Navigating the Pitfalls of Lung Cancer Screening: A Case Study on the Risks and Costs of Negative Screenings.

Lung cancer is the leading cause of cancer-related deaths in the United States. Low-dose computed tomography is the preferred screening method for high-risk individuals. However, with a false-negative rate reaching 15%, this method can underestimate disease prevalence and delay necessary treatment. This case examines a 61-year-old female smoker with chronic obstructive pulmonary disease who initially received a negative result from screening. Her imaging findings were categorized as Lung Imaging Reporting and Data System (Lung-RADS) 2 but advanced to small cell lung carcinoma. This progression emphasizes the imperative of thoroughly evaluating screening results and patient history. False-negative results from screenings have profound implications, leading to delayed diagnoses, adversely affecting patient outcomes, and increasing healthcare costs. The necessity for vigilant follow-up enhanced diagnostic precision and transparent communication about limitations is paramount. An economic analysis emphasizes the significant financial impact of diagnosing lung cancer at advanced stages, highlighting the need for timely and accurate diagnostics. Comprehensive strategies, such as physician education, patient awareness, and stringent quality control, are crucial to improving the efficacy of lung cancer screening. Addressing the issue of false negatives is vital for enhancing early detection rates, decreasing healthcare expenses, and advancing patient care in lung cancer management. Continuous evaluation and adjustment of screening protocols are essential to reduce risks and optimize outcomes.

Reevaluation of negative cervical conizations: Frequency, diagnostic errors, risk factors and management.

OBJECTIVE: Cervical conization is an effective treatment for precancerous lesions. However, in cases where no high-grade lesion is identified in the surgical specimen, managing these patients may be challenging due to the absence of established follow-up protocols for negative conizations. This study aimed to assess the negative conization rates at our institution by histopathological review, identify diagnostic errors, possible risk and recurrence factors and propose follow-up strategies for this group of patients. METHODS: A retrospective study from January-2010 to December-2020 analyzed patients with negative conization including all surgical techniques and procedure indications. Biopsy and cervical conizations slides were reviewed and patients who kept a negative result underwent deeper levels sectioning of the paraffin blocks with immunohistochemical stains application: p16, Ki-67 and geminin. Data were compared with a control group composed by 29 women with CIN3. RESULTS: Out of 1022 conizations, 186 were negative (18.1%), with 151 cases selected for the study after excluding 35 patients. Following pathology review, 4 patients were excluded due to false-positive cervical biopsy results, 16 for false-negative conization results and 9 for hidden dysplasia identified after deeper sectioning. The remaining 122 patients were considered truly negative cones (11.9%) and exhibited IHC staining with p16 positive in 20.4% of cases, low Ki-67 expression, and low geminin score in most cases. Specimens with CIN 1 had higher prevalence of p16 staining, Ki-67 expression and geminin score when compared to absence of neoplasia, nevertheless geminin had no statistical difference. Older age, higher parity and IHC pattern with negative p16, low Ki-67 and geminin expressions were identified as risk factors for negative cones (p<0.05). Only 10 patients recurred for high-grade lesions, with no statistically significant risk factors identified. CONCLUSIONS: The negative conization rate was 11.9%, with diagnostic errors identified across pre-surgical biopsy, cone specimen, and deeper levels. Risk factors included older age, higher parity, low expression of p16, Ki-67 and geminin (p<0.05). Recurrence represented 8.1% of the negative cones, without identification of statistically significant risk factors. Pathological review with deeper level sections and 2-year follow-up are recommended for patients with negative conizations.

Bibliometric evaluation of negative publications from orthopedics and traumatology from the ten most influential journals of 2009-2010 and 2019-2020: A comparative study with the "Orthopedics & Traumatology: Surgery & Research" journal, using the same analysis of submitted and accepted articles.

