BACKGROUND: Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is important for early diagnosis and treatment. However, screening can lead to false-positive results leading to unnecessary follow-up tests and distress. This study evaluated the 11-year performance of the Swiss CF-NBS programme, estimated optimal cut-offs for immunoreactive trypsinogen (IRT), and examined how simulated algorithms would change performance.
METHODS: The Swiss CF-NBS is based on an IRT-DNA algorithm with a second IRT (IRT-2) as safety net. We analysed data from 2011 to 2021, covering 959,006 IRT-1 analyses and 282 children with CF. We studied performance based on European Cystic Fibrosis Society (ECFS) standards including sensitivity, specificity, positive predictive value (PPV), false negative rate, and second heel-prick tests; identified optimal IRT cut-offs using receiver operating characteristics (ROC) curves; and calculated performance for simulated algorithms with different cut-offs for IRT-1, IRT-2, and safety net.
RESULTS: The Swiss CF-NBS showed excellent sensitivity (96 %, 10 false negative cases) but moderate PPV (25 %). Optimal IRT-1 and IRT-2 cut-offs were identified at 2.7 (>99th percentile) and 5.9 (>99.8th percentile) z-scores, respectively. Analysis of simulated algorithms showed that removing the safety net from the current algorithm could increase PPV to 30 % and eliminate >200 second heel-prick tests per year, while keeping sensitivity at 95 %.
CONCLUSIONS: The Swiss CF-NBS program performed well over 11 years but did not achieve the ECFS standards for PPV (≥30 %). Modifying or removing the safety net could improve PPV and reduce unnecessary follow-up tests while maintaining the ECFS standards for sensitivity.

The diagnostic delay of primary antibody deficiencies (PADs) is associated with increased morbidity, mortality, and healthcare costs. Therefore, a screening algorithm was previously developed for the early detection of patients at risk of PAD in primary care. We aimed to clinically validate and optimize the PAD screening algorithm by applying it to a primary care database in the Netherlands.
The algorithm was applied to a data set of 61,172 electronic health records (EHRs). Four hundred high-scoring EHRs were screened for exclusion criteria, and remaining patients were invited for serum immunoglobulin analysis and referred if clinically necessary.
Of the 104 patients eligible for inclusion, 16 were referred by their general practitioner for suspected PAD, of whom 10 had a PAD diagnosis. In patients selected by the screening algorithm and included for laboratory analysis, prevalence of PAD was ~ 1:10 versus 1:1700-1:25,000 in the general population. To optimize efficiency of the screening process, we refitted the algorithm with the subset of high-risk patients, which improved the area under the curve-receiver operating characteristics curve value to 0.80 (95% confidence interval 0.63-0.97). We propose a two-step screening process, first applying the original algorithm to distinguish high-risk from low-risk patients, then applying the optimized algorithm to select high-risk patients for serum immunoglobulin analysis.
Using the screening algorithm, we were able to identify 10 new PAD patients from a primary care population, thus reducing diagnostic delay. Future studies should address further validation in other populations and full cost-effectiveness analyses.
Clinicaltrials.gov record number NCT05310604, first submitted 25 March 2022.

Alzheimer\'s disease and related dementias (ADRD) present a looming public health crisis, affecting roughly 5 million people and 11 % of older adults in the United States. Despite nationwide efforts for timely diagnosis of patients with ADRD, >50 % of them are not diagnosed and unaware of their disease. To address this challenge, we developed ADscreen, an innovative speech-processing based ADRD screening algorithm for the protective identification of patients with ADRD. ADscreen consists of five major components: (i) noise reduction for reducing background noises from the audio-recorded patient speech, (ii) modeling the patient\'s ability in phonetic motor planning using acoustic parameters of the patient\'s voice, (iii) modeling the patient\'s ability in semantic and syntactic levels of language organization using linguistic parameters of the patient speech, (iv) extracting vocal and semantic psycholinguistic cues from the patient speech, and (v) building and evaluating the screening algorithm. To identify important speech parameters (features) associated with ADRD, we used the Joint Mutual Information Maximization (JMIM), an effective feature selection method for high dimensional, small sample size datasets. Modeling the relationship between speech parameters and the outcome variable (presence/absence of ADRD) was conducted using three different machine learning (ML) architectures with the capability of joining informative acoustic and linguistic with contextual word embedding vectors obtained from the DistilBERT (Bidirectional Encoder Representations from Transformers). We evaluated the performance of the ADscreen on an audio-recorded patients\' speech (verbal description) for the Cookie-Theft picture description task, which is publicly available in the dementia databank. The joint fusion of acoustic and linguistic parameters with contextual word embedding vectors of DistilBERT achieved F1-score = 84.64 (standard deviation [std] = ±3.58) and AUC-ROC = 92.53 (std = ±3.34) for training dataset, and F1-score = 89.55 and AUC-ROC = 93.89 for the test dataset. In summary, ADscreen has a strong potential to be integrated with clinical workflow to address the need for an ADRD screening tool so that patients with cognitive impairment can receive appropriate and timely care.

