bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of disease onset chronology on mortality among patients with multimorbidity: A Danish nationwide register study
Authors: Willadsen Tora G , Siersma Volkert , Nicolaisdóttir Dagny R , Køster-Rasmussen Rasmus , Reventlow Susanne , Rozing Maarten 
Published: August 2022

Background Multimorbidity is associated with increased mortality. Certain combinations of diseases are known to be more lethal than others, but the limited knowledge of how the chronology in which diseases develop impacts mortality may impair the development of effective clinical interventions for patients with multimorbidity. Objective To explore if in multimorbidity the chronology of disease onset is associated with mortality. Design: A prospective nationwide cohort study, including 3,986,209 people aged ≥18 years on 1 January 2000, was performed. We included ten diagnosis groups: lung, musculoskeletal, endocrine, mental, cancer, neurological, gastrointestinal, cardiovascular, kidney, and sensory organs. We defined multimorbidity as the presence of at least two diagnoses from two diagnosis groups (out of ten). To determine mortality, logistic regression models were used to calculate odds ratios (OR) and ratio of ORs (RORs). Results For most combinations of multimorbidity, the chronology of disease onset does not change mortality. However, when multimorbidity included mental health diagnoses, mortality was in general higher if the mental health diagnosis appeared first. If multimorbidity included heart and sensory diagnoses, mortality was higher if these developed second. For the majority of multimorbidity combinations, there was excess mortality if multimorbidity was diagnosed simultaneously, rather than consecutively, for example, heart and kidney (3.58 ROR; CI 2.39–5.36), or mental health and musculoskeletal diagnoses (2.38 ROR; CI 1.70–3.32). Conclusions Overall, in multimorbidity, the chronology in which diseases develop is not associated with mortality, with few exceptions. For almost all combinations of multimorbidity, diagnoses act synergistically in relation to mortality if diagnosed simultaneously.
Hypothalamic orexinergic neurons modulate pain and itch in an opposite way: pain relief and itch exacerbation
Authors: Kaneko Tatsuroh , Kuwaki Tomoyuki , Kashiwadani Hideki 
Published: August 2022

AbstractPain and itch are recognized as antagonistic sensations; pain suppresses itch and inhibition of pain generates itch. There is still a lack of evidence about the neural mechanism of the interaction between pain and itch in the central nervous system. In this study, we focused on the orexin (ORX) neurons in the lateral hypothalamus (LH), which mediate various “defense responses” when animals confront stressors. We found that the scratching behaviors induced by the pruritogen were significantly suppressed in ORX-neuron-ablated (ORX-abl) mice. The exaggerated pain behavior and attenuated itch behavior observed in ORX-abl mice indicated that ORX neurons modulate pain and itch in an opposite way, i.e., pain relief and itch exacerbation. In addition, most of the ORX neurons responded to both pain and itch input. Our results suggest that ORX neurons inversely regulate pain- and itch-related behaviors, which could be understood as a defense response to cope with stress environment.
BMAL1 plays a critical role in the protection against cardiac hypertrophy through autophagy in vitro
Authors: Yu Lei , Ren Lei , Dong Linchang 
Published: August 2022

Abstract
Background
Heart disease could result from a malfunction in the core clock gene BMAL1, according to studies conducted on animals and humans in vitro and in vivo. However, in pathological conditions, the role of BMAL1 was not clear. In the present study, we identified a potential link between BMAL1 and cardiac hypertrophy.

Methods
Primary cultured neonatal rat cardiomyocytes were stimulated by Ang II. Cardiomyocytes immunofluorescence analysis was performed to observe the cell size. RT-PCR and Western blot were used to find out the gene and protein expression. Cell apoptosis was measured by TUNEL staining. The Elisa assay was performed which determine the release of cytokines led to the activation of cardiac fibro-blasts in cell-free supernatants. Furthermore, gain- and loss-of-function studies revealed that BMAL1 has an effect on Ang II-induced cardiac hypertrophy.

Results
We found that Ang II-induced cardiac hypertrophy as a result BMAL1 expression was reduced. However, overexpression of BMAL1 could prevent Ang II-induced hypertrophy. Additionally, although BMAL1 overexpression in hypertrophic cardiomyocytes could not prevent hypertrophy, it did reduce the apoptosis of hypertrophic cardiomyocytes after Ang II had induced it. In addition, BMAL1 knockdown did not aggravate Ang II-induced hypertrophy but accelerated its development. Finally, BMAL1 overexpression significantly resisted the effects of Ang II on oxidative stress, autophagy and, cardiac fibrosis in cardiomyocytes.