BACKGROUND: There is a paucity of data in the literature regarding negative articles concerning surgery in orthopedics and trauma. Knowledge pertaining to treatments or techniques which confer a beneficial effect remains important, as does knowledge regarding those which have a null or pejorative effect. Thus, this study was carried out on negative articles in order to: (1) determine their proportion in the ten predominant journals concerning orthopedic and trauma surgery; (2) assess variability in their publication rate depending on the journal and the year, and compare their citation rate to that of positive articles; (3) specify whether a positive article was more likely to be cited compared to a negative article; (4) carry out the same bibliometric analysis with the "Orthopedics & Traumatology: Surgery & Research (OTSR)" journal, and detect possible selection bias for negative articles during the review. HYPOTHESIS: There are fewer negative articles than positive articles in the literature relating to orthopedic and trauma surgery. MATERIAL AND METHOD: The study was carried out using the ten orthopedic and trauma surgery journals with the highest impact factors for the year 2021. Two periods were compared, 2009-2010 and 2019-2020. Among the 17,812 publications obtained, 11,962 publications were retained to carry out the analysis (technical notes, meta-analyses, editorials and letters to the editor were all excluded). An analysis using the same method was carried out on the 3,727 articles submitted to OTSR from 2015 to 2021, which made it possible to compare the rejected articles to the accepted articles. RESULTS: Negative articles represented 11% (1,342/12,023) of the literature relating to orthopedic and trauma surgery. There were differences in the rate of publication of negative articles depending on the journals (from 4.04% to 17.14%) (p<0.0001). The negative article publication rate did not change between the two periods studied: 534/4963 articles (10.76%) in 2009-2010 versus 802/6999 (11.46%) in 2019-2020 (p=0.23). Positive articles were not cited more often than negative ones: no significant difference between the Category Normalized Citation Impact (CNCI) classes (respectively for classes 0;1[/[1;2[/≥ 2 with 45.66% 28.22% and 26.12% for negative articles versus 44.90% 27.46% and 27.64% for positive articles [p=0.4]) and the Top10% (with 18.86% for negative articles versus 20.10% for positive ones [p=0.28]). The OTSR journal had a rate of negative articles of 9.46% which was within the average range of the journals studied. A selection bias (p<0.02) for negative articles during the review of the OTSR journal was identified with fewer negative articles accepted (115/1216 [9.46%]) than positive articles (164/1330 [12.33%]). DISCUSSION: The publication of negative articles varies according to the journals and although it is modest, at only 11%, it is essential because it allows us not to repeat errors but also not to bias the carrying out of meta-analyses, and among other things to avoid useless studies. LEVEL OF EVIDENCE: III; case control study from the literature.

Impact of pharmaceutical care integrated at a psychosocial intervention to reduce caregiver's burden in Alzheimer's disease or related dementias: Negative results at 18 months and difficulties to conduct PHARMAID RCT.

Background: Psychosocial interventions for caregivers of patients with Alzheimer disease and relative dementias (ADRD) reported a caregiver burden improvement. Multicomponent intervention integrating pharmaceutical care has not yet been evaluated while ADRD patients and their caregivers are exposed to high risk of drug-related problems. The PHARMAID study aimed to assess the impact of personalized pharmaceutical care integrated to a psychosocial program on the burden of ADRD caregivers at 18 months. Methods: The PHARMAID RCT was conducted between September 2016 and June 2020 [ClinicalTrials.gov: NCT02802371]. PHARMAID study planned to enroll 240 dyads, i.e. ADRD patients and caregivers, whose inclusion criteria were: outpatient with mild or major neurocognitive disorders due to ADRD, living at home, receiving support from a family caregiver. Three parallel groups compared a control group with two interventional groups: psychosocial intervention and integrated pharmaceutical care at a psychosocial intervention. The main outcome was the caregiver burden assessed by the Zarit Burden Index (ZBI, score range 0-88) at 18 months. Results: Overall, 77 dyads were included (32% of the expected sample size). At 18 months, the mean ZBI scores were 36.7 ± 16.8 in the control group, 30.3 ± 16.3 for the group with psychosocial intervention, and 28.8 ± 14.1 in group with integrated pharmaceutical care at psychosocial intervention. No significant difference was demonstrated between the three groups (p = 0.326). Conclusions: The findings suggest that PHARMAID program had no significant impact on caregiver burden at 18 months. Several limitations have been highlighted and discussed by the authors in order to formulate recommendations for further research.

What to Do if the qPCR Test for SARS-CoV-2 or Other Pathogen Lacks Endogenous Internal Control? A Simple Test on Housekeeping Genes.

Some of the products for the molecular diagnosis of infections do not have an endogenous internal control, and this is necessary to ensure that the result is not a false negative. The aim of the project was to design a simple low-cost RT-qPCR test that can confirm the expression of basic metabolism proteins, thus confirming the quality of genetic material for molecular diagnostic tests. Two successful equivalent qPCR assays for the detection of the GADPH and ACTB genes were obtained. The course of standard curves is logarithmic, with a very high correlation coefficient R2 within the range of 0.9955-0.9956. The reaction yield was between 85.5 and 109.7%, and the detection limit (LOD) with 95% positive probability was estimated at 0.0057 ng/µL for GAPDH and 0.0036 ng/µL for ACTB. These tests are universal because they function on various types of samples (swabs, cytology, etc.) and can complement the diagnosis of SARS-CoV-2 and other pathogens, as well as potentially oncological diagnostics.

