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"The limits of my language are the limits of my mind. All I know is what I have words for" (Wittgenstein). When learning something completely new, we connect the unknown term to an already existing part of our knowledge. We can only build new ideas and insights upon an existing conceptual foundation. In the field of statistics, we educators frequently find ourselves met with great confusion when teaching novices. These students, entirely unfamiliar with even basic statistics, must connect the introduced statistical terms within their personal existing networks of largely non-statistical knowledge. Lecturers, on the other hand, who are well versed in statistics, have deeply internalized the content to be taught and its relevant context. The juxtaposition of the two roles may produce amusement in a lecturer upon gaining insight into the word associations made by the statistical novices. For example, a ‘logistic regression’ does not involve the ‘shipping of goods in economically difficult times,’ though this might seem entirely reasonable and intuitive to the statistics learner. Other times, these different perspectives can lead to headaches and frustration for both learners and their lecturers. In this article, we illustrate how simple statistical terms are initially connected to a student’s pre-exiting knowledge and how these associations change after completing an introductory course in applied statistics. Furthermore, we emphasize the important difference between “term”, “approach”, and “context”. Understanding this fundamental distinction may help improve the communication between the lecturer and the learner. We offer a collection of practical tools for instructors to help promote students’ conceptual understanding in a supportive, mutually-beneficial learning environment.
Background and Objectives
Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established.
Methods
Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature.
Results
A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs.
Conclusion
The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores.
Objective:
The cervical mucus plugs are enriched with proteins of known immunological functions. We aimed to characterize the anti-HIV-1 activity of the cervical mucus plugs against a panel of different HIV-1 strains in the contexts of cell-free and cell-associated virus.
Design:
A cohort of consenting HIV-1-negative and HIV-1-positive pregnant women in labour was recruited from Mthatha General Hospital in the Eastern Cape province of South Africa, from whom the cervical mucus plugs were collected in 6 M guanidinium chloride with protease inhibitors and transported to our laboratories at −80 °C.
Methods:
Samples were centrifuged to remove insoluble material and dialysed before freeze--drying and subjecting them to the cell viability assays. The antiviral activities of the samples were studied using luminometric reporter assays and flow cytometry. Time-of-addition and BlaM-Vpr virus-cell fusion assays were used to pin-point the antiviral mechanisms of the cervical mucus plugs, before proteomic profiling using liquid chromatography-tandem mass spectrometry.
Results:
The proteinaceous fraction of the cervical mucus plugs exhibited anti-HIV-1 activity with inter-individual variations and some degree of specificity among different HIV-1 strains. Cell-associated HIV-1 was less susceptible to inhibition by the potent samples whenever compared with the cell-free HIV-1. The samples with high antiviral potency exhibited a distinct proteomic profile when compared with the less potent samples.
Conclusion:
The crude cervical mucus plugs exhibit anti-HIV-1 activity, which is defined by a specific proteomic profile.
Technological support options for the usage of Brazilian Açaí berries in the European Food Market
(2022)
The highly perishable fruit açaí grows on palm trees in northern Brazil and is colloquially known as a berry with high nutritional value. The seed of the drupe makes up around 85 percent of the fruits weight and only the pulp around the seed is used for human consumption. The manufacturing step after harvest includes the pulping and the preservation of the fruit. The preservation step is necessary, because the açaí pulp contains a high microbial load. There are several preservation processes including the use of chlorinated or ozonated water, alcoholic fermentation, pasteurization, freezing or dehydration. Those techniques are overall not very gentle and have the potential to leave residues in the final product, which can change its typical sensorial characteristics. Therefore, an experiment was conducted, to see if a relatively new gentle preservation method called PEF can reduce the microbial load in an açaí- smoothie.
