Double-Negative Results Matter: A Reevaluation of Sensitivities for Detecting SARS-CoV-2 Infection Using Saliva Versus Nasopharyngeal Swabs.

In a recent systematic review, Bastos et al. (Ann Intern Med. 2021;174(4):501-510) compared the sensitivities of saliva sampling and nasopharyngeal swabs in the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by assuming a composite reference standard defined as positive if either test is positive and negative if both tests are negative (double negative). Even under a perfect specificity assumption, this approach ignores the double-negative results and risks overestimating the sensitivities due to residual misclassification. In this article, we first illustrate the impact of double-negative results in the estimation of the sensitivities in a single study, and then propose a 2-step latent class meta-analysis method for reevaluating both sensitivities using the same published data set as that used in Bastos et al. by properly including the observed double-negative results. We also conduct extensive simulation studies to compare the performance of the proposed method with Bastos et al.'s method for varied levels of prevalence and between-study heterogeneity. The results demonstrate that the sensitivities are overestimated noticeably using Bastos et al.'s method, and the proposed method provides a more accurate evaluation with nearly no bias and close-to-nominal coverage probability. In conclusion, double-negative results can significantly impact the estimated sensitivities when a gold standard is absent, and thus they should be properly incorporated.

Contextualizing involvement in terrorist violence by considering non-significant findings: Using null results and temporal perspectives to better understand radicalization outcomes.

Irrespective of discipline, the publication of null or non-significant findings is rare in the social sciences. For burgeoning fields like terrorism research, this is particularly problematic. As well as increasing the likelihood of Type II errors, the selective reporting of significant findings ultimately impedes progression, hindering comprehensive syntheses of evidence and enabling ill-supported lines of scientific enquiry to persist. This manuscript discusses several structural and individual-level variables which failed to produce significant, linear associations with involvement in terrorist violence in a dataset (N = 206) of right-wing and jihadist extremists active in Europe and North America. After considering methodological factors such as non-random distributions of missing data, we illustrate how certain variables are significantly associated with involvement in terrorist violence at particular periods in a radicalizing individual's lifespan, but not others (i.e., pre- or post-radicalization onset). Moreover, we demonstrate that while some static, binary constructs (such as whether or not a radicalizing individual was exposed to diverse viewpoints) are not associated with terrorist violence, their influence over time produces different associations. We conclude that radicalization may be less about individuals having pre-disposing risk factors, such as biographical stressors, and more about cognitive changes that allow individuals to re-evaluate their lives through the lens of an extremist ideology. We also underline the importance of taking a temporal, rather than static, perspective to better understand the variables associated with the outcomes of radicalization trajectories.

Sentinel Lymph Node Biopsy vs No Axillary Surgery in Patients With Small Breast Cancer and Negative Results on Ultrasonography of Axillary Lymph Nodes: The SOUND Randomized Clinical Trial.

