Index Case Research Articles

Recent HIV infection and associated factors among newly diagnosed HIV cases in the Southwest Ethiopia Regional State: HIV case-based surveillance analysis (2019–2022)

BackgroundGlobally, there were an estimated 39 million people living with HIV with 1.3 million new HIV infections by the end of 2023. The Sub-Saharan Africa accounted 51% of new HIV infections. HIV case-based Surveillance collects data on newly diagnosed HIV cases, recent HIV infections, and other sentinel events, aiding evidence-based decision making. There is limited evidence on these in Ethiopia. The objective of this study is to determine the incidence proportion of recent infections and associated factors among newly diagnosed HIV cases and their distribution by person, place, and time in the Southwest Ethiopia Regional State.MethodsA retrospective analysis was conducted on HIV case-based surveillance dataset (July 2019 to June 2022) from the Southwest Ethiopia Regional State. Recent HIV infection is an infection that acquired within the last 12 months as diagnosed by Asante recency test kits. Data were analyzed using SPSS version 26. ArcGIS version 10.8 was used for mapping recent infections. Logistic regression was employed to identify factors associated with recent infections. In multivariable logistic regression analysis, variables with p-value < 0.05 and an adjusted odds ratio with 95% confidence interval were considered to declare significant association.ResultsA total of 1,167 newly diagnosed HIV cases (eligible cases) were identified. Among these, 786 (67.3%) recency tests were performed. The mean age of individuals with recent infection was 28.4 years. The proportion of recent infection is 89 (11.3%, 95% CI: 11.2, 11.5%). The highest proportion of recent infection is reported from the West Omo zone (42.9%), whereas 13.2% in Bench Sheko zone. Recent infection is significantly associated with age 15–24 years [AOR = 7.14, 95%CI: 2.89,17.57], age 25–34 years [AOR = 5.34, 95%CI: 2.20,12.94], females [AOR = 2.03, 95%CI: 1.26,3.25], and contact history with the index case [AOR = 0.48, 95%CI: 0.28, 0.83]. The incidence of recent infection increased from 86 (in 2019/20) to 132 (in 2022) recent infections per 1,000 newly diagnosed cases.ConclusionsRecent HIV infection is a public health concern in the Southwest Ethiopia Regional State with an increasing incidence. Targeted prevention efforts are necessary, especially for females and younger people.

Challenges and practical considerations in delivering botulinum neurotoxin to adults with congenital neurogenic lower urinary tract dysfunction with history of genitourinary reconstruction

Purpose:While intradetrusor botulinum neurotoxin (BoNT) injection is a well-established treatment of neurogenic detrusor overactivity, its administration in individuals with complex genitourinary (GU) reconstruction can be difficult. The objective of this report is to highlight our institution’s experience with challenges and practical solutions in delivering BoNT to this unique patient population. Materials and Methods:We performed a retrospective review of our institution’s database of adults with congenital neurogenic lower urinary tract dysfunction (NLUTD) with history of complex GU reconstruction who received intradetrusor BoNT injections performed by a single surgeon between 2016 and 2023. In patients with multiple injections, the most recent procedure was used as the index case for analysis. Results:A total of 17 patients were included, with a mean age of 27 years (range 21–46). The most common diagnosis was myelomeningocele (n=13), followed by sacral agenesis (n=2), Williams syndrome (n=1), and urethral atresia (n=1). The most common GU reconstruction was augmentation cystoplasty (n=11). 75% (12/16) of the patients had a continent catheterizable channel (CCC) and 31% (5/16) had undergone prior bladder neck reconstruction or closure. Conclusion:Additional considerations and instruments are required for safe and effective BoNT injections in individuals with congenital NLUTD and reconstruction. Adequate preparation by the staff and the provider may be needed. Our recommendation generally favors the utilization of a flexible cystoscope or a rigid scope with a smaller sheath size to minimize trauma to the CCC, bladder neck, or urethra. Additionally, it is advisable to consider reconstituting BoNT in higher concentrations to enable the administration of fewer injections. Furthermore, performing these procedures in the operating room under anesthesia allows for the development of a well-considered strategy prior to any attempts in the office setting We hope that this manuscript sparks discussion between pediatric urologists and adult urologist to expand our knowledge on strategies needed for delivering BoNT to individuals with complex and restricting GU surgeries.