For this purpose, a PEF-machine was built and verified based on the paper from HEINZ ET AL. [2003]. The self-built machine works efficiently, when there is a reduction of microorganisms like Escherichia coli in apple juice due to the induced Pulsed Electric Fields. If this is the case, the described experiment with açaí-smoothie can be carried out with the self-built PEF- machine. In this experiment the results of the validation of this PEF-machine were not comparable to those from the paper from HEINZ ET AL. [2003]. So, the self-built PEF-machine in Brazil did not work sufficiently. Hence, the experiment which should show that a reduction of microorganisms, such as Escherichia coli, in açaí-smoothie with PEF is possible, was performed in Germany. It was accrued out at ELEA with using the PEFPilotTM Dual. This experiment confirmed the assumption, that microorganisms can be reduced in açaí-smoothie with PEF. Escherichia coli was reduced by 2 logs, Saccharomyces cerevisiae by 3 logs and Lactobacillus plantarum by 6 logs. And a comparison between PEF and the known preservation methods for açaí showed that it can be a compatible alternative.
Moreover, the topic, how açaí fits into the European Food Market is answered within this paper. When offering açaí food products to the European population, ideas can be originated from the well-working Brazilian market. It can be helpful to mix açaí with known European fruits for a better acceptance by the people. Then açaí can help to meet the Europeans needs of the current time for fresh and healthy food, especially when preserved with PEF. Furthermore, it is important to work towards a sustainable supply chain system from the cultivation until the unloading at the destination in Europe. Sustainability is important for the integration in the European market, not only for environmental protection, but also in terms of social stability and marketing purposes. In addition, access requirements, further food-related regulations, and the seasonality of açaí present a major hurdle.
Building on this thesis, further papers shall be written, not only in the field of the preservation of the açaí pulp with PEF, but also in the direction of combined preservation methods for açaí, the sustainable usage of the açaí seeds, product innovations containing the Brazilian fruit or various market research.
Background
A pre-existing neurocognitive disorder (NCD) is a relevant factor for the outcome of surgical patients. To improve understanding of these conditions, we investigated the association between parameters of the cholinergic system and NCD.
Method
This investigation is part of the BioCog project (www.biocog.eu), which is a prospective multicenter observational study including patients aged 65 years and older scheduled for elective surgery. Patients with a Mini-Mental State Examination (MMSE) score ≤23 points were excluded. Neurocognitive disorder was assessed according to the fifth Diagnostic and Statistical Manual of Mental Disorders criteria. The basal forebrain cholinergic system volume (BFCSV) was assessed with magnetic resonance imaging, the peripheral cholinesterase (ChE) activities with point-of-care measurements, and anticholinergic load by analyzing the long-term medication with anticholinergic scales (Anticholinergic Drug Scale [ADS], Anticholinergic Risk Scale [ARS], Anticholinergic Cognitive Burden Scale [ACBS]). The associations of BFCSV, ChE activities, and anticholinergic scales with NCD were studied with logistic regression analysis, adjusting for confounding factors.
Results
A total of 797 participants (mean age 72 years, 42% females) were included. One hundred and eleven patients (13.9%) fulfilled criteria for mild NCD and 82 patients (10.3%) for major NCD criteria. We found that AcetylChE activity was associated with major NCD (odds ratio [95% confidence interval]: [U/gHB] 1.061 [1.010, 1.115]), as well as ADS score ([points] 1.353 [1.063, 1.723]) or ARS score, respectively ([points] 1.623 [1.100, 2.397]) with major NCD. However, we found no association between BFCSV or ButyrylChE activity with mild or major NCD.
Conclusions
AcetylChE activity and anticholinergic load were associated with major NCD. Future research should focus on the association of the cholinergic system and the development of postoperative delirium and postoperative NCD.
Preoperative medication use and development of postoperative delirium and cognitive dysfunction
(2021)
Postoperative delirium (POD) and postoperative (neuro-)cognitive disorder (POCD) are frequent and serious complications after operations. We aim to investigate the association between pre-operative polypharmacy and potentially inappropriate medications and the development of POD/POCD in elderly patients. This investigation is part of the European BioCog project (www.biocog.eu), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini-Mental State Examination score less than or equal to 23 points were excluded. POD was assessed up to 7 days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method (for the intensive care unit [ICU]), and a patient chart review. POCD was assessed 3 months after surgery with a neuropsychological test battery. Pre-operative long-term medication was evaluated in terms of polypharmacy (≥5 agents) and potentially inappropriate medication (defined by the PRISCUS and European list of potentially inappropriate medications [EU(7)-PIM] lists), and associations with POD and POCD were analyzed using logistic regression analysis. Eight hundred thirty-seven participants were included for analysis of POD and 562 participants for POCD. Of these, 165 patients (19.7%) fulfilled the criteria of POD and 60 (10.7%) for POCD. After adjusting for confounders, pre-operative polypharmacy and intake of potentially inappropriate medications could not be shown to be associated with the development of POD nor POCD. We found no associations between pre-operative polypharmacy and potentially inappropriate medications and development of POD and POCD. Future studies should focus on the evaluation of drug interactions to determine whether patients benefit from a pre-operative adjustment.