Importance: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary node staging of patients with early breast cancer (BC), but its necessity can be questioned since surgery for examination of axillary nodes is not performed with curative intent. Objective: To determine whether the omission of axillary surgery is noninferior to SLNB in patients with small BC and a negative result on preoperative axillary lymph node ultrasonography. Design, Setting, and Participants: The SOUND (Sentinel Node vs Observation After Axillary Ultra-Sound) trial was a prospective noninferiority phase 3 randomized clinical trial conducted in Italy, Switzerland, Spain, and Chile. A total of 1463 women of any age with BC up to 2 cm and a negative preoperative axillary ultrasonography result were enrolled and randomized between February 6, 2012, and June 30, 2017. Of those, 1405 were included in the intention-to-treat analysis. Data were analyzed from October 10, 2022, to January 13, 2023. Intervention: Eligible patients were randomized on a 1:1 ratio to receive SLNB (SLNB group) or no axillary surgery (no axillary surgery group). Main Outcomes and Measures: The primary end point of the study was distant disease-free survival (DDFS) at 5 years, analyzed as intention to treat. Secondary end points were the cumulative incidence of distant recurrences, the cumulative incidence of axillary recurrences, DFS, overall survival (OS), and the adjuvant treatment recommendations. Results: Among 1405 women (median [IQR] age, 60 [52-68] years) included in the intention-to-treat analysis, 708 were randomized to the SLNB group, and 697 were randomized to the no axillary surgery group. Overall, the median (IQR) tumor size was 1.1 (0.8-1.5) cm, and 1234 patients (87.8%) had estrogen receptor-positive ERBB2 (formerly HER2 or HER2/neu), nonoverexpressing BC. In the SLNB group, 97 patients (13.7%) had positive axillary nodes. The median (IQR) follow-up for disease assessment was 5.7 (5.0-6.8) years in the SLNB group and 5.7 (5.0-6.6) years in the no axillary surgery group. Five-year distant DDFS was 97.7% in the SLNB group and 98.0% in the no axillary surgery group (log-rank P = .67; hazard ratio, 0.84; 90% CI, 0.45-1.54; noninferiority P = .02). A total of 12 (1.7%) locoregional relapses, 13 (1.8%) distant metastases, and 21 (3.0%) deaths were observed in the SLNB group, and 11 (1.6%) locoregional relapses, 14 (2.0%) distant metastases, and 18 (2.6%) deaths were observed in the no axillary surgery group. Conclusions and Relevance: In this randomized clinical trial, omission of axillary surgery was noninferior to SLNB in patients with small BC and a negative result on ultrasonography of the axillary lymph nodes. These results suggest that patients with these features can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan. Trial Registration: ClinicalTrials.gov Identifier: NCT02167490.

No evidence for magnetic field effects on the behaviour of Drosophila.

Migratory songbirds have the remarkable ability to extract directional information from the Earth's magnetic field1,2. The exact mechanism of this light-dependent magnetic compass sense, however, is not fully understood. The most promising hypothesis focuses on the quantum spin dynamics of transient radical pairs formed in cryptochrome proteins in the retina3-5. Frustratingly, much of the supporting evidence for this theory is circumstantial, largely because of the extreme challenges posed by genetic modification of wild birds. Drosophila has therefore been recruited as a model organism, and several influential reports of cryptochrome-mediated magnetic field effects on fly behaviour have been widely interpreted as support for a radical pair-based mechanism in birds6-23. Here we report the results of an extensive study testing magnetic field effects on 97,658 flies moving in a two-arm maze and on 10,960 flies performing the spontaneous escape behaviour known as negative geotaxis. Under meticulously controlled conditions and with vast sample sizes, we have been unable to find evidence for magnetically sensitive behaviour in Drosophila. Moreover, after reassessment of the statistical approaches and sample sizes used in the studies that we tried to replicate, we suggest that many-if not all-of the original results were false positives. Our findings therefore cast considerable doubt on the existence of magnetic sensing in Drosophila and thus strongly suggest that night-migratory songbirds remain the organism of choice for elucidating the mechanism of light-dependent magnetoreception.

Maternal Risk of Cardiovascular Disease After Use of Assisted Reproductive Technologies.