Differences between Patients with Sporadic and Familial Pheochromocytoma-Is It Possible to Avoid Genetic Testing in Certain Patients?

Pheochromocytoma (PHEO) is a rare neuroendocrine tumour with a strong genetic link, which therefore may modify its clinical behaviour and prognosis. The aim of the study is to evaluate the epidemiological and clinical differences between patients with sporadic and familial PHEO, as well as the specific differences in the index cases. A retrospective analysis of 136 patients in a tertiary hospital (1984-2021). Epidemiological, clinical, and histological variables were analysed. SPSS 28.0 software was used. Univariate and multivariate logistic regression analyses were performed. p < 0.05 was considered statistically significant. 64.71% of the cases (n = 88) presented a genetic mutation (familial cases). Additionally, 32.39% (n = 23) corresponded to index cases and the rest to screening cases. The main differences between patients with familial and sporadic PHEO were age (OR = 0.93 (0.89-0.97)), blood pressure-related symptoms (OR = 0.22 (0.06-0.89)), bilaterality (OR = 15.49 (3.76-63.84)), and size (OR = 0.70 (0.54-0.92)). Among patients with sporadic PHEO and index cases, only bilaterality was significant (OR = 13.53 (1.24-144.34)). Patients with familial PHEO diagnosed by screening differ from sporadic cases in terms of age, clinical features, and size. However, patients with sporadic PHEO only differ from index cases by a lower presence of bilaterality, which reaffirms the importance of genetic screening of patients with PHEO and their relatives.

NFS-02. MEDULLOBLASTOMAS WITH ELP1 PATHOGENIC VARIANTS: A WEAKLY PENETRANT SYNDROME WITH A RESTRICTED SPECTRUM IN A LIMITED AGE WINDOW

Abstract BACKGROUND Medulloblastomas (MB) Sonic hedgehog (SHH) subtype are associated with a cancer predisposition syndrome (CPS) in about 15% of cases, the most frequent being related to ELP1 pathogenic variant (PV). The aim of our study is to better evaluate penetrance of this CPS and detail the characteristics of the related tumors. METHODS Twenty-nine ELP1-mutated MB identified in France were retrospectively reviewed. Molecular characteristics of the tumor and clinical features of the patients were collected; whenever possible, the germline DNA from patients and their relatives were sequenced. RESULTS All patients (sex ratio 16/13) presented with SHH-MB, mostly nodular desmoplastic (n=20/28), between 3 and 15 years of age (median 7.3). All mutations are found in the germline when a constitutional DNA sample was available (n=26). Most tumors (93%) showed a biallelic inactivation of PTCH1, other recurrent alterations concerned the TP53 pathway (including 1 somatic TP53 VP) and activation of MYCN/MYCL signaling. We observed that ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups of MB, similar outcomes (5y-OS = 85%) and no unusual side effects of treatments. Three patients developed a second tumor (2 high-grade gliomas and 1 thyroid carcinoma) within the irradiation fields. All germline PV were inherited from one asymptomatic parent (11 trio). No specific morphological features were mentioned. Only two index cases from the 29 French patients had a previous familial history of MB (occurring in a cousin), with many asymptomatic carriers. Except the MB, no other cancer was significantly associated with the ELP1 PV. CONCLUSIONS the low penetrance, the ‘at risk’ age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with MB, depending on the parents’ request.

SARS-CoV-2 transmission in a highly vulnerable population of Brazil: a household cohort study

Household transmission studies seek to understand the transmission dynamics of a pathogen by estimating the risk of infection from household contacts and community exposures. We estimated within/extra-household SARS-CoV-2 infection risk and associated factors in a household cohort study in one of the most vulnerable neighbourhoods in Rio de Janeiro city. Individuals ≥1 years-old with suspected or confirmed COVID-19 in the past 30 days (index cases) and household members aged ≥1 year were enrolled and followed at 14 and 28 days (study period November/2020-December/2021). RT-PCR testing, COVID-19 symptoms, and SARS-CoV-2 serologies were ascertained in all visits. Chain binomial household transmission models were fitted using data from 2024 individuals (593 households). Extra-household infection risk was 74.2% (95% credible interval [CrI] 70.3-77.8), while within-household infection risk was 11.4% (95% CrI 5.7-17.2). Participants reporting having received two doses of a COVID-19 vaccine had lower extra-household (68.9%, 95% CrI 57.3-77.6) and within-household (4.1%, 95% CrI 0.4-16.6) infection risk. Within-household infection risk was higher among participants aged 10-19 years, from overcrowded households, and with low family income. Contrastingly, extra-household infection risk was higher among participants aged 20-29 years, unemployed, and public transportation users. Our study provides important insights into COVID-19 household/community transmission in a vulnerable population that resided in overcrowded households and who struggled to adhere to lockdown policies and social distancing measures. The high extra-household infection risk highlights the extreme social vulnerability of this population. Prioritising vaccination of the most socially vulnerable could protect these individuals and reduce widespread community transmission. Fundação Oswaldo Cruz, CNPq, FAPERJ, Royal Society, Instituto Serrapilheira, FAPESP.

