Protocol adherence for continuously titrated interventions in randomized trials: an overview of the current methodology and case study.

BACKGROUND: The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration. DISCUSSION: Building upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open-label randomized controlled trial of higher (75-80 mmHg) versus lower (60-65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically-justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically-justified protocol deviations acknowledges clinically sensible bedside decision-making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence. CONCLUSIONS: In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured.

Exploring attitudes toward eating disorders among elite athlete support personnel.

To date, little is known about the beliefs, attitudes, and experiences of athlete support personnel (ASP) working in elite sport toward disordered eating (DE) and eating disorders (EDs). This study seeks to explore this area of mental health, employing an attribution model of stigma as a conceptual lens. Interviews were undertaken with 14 service providers (seven males and seven females) working in high-performance sport in Ireland. In contrast to previous research in the general population, findings revealed that sport-based personnel, in the main, did not hold the individual responsible for the development of their eating disorder. The predominant emotional response of those who had worked with an athlete with a known or suspected eating disorder was anxiety and worry. In line with the findings of previous studies with other health professionals, negative views on the prognosis of those with EDs were expressed by the ASP. Furthermore, confidentiality was found to be a significant barrier to bringing athletes' disclosure of problematic eating or exercise behavior to the fore. The findings of this study add to the limited research exploring attitudes toward EDs in sport and highlights the importance of greater education and openness toward this particular mental health problem.

Advertising and general dental practice: how compliant are practice websites in Australia with legal requirements?

BACKGROUND: The Australian Health Practitioner Regulation Agency (AHPRA) requires general dental practitioners (GDPs) to agree to regulatory advertising guidelines on initial registration and annual renewal. The aim of this study was to determine the compliance of GDPs websites to these requirements. METHODS: A representative sample of GDPs websites from each state and territory in Australia was based on the total AHPRA registrant distribution. Assessment of compliance was used across five domains consisting of 17 criteria related to AHPRA's advertising of regulated health services guidelines, as well as section 133 of the National Law. Inter-rater reliability was estimated using Fleiss's Kappa. RESULTS: One hundred and ninety-two GDPs websites were reviewed with 85% non-compliant with at least one of the legal and regulatory requirements relating to advertising. Of these websites, 52% displayed false and misleading information, 12.8% had offers and inducement without clear terms and conditions, 11.5% used written testimonials, 33.9% created unrealistic expectation of benefit and 39.6% encouraged indiscriminate and unnecessary use of health services. CONCLUSIONS: More than 85% of GDP websites in Australia did not comply with legal and regulatory requirements related to advertising. A multi-stakeholder approach involving AHPRA, professional dental bodies and dental registrants is necessary to improve compliance.

The quality and readability of online molar incisor hypomineralization patient education materials: a systematic analysis.

BACKGROUND: Molar incisor hypomineralization (MIH) is estimated to affect 14% of children worldwide. It is crucial that patients and their families have access to easily comprehensible and reliable MIH-relevant information. This study aims to determine the quality, reliability and readability of online patient education materials about MIH. METHODS: A systematic search strategy was adopted. Five validated tools were used to assess the content of the 21 websites that satisfied inclusion/exclusion criteria. Data analyses were applied via GraphPad Prism software version 9 (GraphPad Software, San Diego, CA, USA). RESULTS: Five (23.8%) websites only satisfied the criteria for understandability and two (9.5%) websites satisfied the criteria for actionability using the Patient Education Materials Assessment Tool (PEMAT). No website contained the Health on the Net (HON)Code Seal and the mean (SD) Journal of the American Medical Association number of benchmarks per website was 1.33/4 (1.02). All websites failed to reach recommended minimum readability levels. Higher PEMAT scores were associated with 'easier' readability. CONCLUSIONS: Online patient education materials related to MIH are lacking in quality and reliability, and are too difficult for most to read easily. The authors of MIH-related online content should consider reference to quality of information tools when developing patient education materials.

Eruption disturbances in the mixed dentition: orthodontic considerations for primary dental care.

The primary dental care clinician is in a prime position to identify deviations from normal dental development. Disturbances can affect any new erupting tooth. The objective of this narrative review is to describe several situations in which eruption disturbances can arise during the mixed dentition. It will provide an overview of the orthodontic considerations of these disturbances in addition to key summary points on interceptive management, based on the best available evidence.