Importance: The use of assisted reproductive technologies (ARTs) is steadily increasing worldwide. The outcomes associated with treatment for an individual's long-term health, including risk of cardiovascular disease (CVD), remain largely unknown, due to the small number of studies and their limited follow-up time. Objective: To study whether the risk of CVD is increased among individuals who have given birth after ART compared with those who have given birth without ART. Design, Setting, and Participants: A registry-based cohort study was conducted using nationwide data from Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1985-2015). Data analysis was conducted from January to August 2022. A total of 2 496 441 individuals with a registered delivery in the national birth registries during the study period were included, and 97 474 (4%) of these gave birth after ART. Exposures: Data on ART conception were available from ART quality registries and/or medical birth registries. Main Outcomes and Measures: Information on CVD was available from patient and cause of death registries. The risk of CVD was estimated with Cox proportional hazards regression, adjusting for age, calendar year of start of follow-up, parity, diagnosis of polycystic ovary syndrome, diabetes, chronic hypertension, and country. Results: Median follow-up was 11 (IQR, 5-18) years. The mean (SD) age of women with no use of ART was 29.1 (4.9) years, and the age of those who used ART was 33.8 (4.7) years. The rate of any CVD was 153 per 100 000 person-years. Individuals who gave birth after using ART had no increased risk of CVD (adjusted hazard ratio [AHR], 0.97; 95% CI, 0.91-1.02), with evidence of heterogeneity between the countries (I2 = 76%; P = .01 for heterogeneity). No significant differences in the risk of ischemic heart disease, cerebrovascular disease, stroke, cardiomyopathy, heart failure, pulmonary embolism, or deep vein thrombosis were noted with use of ART. However, there was a tendency for a modest reduction in the risk of myocardial infarction (AHR, 0.80; 95% CI, 0.65-0.99), with no notable heterogeneity between countries. Conclusions and Relevance: The findings of this study suggest that women who gave birth after ART were not at increased risk of CVD over a median follow-up of 11 years compared with those who conceived without ART. Longer-term studies are needed to further examine whether ART is associated with higher risk of CVD.

The role of chronological age in climate change attitudes, feelings, and behavioral intentions: The case of null results.

Past research has stressed the role of age and generation in climate change discourse, worries, and willingness to act. Therefore, the present paper aimed to examine the role of chronological age (as an arbitrary factor, which represents ageism) in lay people's climate change-related attitudes, feelings, and behavioral intentions. Two experiments in different countries, Australia and Israel, were conducted for this purpose. The first study examined the impact of the age of the speaker, who provides information about the climate crisis and the second examined the impact of the age of the group being blamed for the situation. Outcome variables included perceived responsibility and motivation for the current climate situation in study 1 and perceived climate change-related attitudes, feelings, and behavioral intentions in study 2. In study 1 (n = 250, Australia), the age of the speaker, a climate activist, varied randomly to test the hypothesis that a younger activist would be more influential and increase motivation and responsibility to act compared to an older activist. In study 2 (n = 179, Israel), the age (young vs. old) of the group identified as being responsible for the climate crisis varied randomly, to test the hypothesis that people would be more willing to identify older people as being responsible for the current climate situation, and this would impact climate change-related attitudes, feelings, and behavioral intentions. Both studies resulted in null effects. Additionally, there was no interaction between the age of the respondent and the age of the source of the message or the age group being blamed by the message. The present study has failed to show that strategies that emphasize intergenerational conflict and ageism impact people's attitudes, feelings, and behavioral intentions towards the current climate situation. This possibly can serve as an instigator for strategies that emphasize intergenerational solidarity, rather than conflict, as a guiding principle in future campaigns that advocate climate change adaptation and mitigation measures.

Null results of oxytocin and vasopressin administration on mentalizing in a large fMRI sample: evidence from a randomized controlled trial.

BACKGROUND: Although potential links between oxytocin (OT), vasopressin (AVP), and social cognition are well-grounded theoretically, most studies have included all male samples, and few have demonstrated consistent effects of either neuropeptide on mentalizing (i.e. understanding the mental states of others). To understand the potential of either neuropeptide as a pharmacological treatment for individuals with impairments in social cognition, it is important to demonstrate the beneficial effects of OT and AVP on mentalizing in healthy individuals. METHODS: In the present randomized, double-blind, placebo-controlled study (n = 186) of healthy individuals, we examined the effects of OT and AVP administration on behavioral responses and neural activity in response to a mentalizing task. RESULTS: Relative to placebo, neither drug showed an effect on task reaction time or accuracy, nor on whole-brain neural activation or functional connectivity observed within brain networks associated with mentalizing. Exploratory analyses included several variables previously shown to moderate OT's effects on social processes (e.g., self-reported empathy, alexithymia) but resulted in no significant interaction effects. CONCLUSIONS: Results add to a growing literature demonstrating that intranasal administration of OT and AVP may have a more limited effect on social cognition, at both the behavioral and neural level, than initially assumed. Randomized controlled trial registrations: ClinicalTrials.gov; NCT02393443; NCT02393456; NCT02394054.