Factors that contribute to false-negative results in CT-guided transthoracic lung core-needle biopsy.

Objective: To investigate the possibility of false-negative occurrence of non-specific benign pathological results on CT-guided transthoracic lung core-needle biopsy and identify risk factors for false-negative results. Methods: The clinical, imaging, and surgical data of 403 lung biopsy patients were retrospectively analyzed. Patients were divided into true-negative and false-negative (FN) groups according to the final diagnosis. Univariate analysis was used to compare the variables in two groups for statistical differences, and multivariate analysis was used to clarify the risk factors associated with FN results. Results: Of the 403 lesions, 332 were finally confirmed as benign and 71 to be malignant, with a FN rate of 17.6%. Older patient age (P = 0.01), burr sign (P = 0.00), and pleural traction sign (P = 0.02) were independent risk factors for FN results. The area under the receiver operating characteristic (ROC) curve's area under curve (AUC) was 0.73. Conclusion: CT-guided transthoracic lung core-needle biopsy has a high diagnostic accuracy and low rate of FN results. Older patient age, the burr sign, and the pleural traction sign are independent risk factors for FN results that should be monitored prior to surgery to reduce the risk of FN results.

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.

Negative findings but positive contributions in cardiovascular research.

Researchers have always concluded that results that do not support the hypothesis as unimportant, unworthy, or simply not good enough for publication. However, negative findings are essential for the progress of science and its self-correcting nature. We also believe in the importance and indispensability of negative results. Therefore, in this review, we discussed the factors contributing to the publication bias of negative results and the problems to assess the factuality and validity of negative results. Moreover, we emphasized the importance of reporting negative results in cardiovascular research, including treatments, and suggest that the negative results could clarify previously controversial topics in the treatment of cardiovascular diseases and prompt the translation of research on precision cardiovascular disease prevention and treatment.

Internet use and depressive symptoms among Chinese older adults: Two sides of internet use.

Objective: To explore the relationship between internet use which includes time spent on the internet, internet skills, types of online activities, and depressive symptoms in older adults. Methods: We used 2020 China Family Panel Studies (CFPS) data with 3,171 older adults aged 60 years. Depression symptoms were measured with the Center for Epidemiologic Studies Depression (CES-D), and internet use was measured by time spent on the internet, internet skills, and types of online activities. Multiple linear regression models were used to explore the relationship between internet use and depressive symptoms in older adults. Results: Longer time spent on the internet was associated with higher scores of depressive symptoms (ß = 0.14). Higher internet skills were associated with lower scores of depressive symptoms (ß = -0.42). Watching short-form videos (ß = 1.34) was associated with higher depressive symptom scores, and the use of the WeChat function (ß = -0.96) was associated with lower depressive symptom scores, while online games and online shopping were not significant. Conclusion: The effect of internet use on depressive symptoms in older adults is a double-edged sword. Controlling the time spent on the internet, improving internet skills, and guiding specific a type of online activities in older adults can improve depressive symptoms through rational use.

Use of a web-based portal to return normal individual research results in Early Check: Exploring user behaviors and attitudes.

Early Check is a voluntary, large-scale expanded newborn screening study in North Carolina that uses a self-directed web-based portal for return of normal individual research results (IRR). Little is known about participant perspectives in using web-based portals to receive IRR. This study explored user attitudes and behaviors within the Early Check portal using three methods: (1) a feedback survey available to the consenting parent of participating infants (typically mothers), (2) semi-structured interviews conducted with a subset of parents, and (3) Google Analytics. During an approximate 3-year period, 17 936 newborns received normal IRR and there were 27 812 visits to the portal. Most surveyed parents reported viewing their baby's results (86%, 1410/1639). Parents largely found the portal easy to use to get results, and helpful in understanding the results. However, 10% of parents said it was difficult to find enough information to understand their baby's results. In Early Check, providing normal IRR via the portal made a large-scale study practical, and was highly rated by most users. Return of normal IRR may be particularly amenable to web-based portals, as the consequences to participants from not viewing results are modest, and the interpretation of a normal result is relatively straightforward.

Reporting and interpreting non-significant results in animal cognition research.