Background
Postoperative delirium (POD) is a frequent and serious complication after surgery. Evidence of a relationship between anticholinergic medication and the development of delirium is inconclusive, but studies on POD are rare.
Objectives
The objective of this study was to evaluate the anticholinergic load of preoperative medication in older adult patients and its association with the development of POD.
Methods
This investigation was part of the European BioCog project (http://www.biocog.eu), a prospective multicenter observational study in older adult surgical patients (ClinicalTrials.gov identifier: NCT02265263, 15 October 2014). Patients with a Mini–Mental State Examination score ≤ 23 points were excluded. POD was assessed up to 7 days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method and a patient chart review. The preoperative anticholinergic load was calculated using the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS) and the Anticholinergic Cognitive Burden Scale (ACBS), and associations with POD were analyzed using logistic regression analysis adjusting for age, comorbidities, duration of anesthesia and number of drugs used.
Results
In total, 837 participants were included for analysis, and 165 patients (19.7%) fulfilled the criteria of POD. After adjusting for confounders, we found no association between preoperative anticholinergic load and the development of POD (ADS [points] odds ratio [OR] 0.928; 95% confidence interval [CI] 0.749–1.150; ARS [points] OR 0.832; 95% CI 0.564–1.227; ACBS [points] OR 1.045; 95% CI 0.842–1.296).
Conclusion
This study found no association between the anticholinergic load of drugs used preoperatively and the development of POD in older adult patients without severe preexisting cognitive impairment. Future analyses should examine the influence of intra- and postoperative administration of anticholinergic drugs as well as dosages of and interactions between medications.
BACKGROUND:
Intraoperative electroencephalography (EEG) signatures related to the development of postoperative delirium (POD) in older patients are frequently studied. However, a broad analysis of the EEG dynamics including preoperative, postinduction, intraoperative and postoperative scenarios and its correlation to POD development is still lacking. We explored the relationship between perioperative EEG spectra-derived parameters and POD development, aiming to ascertain the diagnostic utility of these parameters to detect patients developing POD.
METHODS:
Patients aged ≥65 years undergoing elective surgeries that were expected to last more than 60 minutes were included in this prospective, observational single center study (Biomarker Development for Postoperative Cognitive Impairment [BioCog] study). Frontal EEGs were recorded, starting before induction of anesthesia and lasting until recovery of consciousness. EEG data were analyzed based on raw EEG files and downloaded excel data files. We performed multitaper spectral analyses of relevant EEG epochs and further used multitaper spectral estimate to calculate a corresponding spectral parameter. POD assessments were performed twice daily up to the seventh postoperative day. Our primary aim was to analyze the relation between the perioperative spectral edge frequency (SEF) and the development of POD.
RESULTS:
Of the 237 included patients, 41 (17%) patients developed POD. The preoperative EEG in POD patients was associated with lower values in both SEF (POD 13.1 ± 4.6 Hz versus no postoperative delirium [NoPOD] 17.4 ± 6.9 Hz; P = .002) and corresponding γ-band power (POD −24.33 ± 2.8 dB versus NoPOD −17.9 ± 4.81 dB), as well as reduced postinduction absolute α-band power (POD −7.37 ± 4.52 dB versus NoPOD −5 ± 5.03 dB). The ratio of SEF from the preoperative to postinduction state (SEF ratio) was ~1 in POD patients, whereas NoPOD patients showed a SEF ratio >1, thus indicating a slowing of EEG with loss of unconscious. Preoperative SEF, preoperative γ-band power, and SEF ratio were independently associated with POD (P = .025; odds ratio [OR] = 0.892, 95% confidence interval [CI], 0.808–0.986; P = .029; OR = 0.568, 95% CI, 0.342–0.944; and P = .009; OR = 0.108, 95% CI, 0.021–0.568, respectively).
