Management of infusion-related reactions in cancer therapy: strategies and challenges.

Several anticancer therapies have the potential to cause infusion-related reactions (IRRs) in the form of adverse events that typically occur within minutes to hours after drug infusion. IRRs can range in severity from mild to severe anaphylaxis-like reactions. Careful monitoring at infusion initiation, prompt recognition, and appropriate clinical assessment of the IRR and its severity, followed by immediate management, are required to ensure patient safety and optimal outcomes. Lack of standardization in the prevention, management, and reporting of IRRs across cancer-treating institutions represents not only a quality and safety gap but also a disparity in cancer care. The present article, supported by recently published data, was developed to standardize these procedures across institutions and provide a useful tool for health care providers in clinical practice to recognize early signs and symptoms of an IRR and promptly and appropriately manage the event.

Differential photosynthetic plasticity of Amazonian tree species in response to light environments.

To investigate how and to what extent there are differences in the photosynthetic plasticity of trees in response to different light environments, six species from three successional groups (late successional, mid-successional, and pioneers) were exposed to three different light environments [deep shade - DS (5% full sunlight - FS), moderate shade - MS (35% FS) and full sunlight - FS]. Maximum net photosynthesis (Amax ), leaf N partitioning, stomatal, mesophile, and biochemical limitations (SL, ML, and BL, respectively), carboxylation velocity (Vcmax ), and electron transport (Jmax ) rates, and the state of photosynthetic induction (IS) were evaluated. Higher values of Amax , Vcmax , and Jmax in FS were observed for pioneer species, which invested the largest amount of leaf N in Rubisco. The lower IS for pioneer species reveals its reduced ability to take advantage of sunflecks. In general, the main photosynthetic limitations are diffusive, with SL and ML having equal importance under FS, and ML decreasing along with irradiance. The leaf traits, which are more determinant of the photosynthetic process, respond independently in relation to the successional group, especially with low light availability. An effective partitioning of leaf N between photosynthetic and structural components played a crucial role in the acclimation process and determined the increase or decrease of photosynthesis in response to the light conditions.

Global cross-cultural validation of a brief measure for identifying potential suicide risk in 42 countries.

OBJECTIVES: This study aimed to examine the psychometric properties of the P4 suicide screener in a multinational sample. The primary goal was to evaluate the reliability and validity of the scale and investigate its convergent validity by analyzing its correlation with depression, anxiety, and substance use. STUDY DESIGN: The study design is a cross-sectional self-report study conducted across 42 countries. METHODS: A cross-sectional, self-report study was conducted in 42 countries, with a total of 82,243 participants included in the final data set. RESULTS: The study provides an overview of suicide ideation rates across 42 countries and confirms the structural validity of the P4 screener. The findings indicated that sexual and gender minority individuals exhibited higher rates of suicidal ideation. The P4 screener showed adequate reliability, convergence, and discriminant validity, and a cutoff score of 1 is recommended to identify individuals at risk of suicidal behavior. CONCLUSIONS: The study supports the reliability and validity of the P4 suicide screener across 42 diverse countries, highlighting the importance of using a cross-cultural suicide risk assessment to standardize the identification of high-risk individuals and tailoring culturally sensitive suicide prevention strategies.

The "Sniffin' Kids-PT" test: A smell test variant for Portuguese children.

OBJECTIVE: Olfactory tests tailored for children are essential, as diagnosing olfactory dysfunction at these ages can be challenging. The 16-item "Sniffin' Sticks" is reliable and easy to perform. To the best of our knowledge, there is currently no validated olfactory test for the Portuguese pediatric population. This study aimed to adapt and validate the "Sniffin' Sticks" olfactory test for the Portuguese pediatric population. METHODS: Between August 2020 and September 2021, 354 children aged between 6 and 17years old enrolled in the study, 336 healthy children with a normal sense of smell, and 18 anosmic children with Kallmann syndrome. The study consisted of two parts. Firstly, the "Sniffin' Sticks" olfactory identification test was applied to healthy children and the odors with statistically significant low identification rates were excluded. A modified version of "Sniffin' Sticks" was defined and named "Sniffin' Kids-PT" test. Secondly, normative data were assessed and test-retest and validation tests were performed. RESULTS: Apple and Cloves odors were identified with a low rate and were excluded from the "Sniffin' Sticks" olfactory test. In the modified 14-item "Sniffin' Kids-PT", scoring <6 (from 6-8years old), <7 (from 9-11years old) or <8 (from 12-14years old and 15-17years old) was indicative of olfactory dysfunction. The test-retest reliability was good (r=0.81; P<0.001) and the differences between scores of healthy children and anosmic children were statistically significant (U213=13.00; P<0.001). CONCLUSION: The modified "Sniffin' Kids-PT" is a reliable test to discriminate between normosmia and olfactory dysfunction in Portuguese children over 5years old.