How statistically non-significant results are reported and interpreted following null hypothesis significance testing is often criticized. This issue is important for animal cognition research because studies in the field are often underpowered to detect theoretically meaningful effect sizes, i.e., often produce non-significant p-values even when the null hypothesis is incorrect. Thus, we manually extracted and classified how researchers report and interpret non-significant p-values and examined the p-value distribution of these non-significant results across published articles in animal cognition and related fields. We found a large amount of heterogeneity in how researchers report statistically non-significant p-values in the result sections of articles, and how they interpret them in the titles and abstracts. Reporting of the non-significant results as "No Effect" was common in the titles (84%), abstracts (64%), and results sections (41%) of papers, whereas reporting of the results as "Non-Significant" was less common in the titles (0%) and abstracts (26%), but was present in the results (52%). Discussions of effect sizes were rare (<5% of articles). A p-value distribution analysis was consistent with research being performed with low power of statistical tests to detect effect sizes of interest. These findings suggest that researchers in animal cognition should pay close attention to the evidence used to support claims of absence of effects in the literature, and-in their own work-report statistically non-significant results clearly and formally correct, as well as use more formal methods of assessing evidence against theoretical predictions.

Addressing the challenges of symbiont-mediated RNAi in aphids.

Because aphids are global agricultural pests and models for bacterial endosymbiosis, there is a need for reliable methods to study and control their gene function. However, current methods available for aphid gene knockout and knockdown of gene expression are often unreliable and time consuming. Techniques like CRISPR-Cas genome editing can take several months to achieve a single gene knockout because they rely on aphids going through a cycle of sexual reproduction, and aphids often lack strong, consistent levels of knockdown when fed or injected with molecules that induce an RNA interference (RNAi) response. In the hopes of addressing these challenges, we attempted to adapt a new method called symbiont-mediated RNAi (smRNAi) for use in aphids. smRNAi involves engineering a bacterial symbiont of the insect to continuously supply double-stranded RNA (dsRNA) inside the insect body. This approach has been successful in thrips, kissing bugs, and honeybees. We engineered the laboratory Escherichia coli strain HT115 and the native aphid symbiont Serratia symbiotica CWBI-2.3T to produce dsRNA inside the gut of the pea aphid (Acyrthosiphon pisum) targeting salivary effector protein (C002) or ecdysone receptor genes. For C002 assays, we also tested co-knockdown with an aphid nuclease (Nuc1) to reduce RNA degradation. However, we found that smRNAi was not a reliable method for aphid gene knockdown under our conditions. We were unable to consistently achieve the expected phenotypic changes with either target. However, we did see indications that elements of the RNAi pathway were modestly upregulated, and expression of some targeted genes appeared to be somewhat reduced in some trials. We conclude with a discussion of the possible avenues through which smRNAi, and aphid RNAi in general, could be improved in the future.

Parental Psychological Distress of Missed Diagnosis of Down Syndrome at Antenatal Screening: A Rare, but Still Real Occurrence - A Case Report and Review of Literature.

INTRODUCTION: Prenatal screening programs are important components for pregnant women care and are often linked with grief and shock based on gestational age or the diagnosis. Lower/no sensitivity is also associated with these screening programs leading to providing false-negative outputs. CASE PRESENTATION: Present work shows a case of missed antenatal diagnosis of Down syndrome and its persistant medical and psychological impact on the family members. We have also discussed the relevant economic and medical-legal issues related to the context and aimed to maintain an adequate awareness among healthcare to discuss properly these investigations (difference between screening and diagnostic testing), their possible outcome (chances of false results) and enabled the pregnant women/couple to take informed decision on early pregnancy. CONCLUSION: These programs are considered as routine clinical practice in many countries from last few years and are necessary to assess the pros and cons of these programs. One of the prime cons involves the likeliness of obtaining a false-negative result due to lack of 100% sensitivity and specificity.

Pitfalls in clinical genetics.

With the increasing availability of genetic tests, more doctors are offering and ordering such tests for their patients. Ordering a genetic test appears to be a simple process of filling in paperwork, drawing 3 mL of blood in an ethylenediaminetetraacetic acid tube and receiving a test report. This is identical to sending off a full blood count. However, it is far more complex than that. There are many potential pitfalls, as shown by the increasing number of complaints and lawsuits filed against doctors and allied health staff. Furthermore, clinical genetics involves more than just ordering tests; in fact, focusing on genetic tests alone is a potential pitfall. In this review, we discuss the common pitfalls in clinical genetics and how doctors can avoid these pitfalls to ensure patient safety and to safeguard their practice.

Implementing Palliative Care Teams Specialized in Dementia in Two Countries: Experiences of Failure and Success.

