unpredictable. Here, we used field-collected data to investigate how species-specific attributes influenced the degree of exposure, probability of infection, and pathogen intensity, during the emergence of the fungal pathogen
Batrachochytrium dendrobatidis
(
Bd
) in a highly diverse tropical amphibian community. Our findings confirmed that ecological traits commonly evaluated as correlates of decline were positively associated with infection prevalence and intensity at the species level during the outbreak. We identified key hosts that disproportionally contributed to transmission dynamics in this community and found a signature of phylogenetic history in disease responses associated with increased pathogen exposure via shared life-history traits. Our findings establish a framework that could be applied in conservation efforts to identify key species driving disease dynamics under enzootics before reintroducing amphibians back into their original communities. Reintroductions of supersensitive hosts that are unable to overcome infections will limit the success of conservation programmes by amplifying the disease at the community level.

This article is part of the theme issue ‘Amphibian immunity: stress, disease and ecoimmunology’.
Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease
Authors: Liew Felicity , Efstathiou Claudia , Fontanella Sara , Richardson Matthew , Saunders Ruth , Swieboda Dawid , Sidhu Jasmin K. , Ascough Stephanie , Moore Shona C. , Mohamed Noura , Nunag Jose , King Clara , Leavy Olivia C. , Elneima Omer , McAuley Hamish J.C. , Shikotra Aarti , Singapuri Amisha , Sereno Marco , Harris Victoria C , Houchen-Wolloff Linzy , Greening Neil J , Lone Nazir I , Thorpe Matthew , Roger Thompson A. A. , Rowland-Jones Sarah L. , Docherty Annemarie B. , Chalmers James D. , Ho Ling-Pei , Horsley Alexander , Raman Betty , Poinasamy Krisnah , Marks Michael , Kon Onn Min , Howard Luke , Wootton Daniel G. , Quint Jennifer K. , de Silva Thushan I. , Ho Antonia , Chiu Christopher , Harrison Ewen M , Greenhalf William , Kenneth Baillie J. , Semple Malcolm G. , Evans Rachael A. , Wain Louise V. , Brightling Christopher , Turtle Lance , Thwaites Ryan S. , Openshaw Peter J.M. ,   ISARIC4C Investigators and the PHOSP-COVID collaborative group
Published: June 2023

One in ten SARS-CoV-2 infections result in prolonged symptoms termed ‘long COVID’, yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.
Construction and Evaluation of China Elderly Care Service Smart Supply Chain System
Authors: Dai You-Yu , Liu Guanlong
Published: June 2023

With the continuous deepening of the population aging degree, the pressure on social pensions has gradually increased, and the problem of pensions has become a must to be solved. With the development of science and technology, people’s living standard is constantly improving. The demand of the elderly group for old-age service is not only limited to the basic daily life of individuals before; it is moving toward the need for services that make people happier and healthier, how to integrate modern science and technology with the old-age service industry to make it serve the old-age industry better. This research is about constructing and evaluating the intelligent supply chain of Chinese old-age service. Based on the research results of previous scholars, this paper divides the construction of the intelligent supply chain of China endowment service into four aspects: policy aspect, economic aspect, social aspect, and technical aspect; the four significant aspects are divided into the first-level indicators, and 16 second-level indicators are divided under the first-level indicators. The importance and satisfaction of each evaluation index were obtained by distributing questionnaires to the managers who study the supply chain and the employees who are related to the old-age service. After the reliability analysis, the IPA quadrant analysis chart of the evaluation index was constructed using importance-performance analysis. The index of constructing an intelligent supply chain system for China old-age service is given priority, the supply chain system of China old-age service is further improved, and the social security of China old-age service is enlarged.
Life after patent: Drug price dynamics and cost-effectiveness analysis
Authors: Serra-Burriel Miquel , Martin-Bassols Nicolau , Perényi Gellért , Vokinger Kerstin N.
Published: June 2023

This study analyzed the effects of patent expiration on drug prices in eight countries (US, UK, Cana-da, Australia, Japan, France, Germany, and Switzerland) and the impact of these price dynamics in cost-effectiveness assessments. First, using an event study design, we showed that average prices of drugs substantially decreased eight years after patent expiration. Then, to assess the implications of this finding for cost-effectiveness assessments, a theoretical cost-effectiveness model simulated two real-world scenarios: (1) the comparator drug was a generic and the patent of the new drug expired after market entry; (2) the comparator drug was also under patent protection, but the patent expired prior to the patent of the new drug. Not accounting for genericization or patent expiration of the com-parator drug resulted in an underestimation or overestimation of the incremental cost-effectiveness ratios, respectively. Our pricing dynamic estimates can be applied to base-case analyses of cost-effectiveness models.
MaTiLDA: An Integrated Machine Learning and Topological Data Analysis Platform for Brain Network Dynamics
Authors: Prantzalos Katrina , Upadhyaya Dipak , Shafiabadi Nassim , Gurski Nick , Fernandez-BacaVaca Guadalupe , Yoshimoto Kenneth , Sivagnanam Subhashini , Majumdar Amitava , Sahoo Satya S.
Published: June 2023

Topological data analysis (TDA) is a powerful approach for investigating complex relationships in brain networks; however, its application requires substantial domain knowledge in programming, mathematics, and data science, especially in the context of data-driven approaches like machine learning (ML). To address this educational barrier, we introduce MaTiLDA, a graphical user interface that enables exploration of common representations of TDA features and their efficacy in various classical machine learning models. This user-friendly tool is the first graphical user interface built to explore TDA representations in machine learning applications. MaTiLDA provides a user-centric method for characterizing complex neural relationships using TDA techniques. To demonstrate the utility of MaTiLDA in characterizing brain network dynamics, we apply this workflow to a cohort of 4 refractory epilepsy patients and evaluate the predictive performance of various TDA feature representations in a series of ML models.