NFS-04. GENETIC COUNSELLING IN A MULTI-TUMOR PREDISPOSITION SYNDROME: A NOVEL FOUR-GENERATION TUNISIAN PEDIGREE

Abstract BACKGROUND Cancer predisposition syndromes associated with an increased risk of CNS tumors and colorectal polyposis are heterogeneous inherited disorders associated with multiples genes. The delineation of the inheritance pattern and the management of the genetic testing are recommended for optimal care of patients and their families. Our aim was to report a cancer predisposition brain tumor-polyposis syndrome in a four-generation Tunisian consanguineous pedigree characterized by uncommon tumors localizations. METHODS The index case was a 43-year-old infertile woman presented to our genetic counselling because of a suspected familial cancer predisposition syndrome. She consulted for digestive symptoms with epigastralgia. Six adenomatous polyposis of the colon were confirmed histologically. Her sister died of colon cancer at the age of 50. She developed a malignant mesenteric recurrence after surgical resection of a moderately differentiated adenocarcinoma infiltrating the meso fat with lymph node metastases. Their three sisters and brother did not have any cancer. From the same third generation, only one cousin died of a brain cancer identified as a glioblastoma at the age of 43. Their maternal grandmother and her two brothers died of respectively breast, laryngeal and urothelial cancers. The second generation and fourth generation involved healthy members. RESULTS Analysis of the pedigree of this family indicated an autosomal recessive mode of inheritance of the brain tumor-polyposis syndrome. Clinically, there was uncommon association with breast, laryngeal and urothelial cancers in the first generation and brain/colon cancers in the third generation. CONCLUSIONS A recessive multi-tumor predisposition syndrome related to high microsatellite instability resulting in a mismatch repair deficiency seems to be the most reliable diagnosis in this family. Familial NTHL1 tumor and MUTYH associated polyposis syndromes were also suspected. NGS-based testing, from whole exome sequencing to multigene panel testing, is suggested as the most accurate genetic testing in such heterogeneous multi-tumor predisposition syndromes.

Bilateral Adrenocortical Nodular Disease and Cushing's Syndrome.

Primary pigmented nodular adrenocortical disease (PPNAD) and bilateral macronodular adrenocortical disease (BMAD) are 2 forms of adrenocortical nodular diseases causing Cushing's syndrome but are 2 very distinct conditions. PPNAD, affecting mostly young patients with an almost constant severe Cushing's syndrome, is characterized by pigmented micronodules, usually less than 1 cm, not always visible on imaging. On the contrary, BMAD is predominantly diagnosed in the fifth and sixth decades, with highly variable degrees of cortisol excess, from mild autonomous cortisol secretion to overt Cushing's syndrome. BMAD presents as large bilateral adrenal macronodules, easily observed on imaging. Both diseases are often genetically determined: frequently PPNAD is observed in a multiple neoplasia syndrome, Carney complex, and a germline genetic defect is identified in around 80% of index cases, always affecting key actors of the cAMP/protein kinase A (PKA) pathway: mostly PRKAR1A, encoding the PKA 1-alpha regulatory subunit. On the other hand, BMAD appears mostly isolated, and 2 predisposing genes are known at present: ARMC5, accounting for around 20% of index cases, and the recently identified KDM1A, causing the rare presentation with food-dependent Cushing's syndrome, mediated by the ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in adrenal nodules. GIPR was the first demonstrated receptor to illegitimately regulate cortisol secretion in nodular adrenocortical diseases, and a myriad of other receptors and paracrine signals were discovered afterward. The last 30 years were pivotal in the understanding of the genetics and pathophysiology of bilateral adrenocortical nodular diseases, leading to a personalized approach of these fascinating conditions.