Effectiveness of tongue-tie assessment tools in diagnosing and fulfilling lingual frenectomy criteria: a systematic review.

It is unclear how effective tongue-tie classification assessment tools are in diagnosing symptomatic tongue-tie and fulfilling lingual frenectomy criteria. The purpose of this systematic review is to determine and evaluate any association between tongue-tie severity, as measured by pre-treatment assessment tools, and post-operative outcome following tongue-tie division. PubMed, EMBASE, and the Cochrane search engines were used to retrieve articles published between 1947 and 2021. Included studies consisted of patients with symptomatic tongue-tie, assessment by either the Coryllos, Kotlow, or Hazelbaker Assessment Tool for Lingual Frenulum Function (HATLFF) classification tool, and tongue-tie division. A total of 205 abstracts were identified; 31 studies met the criteria for a full-text review, of which, only 14 studies met the criteria for data extraction and analysis. Six studies used the HATLFF, 2 studies used the Kotlow, 5 studies used the Coryllos, and 1 study used a combination of both Kotlow and Coryllos methods. Significant heterogeneity was evident across all studies. No statistical correlation between the two variables could be determined. Although tongue-tie division procedures appear to provide benefits in breastfeeding and speech, there are no data to suggest a statistically significant association between the severity of tongue-tie, and the correct identification of patients who would benefit from tongue-tie division. © 2022 Australian Dental Association.

An assessment of the treatment information contained within the websites of direct-to-consumer orthodontic aligner providers.

BACKGROUND: The use of direct-to-consumer (DTC) orthodontic aligners is growing. The purpose of this study was to evaluate the quality of information contained within the websites of DTC orthodontic aligner providers. METHODS: Websites that satisfied inclusion criteria were assessed for the presence of specific treatment-related features. Four validated quality of information instruments and readability tools were used to evaluate the content of the websites. Descriptive statistical analyses and intra-examiner reliability tests were performed. RESULTS: Twenty-one websites were evaluated. Few websites referred to the need for pre-treatment dental health (38.1%) and indefinite post-treatment retention (23.8%). Most websites (95.2%) were categorized as either 'poor' or 'very poor' according to their DISCERN scores. DISCERN items regarding information bias and treatment risks scored particularly poorly. Cohen's kappa intra-examiner reliability testing for DISCERN scores was 0.81-0.89. Three websites honoured two out of the four Journal of the American Medical Association benchmarks and 18 honoured one benchmark only. The readability scores indicated 'difficult to read' content. CONCLUSIONS: The quality of information contained within the websites of DTC orthodontic aligner providers is poor. Patient consent for DTC aligner treatment based solely on the information contained within the websites is likely to be invalid.

Overcoming the barriers experienced in conducting a medication trial in adults with aggressive challenging behaviour and intellectual disabilities.

BACKGROUND: Aggressive challenging behaviour in people with intellectual disability (ID) is frequently treated with antipsychotic drugs, despite a limited evidence base. METHOD: A multi-centre randomised controlled trial was undertaken to investigate the efficacy, adverse effects and costs of two commonly prescribed antipsychotic drugs (risperidone and haloperidol) and placebo. RESULTS: The trial faced significant problems in recruitment. The intent was to recruit 120 patients over 2 years in three centres and to use a validated aggression scale (Modified Overt Aggression Scale) score as the primary outcome. Despite doubling the period of recruitment, only 86 patients were ultimately recruited. CONCLUSIONS: Variation in beliefs over the efficacy of drug treatment, difficulties within multidisciplinary teams and perceived ethical concerns over medication trials in this population all contributed to poor recruitment. Where appropriate to the research question cluster randomised trials represent an ethically and logistically feasible alternative to individually randomised trials.

Web-based information on orthodontic clear aligners: a qualitative and readability assessment.

