A logical analysis of null hypothesis significance testing using popular terminology.

BACKGROUND: Null Hypothesis Significance Testing (NHST) has been well criticised over the years yet remains a pillar of statistical inference. Although NHST is well described in terms of statistical models, most textbooks for non-statisticians present the null and alternative hypotheses (H0 and HA, respectively) in terms of differences between groups such as (µ1 = µ2) and (µ1 ≠ µ2) and HA is often stated to be the research hypothesis. Here we use propositional calculus to analyse the internal logic of NHST when couched in this popular terminology. The testable H0 is determined by analysing the scope and limits of the P-value and the test statistic's probability distribution curve. RESULTS: We propose a minimum axiom set NHST in which it is taken as axiomatic that H0 is rejected if P-value< α. Using the common scenario of the comparison of the means of two sample groups as an example, the testable H0 is {(µ1 = µ2) and [([Formula: see text] 1 ≠ [Formula: see text] 2) due to chance alone]}. The H0 and HA pair should be exhaustive to avoid false dichotomies. This entails that HA is ¬{(µ1 = µ2) and [([Formula: see text] 1 ≠ [Formula: see text] 2) due to chance alone]}, rather than the research hypothesis (HT). To see the relationship between HA and HT, HA can be rewritten as the disjunction HA: ({(µ1 = µ2) ∧ [([Formula: see text] 1 ≠ [Formula: see text] 2) not due to chance alone]} ∨ {(µ1 ≠ µ2) ∧ [[Formula: see text] 1 ≠ [Formula: see text] 2) not due to (µ1 ≠ µ2) alone]} ∨ {(µ1 ≠ µ2) ∧ [([Formula: see text] 1 ≠ [Formula: see text] 2) due to (µ1 ≠ µ2) alone]}). This reveals that HT (the last disjunct in bold) is just one possibility within HA. It is only by adding premises to NHST that HT or other conclusions can be reached. CONCLUSIONS: Using this popular terminology for NHST, analysis shows that the definitions of H0 and HA differ from those found in textbooks. In this framework, achieving a statistically significant result only justifies the broad conclusion that the results are not due to chance alone, not that the research hypothesis is true. More transparency is needed concerning the premises added to NHST to rig particular conclusions such as HT. There are also ramifications for the interpretation of Type I and II errors, as well as power, which do not specifically refer to HT as claimed by texts.

The NACSTOP Trial: A Multicenter, Cluster-Controlled Trial of Early Cessation of Acetylcysteine in Acetaminophen Overdose.

Historically, intravenous acetylcysteine has been delivered at a fixed dose and duration of 300 mg/kg over 20 to 21 hours to nearly every patient deemed to be at any risk for hepatotoxicity following acetaminophen overdose. We investigated a 12-hour treatment regimen for selected low-risk patients. This was a multicenter, open-label, cluster-controlled trial at six metropolitan emergency departments. We enrolled subjects following single or staggered acetaminophen overdose with normal serum alanine transaminase (ALT) and creatinine on presentation and at 12 hours, and less than 20 mg/L acetaminophen at 12 hours. Patients were allocated to intervention (250 mg/kg over 12-hour) or control (300 mg/kg over 20-hour) regimens by site. The primary outcome was incidence of "hepatic injury" 20 hours following initiation of acetylcysteine treatment, defined as ALT doubling and peak ALT greater than 100 IU/L, indicating the need for further antidotal treatment. Secondary outcomes included incidence of hepatotoxicity (ALT > 1,000 IU/L), peak international normalized ratio (INR), and adverse drug reactions. Of the 449 acetaminophen overdoses receiving acetylcysteine, 100 were recruited to the study. Time to acetylcysteine (median 7 hours [interquartile ratio 6,12] versus 7 hours [6,10]) and initial acetaminophen (124 mg/L [58,171] versus 146 mg/L [66,204]) were similar between intervention and control groups. There was no difference in ALT (18 IU/L [13,22] versus 16 IU/L [13,21]) or INR (1.2 versus 1.2) 20 hours after starting acetylcysteine between groups. No patients developed hepatic injury or hepatotoxicity in either group (odds ratio 1.0 [95% confidence interval 0.02, 50]). No patients represented with liver injury, none died, and 96 of 96 were well at 14-day telephone follow-up. Conclusion: Discontinuing acetylcysteine based on laboratory testing after 12 hours of treatment is feasible and likely safe in selected patients at very low risk of liver injury from acetaminophen overdose.