Expression of IL-17RA in Innate Cells of Patients with Common Variable Immunodeficiency (CVID) and its Clinical Implications.

Summary: Background. Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by B-cell dysfunction and immunoglobulin production deficiency. Dysregulation of interleukin-17 (IL-17) and its receptor IL-17RA have been reported in various immune disorders. This study aimed to investigate the expression of IL-17RA in innate immune cells of CVID patients and its correlation with clinical manifestations. Methods. A cross-sectional study included 22 CVID patients and 14 age- and sex-matched healthy controls. IL-17RA expression was assessed in various immune cell subsets using flow cytometry. Demographic and clinical data were collected, and statistical analysis was performed. Results. CVID patients had elevated IL-17RA expression in neutrophils, non-classical monocytes, and dendritic cells compared to healthy controls. Patients with a history of intestinal microbial colonization, particularly with Campylobacter jejuni and Giardia intestinalis, showed significantly higher IL-17RA expression in innate cells. Elevated IL-17RA expression in monocytes and dendritic cells also correlated with higher fecal calprotectin levels in CVID patients, regardless of microbial colonization. Conclusions. The study suggests that despite previous reports of reduced circulating Th17 cells and IL-17 levels in CVID patients, IL-17RA expression in innate cells may be elevated, potentially indicating altered IL-17 signaling. This heightened IL-17RA expression could contribute to a persistent pro-inflammatory state, possibly due to microbial translocation or other inflammatory factors. The association of IL-17RA expression with gastrointestinal microbial colonization and its correlation with fecal calprotectin underscores the complexity of IL-17RA's role in CVID pathophysiology. Further research in larger cohorts could elucidate the implications of IL-17RA expression in both infectious and non-infectious inflammatory aspects of CVID.

Volumetry after botulinum toxin A: the impact on abdominal wall compliance and endotracheal pressure.

PURPOSE: Botulinum toxin type A (BTA) is an adjuvant tool used in the preoperative optimization of complex hernias before abdominal wall reconstruction (AWR). This study aims to investigate changes in the abdominal cavity and hernia sac dimensions after BTA application. METHOD: A prospective study with 27 patients with a hernia defect of ≥ 10 cm and loss of domain (LOD) ≥ 20% underwent AWR. Computed tomography (CT) measurements and volumetry before and after the application of BTA were performed. Intraoperative and postoperative outcomes were evaluated. RESULTS: Imaging post-BTA revealed hernia width reduction of 1.9 cm (p = 0.002), lateral abdominal wall muscle elongation of 3.1 cm (p < 0.001), hernia volume reduction (HV) from 2.9 ± 0.9L to 2.4 ± 0.8L (p < 0.001), increase in abdominal cavity volume (ACV) from 9.7 ± 2.5L to 10.3L ± 2.4L (p = 0.003), and a reduction in the HV/ACV ratio from 30.2 ± 5% to 23.4 ± 6% (p < 0.001). Fascial closure was achieved in 92.6% of cases and component separation was required in 78%. The average variation in pulmonary plateau pressure was 3.53 cmH2O, and there were no postoperative respiratory failure recorded. At the 90-day follow-up, the wound morbidity rate was 25%, unplanned readmissions were 11%, and hernia recurrence 7.4%. CONCLUSION: BTA produces measurable volumetric changes in abdominal wall and appears to facilitate fascial closure. Further studies are required to determine the role of BTA in the surgical armamentarium for complex hernia repair.

Respiratory virus detection among healthcare professionals in Brazil: work-related contact and episode recurrence during the COVID-19 pandemic.