The influence of triglycerides on small dense low-density lipoprotein cholesterol levels is attenuated in low low-density lipoprotein-cholesterol range: Implications for the negative results of the PROMINENT trial.

The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial failed to show the preventive effects of pemafibrate, a triglyceride (TG)-lowering drug, on atherosclerotic cardiovascular disease in patients with type 2 diabetes and dyslipidemia. We recently reported that TG-lowering with pemafibrate did not decrease the calculated small dense (sd) low-density lipoprotein cholesterol (LDL-C), and speculated that the effect of TG on sdLDL-C is attenuated in low LDL-C levels. This report examined this possibility in 1,508 patients with type 2 diabetes and 670 healthy controls. LDL-C ranges were classified as ≤69, 70-99, 100-139 and 140≤ mg/dL. The slope of the regression curve between sdLDL-C and TG was found to flatten as LDL-C decreased; 0.18, 0.13, 0.10 and 0.04 for controls, and 0.18, 0.13, 0.09 and 0.07 for diabetes patients. Correspondingly, the lower the LDL-C range, the lower the sdLDL-C/TG ratio. These results suggest that when LDL-C is tightly controlled, TG-lowering has only a weak inhibitory effect on sdLDL-C.

NEgatiVE results in Radiomics research (NEVER): A meta-research study of publication bias in leading radiology journals.

PURPOSE: The purpose of this study was to conduct a meta-research of radiomics-related articles for the publication of negative results, with a focus on the leading clinical radiology journals due to their purportedly high editorial standards. METHODS: A literature search was performed in PubMed to identify original research studies on radiomics (last search date: August 16th, 2022). The search was restricted to studies published in Q1 clinical radiology journals indexed by Scopus and Web of Science. Following an a priori power analysis based on our null hypothesis, a random sampling of the published literature was conducted. Besides the six baseline study characteristics, a total of three items about publication bias were evaluated. Agreement between raters was analyzed. Disagreements were resolved through consensus. Statistical synthesis of the qualitative evaluations was presented. RESULTS: Following a priori power analysis, we included a random sample of 149 publications in this study. Most of the publications were retrospective (95%; 142/149), based on private data (91%; 136/149), centered on a single institution (75%; 111/149), and lacked external validation (81%; 121/149). Slightly fewer than half (44%; 66/149) made no comparison to non-radiomic approaches. Overall, only one study (1%; 1/149) reported negative results for radiomics, yielding a statistically significant binomial test (p < 0.0001). CONCLUSION: The top clinical radiology journals almost never publish negative results, having a strong bias toward publishing positive results. Almost half of the publications did not even compare their approach with a non-radiomic method.

Nitrite-negative results in urinary tract infection by Enterobacterales: does the nitrite dipstick test have low sensitivity?

Urinary tract infection (UTI) is one of the most common bacterial infections among humans. Urine culture is the gold standard diagnostic method for UTI; however, the dipstick test for nitrite is a widely used method signalling the presence of urinary nitrate-reducing bacteria. Unlike the gold standard, the dipstick test is easy to perform, while it is also less time-consuming and less expensive, and produces a result in a few minutes. This study investigates the sensitivity of the dipstick test for nitrite compared with the Griess test in urine samples from UTI caused by Enterobacterales species. We used the Griess test, which is the gold standard in nitrite measurement, to determine the sensitivity of the nitrite dipstick test. Semiquantitative urine culture was performed using standard procedures, and Enterobacterales identification was performed by manual conventional biochemical tests. In the first sample selection, 3 % (8/267) of urine samples suspected of UTI, analysed from March to April 2016, were nitrite-negative by dipstick test but positive for Enterobacterales in the urine culture. In the second sample selection, 5 % (2/44) of urine samples from October to December 2022 were also nitrite-negative but showed urine Enterobacterales isolation. All nitrite-negative dipstick results were consistent with the Griess test. Escherichia coli was the most prevalent bacterium, followed by Klebsiella pneumoniae, independent of sample selection. The dipstick test is a safe alternative for investigating nitrite in urine samples. We believe that the cause of nitrite-negative results is a lack of dietary nitrate, dilution of urine and exogenous interference (e.g. ascorbic acid). These findings support the idea that standard urine culture is necessary to rule out UTI.