Impact of COVID-19 on immunocompromised populations during the Omicron era: insights from the observational population-based INFORM study.

Background: Immunocompromised individuals are not optimally protected by COVID-19 vaccines and potentially require additional preventive interventions to mitigate the risk of severe COVID-19. We aimed to characterise and describe the risk of severe COVID-19 across immunocompromised groups as the pandemic began to transition to an endemic phase. Methods: COVID-19-related hospitalisations, intensive care unit (ICU) admissions, and deaths (01/01/2022-31/12/2022) were compared among different groups of immunocompromised individuals vs the general population, using a retrospective cohort design and electronic health data from a random 25% sample of the English population aged ≥12 years (Registration number: ISRCTN53375662). Findings: Overall, immunocompromised individuals accounted for 3.9% of the study population, but 22% (4585/20,910) of COVID-19 hospitalisations, 28% (125/440) of COVID-19 ICU admissions, and 24% (1145/4810) of COVID-19 deaths in 2022. Restricting to those vaccinated with ≥3 doses of COVID-19 vaccine (∼84% of immunocompromised and 51% of the general population), all immunocompromised groups remained at increased risk of severe COVID-19 outcomes, with adjusted incidence rate ratios (aIRR) for hospitalisation ranging from 1.3 to 13.1. At highest risk for COVID-19 hospitalisation were individuals with: solid organ transplant (aIRR 13.1, 95% confidence interval [95% CI] 11.2-15.3), moderate to severe primary immunodeficiency (aIRR 9.7, 95% CI 6.3-14.9), stem cell transplant (aIRR 11.0, 95% CI 6.8-17.6), and recent treatment for haematological malignancy (aIRR 10.6, 95% CI 9.5-11.9). Results were similar for COVID-19 ICU admissions and deaths. Interpretation: Immunocompromised individuals continue to be impacted disproportionately by COVID-19 and have an urgent need for additional preventive measures beyond current vaccination programmes. These data can help determine the immunocompromised groups for which targeted prevention strategies may have the highest impact. Funding: This study was funded by AstraZeneca UK.

Utility of non-contrast head computed tomography in poisoned patients.

OBJECTIVE: To investigate the utility of non-contrast head computed tomography (CT) in poisoned patients. METHODS: A retrospective cohort study of patients referred to a toxicology unit between August 2010 and December 2017. Our database yielded patients who underwent head CT at presentation to the ED. Pre-specified information was compiled from the medical records. RESULTS: There were 6261 presentations of which 1142 underwent head CT (17%). Median age was 41 years, and 437 (38%) were female. There were 492 (43%) recreational ingestions and 466 (41%) deliberate self-poisonings. The commonest agents were sedatives 376 (33%) and opioids 282 (24%); 334 (29%) cases were intubated. Signs of head injury were found in 153 cases (13%) and focal neurological signs in 68 (6%). No acute pathology was reported in 884 head CTs (77%), chronic changes in 193 (17%) and incidental findings in 26 (2%). Acute pathology was found in 39 (4%) patients: 15 with hypoxic-ischaemic injury, three infarctions, nine with intra-cranial haemorrhage, 11 facial bone fractures and one retro-bulbar haematoma. No patient required an immediate surgical intervention, and only one patient had a change to clinical treatment. Acute head CT pathology was associated with at least one of the following clinical features: need for intubation, signs of head injury, seizure, headache, and unexpected neurological signs. CONCLUSION: Non-contrast head CT is a low-yield investigation in patients presenting with poisoning. Consideration should be given as to whether the clinical presentation is consistent with the expected toxidrome and whether the patient would benefit from head CT.

Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose (2NAC study).

BACKGROUND: Previous studies of paracetamol overdose treatment show that a 2-bag, 20-h intravenous (IV) acetylcysteine regimen decreased the incidence of non-allergic anaphylactic reactions compared to the 3-bag, 21 h IV regimen, but have not examined efficacy of the 20-h 2 bag regimen. METHODS: This was a multi-centre observational study of paracetamol overdose presentations treated with a 2-bag IV acetylcysteine regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) compared to a 3-bag regimen, performed from 2009 to 2019. Patients were referred from the emergency department to the inpatient toxicology units for continued management. For the primary non-inferiority analysis: subjects had single, acute ingestions, a serum paracetamol-concentration performed 4 to 8-h post-ingestion. The primary outcome was development of acute liver injury (ALI), defined as peak ALT>150 U/L; and > double admission baseline ALT (for presentations within 24 h post-overdose). Secondary outcomes included adverse reactions to acetylcysteine (cutaneous and systemic). FINDING: Out of 6419 paracetamol overdoses, 2763 received acetylcysteine. For the primary analysis, 1003 received the 2-bag and 783 the 3-bag acetylcysteine regimen. When presentation bloods were performed 4 to 8-h post-overdose, 21 (3.1%) developed ALI with the 2-bag regimen vs 16 (2.9%) with the 3-bag regimen (Difference: 0.2%, 95%CI:-1.6 to 2.2). The incidence of hepatotoxicity was: 1.2% (n = 8) with the two-bag regimen and 1.6% (n = 9) with the three-bag regimen (Difference -0.4%, 95%CI -1.75, 0.91). When presentation bloods were performed 8 to 24-h post-overdose, 70 (21%) developed ALI with the 2-bag regimen vs 46 (23%) with the 3-bag regimen (Difference: -2%, 95%CI -9.12 to 5.36). There were significantly less cutaneous and systemic non-allergic anaphylactic reactions recorded after treatment with the two-bag than the three-bag regimen (1.3% [n = 17] and 7.1% [n = 65], Difference: -5.8%, 95%CI -7.6 to -4.0, p < 0.0001), respectively. INTERPRETATION: A two-bag intravenous acetylcysteine regimen was found to be non-inferior to the three-bag regimen with regards to efficacy in preventing acute liver injury for early presentations of paracetamol overdose. No important differences were seen for any other presentations. The two-bag regimen also decreased the incidence of both non-allergic anaphylactic reactions and gastrointestinal adverse events from acetylcysteine treatment. FUNDING: AW is funded by a National Health and Medical Research Council (NHMRC) Early Career Fellowship ID 1159907. GI is funded by a NHMRC Senior Research Fellowship ID 1061041. The NHMRC had no role in the design, writing of this manuscript. The corresponding author (AW) had full access to all the data in the study and final responsibility for the decision to submit the manuscript for publication.

Analysis of an 8-hour acetylcysteine infusion protocol for repeated supratherapeutic ingestion (RSTI) of paracetamol.