Conclusions
Our results showed that overexpression of BMAL1 effectively resisted cardiac hypertrophy induced by Ang II. Our findings provided a novel potential target for the treatment of cardiac hypertrophy.
Undergraduate nursing students’ knowledge of and attitudes toward people with alzheimer’s disease
Authors: Aljezawi Ma’en , Al Qadire Mohammad , Suliman Mohammad , Al Omari Omar , Khalaf Atika 
Published: August 2022

AbstractAs the population ages, the number of people living with Alzheimer's disease is expected to grow; consequently, nursing students are expected to care for more people with Alzheimer's disease in their future careers. Exploring nursing students' level of knowledge and attitudes is essential here to fill any knowledge gap and enhance attitudes. For this reason, the current study aimed to measure the knowledge of and attitudes toward people living with Alzheimer's disease among undergraduate Jordanian nursing students. A descriptive cross-sectional design was utilized. Data were collected through an online questionnaire consisting of the Alzheimer's Disease Knowledge Scale (ADKS) and Dementia Attitudes Scale (DAS). A third part contained questions about previous formal education about Alzheimer's disease, reading Alzheimer's research, and the need for formal education about Alzheimer's disease. The study targeted all undergraduate Jordanian nursing students. A total of 275 students agreed to participate and completed the questionnaire. Jordanian nursing students had low knowledge regarding people living with Alzheimer's disease, with a mean ADKS score of 18.3 out of 30; however, their attitudes were positive, with a mean DAS score of 91 out of 140. There was no statistical difference in attitude or knowledge between different academic levels. The majority of students (90.5%) expressed their desire to have a formal education regarding Alzheimer's disease. Knowledge regarding people with Alzheimer's disease could be improved through training and education. Positive attitudes reported by students could augment the learning process.
Indicator-activities to apply primary health care principles in national or large-scale community health worker programs in low-and middle-income countries: a Delphi exercise
Authors: Perveen Shagufta , Laurence Caroline , Mahmood Mohammad Afzal 
Published: August 2022

AbstractIntroductionPrimary Health Care (PHC) gained considerable momentum in the past four decades and led to improved health outcomes across a wide variety of settings. In low-and middle-income countries (LMICs), national or large-scale Community Health Worker Programs (CHWPs) are considered as vehicles to incorporate PHC principles into healthcare provision and are an essential aspect of the PHC approach to achieve health for all and sustainable development goals. The success of CHWPs is rooted in the application of PHC principles. However, there is evidence that shows patchy implementation of PHC principles across national CHWPs in LMICs. This may reflect the lack of information on what activities would illustrate the application of these principles in CHWPs. This study aimed to identify a set of core/indicator-activities that reflect the application of PHC principles by CHWPs in LMICs.MethodsA two-round modified Delphi study was undertaken with participants who have extensive experience in planning, implementation and evaluation of CHWPs. Survey design and analysis was guided by the four PHC principles namely Universal Health Coverage, Community Participation, Intersectoral Coordination and Appropriateness. Responses were collected using a secure online survey program (survey monkey). In round one, participants were asked to list ‘core activities’ that would reflect the application of each PHC principle and its sub-attributes and challenges to apply these principles in CHWPs. In round two, participants were asked to select whether they agree or disagree with each of the activities and challenges. Consensus was set a priori at 70% agreement of participants for each question.ResultsSeventeen participants from 15 countries participated in the study. Consensus was reached on 59 activities reflecting the application of PHC principles by CHWPs. Based on participants’ responses, a set of 29 indicator-activities for the four PHC principles was developed with examples for each indicator-activity.ConclusionThese indicator-activities may provide guidance on how PHC principles can be implemented in CHWPs. They can be used in the development and evaluation of CHWPs, particularly in their application of PHC principles. Future research may focus on testing the utility of indicator-activities on CHWPs in LMICs.
Associations with oral health indices for obesity risk among Japanese men and women: results from the baseline data of a cohort study
Authors: Tanaka Hiroko , Nakano Mirei , Kuriki Kiyonori ,   Shizuoka-Sakuragaoka J-MICC Study Group
Published: August 2022

Abstract
Background
Oral health is composed of various oral health indices (OHIs), such as oral self-care habits, oral hygiene, oral function, and mastication ability. Oral self-care habits have frequently been examined for obesity risk. This study aimed to comprehensively clarify the association between OHIs and obesity risk.