OBJECTIVES: Since the beginning of the COVID-19 pandemic, changes in the circulation of respiratory viruses have been observed after measures to control the spread of SARS-CoV-2 were implemented. In this sense, we aimed to understand the circulation of the respiratory virus and its impact in a controlled healthy population of healthcare professional (HCP) volunteers in phase III of the clinical trial of the ChadOx nCoV1 conducted in São Paulo, Brazil. STUDY DESIGN: This was a nested observational cohort study within a clinical trial. METHODS: We performed RT-qPCR to detect SARS-CoV-2, influenza virus A and B (IVA and IVB), respiratory syncytial virus (RSV), human rhinovirus (HRV), human metapneumovirus (hMPV), human coronaviruses (hCoVs: HKU-1, NL63, OC43, and 229-E), parainfluenza virus (PiV) I-IV, and q-PCR for adenovirus in nasopharyngeal and oropharyngeal samples obtained from HCP enrolled in the clinical trial to assess respiratory viruses infection among vaccinated and non-vaccinated. RESULTS: From July 2020 to January 2022, 876 samples were included from 737 volunteers (median age: 33 years, 62.9% female). New episodes were registered for 119 individuals. We observed an overall positivity of 37.7% for SARS-CoV-2 and 16.4% for other respiratory viruses; HRV was the second most detected virus (8%), followed by RSV (2.4%). Fully vaccinated individuals accounted for 53.3% of collected samples, and 52.9% presented at least one respiratory virus infection, with SARS-CoV-2 being the most predominant etiologic agent (62.3%). Influenza and hMPV were not detected among the tested samples. Among the subjects that presented more than one episode, SARS-CoV-2 and HRV infections were related to direct contact with patients (P < 0.002). CONCLUSIONS: Data show high infection rates among HCPs even under mask policies and contact precautions, highlighting the need for improvement in infection control measures in this population regardless of the vaccination program.

Preinterventional Third-Molar Assessment Using Robust Machine Learning.

Machine learning (ML) models, especially deep neural networks, are increasingly being used for the analysis of medical images and as a supporting tool for clinical decision-making. In this study, we propose an artificial intelligence system to facilitate dental decision-making for the removal of mandibular third molars (M3M) based on 2-dimensional orthopantograms and the risk assessment of such a procedure. A total of 4,516 panoramic radiographic images collected at the Center of Dental Medicine at the University of Zurich, Switzerland, were used for training the ML model. After image preparation and preprocessing, a spatially dependent U-Net was employed to detect and retrieve the region of the M3M and inferior alveolar nerve (IAN). Image patches identified to contain a M3M were automatically processed by a deep neural network for the classification of M3M superimposition over the IAN (task 1) and M3M root development (task 2). A control evaluation set of 120 images, collected from a different data source than the training data and labeled by 5 dental practitioners, was leveraged to reliably evaluate model performance. By 10-fold cross-validation, we achieved accuracy values of 0.94 and 0.93 for the M3M-IAN superimposition task and the M3M root development task, respectively, and accuracies of 0.9 and 0.87 when evaluated on the control data set, using a ResNet-101 trained in a semisupervised fashion. Matthew's correlation coefficient values of 0.82 and 0.75 for task 1 and task 2, evaluated on the control data set, indicate robust generalization of our model. Depending on the different label combinations of task 1 and task 2, we propose a diagnostic table that suggests whether additional imaging via 3-dimensional cone beam tomography is advisable. Ultimately, computer-aided decision-making tools benefit clinical practice by enabling efficient and risk-reduced decision-making and by supporting less experienced practitioners before the surgical removal of the M3M.

Anatomical and histochemical characterization of stem and leaves of Bauhinia pulchella Benth. (Fabaceae).

