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Repurposing nitric oxide donating drugs in cancer therapy through immune modulation

J Exp Clin Cancer Res. 2023 Jan 14;42(1):22. doi: 10.1186/s13046-022-02590-0.

ABSTRACT

BACKGROUND: Nitric oxide-releasing drugs are used for cardiovascular diseases; however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice.

METHODS: The effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA sequencing.

RESULTS: Low doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NOD/SCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8+ T cells with activation gene signatures, as indicated by single-cell RNA sequencing. Flow cytometry analysis confirmed an increase in infiltrating CD8+ T cells and dendritic cells. The antitumor effect of nitric oxide donors was abolished by depletion of CD8+ T cells, indicating the requirement for CD8+ T cells. Tumor inhibition correlated with a decrease in a subtype of protumor macrophages and an increase in a subset of Arg1-positive macrophages expressing antitumor gene signatures. The increase in this subset of macrophages was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin induced an additive cancer therapeutic effect in two immunocompetent animal models. The enhanced therapeutic effect was accompanied by an increase in the cells expressing the gene signature of NK cell.

CONCLUSIONS: Low concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8+ T cells are essential for antitumor effects. In addition, low-dose nitric oxide donors may be combined with chemotherapeutic drugs in cancer therapy in the future.

PMID:36639681 | DOI:10.1186/s13046-022-02590-0

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Bacteria spatial tracking in Urban Park soils with MALDI-TOF Mass Spectrometry and Specific PCR

BioData Min. 2023 Jan 14;16(1):1. doi: 10.1186/s13040-022-00318-6.

ABSTRACT

Urban parks constitute one of the main leisure areas, especially for the most vulnerable people in our society, children, and the elderly. Contact with soils can pose a health risk. Microbiological testing is a key aspect in determining whether they are suitable for public use. The aim of this work is to map the spatial distribution of potential dangerous Enterobacteria but also bioremediation useful (lipase producers) isolates from soils in an urban park in the area of Valencia (Spain). To this end, our team has collected 25 samples of soil and isolated 500 microorganisms, using a mobile application to collect information of the soil samples (i.e. soil features, temperature, humidity, etc.) with geolocation. A combined protocol including matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) and 16S rDNA sequencing PCR has been established to characterize the isolates. The results have been processed using spatial statistical techniques (using Kriging method), taking into account the number of isolated strains, also proving the reactivity against standard pathogenic bacterial strains (Escherichia coli, Bacillus cereus, Salmonella, Pseudomonas and Staphylococcus aureus), and have increased the number of samples (to 896 samples) by interpolating spatially each parameter with this statistical method. The combined use of methods from biology and computer science allows the quality of the soil in urban parks to be predicted in an agile way, which can generate confidence in its use by citizens.

PMID:36639651 | DOI:10.1186/s13040-022-00318-6

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Substance use disorder and alcohol consumption patterns among Dutch physicians: a nationwide register-based study

Addict Sci Clin Pract. 2023 Jan 13;18(1):4. doi: 10.1186/s13722-022-00356-9.

ABSTRACT

PURPOSE: Problematic substance use and Substance Use Disorders (SUD) are common in all layers of the population. Several studies suggest higher prevalence rates of problematic substance use among physicians compared to the general population, which is harmful for themselves and potentially impairs quality of care. However, nationwide comparison with a highly educated reference group is lacking. Using nationwide register data, this study compared the prevalence of clinical SUD diagnoses and alcohol consumption patterns between physicians and a highly educated reference population.

METHODS: A retrospective study was performed using registry data from 2011 up to and including 2019, provided by Statistics Netherlands. From the data, a highly educated reference group was selected and those with an active medical doctor registration were identified as “physicians”. Clinical SUD diagnoses were identified by DSM-IV codes in mental healthcare registries. Benchmark analyses were performed, without statistical testing, to compare the prevalence of SUD diagnoses and alcohol consumption patterns between physicians and the reference population.

RESULTS: Clinical SUD diagnoses were found among 0.3% of the physicians and 0.5% of the reference population, with higher proportions of sedative use disorder among physician patients. Among drinkers, the prevalence rates of heavy and excessive drinking were respectively 4.0% and 4.3% for physicians and 7.7% and 6.4% for the reference population.