OBJECTIVES: In Australia, the treatment guideline for patients with repeated supratherapeutic ingestion (RSTI) of paracetamol recommends an abbreviated acetylcysteine regimen if the paracetamol concentration is low (<10 mg/L) and alanine aminotransferase (ALT) is normal or static after 8 hours of infusion. There are currently no studies of this recommendation. METHOD: A retrospective review of paracetamol overdose presentations from October 2009 to August 2016 in two hospital toxicology networks was performed. All cases of RSTI treated with acetylcysteine were extracted. RESULTS: Of the 2249 paracetamol overdose presentations, 91 cases of RSTI were treated with acetylcysteine. Median time to initial blood tests was 6 hours post-last paracetamol dose (IQR 4-6). Sixty-three (69%) presentations had an initial detectable paracetamol concentration, median 30 mg/L (IQR 18-60). Median ALT on presentation was 48 IU/L (IQR 18-109). After 8 hours of acetylcysteine infusion, median ALT was 34 IU/L (IQR 16-71) in those receiving abbreviated treatment and 74 IU/L (IQR 40-231) in those continuing acetylcysteine. Thirty-nine presentations (43%) had an abbreviated regimen. Nine (10%) patients had an initial ALT ≥50 IU/L and subsequently developed hepatotoxicity (ALT >1000 IU/L). No patients with an initial ALT <50 IU/L developed hepatotoxicity. Median duration of acetylcysteine infusion for those receiving a non-abbreviated regimen was 20 hours (IQR 20-25) vs. 10.4 hours (IQR 4.8-12.0) who received an abbreviated regimen. There were no re-presentations with hepatotoxicity. CONCLUSIONS: An 8-hour acetylcysteine infusion regimen for treatment of paracetamol RSTI may be safe and is likely to reduce length of stay for patients at low risk of hepatotoxicity. Larger prospective studies are needed to examine the efficacy of this abbreviated acetylcysteine protocol.

Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose.

OBJECTIVE: Acetylcysteine (NAC), an effective antidote for paracetamol poisoning, is commonly associated with adverse reactions. This has been postulated to be related to the rapid initial infusion rate (150 mg/kg over 1 h) of the traditional three-bag protocol. We hypothesized that a slower rate would result in fewer adverse reactions. Our institution in Western Sydney moved to a modified two-bag protocol in February 2015 - first bag: 200 mg/kg over 4 h (50 mg/kg/h) and second bag: (100 mg/kg over 16 h). METHODS: Data was extracted from our database on paracetamol overdoses treated with NAC from August 2010 to September 2016. We compared adverse reactions in patients receiving the modified two-bag protocol with a historical control (traditional three-bag regimen with initial bolus of 150 mg/kg/h). RESULTS: Over the study period 1011 paracetamol poisonings presented to our toxicology service, of which 476 required NAC (three-bag = 313, two-bag = 163). Demographic characteristics of the two groups were similar. Fewer anaphylactoid reactions (itch, rash, and swelling) occurred using the two-bag regimen (14% versus 5%, p = .002), a relative reduction of 66%. Similarly, there were fewer prescriptions of anti-allergy medications in the two-bag group (11% versus 4%, p = .01). There was no difference in incidence of hepatotoxicity. CONCLUSIONS: Adverse reactions to NAC were less common with the two-bag regimen. These results add to the accumulating evidence that reducing the initial NAC infusion rate reduces the risk of adverse reactions.

Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen.

INTRODUCTION: Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol-aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen. METHODS: We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L). RESULTS: Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500 mg/L × IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000 mg/L × IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase. CONCLUSIONS: The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.

Food-induced methemoglobinemia: A systematic review.

Methemoglobinemia is a sporadic, potentially fatal disease of poor tissue oxygenation in which ferrous hemoglobin (Fe2+ ) is oxidized to the ferric (Fe3+ ) state, rendering it incapable of binding oxygen (O2 ). Fortunately, it is diagnosable and treatable. Here, we present a systematic review of food-induced methemoglobinemia. PubMed and Embase databases were searched using the term "methemoglobin*," for articles up to December 31, 2020. Inclusion criteria were confirmed or probable cases of methemoglobinemia with an oxidant confirmed in food or body tissue samples, or the oxidant likely to have come from food. We found 97 articles describing 568 cases. Median age was 6 years (range: 2 weeks to 80 years). Median methemoglobin fraction was 30% (n = 142). Oxidizing agents were predominantly nitrites and nitrates. The commonest type of presentation was children eating vegetables (30%), followed by accidental ingestions (27%), and meat curing misadventures (22%). Favism was found to result in mild methemoglobinemia, highest fraction reported was 15.8%. Of the 35 deaths, 32 were from accidental ingestions (91%). In some fatal cases, diagnosis was likely delayed or missed, and antidote was not administered. The majority of cases survived, even with severe methemoglobin levels of up to 89%, provided that methylene blue was administered. Treatment with methylene blue alone resulted in an average methemoglobin drop of 39.1% (n = 22). Methemoglobinemia cases continue to occur due to accidental exposure, meat curing misadventures, and babies ingesting nitrate-rich vegetables which have been inappropriately stored. Early recognition of the toxidrome, instituting antidote treatment, and notifying public health authorities are key to improved outcomes.