Upper tract urothelial carcinoma (UTUC) is the third most common malignancy associated with Lynch syndrome (LS). The current European urology guidelines recommend screening for LS in patients with UTUC up to the age of 60 years. In this study, we examined a cohort of patients with UTUC for potential association with LS in order to establish the sensitivity of current guidelines in detecting LS. A total of 180 patients with confirmed diagnosis of UTUC were enrolled in the study during a 12-year period (2010-2022). Loss of DNA-mismatch repair proteins (MMRp) expression was identified in 15/180 patients (8.3%). Germline analysis was eventually performed in 8 patients confirming LS in 5 patients (2.8%), including 4 germline mutations in MSH6 and 1 germline mutation in MSH2. LS-related UTUC included 3 females and 2 males, with a mean age of 66.2 years (median 71 years, range 46-75 years). Four of five LS patients (all with MSH6 mutation) were older than 65 years (mean age 71.3, median 72 years). Our findings indicate that LS-associated UTUCs can occur in patients with LS older than 60 years. In contrast to previous studies which used mainly highly pre-selected populations with already diagnosed LS, the most frequent mutation in our cohort involved MSH6 gene. All MSH6 mutation carriers were > 65 years, and UTUC was the first LS manifestation in 2/4 patients. Using current screening guidelines, a significant proportion of patients with LS-associated UTUC may be missed. We suggest universal immunohistochemical MMRp screening for all UTUCs, regardless of age and clinical history.

DNA sequences containing at least four runs of repetitive cytosines can fold into tetra-helical structures called i-Motifs (iMs). The interest in these DNA secondary structures is increasing due to their therapeutical and technological applications. Still, limited knowledge of their folding requirements is currently available. We developed a novel step-by-step pipeline for the systematic screening of putative iM-forming model sequences. Focusing on structures comprising only three cytosine-cytosine+ base pairs, we investigated what the minimal lengths of the loops required for formation of an intra-molecular iM are. Our data indicate that two and three nucleotides are required to connect the strands through the minor and majorgrooves of the iM, respectively. Additionally, they highlight an asymmetric behavior according to the distribution of the cytosines. Specifically, no sequence containing a single cytosine in the first and third run was able to fold into intra-molecular iMs with the same stability of those formed when the first and the third run comprise two cytosines. This knowledge represents a step forward toward the development of prediction tools for the proper identification of biologically functional iMs, as well as for the rational design of these secondary structures as technological devices.

UNASSIGNED: Multiple myeloma (MM) is one of the hematologic malignancies with a greater delay in diagnosis. Laboratories receive numerous MM screening test requests without a specific suspicion, which entails a substantial workload and reduces the efficiency of laboratories. Objective: to increase the efficacy of MM screening protocols.
UNASSIGNED: The results of serum protein electrophoresis (SPEP), serum protein immunofixation electrophoresis (SIFE), urine protein immunofixation electrophoresis, and serum free light chain assays of 75 patients with MM, three with amyloidosis, and a patient with solitary plasmocytoma were collected. The frequency of a set of biochemical alterations in these patients was compared with that in controls (n=120). A validation of the screening algorithm was carried out in 261 consecutive patients with a clinical or analytical suspicion of MM.
UNASSIGNED: SPEP+SFLC or SIFE+SFLC (98% sensitivity) were the screening algorithms with the highest sensitivity. Prospectively, the SPEP + SFLC detected 27 of the 28 confirmed cases of MG and saved 15 h of work. Alterations in five of the six parameters studied were more frequent in the study group, with a cumulative value of ≥3 parameters altered (61.1 vs. 1.7%) (positive predictive value: 85%; negative predictive value: 94%).
UNASSIGNED: The SPEP+SFLC screening protocol demonstrated the highest sensitivity and was the least time-consuming protocol. In addition, this protocol improves diagnostic sensitivity and laboratory performance.

The global epidemiological situation of COVID-19 remains serious. The rapid hunting of SARS-CoV-2 infection is the key means for preventing transmission.
A total of 40,689 consecutive overseas arrivals were screened for SARS-CoV-2 infection based on PCR and serologic testing. The yield and efficiency of different screening algorithms were evaluated.
Among the 40,689 consecutive overseas arrivals, 56 (0.14%) subjects were confirmed to have SARS-CoV-2 infection. The asymptomatic rate was 76.8%. When the algorithm based on PCR alone was used, the identification yield of a single round of PCR (PCR1) was only 39.3% (95% CI: 26.1-52.5%). It took at least four rounds of PCR to achieve a yield of 92.9% (95% CI: 85.9-99.8%). Fortunately, an algorithm based on a single round of PCR combined with a single round of serologic testing (PCR1+ Ab1) greatly improved the screening yield to 98.2% (95% CI: 94.6-100.0%) and required 42,299 PCR and 40,689 serologic tests that cost 6,052,855 yuan. By achieving a similar yield, the cost of PCR1+ Ab1 was 39.2% of that of four rounds of PCR. For hunting one case in PCR1+ Ab1, 769 PCR and 740 serologic tests were required, costing 110,052 yuan, which was 63.0% of that of the PCR1 algorithm.
Comparing an algorithm based on PCR alone, PCR combined with a serologic testing algorithm greatly improved the yield and efficiency of the identification of SARS-CoV-2 infection.