BACKGROUND: Data regarding the quality of information (QOI) related to orthodontic clear aligners (OCAs) on the internet are lacking. The aim of the present investigation was to assess the quality and readability of websites providing information regarding OCAs to prospective patients. METHODS: Three search terms were entered separately into three search engines. Four validated QOI instruments were used to determine the QOI and readability of the content contained within the websites that satisfied predetermined criteria. Descriptive statistical analyses and intrarater testing for DISCERN scores were calculated. RESULTS: Forty-nine websites satisfied inclusion/exclusion criteria. General dentists (44.9%) and specialist orthodontists (26.5%) authored the majority of websites. One website contained the Health on the Net (HON) code seal. Cohen's kappa for DISCERN scores was good (0.87). The overall mean (SD) DISCERN score was 38.55 (8.00)/80, range 26-60. The websites authored by 'Direct-to-consumer' OCA providers recorded the lowest DISCERN mean score (33/80). One website contained all four Journal of the American Medical Association (JAMA) benchmarks. The mean (SD) Flesch Reading Ease score was 53.92 (9.08), range 36-82.5. CONCLUSIONS: The QOI of the website content related to OCAs is poor and is 'fairly difficult' to read. Website authors should consider using QOI instruments and readability tools to enable the delivery of evidence-based and easily readable information regarding OCAs to prospective patients.

An evaluation of the conservative dual-criterion method for teaching university students to visually inspect AB-design graphs.

The present study evaluated the effects of both a traditional lecture and the conservative dual-criterion (CDC) judgment aid on the ability of 6 university students to visually inspect AB-design line graphs. The traditional lecture reliably failed to improve visual inspection accuracy, whereas the CDC method substantially improved the performance of each participant.

Neither baseline tests of molecular hypercoagulability nor D-dimer levels predict deep venous thrombosis in critically ill medical-surgical patients.

OBJECTIVE: Predicting patients who are harboring asymptomatic deep venous thrombosis (DVT), or who are at particular risk of developing DVT, is a desirable clinical goal since prevention or early treatment of DVT might reduce the risk of fatal pulmonary embolism. Thus validation of simple laboratory tests that reliably predict venous thromboembolism (VTE) would be clinically very important. Tests that might be useful for these applications include markers of hypercoagulability (predicting patients at risk of DVT) and D-dimer (predicting which patients may have acute DVT). METHODS: In a prospective cohort study we measured a panel of hypercoagulability markers at the time of ICU admission, and six commercial D-dimer assays were performed serially during the ICU stay in medical-surgical ICU patients who were screened for DVT with biweekly lower limb compression ultrasonography. Ultrasonography was also performed at the time of any clinically suspected DVT events. We matched cases with DVT with controls without DVT for length of stay in the ICU to generate receiver operating characteristics (ROC) curves. RESULTS: One hundred ninety-seven patients were enrolled. Blood was collected on a total of 763 occasions (median number of occasions per patient: 3, range 1-21). None of the assays predicted DVT, as indicated by the areas under the ROC curves, that did not differ significantly from 50%. CONCLUSION: In critically ill patients, neither tests of hypercoagulability nor D-dimer levels predict patients at risk of DVT and thus they should not be used to guide diagnostic testing for DVT.

Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insufficiency.

PURPOSE: Thromboprophylaxis with low-molecular-weight heparin (LMWH) may be more effective than unfractionated heparin but also more likely to bioaccumulate and potentially cause bleeding in patients with renal insufficiency. The objectives of this study were to assess, among medical-surgical patients in the intensive care unit receiving dalteparin 5,000 IU daily for thromboprophylaxis, (1) the relationship between renal dysfunction and LMWH bioaccumulation as measured by trough anti-Xa levels, (2) the relationship between renal dysfunction and risk of bleeding as measured by a surrogate marker (peak anti-Xa levels), and (3) the relationship between anti-Xa levels, bleeding events, and thrombotic events. MATERIALS AND METHODS: In this prospective single-center cohort study, we enrolled patients 18 years or older, expected to stay 72 hours or longer, and with a creatinine clearance 30 mL/min or higher at intensive care unit admission. We administered 5,000 IU dalteparin subcutaneously each day. The main phase 1 objective was to detect bioaccumulation of dalteparin by measuring trough anti-Xa levels (22-23 hours post dalteparin). The main phase 2 objective was to examine the relationship between renal dysfunction and peak anti-Xa levels (4 hours post dalteparin). We recorded creatinine clearance daily and bleeding and thrombotic events, blinded to anti-Xa levels. RESULTS: We enrolled 19 patients aged 62.7 (13.2) years with an APACHE II score of 23.5 (9.4). We measured trough anti-Xa levels on 185 occasions in 19 patients; we measured peak anti-Xa levels on 113 occasions in 11 patients. We identified no bioaccumulation of LMWH in this study, as detected by trough anti-Xa levels. Most peak anti-Xa levels were in the conventional prophylactic range. CONCLUSIONS: When administered in prophylactic doses to critically ill patients with a wide range of calculated creatinine clearances, we found no evidence of bioaccumulation of dalteparin. If dalteparin does not bioaccumulate, it may be an attractive alternative agent for thromboprophylaxis.

