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[This corrects the article DOI: 10.3389/fgene.2024.1384094.].

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Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007-2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice.

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Fine needle aspiration cytology (FNAC) is a useful tool in the evaluation of lymphadenopathy. It is a safe and minimally invasive procedure that provides preoperative details for subsequent treatment. It can also diagnose the majority of malignant tumors. However, there are some instances where the diagnosis of tumors remains obscure. To address this, we re-analyzed the misinterpreted patients' samples using mRNA sequencing technology and then identified the characteristics of non-Hodgkin's lymphoma that tend to be under-diagnosed. To decipher the involved genes and pathways, we used bioinformatic and biological analysis approaches, identifying the response to oxygen species, inositol phosphate metabolic processes, and peroxisome and PPAR pathways as possibly being involved with this type of tumor. Notably, these analyses identified FOS, ENDOG, and PRKAR2B as hub genes. cBioPortal, a multidimensional cancer genomics database, also confirmed that these genes were associated with lymphoma patients. These results thus point to candidate genes that could be used as biomarkers to minimize the false-negative rate of FNAC diagnosis. We are currently pursuing the development of a gene chip to improve the diagnosis of lymphadenopathy patients with the ultimate goal of improving their prognosis.

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Ten years after the implementation of the French Plan on Alzheimer's Disease (2008-2012), the present study aimed at describing the situation of the persons living with dementia in terms of diagnosis and high-risk situations (living alone, continuing driving, inability to handle budget and to manage medication). Among the 115 dementia cases followed-up in the AMI population-based cohort on aging in 2018 (i.e. ten years after the launch of the Plan), the prevalence of under-diagnosis was similar to the one estimated ten years earlier (53.0% vs. 55.6%). Almost all cases (95.3%) were concerned by high-risk situations (61.2% were unable to handle finances, 48.2% were living alone, 27.1% continued driving). Being diagnosed as demented was not associated with a lower frequency of high-risk situations, excepting for driving (16.7% vs. 37.2%). Ten years after the beginning of the French Alzheimer's Plan, dementia remains a hidden syndrome, with a frequent inadequate management of high-risk situations.

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Background: Autism has long been viewed as a paediatric condition, meaning that many autistic adults missed out on a diagnosis as children when autism was little known. We estimated numbers of diagnosed and undiagnosed autistic people in England, and examined how diagnostic rates differed by socio-demographic factors. Methods: This population-based cohort study of prospectively collected primary care data from IQVIA Medical Research Data (IMRD) compared the prevalence of diagnosed autism to community prevalence to estimate underdiagnosis. 602,433 individuals registered at an English primary care practice in 2018 and 5,586,100 individuals registered between 2000 and 2018 were included. Findings: Rates of diagnosed autism in children/young people were much higher than in adults/older adults. As of 2018, 2.94% of 10- to 14-year-olds had a diagnosis (1 in 34), vs. 0.02% aged 70+ (1 in 6000). Exploratory projections based on these data suggest that, as of 2018, 463,500 people (0.82% of the English population) may have been diagnosed autistic, and between 435,700 and 1,197,300 may be autistic and undiagnosed (59-72% of autistic people, 0.77%-2.12% of the English population). Age-related inequalities were also evident in new diagnoses (incidence): c.1 in 250 5- to 9-year-olds had a newly-recorded autism diagnosis in 2018, vs. c.1 in 4000 20- to 49-year-olds, and c.1 in 18,000 people aged 50+. Interpretation: Substantial age-related differences in the proportions of people diagnosed suggest an urgent need to improve access to adult autism diagnostic services. Funding: Dunhill Medical Trust, Economic and Social Research Council, Medical Research Council, National Institute for Health Research, the Wellcome Trust, and the Royal College of Psychiatrists.