Accessible Modelling of Complexity in Health (AMoCH) and associated data flows: asthma as an exemplar.

Background Modelling is an important part of information science. Models are abstractions of reality. We use models in the following contexts: (1) to describe the data and information flows in clinical practice to information scientists, (2) to compare health systems and care pathways, (3) to understand how clinical cases are recorded in record systems and (4) to model health care business models.Asthma is an important condition associated with a substantial mortality and morbidity. However, there are difficulties in determining who has the condition, making both its incidence and prevalence uncertain.Objective To demonstrate an approach for modelling complexity in health using asthma prevalence and incidence as an exemplar.Method The four steps in our process are:1. Drawing a rich picture, following Checkland's soft systems methodology;2. Constructing data flow diagrams (DFDs);3. Creating Unified Modelling Language (UML) use case diagrams to describe the interaction of the key actors with the system;4. Activity diagrams, either UML activity diagram or business process modelling notation diagram.Results Our rich picture flagged the complexity of factors that might impact on asthma diagnosis. There was consensus that the principle issue was that there were undiagnosed and misdiagnosed cases as well as correctly diagnosed. Genetic predisposition to atopy; exposure to environmental triggers; impact of respiratory health on earnings or ability to attend education or participate in sport, charities, pressure groups and the pharmaceutical industry all increased the likelihood of a diagnosis of asthma. Stigma and some factors within the health system diminished the likelihood of a diagnosis. The DFDs and other elements focused on better case finding.Conclusions This approach flagged the factors that might impact on the reported prevalence or incidence of asthma. The models suggested that applying selection criteria may improve the specificity of new or confirmed diagnosis.

Reducing the need for general anaesthesia in children: use of LAT gel in treating facial lacerations.

Facial lacerations in children are common emergencies that often require debridement and closure under general anaesthesia because of poor cooperation by the patient. General anaesthesia in children is not without risk so any technique that avoids its use is beneficial. LAT gel (lidocaine, adrenaline, and tetracaine) is a topical anaesthetic, which is ideal for suturing facial lacerations in children. In our experience its use has resulted in the effective treatment of these injuries, and has reduced distress and discomfort, and the need for hospital admission and general anaesthesia.

Postoperative complications after major head and neck surgery with free flap repair--prevalence, patterns, and determinants: a prospective cohort study.

This study aims to give a better understanding of the prevalence, patterns, and determinants of postoperative complications, to evaluate the Clavien-Dindo classification of surgical complications, and to set out a protocol to improve postoperative recovery. Over a period of 27 months we studied 192 patients who had had major head and neck operations with free flaps. Data on complications were gathered prospectively along with patients' details, comorbidities, factors indicative of the magnitude of the surgical insult, and variations in perioperative care. Complications were classified according to the Clavien-Dindo system. Outcomes analysed comprised any complication, major complications (Clavien-Dindo III and above), wound complications, and pulmonary complications. A total of 64% of patients had complications, and in around one third they were serious; wound and pulmonary complications were the most common. Factors significantly associated with complications reflected an interaction between coexisting conditions of the patient at operation and the magnitude of the surgery. Perioperative interventions to ensure preoperative optimisation of patients, and to lessen the systemic inflammatory response that results from operation offer the best prospect of reducing the burden of surgical complications. A protocol to improve recovery after operation would be appropriate. The Clavien-Dindo classification of surgical complications is useful in this group.