Bauhinia pulchella Benth. (Fabaceae), is native to Brazil and popularly known as pata-de-bode. In folk medicine, it is used to treat diabetes. Pharmacological studies have demonstrated different properties, such as cytotoxic and antioxidant, and different chemical constituents, such as essential oil, triterpenoids, steroids, among others. In order to highlight the morphological differences of the species B. pulchella from the others of the genus, and its pharmacological potential, the present study aimed to carry out the anatomical and histochemical characterization of the stem and leaves of B. pulchella. Usual methods in plant anatomy were used in the preparation of semi-permanent slides containing cross sections of the stem, petiole and leaf blade and paradermal sections of the leaf blade for analysis in light microscopy and polarized light. Histochemical tests were also performed to localize the metabolites in the stem and leaf blade. The stem of B. pulchella has a cylindrical outline, the bark is composed of 7-8 layers of cells and discontinuously distributed sclerenchyma; petiole presents flat convex contour, prominences in the adaxial region, concentric amphicrivral vascular bundle, surrounding a small concentric anfivasal intramedullary bundle, adaxially two accessory bundles and tector trichomes; leaf blade with anisocytic and tetracytic stomata on the adaxial surface and anisocytic, tetracytic and anomocytic on the abaxial surface; and midrib with plain-convex outline, 1-2 layers of collenchyma and covering trichomes. Characteristics that differ from other species of the genus Bauhinia. Alkaloids, phenolic compounds, lipophilic compounds, lignin, triterpenes, steroids and tannins were observed in the species. The results are fundamental for the pharmacobotanical standardization of the studied species.

Spectrally Sharp Near-Field Thermal Emission: Revealing Some Disagreements between a Casimir-Polder Sensor and Predictions from Far-Field Emittance.

Near-field thermal emission largely exceeds blackbody radiation, owing to spectrally sharp emission in surface polaritons. We turn the Casimir-Polder interaction between Cs(7P_{1/2}) and a sapphire interface into a sensor sharply filtering, at 24.687 THz, the near-field sapphire emission at ∼24.5 THz. The temperature evolution of the sapphire mode is demonstrated. The Cs sensor, sensitive to both dispersion and dissipation, suggests the polariton to be redshifted and sharper, as compared, up to 1100 K, to predictions from far-field sapphire emission, affected by birefringence and multiple resonances.

Systematic review and meta-analysis of the pre-operative application of botulinum toxin for ventral hernia repair.

PURPOSE: Surgical repair of large hernia defects requires detailed pre-operative planning, particularly in cases with loss of domain. This situation often hampers mid-line reconstruction, even after component separation, when the size of the hernia is disproportional to the volume of the abdominal area. In this case, other strategies may be needed to place the viscera back into the abdominal cavity after reducing the hernia sac. The administration of botulinum toxin prior to the surgical procedure has been indicated as an adjunct for more complex cases. This results in stretching of the lateral musculature of the abdomen, allowing midline approximation. In addition, the application of botulinum toxin alone has been investigated as a means of downstaging in the management of ventral hernias, thereby precluding component separation and enabling primary closure of the midline by placement of mesh within the retromuscular space using the Rives Stoppa technique. METHODS: Systematic review of the literature for observational studies involving patients undergoing pre-operative application of botulinum toxin for ventral hernia repair was conducted according to the PRISMA guidelines. RESULTS: Advance of the lateral musculature of the abdomen by an average of 4.11 cm with low heterogeneity, as well as low rates of surgical site infection (SSI), surgical site occurrences (SSO) and recurrence, was shown. CONCLUSION: Pre-operative application of botulinum toxin for ventral hernia repair promoted an increase in the length of the lateral musculature of the abdomen which can help improve the outcomes of morbidity and recurrence.

Allergic emergencies in the prehospital setting: a 5 year retrospective study.

Summary: Background. Patients with severe allergic conditions often request support from the prehospital emergency services given the rapid, unexpected and potentially life-threatening nature of the reactions, such as anaphylaxis. Studies regarding prehospital incidents for allergic conditions are scarce. This study aimed to characterize prehospitalar medical requesting assistance due to suspected hypersensitivity reactions (HSR). Methods. Retrospective study of allergic-related requesting assistances between 2017-2022 of a Portuguese emergency dispatch centre - Emergency and Resuscitation Medical Vehicle (VMER), in Coimbra University Hospital. Demographic and clinical variables were analysed, including clinical manifestations, anaphylaxis severity grading, therapeutic interventions, and post-incident allergic work-up. Regarding anaphylactic events, three diagnosis timings were compared: on-site, hospital emergency department and Investigator-diagnosis based on data reviewed. Results. Out of 12689 VMER requesting assistances, 210 (1.7%) were classified as suspected HSR reactions. After on-site medical evaluation, 127 (60.5%) cases maintained the HSR classification (median age 53 years; 56% males) and the main diagnoses included HSR to Hymenoptera venom (29.9%), food allergy (29.1%), and pharmaceutical drugs (25.5%). Anaphylaxis was assumed on-site in 44 (34.7%) cases, in the hospital emergency department in 53 cases (41.7%) and by investigators in 76 (59.8%) cases. Regarding management, epinephrine was administered on-site in 50 cases (39.4%). Conclusions. The main reason for prehospital requesting assistance was HSR to Hymenoptera venom. A high proportion of incidents met the criteria for anaphylaxis and despite the inherent difficulties of the prehospital setting, many of the on-site diagnoses agreed with the criteria. Regarding management, epinephrine was underused in this setting. Referral to specialized consultation is crucial for the management of prehospital incidents.