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AIM: In this study, it was aimed to investigate the reliability of total prostate-specific antigen (t-PSA) in prostate cancer screening in hyperglycemic (≥126 mg/dL) individuals. METHODS: This research was planned as a cross-sectional retrospective study. Three hundred eleven cases which underwent biopsy with the suspicion of prostate cancer in the hospital were included in the study. Prostate cancer risk groups were categorized as low, intermediate and high. Those with fasting blood glucose (FBG) levels lower than 126 mg/dL were considered as the normoglycemia group. RESULTS: It was determined that the t-PSA measurement was higher in the patient group with cancer (P < .001). It was determined that the median t-PSA levels of the intermediate and high cancer groups were higher than the low cancer group (P < .001 and P = .001, respectively). t-PSA was found to be associated with increased cancer risk in cases with FBG <126. However, an increase in t-PSA values in cases with FBG ≥126 was not associated with increased prostate cancer. There is no relationship between FBG measurement and t-PSA measurement (rs=0.05, P = .446). In addition, it was determined that the t-PSA measurements of patients with FBG ≥126 and FBG<126 did not differ (P = .962). CONCLUSIONS: As a contribution to literature, we found that the t-PSA test lost its sensitivity in cases with plasma glucose levels above normal. Loss of sensitivity may result in underdiagnosis in prostate cancer and this, in turn, results in diagnosis of the cancer at a later stage. In the future, it may be necessary to adopt a different approach in prostate cancer screening in hyperglycemic cases.

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Monkeypox is an emerging zoonotic disease caused by the monkeypox virus, which is an infectious agent belonging to the genus Orthopoxvirus. Currently, commencing from the end of April 2022, an outbreak of monkeypox is ongoing, with more than 43,000 cases reported as of 23 August 2022, involving 99 countries and territories across all the six World Health Organization (WHO) regions. On 23 July 2022, the Director-General of the WHO declared monkeypox a global public health emergency of international concern (PHEIC), since the outbreak represents an extraordinary, unusual, and unexpected event that poses a significant risk for international spread, requiring an immediate, coordinated international response. However, the real magnitude of the burden of disease could be masked by failures in ascertainment and under-detection. As such, underestimation affects the efficiency and reliability of surveillance and notification systems and compromises the possibility of making informed and evidence-based policy decisions in terms of the adoption and implementation of ad hoc adequate preventive measures. In this review, synthesizing 53 papers, we summarize the determinants of the underestimation of sexually transmitted diseases, in general, and, in particular, monkeypox, in terms of all their various components and dimensions (under-ascertainment, underreporting, under-detection, under-diagnosis, misdiagnosis/misclassification, and under-notification).

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BACKGROUND: Asthma is the commonest chronic respiratory tract disease in children. In low-income countries, challenges exist in asthma diagnosis. In surveys done in children, the prevalence of 'asthma' defined by symptoms is high compared to 'doctor diagnosed asthma'. The questions answered by this review are (i) What challenges have been experienced in the diagnosis of asthma in children? (ii) What solutions will address these challenges? METHODS: The Arksey and O'Malley's framework for scoping reviews was used for the study methodology, while the PRISMA-ScR checklist guided the reporting process. Electronic databases: PubMed Central, EMBASE and Google Scholar were searched. Primary quantitative and qualitative studies and reviews from 2010 to 2021, from Nigeria, South Africa and Uganda written in English or translated to English, which answered the study questions were included. The author, title, country, study type, methods, purpose, findings and references were captured onto a predefined data collection table. The 'Preview, Question, Read, Summarise' system was used and a narrative report was used to summarise the findings. RESULTS: A total of 28 studies were included. The causes of under-diagnosis of asthma include lack of community knowledge and perception of asthma, poor accessibility to health care, strained health systems, lack of diagnostic tests including spirometry, low levels of knowledge among health-care workers and lack of or non-implementation of asthma guidelines. Strategies to improve asthma diagnosis will include community and school based education programmes, revision of asthma diagnostic terms, guideline development and implementation and health systems strengthening. CONCLUSION: This scoping review provides research evidence for policy makers and health-workers involved in the care of asthmatic children on challenges faced in asthma diagnosis and strategies to improve asthma diagnosis.