CONCLUSION: Prevalence rates of SUD diagnoses were fairly comparable between physicians and the highly educated reference population, but physicians displayed more favorable alcohol consumption patterns. The use of sedatives by physicians might deserve attention, given the relatively higher prevalence of sedative use disorder among physicians. Overall, we observed relatively low prevalence rates of SUD diagnoses and problematic alcohol use, which may reflect a treatment gap and social desirable answers.

PMID:36639645 | DOI:10.1186/s13722-022-00356-9

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Implementing electronic patient reported outcomes in inflammatory bowel disease: patient participation, score reliability and validity

Health Qual Life Outcomes. 2023 Jan 13;21(1):2. doi: 10.1186/s12955-023-02087-0.

ABSTRACT

BACKGROUND: Patient-reported outcome measures (PROMs) are recommended for assessing patient-centered outcomes in inflammatory bowel disease (IBD). The main aims were to assess the level of participation in an electronic PROM (ePROM) data collection system among patients with IBD, and evaluate reliability and validity of the resulting scores.

METHODS: Patients included in the IBD registry of Maccabi Healthcare Services, a state-mandated healthcare provider for over 2.6 million people in Israel, were invited to complete the IBD-Control measure and a general health item, with follow-up ePROMs at 3 and 6 months including a global rating of change item. Descriptive statistics were used to compare patient characteristics by participation rate, and assess survey completion time. Initial scores were assessed for internal consistency reliability using Cronbach’s alpha. Test-retest reliability was assessed using the intraclass correlation coefficient from paired scores of patients identified as unchanged between the initial and first follow-up. Construct validity was assessed by the ability of IBD-control scores to discriminate between patient sub-groups in expected ways. Empirical validity was assessed using ePROM score correlations with laboratory markers of disease activity. Score coverage was also assessed.

RESULTS: A total of 13,588 patients were invited to participate [Mean age = 49 years (SD = 17); females = 51%]. Participation rate was 31.5%. Participants compared to non-participants were slightly older, were more likely to be female, to have a history of biologic treatment, to have higher socio-economic status, and to be more experienced in the usage of the digital patient portal. Median survey completion time was approximately 1:30 min. Internal consistency and test-retest reliability were 0.86 and 0.98, respectively. Scores discriminated between patient sub-groups in clinically expected ways, with expected correlations to laboratory markers of disease activity. A notable ceiling effect was observed (> 15%) for IBD-Control scores.

CONCLUSIONS: Feasibility, reliability, and validity of the ePROM system was supported for measuring the level of perceived disease control in patients diagnosed with IBD in Israel. Additional research is needed to identify ways to increase patient participation, assess clinical implications of the identified measurement ceiling of the IBD-control, and evaluate the added value of the derived scores in support of clinical decision making.

PMID:36639633 | DOI:10.1186/s12955-023-02087-0

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Behavioural Change Techniques in Health Coaching-Based Interventions for Type 2 Diabetes: A Systematic Review and Meta-Analysis

BMC Public Health. 2023 Jan 13;23(1):95. doi: 10.1186/s12889-022-14874-3.

ABSTRACT

BACKGROUND: Given the high rates globally of Type 2 Diabetes Mellitus (T2DM), there is a clear need to target health behaviours through person-centred interventions. Health coaching is one strategy that has been widely recognised as a tool to foster positive behaviour change. However, it has been used inconsistently and has produced mixed results. This systematic review sought to explore the use of behaviour change techniques (BCTs) in health coaching interventions and identify which BCTs are linked with increased effectiveness in relation to HbA1C reductions.

METHODS: In line with the PICO framework, the review focused on people with T2DM, who received health coaching and were compared with a usual care or active control group on HbA1c levels. Studies were systematically identified through different databases including Medline, Web of science, and PsycINFO searches for relevant randomised controlled trials (RCTs) in papers published between January 1950 and April 2022. The Cochrane collaboration tool was used to evaluate the quality of the studies. Included papers were screened on the reported use of BCTs based on the BCT taxonomy. The effect sizes obtained in included interventions were assessed by using Cohen’s d and meta-analysis was used to estimate sample-weighted average effect sizes (Hedges’ g).