Much is known about palliative care needs of persons with dementia and their family. Less is known about how to successfully implement models that address those needs. We present specialist models in the Netherlands (2017-2018) and Northern Ireland (2016-2017) contrasting its evaluations. From implementation failure in the Netherlands compared with successful implementation in Northern Ireland, we learn that recognizing roles and competencies among all involved is essential in developing effective partnership relationships. All of this is facilitated by referral before the end of life and offering various training programs and in-patient and out-patient services and therapies to show benefits early.

Pitfalls in clinical genetics

With the increasing availability of genetic tests, more doctors are offering and ordering such tests for their patients. Ordering a genetic test appears to be a simple process of filling in paperwork, drawing 3 mL of blood in an ethylenediaminetetraacetic acid tube and receiving a test report. This is identical to sending off a full blood count. However, it is far more complex than that. There are many potential pitfalls, as shown by the increasing number of complaints and lawsuits filed against doctors and allied health staff. Furthermore, clinical genetics involves more than just ordering tests; in fact, focusing on genetic tests alone is a potential pitfall. In this review, we discuss the common pitfalls in clinical genetics and how doctors can avoid these pitfalls to ensure patient safety and to safeguard their practice.

Molecular Diagnostic Tools against SARS-CoV-2 in Poland in 2022.

The most effective way to stop the spread of COVID-19 (coronavirus disease 2019) is to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and isolate those infected as soon as possible. More than 1000 types of molecular and antigen-based immunoassay tests to detect SARS-CoV-2 are now commercially available worldwide. In this review, we present the possibilities of molecular diagnostics available in Poland in 2022. We provide a description of what samples have proven useful to confirm SARS-CoV-2 infection, we describe what methods are used, as well as what safeguards can and should be used to prevent false-negative and false-positive results, and finally we review the products that diagnostic laboratories have to choose from. We also describe diagnostic problems associated with the mutation of the virus.

Negative results of bronchoalveolar lavage fluid metagenomic next-generation sequencing in critically ill patients.

Objective: Reports on negative results of metagenomic next-generation sequencing (mNGS) are scarce. We aimed to explore the diagnostic value of negative results in bronchoalveolar lavage fluid (BALF) mNGS and how to deal with the negative results in patients with severe respiratory disease. Methods: A retrospective analysis was performed on patients suspected severe community-acquired pneumonia who were admitted to the respiratory intensive care unit of the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2021. According to the final diagnosis as the reference standard, the negative results of mNGS were divided into a true negative group and a false negative group. For enrolled patients, we recorded their demographic data, imaging results, laboratory results, therapeutic processes, and prognoses. Results: A total of 21 patients were enrolled in this study, including 16 true negative patients and 5 false negative patients. In the true negative group, interstitial lung diseases were the most and neoplastic diseases were following. In addition to mNGS, 9 patients underwent pathological examination, 7 patients were finally diagnosed by medical history, autoantibodies, and point-of-care (POC) ultrasound. 14 patients eventually discontinued antibiotics, 2 patients underwent antibiotic de-escalation, the average interval time of treatment adjustment was 3.56 ± 2.00 days. In the false negative group, the leading missed pathogen was fungi, followed by tuberculosis bacilli. In contrast to 2 patients underwent pathological examination, 3 patients were confirmed by routine microbiological tests. Conclusions: Negative results of BALF mNGS can help to rule out infection, but missed diagnoses may also exist. It should be re-evaluated with other clinical informations. Pathological examination or repeated mNGS may be viable options when the diagnosis cannot be confirmed.

False Negative Results in Cervical Cancer Screening-Risks, Reasons and Implications for Clinical Practice and Public Health.

False negative (FN) results in cervical cancer (CC) screening pose serious risks to women. We present a comprehensive literature review on the risks and reasons of obtaining the FN results of primary CC screening tests and triage methods and discuss their clinical and public health impact and implications. Misinterpretation or true lack of abnormalities on a slide are the reasons of FN results in cytology and p16/Ki-67 dual-staining. For high-risk human papillomavirus (HPV) molecular tests, those include: truly non-HPV-associated tumors, lesions driven by low-risk HPV types, and clearance of HPV genetic material before sampling. Imprecise disease threshold definition lead to FN results in visual inspection with acetic acid. Lesions with a discrete colposcopic appearance are a source of FN in colposcopic procedures. For FAM19A4 and hsa-miR124-2 genes methylation, those may originate from borderline methylation levels. Histological misinterpretation, sampling, and laboratory errors also play a role in all types of CC screening, as well as reproducibility issue, especially in methods based on human-eye evaluation. Primary HPV-based screening combined with high quality-assured immunocytochemical and molecular triage methods seem to be an optimal approach. Colposcopy with histological evaluation remains the gold standard for diagnosis but requires quality protocols and assurance measures.