CFP, the putative cercosporin transporter of Cercospora kikuchii, is required for wild type cercosporin production, resistance, and virulence on soybean.

Many species of the fungal genus Cercospora, including the soybean pathogen C. kikuchii, produce the phytotoxic polyketide cercosporin. Cercosporin production is induced by light. Previously, we identified several cDNA clones of mRNA transcripts that exhibited light-enhanced accumulation in C. kikuchii. Targeted disruption of the genomic copy of one of these, now designated CFP (cercosporin facilitator protein), results in a drastic reduction in cercosporin production, greatly reduced virulence of the fungus to soybean, and increased sensitivity to exogenous cercosporin. Sequence analysis of CFP reveals an 1,821-bp open reading frame encoding a 65.4-kDa protein similar to several members of the major facilitator superfamily (MFS) of integral membrane transporter proteins known to confer resistance to various antibiotics and toxins in fungi and bacteria. We propose that CFP encodes a cercosporin transporter that contributes resistance to cercosporin by actively exporting cercosporin, thus maintaining low cellular concentrations of the toxin.

Strategies of invasive ventilatory support in ARDS.

Acute respiratory distress syndrome is a common cause of morbidity and mortality in intensive care units. For the most part, the mortality of this syndrome has arguably not decreased since the syndrome was originally described. One of the major reasons for this lack of reduction in mortality may be related to adherence to more traditional ventilatory strategies that have the potential to cause ventilator-induced lung injury. Ventilator strategies that attempt to limit ventilator-induced lung injury and accept permissive hypercapnia have successfully demonstrated a marked reduction in mortality in uncontrolled settings. So encouraging are these reductions that there has been a subtle shift in philosophy of mechanical ventilation toward using lung-protective ventilatory strategies at all times. With broad acceptance of this shift in philosophy, and the use of recently standardized clinical definitions for controlled studies, we optimistically anticipate improved mortality rates for acute respiratory distress syndrome.

The timing of tracheotomy: a systematic review.

STUDY OBJECTIVE: To examine the impact of the timing of tracheotomy on the duration of mechanical ventilation, the secondary changes to the trachea, and the clinical course of critically ill patients in the ICU. DESIGN: A systematic review of the literature. METHODS: Two independent reviewers conducted a MEDLINE search for relevant literature in the form of randomized or observational controlled clinical studies. Studies were selected for review by criteria determined a priori; and the methodologic quality of selected studies was evaluated by duplicate independent review, also using criteria determined a priori. RESULTS: Five studies were identified, of which three were quasirandomized and none were blinded. Agreement between reviewers of methodologic quality was high (kappa=0.87). CONCLUSIONS: There is insufficient evidence to support that the timing of tracheotomy alters the duration of mechanical ventilation or extent of airway injury in critically ill patients.

Qualitative studies on the patient's experience of weaning from mechanical ventilation.

In contrast to primarily deductive quantitative research, qualitative research aims to interpret data to develop theoretical insights that describe and explain phenomena such as interactions, experiences, roles, perspectives, and organizations. In this review, we summarize qualitative studies that used primarily in-depth personal interviews as a data collection method and a grounded theory analytic approach. The liberal use of illustrative excerpts and interpretive descriptions offer clinicians vicarious accounts of patient experiences of weaning from mechanical ventilation. Important experiences of patients during their weaning from mechanical ventilation included frustration, uncertainty, hopelessness, fear, and lack of mastery. The extent to which, in at least some patients, these experiences were determinants of weaning failure, consequences of weaning failure, or both, was difficult to establish. An assumption of this genre of research is that if clinicians understand the lived experiences of patients, they can better appreciate patient needs during the weaning process, and by inference, their role as clinicians during weaning from mechanical ventilation.