RESULTS: Twenty RCTs with a total sample size of 3222 were identified. Random effects meta-analysis estimated a small-sized statistically significant effect of health coaching interventions on HbA1c reduction (g+ = 0.29, 95% CI: 0.18 to 0.40). A clinically significant HbA1c decrease of ≥5 mmol/mol was seen in eight studies. Twenty-three unique BCTs were identified in the reported interventions, with a mean of 4.5 (SD = 2.4) BCTs used in each study. Of these, Goal setting (behaviour) and Problem solving were the most frequently identified BCTs. The number of BCTs used was not related to intervention effectiveness. In addition, there was little evidence to link the use of specific BCTs to larger reductions in HbA1c across the studies included in the review; instead, the use of Credible source and Social reward in interventions were associated with smaller reductions in HbA1c.

CONCLUSION: A relatively small number of BCTs have been used in RCTs of health coaching interventions for T2DM. Inadequate, imprecise descriptions of interventions and the lack of theory were the main limitations of the studies included in this review. Moreover, other possible BCTs directly related to the theoretical underpinnings of health coaching were absent. It is recommended that key BCTs are identified at an early stage of intervention development, although further research is needed to examine the most effective BCTs to use in health coaching interventions.

TRIAL REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021228567 .

PMID:36639632 | DOI:10.1186/s12889-022-14874-3

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Psychiatric presentations and admissions during the first wave of Covid-19 compared to 2019 in a psychiatric emergency department in Berlin, Germany: a retrospective chart review

BMC Psychiatry. 2023 Jan 14;23(1):38. doi: 10.1186/s12888-023-04537-x.

ABSTRACT

BACKGROUND: Most studies agree that the Covid-19 pandemic and the subsequent lockdown had a negative impact on mental health. On the other hand, international studies have shown that psychiatric emergency departments (pED) experienced a decrease in presentations and admissions.

METHODS: Retrospective chart review of all pED presentations and admissions during the first wave of Covid-19 pandemic in Germany (Covid-19 period: 3/2/20 to 05/24/20) in a psychiatric hospital in Berlin compared to 1 year earlier (pre-Covid-19 period). Descriptive statistics and logistic regression were performed.

RESULTS: We observed no statistical significant changes in overall pED presentations and overall hospital admissions during the Covid-19 period compared to the pre-Covid-19 period (813 vs. 894, – 9.1%, p = 0.064 and (363 vs. 437, – 16.9%, p = 0.080 respectively). In the subgroup analysis, less patients with depressive disorders (p = 0.035) and with personality disorders (p = 0.002) presented to the pED, a larger number of presentations with schizophrenia was observed (p = 0.020). In the Covid-19 period, less patients with substance use disorder and paranoid schizophrenia were admitted to the hospital via the pED than in the pre-Covid-19 period (p = 0.035 and p = 0.006, respectively). Bed capacity was reduced in the Covid-19 period by – 32.8% (p < 0.001). Presentations in police custody were 13.7% (p = 0.029) higher during the Covid-19 compared to pre-Covid-19 period, with higher rates in female presentations (p = 0.008) and suicide attempts (p = 0.012) and less hospital admissions (p = 0.048). Logistic regression analyses revealed that positive predictors for pED presentation during Covid-19 period were police custody (p < 0.001), being redirected from another hospital (p < 0.001), suicide attempt (p = 0.038), suicidal thoughts (p = 0.004), presentation with paranoid schizophrenia (p = 0.001) and bipolar and manic disorders (p = 0.004), negative predictors were hospital admission (p < 0.001), depressive disorders (p = 0.021) and personality disorders (p < 0.001).

CONCLUSIONS: A larger number of presentations in police custody during the Covid-19 period may represent untreated medical needs. This was seen predominantly in female patients, suggesting this subgroup might have suffered particularly under lockdown measures. Patients with paranoid schizophrenia were the only subgroup, which increased in absolute numbers, also suggesting a particular lockdown effect. Reduced bed capacity due to infection curbing measures is suggestive to have played an important role in augmenting the threshold for hospital admissions.