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BACKGROUND: Incidental carcinoma gall bladder and benign disease in radical cholecystectomy specimen is the cause of concern. We attempted to find out the incidence and reasons thereof in the present study. METHODS: Present study is a retrospective analysis of a prospectively maintained database between July 2002 and July 2019. All patients with a diagnosis of carcinoma gall bladder admitted for surgery were included. RESULTS: Out of 148 patients, 110 patients had carcinoma gall bladder (CAGB), while 38 patients (25.7%) had incidental carcinoma (under-diagnosis). Radical resection was done in 61/110 (55.4%) patients with clinical CAGB, where 15 (24.6%) patients had benign pathology ("over-diagnosis"). Overdiagnosis was due to xanthogranulomatous cholecystitis (n = 9), chronic cholecystitis (n = 2), tuberculosis (n = 2) and IgG4 related cholecystitis (n = 2). Among 61 patients, a history of weight loss and anorexia were significantly associated with malignancy. Asymmetrical wall thickness was significantly more common in benign mimickers. Among patients with incidental carcinoma, preoperative ultrasonography reported normal wall thickness of gall bladder in 28 (73.7%), thickened gall bladder wall in 6, and polyp in 3 patients. The resectability rate among incidental carcinoma was 27/38 (71.05%). CONCLUSION: Over-diagnosis of the carcinoma gall bladder was present in 24.6%. On the other hand, incidental carcinoma comprised 25.7% of all admissions for carcinoma gall bladder with resectability of 71%.

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Following stroke, individuals require ongoing screening, diagnosis and monitoring for cognitive impairment. Services and policies around these vary widely between settings, and reports from many countries highlight persistent under-diagnosis of cognitive impairment in the months and years after stroke. Missed and delayed diagnosis of post-stroke cognitive impairment, including dementia, are important factors in shaping the experiences of people so affected and their family members, especially in low- and middle-income countries. Drawing upon ethnographic research conducted in Malaysia, this article draws upon three case studies to examine the continued health-seeking behaviour after the appearance of salient cognitive and behavioural symptoms that occurred after stroke. Findings highlight the challenges in getting formal diagnostic clarity for cognitive and behavioural symptoms in a rural setting within a middle-income country. No study participants sought help for memory or cognitive problems, partly due to limited lay awareness of cognitive impairment but more significantly due to health service factors. Despite their elevated risk for dementia, participants were not monitored for cognitive impairment during any follow-up care in various health facilities. Furthermore, caregivers' attempts to seek help when behavioural issues became untenable were met with multiple health system barriers. The journey was complicated by the meanings attached to the reactions towards cognitive symptoms at the community level. We suggest that strategies seek to increase the awareness of post-stroke cognitive and behavioural symptoms, and incorporate clear treatment pathways into the long-term care plans of community-dwelling stroke survivors.

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Recently, the "Choosing Wisely" initiative has gained traction and high-value care has garnered attention. However, the actual situation of high-value care is different between developed and developing countries. To elucidate this, we highlight the differences between the high-value care provided by healthcare systems in Japan and Myanmar, as representations of developed and developing countries, respectively. Despite the total numbers of magnetic resonance imaging (MRI) equipment in Japan being 400 times higher than in Myanmar, and gross domestic product per capita being 32 times higher in Japan, the individual costs (out of pocket expenditures) per MRI scan are the same (USD 60). However, the total cost per MRI scan is different, implying that differing healthcare costs indicate the existence of over- and under-diagnosis problems among different countries. This study suggests that detailed patient histories and physical examinations are important for selecting relevant diagnostic imaging and reducing unnecessary imaging.