DIPG-59. RADIATION-INDUCED DIPG IN A CHILD PREVIOUSLY IRRADIATED FOR CRANIOPHARYNGIOMA: CASE REPORT AND LITERATURE REVIEW

Abstract BACKGROUND Radiation-induced second malignancies occur in a subset of patients following cranial radiation therapy (RT). In Craniopharyngioma (CP), adjuvant RT is commonly recommended for residual tumor or recurrence, and radiation-induced malignant gliomas (RIMGs) are rarely reported. METHODS We report a case of radiation-induced diffuse intrinsic pontine glioma (DIPG) in pediatric Craniopharyngioma and conducted a review of previously reported cases. RESULTS A 14-year-old boy presented with complaints of headaches and vomiting for 1 month; difficulty in walking, and slurred speech for 1 week, with Lansky Performance Score (LPS) of 20. Eight years before this admission, he underwent surgical excision and 3D-conformal RT for Craniopharyngioma. His recent MRI brain was suggestive of DIPG and after a multidisciplinary discussion re-irradiation (30Gy in 10 fractions) was given. He has been alive for 5 months since diagnosis with improved symptoms and LPS (70). Including the index case, 19 cases of RIMGs in CP were identified. All except one were reported from high-income countries. Only 4 involved the pons/brainstem. The median age at CP diagnosis was 7.0 years (2.0-22.0 years), and with RIMG was 18 (6.8-41.0 years). Median latency period was 10.0 years (4.5-25.0 years). The female-to-male ratio was 1.8:1. The median previous RT dose was 54.8 Gy (49.3-60.1 Gy) with 37% cases treated with 3D conformal and 37% with conventional RT (not specified in 26%). Cerebral cortex (66.6%) was the most common site for the RIMG with temporal lobe predisposition. Chemotherapy was given in 56%, surgical excision in 50% and repeat RT in 31% cases with a median survival of 4 months (0-13 months). CONCLUSION We report the first case of radiation-induced DIPG in pediatric Craniopharyngioma in an LMIC. RIMG appears to be a rare occurrence in CP and doesn’t seem to be associated with the RT type. The overall prognosis is extremely poor.

HGG-19. H3- AND IDH-WILDTYPE DIFFUSE PAEDIATRIC-TYPE HIGH-GRADE GLIOMA WITHMYCN-AMPLIFICATION: AN INDICATION CRITERION FOR LI-FRAUMENI SYNDROME TESTING

Abstract BACKGROUND: In the current World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) (5th edition), the introduction of a molecular layer to the integrated diagnosis not only helps to characterize and prognosticate paediatric CNS tumors but the molecular alteration may predict a potential therapeutic option with a targeted agent. Furthermore, certain gene alterations may be a presage of germline alterations or cancer predisposition syndromes, portending significant implications to the index patients and their families. We report a 5-year-old boy diagnosed with non-metastatic left hemispheric H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification, who was subsequently found to have Li-Fraumeni syndrome. He presented with a 3-day history of facial asymmetry, unsteady gait and right sided weakness. There was no family history of malignancy. Initial MRI revealed a restricting and enhancing solid cystic lesion (5.9 x 4.3 x 5.8cm) in the left frontal-temporal-parietal region. Tumor debulking was performed. Histopathological examination by the local pathologist revealed features of high-grade glioma. Second pathology review with next generation sequencing confirmed H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification and TP53 p.Y103* mutation. He was started on focal radiotherapy and oral temozolomide but succumbed to local and metastatic progressive disease. After genetic counselling, his DNA extracted from blood was sent for targeted exome sequencing and germline mutation of TP53 was demonstrated. Cascade screening of the family members were negative of TP53 mutation. Guerrini-Rousseau et al reported that 57% (n=7) of H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification harboured germline TP53 pathogenic variants. This case further highlights the importance of screening of Li-Fraumeni syndrome in patient with H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification even in the absence of a family history.