PMID:36639626 | DOI:10.1186/s12888-023-04537-x

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Ultrasound measurement of optic nerve sheath diameter in a healthy adult Colombian population

BMC Neurol. 2023 Jan 13;23(1):16. doi: 10.1186/s12883-023-03062-4.

ABSTRACT

BACKGROUND: Measurement of the optic nerve sheath diameter (ONSD) provides a rapid, safe, and easy method for detecting increased intracranial pressure (ICP). However, the normal mean and upper limit values may vary according to sex, age, ethnicity, and ultrasound technique.

AIM: We aimed to obtain the mean ONSD in a healthy Colombian adult population and to correlate it with demographic and anthropometric measures.

METHODS: In a prospective study using a 10-13 MHz linear ultrasound probe, eye transverse diameter (ETD) and ONSD in the transverse (ONSD-TP) and sagittal planes (ONSD-SP) were measured in healthy adult volunteers in Bogota, Colombia.

RESULTS: A total of 100 healthy subjects were included, with a mean age of 26,7 ± 8,3 years and 62 women. The mean ETD, ONSD-TP and ONSD-SP was 23.11 mm (95% confidence interval (CI): 22.90 mm-23.32 mm), 3.96 mm (95% CI: 3.85 mm-4.07 mm) and 4.0 mm (95% CI: 3.90 mm-4.11 mm), respectively. The ONSD in both planes ranged from 2.35 mm to 5.20 mm. There was a significant correlation between ONSD-SP and ONSD-TP (p < 0.0001) but no correlation between the ocular measures and demographic or anthropometric variables (p > 0.05). The intraclass correlation between the eyes was statistically significant.

CONCLUSION: Our study shows that ultrasound-measured ONSD in healthy adults in Colombia is similar to that found worldwide. An ONSD of 5.5 mm may be considered the upper limit for healthy adults in Colombia. ONSD can be measured in either plane; there is a good correlation between the two eyes; and ONSD is not modified by demographic or anthropometric characteristics.

PMID:36639617 | DOI:10.1186/s12883-023-03062-4

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Missing the forest-plot for the trees

Diabetologia. 2023 Jan 14. doi: 10.1007/s00125-022-05862-8. Online ahead of print.

ABSTRACT

Systematic reviews and meta-analyses are methods increasingly used in biomedical research since their introduction in the 1970s. They serve to replace other non-systematic and cherry-picked narrative reviews, which are highly variable in their approach, structure and content. Their increase in popularity parallels the increase in overall scientific output, and when properly conducted, systematic reviews can contribute highly impactful summaries of a fast-growing evidence base. Meta-analyses offer statistical summaries, called forest plots, which similarly provide a powerful synopsis unachievable by individual studies. Thus, it is not difficult to imagine why systematic reviews are published more often. Should scientists be concerned by the accelerated output of research, from systematic reviews or other? If quantity comes at the expense of quality, then yes, of course; but should important manuscripts be rationed out otherwise? A new scientific technique can seem scary at first, especially to the researcher who is unfamiliar with its application or uncertain of its validity. In that case, we should become familiar with new and popular methods, and understand their strengths and limitations. There is a rightful place for systematic reviews and meta-analyses among respectable research tools. Importantly, however, despite standard operating procedures and best practices, the quality of systematic reviews today is highly variable, warranting serious concerns for quantity exceeding quality. Therefore, the appropriate response should be to instil researchers with an appreciation for the complexity of conducting and interpreting a systematic review and meta-analysis, to create more knowledgeable authors, reviewers and editors, who collectively will improve, rather than dismiss, these important scientific contributions.

PMID:36639571 | DOI:10.1007/s00125-022-05862-8

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Incidence of muscle wasting in the critically ill: a prospective observational cohort study

Sci Rep. 2023 Jan 13;13(1):742. doi: 10.1038/s41598-023-28071-8.