BACKGROUND: The positive predictive value (PPV) of high risk factor questionnaire (HRFQ) plus fecal immunochemical test (FIT) as preliminary screening strategy for colorectal-related neoplasia is relatively low. We aim to explore independent factors associated with PPVs of HRFQ combined FIT for selecting high risk individuals for colonoscopy.
METHODS: A total of 6971 residents were enrolled in a community-based screening program. Participants who had positive results of HRFQ and/or FIT and subsequently received colonoscopy were involved. The associations of socio-demographic factors, lifestyle behaviors, and high risk factors of colorectal cancer with PPVs of HRFQ, FIT, and their combination were evaluated by multivariable logistic regression models.
RESULTS: Among 572 involved cases, 249 (43.5%) colorectal neoplasms were detected by colonoscopy, including 71 advanced adenoma (12.4%) and 9 colorectal cancer (CRC) (1.6%). The PPVs of preliminary screening were 43.5% for total colorectal neoplasms, 14.0% for advanced neoplasm, and 1.6% for CRC. Adding positive HRFQ to FIT could improve the PPV from 3.5 to 8.0% for detecting CRC. Preliminarily screened positive individuals who were males [adjusted odds ratio (AOR): 1.95, 95% CI 1.31, 2.90; p  < 0.001], elders (> 60 years) (AOR: 1.70, 95% CI 1.17, 2.46; p  = 0.005), or ex-/current smokers (AOR: 3.04, 95% CI 1.31, 7.09; p  = 0.10) had higher odds of PPVs of detecting colorectal neoplasms.
CONCLUSIONS: Combining HRFQ and FIT could largely improve PPVs for screening advanced neoplasm and CRC. Gender and age-specific FIT cut-off values as well as initiating ages for CRC screening might be recommended to improve the accuracy and effectiveness of current screening algorithm.

COVID-19 quickly immobilized healthcare systems in the United States during the early stages of the outbreak. While much of the ensuing response focused on supporting the medical infrastructure, Columbia University College of Dental Medicine pursued a solution to triage and safely treat patients with dental emergencies amid the pandemic. Considering rapidly changing guidelines from governing bodies, dental infection control protocols, and our clinical faculty\'s expertise, we modeled, built, and implemented a screening algorithm, which provides decision support as well as insight into COVID-19 status and clinical comorbidities, within a newly integrated electronic health record (EHR). Once operationalized, we analyzed the data and outcomes of its utilization and found that it had effectively guided providers in triaging patient needs in a standardized methodology. This article describes the algorithm\'s rapid development to assist faculty providers in identifying patients with the most urgent needs, thus prioritizing treatment of dental emergencies during the pandemic.

OBJECTIVE: Patient selection for robotically assisted mitral valve repair remains controversial. We assessed outcomes of a conservative screening algorithm developed to select patients with degenerative mitral valve disease for robotic surgery.
METHODS: From January 2014 to January 2019, a screening algorithm that included transthoracic echocardiography and computed tomography scanning was rigorously applied by 3 surgeons to assess candidacy of 1000 consecutive patients with isolated degenerative mitral valve disease (age 58 ± 11 years, 67% male) for robotic surgery. Screening results and hospital outcomes of those selected for robotic versus sternotomy approaches were compared.
RESULTS: With application of the screening algorithm, 605 patients were selected for robotic surgery. Common reasons for sternotomy (n = 395) were aortoiliac atherosclerosis (n = 74/292, 25%), femoral artery diameter <7 mm (n = 60/292, 20%), mitral annular calcification (n = 83/390, 21%), aortic regurgitation (n = 100/391, 26%), and reduced left ventricular function (n = 126/391, 32%). Mitral valve repair was accomplished in 996. Compared with sternotomy, patients undergoing robotic surgery had less new-onset atrial fibrillation (n = 144/582, 25% vs n = 125/373, 34%; P = .002), fewer red blood cell transfusions (n = 61/601, 10% vs 69/395, 17%; P < .001), and shorter hospital stay (5.2 ± 2.9 days vs 5.9 ± 2.1 days; P < .001). No hospital deaths occurred, and occurrence of postoperative stroke in the robotic (n = 3/605, 0.50%) and sternotomy (n = 4/395, 1.0%; P = .3) groups was similar.
CONCLUSIONS: This conservative screening algorithm qualified 60% of patients with isolated degenerative mitral valve disease for robotic surgery. Outcomes were comparable with those obtained with sternotomy, validating this as an approach to select patients for robotic mitral valve surgery.