The effect of elevated intraocular oxygen on organelle degradation in the embryonic chicken lens.

In the vertebrate lens, nuclei and other cytoplasmic organelles are degraded in fiber cells situated in the center of the tissue. This is believed to ensure the transparency of the tissue. The mechanism that triggers this process is unknown. We hypothesized that standing gradients of oxygen generated within the tissue may serve as a spatial cue for organelle degradation. To examine this possibility, we incubated fertilized chicken eggs under hyperoxic (50% O(2)) or normoxic (21% O(2)) conditions. Hyperoxic treatment was initiated on the seventh day of embryonic development (E7), five days before organelle degradation normally commences in the lens core. Hyperoxia was maintained until E17. Under normoxic conditions, the partial pressure of oxygen (P(O)) within the vitreous compartment was low. Direct measurement of P(O) using an optode oxygen sensor indicated values of 1.3 kPa and 0.4 kPa for the mid- and anterior vitreous, respectively. Similarly, treatment with pimonidazole, a bio-reductive hypoxia marker, led to the formation of immuno-positive protein adducts within the lens, suggesting that the embryonic lens is chronically hypoxic in situ. Following hyperoxic treatment, vitreous P(O) significantly increased, although pimonidazole staining in the lens was not markedly affected. Confocal microscopy of slices prepared from hyperoxic lenses revealed a significant increase in the size of the lens relative to age-matched normoxic controls. By E13, an organelle-free zone (OFZ) was present in the center of normoxic and hyperoxic lenses. However, in hyperoxic lenses, the OFZ was consistently smaller, and the distance from the lens surface to the border of the OFZ significantly larger, than in normoxic controls. These observations suggest that hyperoxia delays organelle breakdown and are consistent with a model in which hypoxia in the deep cortical layers of the normal lens serves as a trigger for the organelle loss process.

Regulation of tissue oxygen levels in the mammalian lens.

Opacification of the lens nucleus is a major cause of blindness and is thought to result from oxidation of key cellular components. Thus, long-term preservation of lens clarity may depend on the maintenance of hypoxia in the lens nucleus. We mapped the distribution of dissolved oxygen within isolated bovine lenses and also measured the rate of oxygen consumption (QO2) by lenses, or parts thereof. To assess the contribution of mitochondrial metabolism to the lens oxygen budget, we tested the effect of mitochondrial inhibitors on (QO2) and partial pressure of oxygen (PO2). The distribution of mitochondria was mapped in living lenses by 2-photon microscopy. We found that a steep gradient of PO2 was maintained within the tissue, leading to PO2 < 2 mmHg in the core. Mitochondrial respiration accounted for approximately 90% of the oxygen consumed by the lens; however, PO2 gradients extended beyond the boundaries of the mitochondria-containing cell layer, indicating the presence of non-mitochondrial oxygen consumers. Time constants for oxygen consumption in various regions of the lens and an effective oxygen diffusion coefficient were calculated from a diffusion-consumption model. Typical values were 3 x 10(-5) cm(2) s(-1) for the effective diffusion coefficient and a 5 min time constant for oxygen consumption. Surprisingly, the calculated time constants did not differ between differentiating fibres (DF) that contained mitochondria and mature fibres (MF) that did not. Based on these parameters, DF cells were responsible for approximately 88% of lens oxygen consumption. A modest reduction in tissue temperature resulted in a marked decrease in (QO2) and the subsequent flooding of the lens core with oxygen. This phenomenon may be of clinical relevance because cold, oxygen-rich solutions are often infused into the eye during intraocular surgery. Such procedures are associated with a strikingly high incidence of postsurgical nuclear cataract.