Definición y caracterización del fenómeno “Diagnóstico Lastre Generado por Medicamentos” / Definition and characterization of the phenomenon "Diagnosis of Drug-Generated Ballast"

Proponemos el presente estudio para la identifica-ción del fenómeno "Diagnóstico Lastre Generado por Medicamentos" (DLGM), que es la traducción farmacéutica de la interpretación médica de un problema de salud generado por medicamentos y atribuido a causas clínicas con la consiguiente pérdida de identidad que limita su identificación y manejo. No habrá mejoría de la enfermedad si no se corrige la causa del problema, por lo que cabe esperar un empeoramiento y persistencia de la enfermedad marcados por el fracaso farmacote-rapéutico, convirtiendo el problema de salud en un verdadero lastre para los pacientes a la espera de ser identificado.La propuesta de un algoritmo de caracterización del problema como herramienta de cribado se ha aplicado a 10 pacientes en el servicio de segui-miento farmacoterapéutico, confirmando la sospe-cha de DLGM, y demostrando que las reacciones adversas a medicamentos habían adquirido la identidad de una enfermedad. Un DLGM podría defi-nirse como la entidad que surge al diagnosticar una enfermedad sobre un resultado negativo asociado al uso del medicamento y que, por tanto, no recibe el tratamiento adecuado.La identificación del fenómeno DLGM permite detectar muchos resultados negativos asociados a la medicación (RNM) y contribuye a su adecuado tratamiento.No identificar un DLGM complica el estado clínico del paciente y limita su recuperación. (AU)

The present study was proposed for the identifica-tion the phenomenon "Diagnosis load Generated by Medications" (DLGM), which is the pharmaceutical translation to the medical interpretation of a health problem generated by medications and attributed to clinical causes with the consequent loss of iden-tity limiting its identification and handling. There will be no improvement of the desease if the cause of the problem is not corrected, so worsening and persistence of the disease marked by pharmaco-therapeutic failure is to be expected, making the health problem a real burden for patients to waiting to be identified.The proposal of an algorithm characterising the problem as a screening tool has been applied to 10 patients in the pharmacotherapeutic monitoring service, confirming the suspicion of DLGM, and demonstrating that adverse drugs reactions had acquired the identity of a disease. DLGM could be defined as the entity that arises from diagnosing a disease on a negative results associated to medici-ne use and that therefore does not receive adequa-te treatment.The identification of the DLGM phenomenon allows the detection of many Negative Outcomes Relea-ted to Mediccines (NOMs) and contributes to their adequate treatment.Not identifying DLGM complicates the clinical con-dition of the patient and his/her recovery. (AU)

Is a boat bigger than a ship? Null results in the investigation of vowel sound symbolism on size judgements in real language.

Sound symbolism is the phenomenon by which certain kinds of phonemes are associated with perceptual and/or semantic properties. In this article, we explored size sound symbolism (i.e., the mil/mal effect) in which high-front vowels (e.g., /i/) show an association with smallness, while low-back vowels (e.g., /ɑ/) show an association with largeness. This has previously been demonstrated with nonwords, but its impact on the processing of real language is unknown. We investigated this using a size judgement task, in which participants classified words for small or large objects, containing a small- or large-associated vowel, based on their size. Words were presented auditorily in Experiment 1 and visually in Experiment 2. We did not observe an effect of vowel congruence (i.e., between object size and the size association of its vowel) in either of the experiments. This suggests that there are limits to the impact of sound symbolism on the processing of real language.