ABSTRACT

Loss of muscle mass occurs rapidly during critical illness and negatively affects quality of life. The incidence of clinically significant muscle wasting in critically ill patients is unclear. This study aimed to assess the incidence of and identify predictors for clinically significant loss of muscle mass in this patient population. This was a single-center observational study. We used ultrasound to determine the rectus femoris cross-sectional area (RFcsa) on the first and seventh day of ICU stay. The primary outcome was the incidence of significant muscle wasting. We used a logistic regression model to determine significant predictors for muscle wasting. Ultrasound measurements were completed in 104 patients. Sixty-two of these patients (59.6%) showed ≥ 10% decreases in RFcsa. We did not identify any predictor for significant muscle wasting, however, age was of borderline significance (p = 0.0528). The 28-day mortality rate was higher in patients with significant wasting, but this difference was not statistically significant (30.6% versus 16.7%; p = 0.165). Clinically significant muscle wasting was frequent in our cohort of patients. Patient age was identified as a predictor of borderline significance for muscle wasting. The results could be used to plan future studies on this topic.Trial registration: ClinicalTrials.gov NCT03865095, date of registration: 06/03/2019.

PMID:36639540 | DOI:10.1038/s41598-023-28071-8

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Screening of Mild Cognitive Impairment Through Conversations With Humanoid Robots: Exploratory Pilot Study

JMIR Form Res. 2023 Jan 13;7:e42792. doi: 10.2196/42792.

ABSTRACT

BACKGROUND: The rising number of patients with dementia has become a serious social problem worldwide. To help detect dementia at an early stage, many studies have been conducted to detect signs of cognitive decline by prosodic and acoustic features. However, many of these methods are not suitable for everyday use as they focus on cognitive function or conversational speech during the examinations. In contrast, conversational humanoid robots are expected to be used in the care of older people to help reduce the work of care and monitoring through interaction.

OBJECTIVE: This study focuses on early detection of mild cognitive impairment (MCI) through conversations between patients and humanoid robots without a specific examination, such as neuropsychological examination.

METHODS: This was an exploratory study involving patients with MCI and cognitively normal (CN) older people. We collected the conversation data during neuropsychological examination (Mini-Mental State Examination [MMSE]) and everyday conversation between a humanoid robot and 94 participants (n=47, 50%, patients with MCI and n=47, 50%, CN older people). We extracted 17 types of prosodic and acoustic features, such as the duration of response time and jitter, from these conversations. We conducted a statistical significance test for each feature to clarify the speech features that are useful when classifying people into CN people and patients with MCI. Furthermore, we conducted an automatic classification experiment using a support vector machine (SVM) to verify whether it is possible to automatically classify these 2 groups by the features identified in the statistical significance test.

RESULTS: We obtained significant differences in 5 (29%) of 17 types of features obtained from the MMSE conversational speech. The duration of response time, the duration of silent periods, and the proportion of silent periods showed a significant difference (P<.001) and met the reference value r=0.1 (small) of the effect size. Additionally, filler periods (P<.01) and the proportion of fillers (P=.02) showed a significant difference; however, these did not meet the reference value of the effect size. In contrast, we obtained significant differences in 16 (94%) of 17 types of features obtained from the everyday conversations with the humanoid robot. The duration of response time, the duration of speech periods, jitter (local, relative average perturbation [rap], 5-point period perturbation quotient [ppq5], difference of difference of periods [ddp]), shimmer (local, amplitude perturbation quotient [apq]3, apq5, apq11, average absolute differences between the amplitudes of consecutive periods [dda]), and F0cov (coefficient of variation of the fundamental frequency) showed a significant difference (P<.001). In addition, the duration of response time, the duration of silent periods, the filler period, and the proportion of fillers showed significant differences (P<.05). However, only jitter (local) met the reference value r=0.1 (small) of the effect size. In the automatic classification experiment for the classification of participants into CN and MCI groups, the results showed 66.0% accuracy in the MMSE conversational speech and 68.1% accuracy in everyday conversations with the humanoid robot.

CONCLUSIONS: This study shows the possibility of early and simple screening for patients with MCI using prosodic and acoustic features from everyday conversations with a humanoid robot with the same level of accuracy as the MMSE.

PMID:36637896 | DOI:10.2196/42792