Trials comparing alternative weaning modes and discontinuation assessments.

We identified 16 randomized controlled trials (RCTs) of methods for weaning patients from mechanical ventilation, 8 of which were trials of discontinuation assessment strategies, 5 of which were trials of stepwise reduction in mechanical ventilatory support, and 3 of which were trials comparing alternative ventilation modes for weaning periods lasting < 48 h. We found that different thresholds for deciding when a patient is ready for a trial of spontaneous breathing, different criteria for a successful trial, and different thresholds for extubation may overwhelm the impact of alternative ventilation strategies. Nevertheless, the results of these studies suggest the possibility that multiple daily T-piece weaning or pressure support may be superior to synchronized intermittent mandatory ventilation. Other RCTs suggest that early extubation with the back-up institution of noninvasive positive-pressure ventilation as needed may be a useful strategy in selected patients.

Trials of miscellaneous interventions to wean from mechanical ventilation.

We found eight randomized controlled trials (RCTs) of miscellaneous interventions that were designed to facilitate the process of weaning from mechanical ventilation. The two RCTs of high-fat/low-carbohydrate enteral nutrition found favorable physiologic effects on CO2 production and respiratory quotient, rendering this type of nutrition potentially useful in patients with impaired ventilatory reserve; however, no conclusions can be made about the outcomes of the duration of ventilation and weaning success. The two RCTs of postextubation use of noninvasive ventilation are conflicting, showing potential short-term physiologic benefit in one study, but no benefit in terms of reintubation rates or other morbidity. These RCTs are less promising than other applications of noninvasive ventilation such as those in patients with COPD exacerbations. One RCT showed no improvement in success of weaning with exogenous growth hormone administration. In the setting of very frequent baseline blood gas analyses, one RCT of oximetry and capnography was associated with significantly fewer blood gas analyses. Biofeedback to enhance safe and rapid weaning showed a dramatically lower duration of ventilation in one RCT that did not report the weaning methods used. One RCT of preextubation acupuncture showed lower rates of laryngospasm in the acupuncture group. Overall, these studies were underpowered for clinically important outcomes. Multidisciplinary, patient-centered, holistic, and non-pulmonary approaches to weaning may provide additional safe, effective adjunctive methods of hastening liberation from mechanical ventilation.

Trials comparing early vs late extubation following cardiovascular surgery.

We identified 10 randomized trials that compared alternative management approaches to patient care during and following cardiovascular surgery. One overall strategy involved a modification of anesthesia, in particular, a reduction in the dosage of fentanyl and benzodiazepine or the substitution of fentanyl for propofol (five randomized controlled trials [RCTs]). Pooled results show a shorter duration of ventilation (7 h) and a shorter duration of hospital stay (approximately 1 day) associated with lower anesthetic doses. The second strategy involved early vs late extubation once patients were admitted to the ICU (five RCTs). Pooled results show a shorter duration of ventilation (13 h) and a shorter duration of ICU stay (half a day) associated with early extubation. An additional 8 nonrandomized trials had findings that were consistent with the 10 RCTs. Reintubation, complications, and mortality rates were too low to draw conclusions about these outcomes. Overall, these studies indicate that anesthetic, sedation, and early-extubation strategies in selected cardiac surgery patients are associated with a shorter duration of mechanical ventilation and shorter lengths of ICU and hospital stays.

Trials of corticosteroids to prevent postextubation airway complications.

We identified three randomized controlled trials (RCTs) that addressed whether preextubation steroid administration reduces postextubation complications in children. The pooled analysis of primary extubation in children demonstrated significantly less stridor (relative risk [RR], 0.57; 95% confidence interval [CI], 0.40 to 0.81) and a trend toward less reintubation (RR, 0.50; 95% CI, 0.02 to 13.87) with corticosteroids. One non-RCT in children who had failed extubation the first time found a significant reduction in duration of prolonged reintubation (> or = 6 days) and in failed reextubations. The four RCTs in adults reported very low reintubation rates, and no conclusions can be drawn. Only one RCT assessed postextubation stridor and found little difference. Overall, we found that corticosteroids decreased the risk of postextubation stridor in children by about 40%. However, the effect of corticosteroids in children and adults to reduce postextubation complications such as reintubation is uncertain.