Methods
We collected data for 15 questions on the four OHIs and measured the body mass index of 3494 men and 2552 women aged 35–79 years. Obesity was defined as a body mass index ≥25 kg/m2. The four OHIs were scored by the corresponding questions (good as “reference”), and the summed score was defined as “comprehensive OHI”, that is, the fifth OHI. Each lowest tertile score was used as “reference”. Using multiple logistic regression analysis, odds ratios (ORs), 95% confidence intervals (CIs), and p-values for trends were estimated.

Results
In the men and women, the ORs were 1.37 (1.11–1.67, < 0.01) and 2.48 (1.80–3.42, < 0.01) for oral self-care habits, and 1.78 (1.42–2.24, < 0.01) and 3.06 (2.12–4.43, < 0.01) for tooth brushing frequency, respectively. Moreover, in men, a significant trend was found for “harder rinsing out your mouth”, related to “oral function”. In women, the ORs were 1.74 (1.28–2.36, < 0.01) and 1.43 (1.00–2.06, < 0.01) for “comprehensive OHI” and “longer meal time” related to “mastication ability”, respectively.

Conclusions
Our findings showed that obesity risk was associated with poor of oral health, which were comprehensively composed of various OHIs, among middle-aged and older Japanese men and women.
Undernotification and underreporting of tuberculosis in Zambia: a national data quality assessment
Authors: Lungu P. S. , Kabaso M. E. , Mihova R. , Silumesii A. , Chisenga T. , Kasapo C. , Mwaba I. , Kerkhoff A. D. , Muyoyeta M. , Chimzizi R. , Malama K. 
Published: August 2022

Abstract
Background
Despite national implementation of several high impact interventions and innovations to bolster tuberculosis (TB) detection and improve quality of TB services in Zambia, notifications have been declining since 2004. A countrywide data quality assessment (DQA) of Zambia’s National TB and Leprosy Programme (NTLP) was undertaken to quantify the degree to which undernotification and underreporting of TB notifications may be occurring.

Methods
The NTLP conducted a retrospective DQA of health facilities in high burden districts in all ten Zambian provinces. Multiple routine programmatic data sources were triangulated through a multi-step verification process to enumerate the total number of unique TB patients diagnosed between 1st January and 31st August 2019; both bacteriologically confirmed and clinically diagnosed TB patients were included. Undernotification was defined as the number of TB patients identified through the DQA that were not documented in facility treatment registers, while underreporting was defined as the number of notified TB cases not reported to the NTLP.

Results
Overall, 265 health facilities across 55 districts were assessed from which 28,402 TB patients were identified; 94.5% of TB patients were ≥ 15 years old, 65.1% were male, 52.0% were HIV-positive, and 89.6% were a new/relapse case. Among all TB cases, 32.8% (95%CI: 32.2–33.3) were unnotified. Undernotification was associated with age ≥ 15 years old (adjusted prevalence odds ratio [aPOR] = 2.4 [95%CI: 2.0–2.9]), HIV-positive status (aPOR = 1.6 [95%CI: 1.5–1.8]), being a new/relapse TB case (aPOR = 17.5 [95%CI: 13.4–22.8]), being a clinically diagnosed TB case (aPOR = 4.2 [95%CI:3.8–4.6]), and being diagnosed at a hospital (range, aPOR = 1.5 [95%CI: 1.3–1.6] to 2.6 [95%CI: 2.3–2.9]). There was substantial heterogeneity in the proportion of unnotified TB cases by province (range, 18.2% to 43.6%). In a sub-analysis among 22,199 TB patients with further data available, 55.9% (95%CI: 55.2–56.6) were notified and reported to the NTLP, 32.8% (95%CI: 32.2–33.4) were unnotified, and 11.3% (95%CI: 10.9–11.7) went unreported to the NTLP.