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Resumen Objetivo: El Trastorno por Déficit de Atención con Hiperactividad/impulsividad (TDAH) es una de las dificultades de aprendizaje más comunes en las escuelas chilenas. Se caracteriza por un patrón de funcionamiento atípico en atención e inhibición, con fuerte compromiso de otras funciones ejecutivas. Uno de los desafíos que plantea este trastorno está referido al proceso de diagnosis, el cual no suele ser suficientemente preciso. Se pretende explorar las diferencias en la distribución de dos muestras de estudiantes con y sin TDAH diagnosticadas con una escala de observación conductual a través de la evaluación de las funciones ejecutivas de atención, inhibición y flexibilidad cognitiva. Método: En este estudio se evaluó a 132 escolares, 66 con TDAH y 66 sin TDAH, en las variables de atención, inhibición y flexibilidad cognitiva de un colegio de la ciudad de Concepción en Chile. Se contrastó el rendimiento cognitivo con los diagnósticos y se reagrupó a los estudiantes en los subtipos conocidos del trastorno. Resultados: La evaluación neuropsicológica mostró que en el grupo con TDAH había alumnos que no cumplían los criterios diagnósticos para estar incluidos en él. En el grupo sin TDAH se observó un fenómeno semejante. En ambos grupos la evaluación neuropsicológica de la atención y la inhibición resultaron útiles para diagnosticar con mayor certeza y para determinar el subtipo al que pertenecía cada estudiante con TDAH detectado. La flexibilidad cognitiva solo permitió diferenciar a los sujetos con y sin TDAH. Conclusiones: En ambos grupos estudiados fue posible encontrar sujetos mal diagnosticados; el sobrediagnóstico fue de 43,93 % en el grupo con TDAH, mientras que el infradiagnóstico fue de 42,42 % en el grupo sin TDAH.

Abstract Objective: Attention Deficit Hyperactivity/Impulsivity Disorder (ADHD) is one of the most common learning difficulties in Chilean schools. It is characterized by an atypical functioning pattern in attention and inhibition, strongly compromising other executive functions. One of the challenges posed by this disorder is the diagnosis process, which is often not sufficiently accurate. The intention is to study the distribution of two students samples, with and without ADHD, diagnosed by a behavioral observation scale through the evaluation of attention, inhibition, and cognitive flexibility executive functions. Method: This study evaluated 132 students, 66 with ADHD and 66 without ADHD, considering the attention, inhibition, and cognitive flexibility variables of a school in the city of Concepción in Chile. Cognitive performance was contrasted with the diagnoses, and students were regrouped in the disorder known subtypes. Results: The neuropsychological evaluation showed that in the ADHD group, there were students who did not meet the diagnostic criteria to be included in the group. A similar phenomenon was observed in the group without ADHD. In both the groups, the neuropsychological evaluation of attention and inhibition was useful in providing a more certain dignosis and in determining the subtype to which each student detected with ADHD belonged. Cognitive flexibility was only useful in differentiating betwen the subjects with and without ADHD. Conclusions: In both the groups studied, it was possible to find misdiagnosed subjects; the overdiagnosis was 43,93 % in the ADHD group, while the under-diagnosis was 42,42 % in the group without ADHD.

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BACKGROUND: Despite widespread use, the accuracy of the diagnostic test for SARS-CoV-2 infection is poorly understood. The aim of our work was to better quantify misclassification errors in identification of true cases of COVID-19 and to study the impact of these errors in epidemic curves using publicly available surveillance data from Alberta, Canada and Philadelphia, USA. METHODS: We examined time-series data of laboratory tests for SARS-CoV-2 viral infection, the causal agent for COVID-19, to try to explore, using a Bayesian approach, the sensitivity and specificity of the diagnostic test. RESULTS: Our analysis revealed that the data were compatible with near-perfect specificity, but it was challenging to gain information about sensitivity. We applied these insights to uncertainty/bias analysis of epidemic curves under the assumptions of both improving and degrading sensitivity. If the sensitivity improved from 60 to 95%, the adjusted epidemic curves likely falls within the 95% confidence intervals of the observed counts. However, bias in the shape and peak of the epidemic curves can be pronounced, if sensitivity either degrades or remains poor in the 60-70% range. In the extreme scenario, hundreds of undiagnosed cases, even among the tested, are possible, potentially leading to further unchecked contagion should these cases not self-isolate. CONCLUSION: The best way to better understand bias in the epidemic curves of COVID-19 due to errors in testing is to empirically evaluate misclassification of diagnosis in clinical settings and apply this knowledge to adjustment of epidemic curves.