The MaTiLDA application can be accessed throughhttps://bmhinformatics.case.edu/nic/MaTiLDA
User adherence and perceptions of a Volunteer-Led Telemonitoring and Teleorientation Service for COVID-19 community management in Peru: The COVIDA project
Authors: Escobar-Agreda Stefan , Silva-Valencia Javier , Soto-Becerra Percy , Reategui-Rivera C. Mahony , De la Cruz-Torralva Kelly , Chahuara-Rojas Max , Hernandez-Iriarte Bruno , Espinoza-Herrera Daniel Hector , Delgado Carlos A. , Matassini Eyzaguirre Silvana M. , Vargas-Herrera Javier , Rojas-Mezarina Leonardo
Published: June 2023

Background

During the pandemic in Peru, the COVIDA project proposed an innovative way to provide telemonitoring and teleorientation to COVID-19 pandemics led by health student volunteers. However, it has not been described how this interaction is perceived from the user’s perspective. The aim of this study is to describe the adherence and perceptions of users about COVIDA.

Methods

A mixed-method study was conducted to evaluate the adherence and perceptions of COVIDA users. This telehealth intervention implemented in Peru from August to December 2020 involved daily phone-calls by volunteer students to monitor registered users for 14 days or until a warning sign was identified. The volunteers also provided teleorientation to address the users’ needs and concerns. Quantitative analysis described the characteristics of users and assessed the factors related to adherence to the service. Qualitative analysis trough semi-structured interviews evaluated the user’s perceptions about the service.

Results

Of the 778 users enrolled in COVIDA, 397 (54.7%) were female and had a mean age of 41 years (SD: 15.3). During the monitoring, 380 users (44.4%) developed symptoms, and 471 (55.5%) showed warning signs for COVID-19. The overall median of adherence was 93% (p25:36%, p75:100%). Among those users who did not develop warning symptoms, a high level of adherence (>66%) was seen predominantly in users that developed symptoms and those with a positive COVID-19 test (p<0.05). Users referred that the information provided by volunteers was clear and valuable and, their accompaniment provided them with emotional support. Communications via phone calls were developed fluently without interruptions.

Conclusions

COVIDA represented an affordable, well-accepted, and perceived alternative model for telemonitoring, teleorientation and emotional support from student volunteers to users with diseases such as COVID-19 in a context of overwhelmed demand for healthcare services.
Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci
Authors: Soriano Victor Lopez , Rey Alfredo Dueñas , Mukherjee Rajarshi ,   Genomics England Research Consortium, Coppieters Frauke , Bauwens Miriam , Willaert Andy , De Baere Elfride
Published: June 2023

Cross-species genome comparisons have revealed a substantial number of ultraconserved non-coding elements (UCNEs). Several of these elements have proved to be essential tissue- and cell type-specificcis-regulators of developmental gene expression. Here, we characterized a set of UCNEs as candidate CREs (cCREs) during retinal development and evaluated the contribution of their genomic variation to rare eye diseases, for which pathogenic non-coding variants are emerging. Integration of bulk and single-cell retinal multi-omics data revealed 594 genes under potentialcis-regulatory control of UCNEs, of which 45 are implicated in rare eye disease. Mining of candidatecis-regulatory UCNEs in WGS data derived from the rare eye disease cohort of Genomics England revealed 178 ultrarare variants within 84 UCNEs associated with 29 disease genes. Overall, we provide a comprehensive annotation of ultraconserved non-coding regions acting as cCREs during retinal development which can be targets of non-coding variation underlying rare eye diseases.
Importation models for travel-related SARS-CoV-2 cases reported in Newfoundland and Labrador during the COVID-19 pandemic
Authors: Mohammadi Zahra , Cojocaru Monica , Arino Julien , Hurford Amy
Published: June 2023

During the COVID-19 pandemic, the World Health Organization updated guidelines for travel measure implementation to recommend consideration of a region’s specific epidemiological, health system, and socioeconomic context. Region-specific data, analysis, and models are needed to support risk assessment frameworks based on these updated guidelines. During the pandemic, the Canadian province of Newfoundland and Labrador (NL) implemented travel measures that applied to non-residents of NL, and NL residents that worked outside the province. We found that during the pandemic travel to NL decreased by 82%, and the percentage of travelers arriving from Québec decreased from 14% to 4%. Daily travel-related cases are predicted by generalized linear models that consider the product of travel volume and prevalence proportion at travelers’ jurisdictions of origin (Canada), and travel volume only (international). A mechanistic model, formulated independently of the travel-related case data, predicts travel-related cases reasonably well. During the pandemic in NL, importation modelling was well-supported by daily public reporting of travel-related cases. Travel-related case data, and daily travel volume data, are needed to support the development and refinement of importation models to inform decisions regarding travel measure implementation during a public health emergency.