Chronic BMAA exposure combined with TDP-43 mutation elicits motor neuron dysfunction phenotypes in mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an average age-of-onset of ∼60 years and is usually fatal within 2-5 years of diagnosis. Mouse models based upon single gene mutations do not recapitulate all ALS pathological features. Environmental insults may also contribute to ALS, and ß-N-methylamino-L-alanine (BMAA) is an environmental toxin linked with an increased risk of developing ALS. BMAA, along with cycasin, are hypothesized to be the cause of the Guam-ALS epicenter of the 1950s. We developed a multihit model based on low expression of a dominant familial ALS TDP-43 mutation (Q331K) and chronic low-dose BMAA exposure. Our two-hit mouse model displayed a motor phenotype absent from either lesion alone. By LC/MS analysis, free BMAA was confirmed at trace levels in brain, and were as high as 405 ng/mL (free) and 208 ng/mL (protein-bound) in liver. Elevated BMAA levels in liver were associated with dysregulation of the unfolded protein response (UPR) pathway. Our data represent initial steps towards an ALS mouse model resulting from combined genetic and environmental insult.

Double aortic arch: implications of antenatal diagnosis, differential growth of arches during pregnancy, associated abnormalities and postnatal outcome.

OBJECTIVES: To evaluate the prenatal characteristics of double aortic arch (DAA), assess the relative size of the arches and their growth during pregnancy, describe associated cardiac, extracardiac and chromosomal/genetic abnormalities and review postnatal presentation and clinical outcome. METHODS: This was a retrospective cohort study of all fetuses with a confirmed diagnosis of DAA seen in five specialized referral centers in London, UK, between October 2012 and November 2019. Cases were identified from the hospitals' fetal databases. Fetal echocardiographic findings, intracardiac and extracardiac abnormalities, genetic defects, computed tomography (CT) findings and postnatal clinical presentation and outcome were evaluated. RESULTS: A total of 79 fetuses with DAA were included. Of those assessed postnatally, 48.6% had an atretic left aortic arch (LAA), while 5.1% had an atretic LAA at the first fetal scan and were misdiagnosed antenatally with right aortic arch (RAA). The LAA was atretic in 55.8% of those who underwent CT. DAA was an isolated abnormality in 91.1% of cases; 8.9% of patients had an additional intracardiac abnormality and 2.5% had both intra- and extracardiac abnormalities. Among the 52 cases that underwent genetic testing, 11.5% had genetic abnormalities and, specifically, the 22q11 microdeletion was identified in 3.8% of patients. At a median follow-up of 993.5 days, 42.5% of patients had developed symptoms of tracheoesophageal compression (5.5% during the first month after birth) and 56.2% had undergone intervention. Statistical analysis using the χ-square test showed no significant relationship between morphology of DAA (patency of both aortic arches vs atretic LAA) and the need for intervention (P = 0.134), development of vascular ring symptoms (P = 0.350) or evidence of airway compression on CT (P = 0.193). CONCLUSIONS: Most cases of DAA can be diagnosed easily at midgestation, as typically both arches are patent with a dominant RAA at this stage. However, we found that the LAA had become atretic in approximately half of the cases postnatally, supporting the theory of differential growth of the arches during pregnancy. DAA is usually an isolated abnormality; however, thorough assessment is required to exclude associated intra- and extracardiac anomalies and to determine the need for invasive prenatal genetic testing. Postnatally, early clinical assessment is needed and CT scan should be considered, irrespective of the presence of symptoms. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Possible association between the lrrk2 gene and anxiety behavior: a systematic literature review.