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Hb A'2 (or Hb B2) (HBD: c.49G>C) is the most frequent δ chain variant that has been described in Africa but not in Thailand. We report here a 10-month-old Thai infant with compound heterozygosity for ß0 codon 17 (A>T; HBB: c.52A>T) and ß+ IVS II-654 (C>T; HBB: c.316-197C>T). Under diagnosed ß-thalassemia (ß-thal) in her father, who carries Hb A'2 and a heterozygous ß0 codon 17 mutation, and the mother, who carries a heterozygous ß+ IVS II-654 mutation, was noted. Although Hb A'2 does not cause any problems, heterozygosity for Hb A'2 can lead to under diagnosis of ß-thal in Hb A'2 samples. This case highlights the importance of Hb A'2 in prenatal diagnosis (PND). Thus, molecular analysis for ß-thal mutations should be carried out when a small peak presents at the retention time (RT) of 4.71 min. on high performance liquid chromatography (HPLC) and the summation level of this peak and Hb A2 was equal or higher than 4.0%.

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BACKGROUND: Little is known about atopic dermatitis (AD) among children in Puerto Rico. OBJECTIVE: To examine risk factors and identify approaches to better diagnose AD in Puerto Rican children. METHODS: Case-control study of AD among 540 children aged 6-14 years in San Juan, Puerto Rico. AD was defined as: 1) physician-diagnosed AD, 2) RAST-AD: AD symptoms plus ≥1 positive IgE to allergens, and 3) STR-AD: AD-symptoms and skin test reactivity to ≥1 allergen. Logistic regression was used for the multivariable analysis. We also evaluated the diagnostic performance of various approaches by comparing their sensitivity, specificity, positive predicted value [PPV], negative predictive value [NPV], and area under curve [AUC]). RESULTS: Of the 70 children with STR-AD, only 5 (7.1%) had PD-AD. In children without asthma, a positive IgE to Dermatophagoides (D.) pteronyssinus and signs of mold/mildew at home were significantly associated with 3.3 and 5 times increased odds of STR-AD, respectively. Among children with asthma, private/employer-based health insurance and a positive IgE to D. pteronyssinus were each significantly associated with approximately twofold increased odds of STR-AD. A combination of current eczema symptoms and a positive IgE to D. pteronyssinus yielded a sensitivity ≥ 70%, specificity and NPV ≥ 95%, PPV ≥ 88%, and an AUC ≥ 0.85 for STR-AD. Replacing a positive IgE to D. pteronyssinus with a positive IgE to ≥1 allergen slightly increased sensitivity without affecting other parameters. CONCLUSIONS: AD is markedly under-diagnosed by physicians in Puerto Rico. This could be improved by assessing eczema symptoms and measuring IgEs to common allergens.

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BACKGROUND AND PURPOSE: Investigation of the geographic variation in asthma prevalence can improve our understanding of asthma etiology and management. The purpose of our investigation was to compare the prevalence of asthma and wheeze among adolescents living in two distinct international regions and to investigate reasons for observed differences. METHODS: A cross-sectional survey of 13-14 year olds was completed in Saskatoon, Canada (n=1200) and Skopje, Republic of Macedonia (n=3026), as part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase 3 study. Surveys were self-completed by students following the ISAAC protocol. Multiple logistic regression models were used to investigate associations with reports of asthma and current wheeze. A mediation analysis was then completed. RESULTS: Asthma prevalence was much higher in Saskatoon than Skopje (21.3% vs. 1.7%) as was the prevalence of current wheeze (28.2% vs. 8.8%). Higher paracetamol (acetaminophen) use was a consistent risk factor for asthma and wheeze in both locations and showed dose-response relationships. In both countries, paracetamol use and physical activity mediated some of the association for both asthma and wheeze. In Saskatoon, among those with current wheeze, 42.6% reported ever having a diagnosis of asthma compared to 10.2% among Skopje adolescents. CONCLUSIONS: The results suggest that the variation in risk factors between the two locations may explain some of the differences in the prevalence of asthma and wheeze between these two study sites. However, diagnostic labeling patterns should not be ruled out as another potential explanatory factor.