Conclusions
The findings from Zambia’s first countrywide TB programme DQA demonstrate substantial undernotification and underreporting of TB cases across all provinces. This underscores the urgent need to implement a robust and integrated data management system to facilitate timely registration and reporting of all TB patients who are diagnosed and treated.
Explorative study on scale cortisol accumulation in wild caught common dab (Limanda limanda)
Authors: Vercauteren Maaike , Ampe Bart , Devriese Lisa , Moons Christel Palmyre Henri , Decostere Annemie , Aerts Johan , Chiers Koen 
Published: August 2022

Abstract
Background
Flatfish live in a diverse marine ecosystem that is changing due to natural variations and anthropogenic influences. These changes can evoke a stress response mainly resulting in production of the glucocorticoid cortisol, which mediates effects on various levels of biological organization. The finding that cortisol accumulates in fish scales, offering a retrospective view on cortisol production, provides opportunities to use this matrix for chronic stress assessment. The present study is the first to gather information on scale cortisol concentration in wild-caught common dab (Limanda limanda), based on a two-pronged approach using (1) field measurements and (2) a laboratory in vivo-study where wild-caught dab were fed by cortisol-spiked feed during 30 or 90 days to demonstrate the possible accumulation of cortisol in the scales and to evaluate its impact on fish health.

Results
Based on the field measurements, the average scale cortisol concentration in wild-caught fish was 0.0034 ± 0.0046 µg kg−1 scale (n = 67). This indicates that wild common dab is indeed able to incorporate cortisol in the scales.
Based on the experimental data, the cortisol-fed fish showed an increased plasma cortisol concentration (80.16 ± 82.58 µg L−1) compared to the control group (4.54 ± 9.57 µg L−1) after 30 days of cortisol feeding. The increase in plasma cortisol concentration was positively correlated with an increased cortisol concentration in the scale after 30 days of cortisol-spiked feeding. This correlation was, however, no longer observed after 90 days of cortisol-spiked feeding. Interestingly, cortisol concentration of the scales on the pigmented side was significantly higher compared to the non-pigmented side. Some health parameters such as epidermal thickness, body condition and Ichthyobodo sp. parasitic infection showed a correlation with scale cortisol concentration after 30 days.

Conclusions
We have demonstrated that common dab is able to accumulate cortisol in its scales. This seems to occur proportionally to circulating concentrations of plasma cortisol in fish fed with cortisol supplemented feed after 30 days.
Predictive potential of ACE phenotyping in extrapulmonary sarcoidosis
Authors: Danilov Sergei M. , Kurilova Olga V. , Sinitsyn Valentin E. , Kamalov Armais A. , Garcia Joe G. N. , Dudek Steven M. 
Published: August 2022

AbstractElevated ACE expression in tissues (reflected by blood ACE levels) is associated with increased risk of cardiovascular diseases and is also a marker for granulomatous diseases. We developed a new approach for characterization of ACE status in the blood—ACE phenotyping and established normal values of ACE levels 50–150% of control pooled plasma. ACE phenotyping was performed in citrated plasma of 120 patients with known interstitial lung diseases. In the 1st set of 100 patients we found 22 patients with ACE levels > 150%; ACE phenotyping also objectively identified the presence of ACE inhibitors in the plasma of 15 patients. After excluding these patients and patient with ACE mutation that increases ACE shedding, 17 patients were identified as a suspicious for systemic sarcoidosis based on elevation of blood ACE (> 150% of mean). A new parameter that we have established–ACE immunoreactivity (with mAb 9B9)—allowed us to detect 22 patients with decreased values (< 80%) of this parameter, which may indicate the presence of ACE in the blood that originates from macrophages/dendritic cells of granulomas. In the remaining 20 patients, this new parameter (mAbs binding/activity ratio) was calculated using 3 mAbs (9B9, 3A5 and i1A8—having overlapping epitopes), and 8 patients were identified as having decreases in this parameter, thus increasing dramatically the sensitivity for detection of patients with systemic sarcoidosis. Whole body PET scan confirmed extrapulmonary granulomas in some patients with lower immunoreactivity towards anti-ACE mAbs. ACE phenotyping has novel potential to noninvasively detect patients with systemic sarcoidosis.
Critical policies disparity of the first and second waves of COVID-19 in the United Kingdom
Authors: Yang Manfei , Shi Leiyu , Chen Haiqian , Wang Xiaohan , Jiao Jun , Liu Meiheng , Yang Junyan , Sun Gang 
Published: August 2022

Abstract
Objective
This study aims to compare the differences in COVID-19 prevention and control policies adopted by the United Kingdom (UK) during the first wave (31 January 2020 to 6 September 2020) and the second wave (7 September 2020 to 12 April 2021), and analyze the effectiveness of the policies, so as to provide empirical experience for the prevention and control of COVID-19.
Methods We systematically summarized the pandemic prevention and control policies of the UK from official websites and government documents, collated the epidemiological data from 31 January 2020 to 12 April 2021, and analyzed the effectiveness of the two waves of pandemic prevention and control policies.