Alterations to the LRRK2 gene have been associated with Parkinson's disease and alcohol consumption in animals and humans. Furthermore, these disorders are strongly related to anxiety disorders (ADs). Thus, we investigated how the LRRK2 gene might influence anxiety in humans and mice. We elaborated a systematic review based on the PRISMA Statement of studies that investigated levels of anxiety in animal or human models with alterations in the LRRK2 gene. The search was conducted in the PubMed, Scopus, and Web of Science databases, and in reference lists with descriptors related to ADs and the LRRK2. From the 62 articles assessed for eligibility, 16 were included: 11 conducted in humans and seven, in mice. Lrrk2 KO mice and the LRRK2 G2019S, LRRK2 R1441G, and LRRK2 R1441C variants were addressed. Five articles reported an increase in anxiety levels concerning the LRRK2 variants. Decreased anxiety levels were observed in two articles, one focusing on the LRRK2 G2019S and the other, on the Lrrk2 KO mice. Eight other articles reported no differences in anxiety levels in individuals with Lrrk2 alterations compared to their healthy controls. This study discusses a possible influence between the LRRK2 gene and anxiety, adding information to the existing knowledge respecting the influence of genetics on anxiety.

Lacticaseibacillus rhamnosus attenuates acute lung inflammation in a murine model of acute respiratory distress syndrome: Relevance to cytokines associated to STAT4/T-bet and STAT3/RORÉ£t".

The Th1 cytokines production associated to signal transducer and activator of transcription 4 (STAT4) signaling amplifies the pro-inflammatory response in acute respiratory distress syndrome (ARDS). The anti-inflammatory action of commensal bacteria has been described as a secondary effect dependent on IL-10- secreting Treg cells that can act in organs far from the gut, including the lung. Despite it, no data is showing whether the previous reported anti-inflammatory action of probiotics is associated with its immunomodulatory effect dependent on Treg cells in a murine model of ARDS. Therefore, herein we focused on the short-term pretreatment effect with Lacticaseibacillus rhamnosus (Lr) in STAT4-associated Th1 cytokines as well as in population of IL-10- secreting Treg cells in a murine model of ARDS. Assays were performed in experimental groups divided into control, LPS, and Lr + LPS. Total and differential cells from bronchoalveolar lavage fluid (BALF) were counted through microscopy and the IL-10, IL-12, IL-17, IL-18, IL-22, IL-23, IL-27, IFN-γ, MMP-9, and TIMP were measured by ELISA. The peribronchial neutrophils were assessed using morphometry and for pulmonary edema was measured by Evans blue dye extravasation. The gene expression for STAT4, T-bet, STAT3, RORÉ£t, STAT5, and Foxp3 were measured by Real-Time PCR. Population of IL-10-secreting Treg cells was performed by flow cytometer. Data showed that pretreatment with Lr attenuated the number of inflammatory cells, secretion of both Th1 and Th17 cytokines, expression of STAT4/T-bet and STAT3/RORÉ£t in lung as well as alterations in lung morphometry. Otherwise, Lr was not efficient to restore mRNA expression for STAT5 and Foxp3 expression and population of IL-10-secreting Treg cells. Thus, beneficial effect of short-term pretreatment with Lr in murine model of ARDS is not dependent on an increased immunomodulatory action of IL-10-secreting Treg cells, however the anti-inflammatory effect of Lr has as target the Th1 and Th17 cytokines as well as signaling involving the STAT4/T-bet and STAT3/RORÉ£t.

Chest calcifications beyond the lung parenchyma-A review.

OBJECTIVE: Thoracic calcifications are frequently found in chest radiographs and CTs, occurring in a wide variety of disorders. Although most calcifications are harmless sequelae of previous disease, they provide important information to establish the diagnosis. This article reviews the different types of calcified lesions found in the chest, focusing on lesions outside the lung parenchyma. A location-based approach to the differential diagnosis is used, while providing the reader with diagnostic pearls and discussing the clinical importance of the different types of calcifications. CONCLUSION: Chest calcifications are a common finding in routine chest imaging. Understanding the different etiologies and radiologic manifestations provide the radiologist with the necessary tools to elaborate a differential diagnosis, as well as to correctly differentiate the findings that need further work-up from the ones that can be dismissed.