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BACKGROUND: Prostate cancer antigen 3 (PCA3) is a prostate cancer diagnostic biomarker that has been clinically validated. The limitations of the diagnostic role of PCA3 in initial biopsy and the prognostic role are not well established. Here, we elucidate the limitations of tissue PCA3 to predict high grade tumors in initial biopsy. RESULTS: PCA3 has a bimodal distribution in both biopsy and radical prostatectomy (RP) tissues, where low PCA3 expression was significantly associated with high grade disease (p<0.001). PCA3 had a poor performance of predicting high grade disease in initial biopsy (GS≥8) with 55% sensitivity and high false negative rates; 42% of high Gleason (≥8) samples had low PCA3. In RP, low PCA3 is associated with adverse pathological features, clinical recurrence outcome and greater probability of metastatic progression (p<0.001). MATERIALS AND METHODS: A total of 1,694 expression profiles from biopsy and 10,382 from RP patients with high risk tumors were obtained from the Decipher Genomic Resource Information Database (GRIDTM)prostate cancer database. The primary clinical endpoint was distant metastasis-free survival for RP and high Gleason grade for biopsy. Logistic regression analyses and Cox proportional hazards models were used to evaluate the association of PCA3 with clinical variables and risk of metastasis. CONCLUSIONS: There is high prevalence of high grade tumors with low PCA3 expression in the biopsy setting. Therefore, urologists should be warned that using PCA3 as stand-alone test may lead to high rate of under-diagnosis of high grade disease in initial biopsy setting.

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Introduction. The presented study of 4,535 children aged 7-17 years in the Upper Silesian region of Poland yielded 186 cases of previously known asthma, and 44 children with newly diagnosed asthma. The aim of the presented study was to identify non-medical factors that could explain why children with a newly established diagnosis ('undiagnosed asthma') had not been diagnosed in the past. Materials and method. The study was performed according to a case-control design. Parents of the children answered questionnaires on socio-economic status and family-related factors. Statistical determinants of undiagnosed asthma were explored using raw (OR) and logistic odds ratios with their 95% confidence intervals (logOR, 95%CI). Results. Children with undiagnosed asthma were younger compared to the group with previously known asthma (11.3±2.1 vs. 12.6±2.5 years; p=0.0008). Newly diagnosed cases were more frequent in children who had less parental attention (less than 1 hour/day spent by parent with child - OR=4.36; 95%CI: 1.76-10.81) and who were not registered with specialized health care (OR=2.20; 95%CI: 0.95-5.06). Results of logistic regression analysis suggest that under-diagnosis of asthma is related to age below 12 years - logOR = 3.59 (95%CI: 1.28-10.36), distance to a health centre > 5 km - logOR = 3.45 (95%CI: 1.05-11.36), time spent with child < 1 hour/day - logOR = 6.28 (95%CI: 1.98-19.91). Conclusion. Among non-medical determinants of undiagnosed asthma the age of a child plays a major role. Another factors of importance is the large distance between residence and health centre, and low parental attention at home.

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Mucoepidermoid Carcinoma (MEC) is the most common malignant neoplasm of salivary gland origin. However, its morphologic heterogeneity poses difficulty in interpretation. In the present series we discuss the morphologic features of MEC, limitations and pitfalls in its diagnosis on Fine Needle Aspiration Cytology (FNAC). Fourteen cases of suspected MEC were evaluated cytologically followed by histopathological examination for confirmation. A definite cytological diagnosis was rendered in nine cases; three of the remaining five were underdiagnosed as abscess, pleomorphic adenoma and mucus cyst. Of the remaining two cases, one case each of sebaceous carcinoma and sialadenitis was mislabeled as MEC on cytology. A satisfactory aspirate composed of intermediate cells, mucin secreting cells and squamous cells in a mucinous background may not be obtained in all cases of low grade MEC. High grade MEC can be classified as squamous cell carcinoma. Hence, awareness of confounding factors with clinicopathologic correlation and judicious use of frozen section can help in minimizing errors.