Results
The main pandemic prevention and control policies adopted by the UK include surveillance and testing measures, border control measures, community and social measures, blockade measures, health care measures, COVID-19 vaccination measure, and relaxed pandemic prevention measures. The new cases per day curve showed only one peak in the first wave and two peaks in the second wave. The number of new cases per million in the second wave was much higher than that in the first wave, and the curve fluctuated less. The difference between mortality per million was small, and the curve fluctuated widely.

Conclusion
During the first and second waves of COVID-19, the UK implemented three lockdowns and managed to slow the spread of the pandemic. The UK’s experience in mitigating the second wave proves that advancing COVID-19 vaccination needs to be accompanied by ongoing implementation of non-pharmacological interventions to reduce the transmission rate of infection. And a stricter lockdown ensures that the containment effect is maximized during the lockdown period. In addition, these three lockdowns featured distinct mitigation strategies and the UK’s response to COVID-19 is mitigation strategy that reduce new cases in the short term, but with the risk of the pandemic rebound.
Very severe immune thrombocytopenia following SARS-CoV-2 vaccination requiring splenectomy: a case report
Authors: Weiner Marc , Rodriguez-Vigouroux Robert , Masouridi-Levrat Stavroula , Samii Kaveh 
Published: August 2022

Abstract
Background
Some conventional vaccines have been recognized as a cause of secondary immune thrombocytopenia (ITP). According to recent publications, mRNA vaccines are probably associated with an increased risk of ITP.

Case presentation
Our patient developed severe ITP one week after the second dose of COVID-19 mRNA vaccine. Medical management was not effective, requiring splenectomy to obtain sustained remission.

Conclusion
Considering the temporality and immunological hypothesis, we consider the vaccine to be the trigger of this ITP. To our knowledge, our case is, to date, the most severe case of ITP reported following SARS-CoV-2 vaccination and could help for the therapeutic management of similar patients.
Shorter telomere length is associated with COVID-19 hospitalization and with persistence of radiographic lung abnormalities
Authors: Retuerto Miriam , Lledó Ana , Fernandez-Varas Beatriz , Guerrero-López Rosa , Usategui Alicia , Lalueza Antonio , García-García Rocío , Mancebo Esther , Paz-Artal Estela , Sastre Leandro , Perona Rosario , Pablos José L. 
Published: August 2022

Abstract
Background
Age and comorbidity are the main determinants of COVID-19 outcome. Shorter leukocyte telomere length (TL), a hallmark of biological aging, has been associated with worse COVID-19 outcomes. We sought to determine TL in patients with severe COVID-19 requiring hospitalization to analyze whether clinical outcomes and post-COVID-19 manifestations are associated with shorter TL.

Results
We analyzed 251 patients with PCR-confirmed COVID-19, hospitalized in the first months of the pandemics. We determined TL in PBL at admission by quantitative-PCR (qPCR) analysis in patients. A healthy cohort from the same area with a similar age range (n = 169) was used to calculate TL Z-scores. After hospital discharge, 144 COVID-19 survivors were followed-up for persistent COVID-19 manifestations. A second TL determination was performed in a smaller group of 63 patients 1 year later and compared with baseline TL.
Hospitalized COVID-19 patients had a decreased baseline age-adjusted TL Z-score compared to the reference group. No differences in Z-scores were observed in patients with different COVID-19 outcomes, classified as WHO ordinal scores. In 144 patients, followed for a median of 8 months, post-COVID manifestations were not associated to differences in TL. Persistence of lung radiographic abnormalities was associated with shorter baseline TL. In patients with a second TL determination, further telomere shortening (TS) was observed in 35% and telomere lengthening in 49%. Patients with further TS had suffered a more severe disease.

Conclusion
Shorter TL is associated with COVID-19 hospitalization but not with hospital clinical outcomes nor with persistent post-COVID-19 manifestations. Delayed resolution of radiographic lung abnormalities was also associated with shorter TL.