CONCLUSIONS:
Lower preoperative SEF, absence of slowing in EEG while transitioning from preoperative state to unconscious state, and lower EEG power in relevant frequency bands in both these states are related to POD development. These findings may suggest an underlying pathophysiology and might be used as EEG-based marker for early identification of patients at risk to develop POD.
The benzodiazepine, midazolam, is one of the most frequently used sedatives in intensive care medicine, but it has an unfavorable pharmacokinetic profile when continuously applied. As a consequence, patients are frequently prolonged and more deeply sedated than intended. Due to its distinct pharmacological features, including a cytochrome P450-independent metabolization, intravenous lormetazepam might be clinically advantageous compared to midazolam. In this retrospective cohort study, we compared patients who received either intravenous lormetazepam or midazolam with respect to their survival and sedation characteristics. The cohort included 3314 mechanically ventilated, critically ill patients that received one of the two drugs in a tertiary medical center in Germany between 2006 and 2018. A Cox proportional hazards model with mortality as outcome and APACHE II, age, gender, and admission mode as covariates revealed a hazard ratio of 1.75 [95% CI 1.46–2.09; p < 0.001] for in-hospital mortality associated with the use of midazolam. After additionally adjusting for sedation intensity, the HR became 1.04 [95% CI 0.83–1.31; p = 0.97]. Thus, we concluded that excessive sedation occurs more frequently in critically ill patients treated with midazolam than in patients treated with lormetazepam. These findings require further investigation in prospective trials to assess if lormetazepam, due to its ability to maintain light sedation, might be favorable over other benzodiazepines for sedation in the ICU.
Background
There is no consensus on the instruments for diagnosis of post-intensive care syndrome (PICS). We present a proposal for a set of outcome measurement instruments of PICS in outpatient care.
Methods
We conducted a three-round, semi-structured consensus-seeking process with medical experts, followed each by exploratory feasibility investigations with intensive care unit survivors (n1 = 5; n2 = 5; n3 = 7). Fourteen participants from nine stakeholder groups participated in the first and second consensus meeting. In the third consensus meeting, a core group of six clinical researchers refined the final outcome measurement instrument set proposal.
Results
We suggest an outcome measurement instrument set used in a two-step process. First step: Screening with brief tests covering PICS domains of (1) mental health (Patient Health Questionnaire-4 (PHQ-4)), (2) cognition (MiniCog, Animal Naming), (3) physical function (Timed Up-and-Go (TUG), handgrip strength), and (4) health-related quality of life (HRQoL) (EQ-5D-5L). Single items measure subjective health before and after the intensive care unit stay. If patients report new or worsened health problems after intensive care unit discharge and show relevant impairment in at least one of the screening tests, a second extended assessment follows: (1) Mental health (Patient Health Questionnaire-8 (PHQ-8), Generalized Anxiety Disorder Scale-7 (GAD-7), Impact of Event Scale – revised (IES-R)); (2) cognition (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Trail Making Test (TMT) A and B); (3) physical function (2-Minute Walk Test (2-MWT), handgrip strength, Short Physical Performance Battery (SPPB)); and (4) HRQoL (EQ-5D-5L, 12-Item WHO Disability Assessment Schedule (WHODAS 2.0)).
Conclusions
We propose an outcome measurement instrument set used in a two-step measurement of PICS, combining performance-based and patient-reported outcome measures. First-step screening is brief, free-of-charge, and easily applicable by health care professionals across different sectors. If indicated, specialized healthcare providers can perform the extended, second-step assessment. Usage of the first-step screening of our suggested outcome measurement instrument set in outpatient clinics with subsequent transfer to specialists is recommended for all intensive care unit survivors. This may increase awareness and reduce the burden of PICS.