Possible association of dose rate and the development of late visual toxicity for patients with intracranial tumours treated with pencil beam scanned proton therapy

Background and purposeRare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at unusually low dose levels and are thus difficult to understand considering dose metrics only. When transitioning from double scattering to pencil beam scanning, little consideration was given to increased dose rates observed with the latter delivery paradigm. We explored if dose rate related metrics could provide additional predicting factors for the development of late visual toxicities.Materials and methodsRadiation-induced intracranial visual pathway lesions were delineated on MRI for all index cases. Voxel-wise maximum dose rate (MDR) was calculated for 2 patients with observed optic nerve toxicities (CTCAE grade 3 and 4), and 6 similar control cases. Additionally, linear energy transfer (LET) related dose enhancing metrics were investigated.ResultsFor the index cases, which developed toxicities at low dose levels (mean, 50 GyRBE), some dose was delivered at higher instantaneous dose rates. While optic structures of non-toxicity cases were exposed to dose rates of up to 1 to 3.2 GyRBE/s, the pre-chiasmatic optic nerves of the 2 toxicity cases were exposed to dose rates above 3.7 GyRBE/s. LET-related metrics were not substantially different between the index and non-toxicity cases.ConclusionsOur observations reveal large variations in instantaneous dose rates experienced by different volumes within our patient cohort, even when considering the same indications and beam arrangement. High dose rate regions are spatially overlapping with the radiation induced toxicity areas in the follow up images. At this point, it is not feasible to establish causality between exposure to high dose rates and the development of late optic apparatus toxicities due to the low incidence of injury.

Household Transmission of Tinea Infections: Analysis of a Large Commercial Health Insurance Claims Database, United States, 2021.

Among 207 914 multimember households with a tinea case, a secondary case was diagnosed in another household member in 8.5%. Excluding same-day diagnoses (20%), the median time from index case to first secondary case was 138 days. To prevent household tinea transmission, appropriate treatment and strategies to reduce environmental contamination are needed.

Limited Added Diagnostic Value of Whole Genome Sequencing in Genetic Testing of Inherited Retinal Diseases in a Swiss Patient Cohort.

The purpose of this study was to assess the added diagnostic value of whole genome sequencing (WGS) for patients with inherited retinal diseases (IRDs) who remained undiagnosed after whole exome sequencing (WES). WGS was performed for index patients in 66 families. The datasets were analyzed according to GATK's guidelines. Additionally, DeepVariant was complemented by GATK's workflow, and a novel structural variant pipeline was developed. Overall, a molecular diagnosis was established in 19/66 (28.8%) index patients. Pathogenic deletions and one deep-intronic variant contributed to the diagnostic yield in 4/19 and 1/19 index patients, respectively. The remaining diagnoses (14/19) were attributed to exonic variants that were missed during WES analysis due to bioinformatic limitations, newly described loci, or unclear pathogenicity. The added diagnostic value of WGS equals 5/66 (9.6%) for our cohort, which is comparable to previous studies. This figure would decrease further to 1/66 (1.5%) with a standardized and reliable copy number variant workflow during WES analysis. Given the higher costs and limited added value, the implementation of WGS as a first-tier assay for inherited eye disorders in a diagnostic laboratory remains untimely. Instead, progress in bioinformatic tools and communication between diagnostic and clinical teams have the potential to ameliorate diagnostic yields.

Low Prognostic Nutritional Index Predicts In-Hospital Complications and Case Fatality in Patients with Spontaneous Intracerebral Hemorrhage: A Retrospective Study.

Spontaneous intracerebral hemorrhage (ICH) is associated with high case fatality and significant healthcare costs. Recent studies emphasize the critical role of nutritional status in affecting outcomes in neurological disorders. This study investigates the relationship between the Prognostic Nutrition Index (PNI) and in-hospital complications and case fatality among patients with ICH. A retrospective analysis was performed using data from the Changhua Christian Hospital Clinical Research Database between January 2015 and December 2022. Patients under 20 or over 100 years of age or with incomplete medical data were excluded. We utilized restricted cubic spline models, Kaplan-Meier survival analysis, and ROC analysis to assess the association between PNI and clinical outcomes. Propensity score matching analysis was performed to balance these clinical variables between groups. In this study, 2402 patients with spontaneous ICH were assessed using the median PNI value of 42.77. The cohort was evenly divided between low and high PNI groups, predominantly male (59.1%), with an average age of 64 years. Patients with lower PNI scores at admission had higher in-hospital complications and increased 28- and 90-day case fatality rates. Our study suggests that PNI could serve as a valuable marker for predicting medical complications and case fatality in patients with spontaneous ICH.

Familial Mediterranean fever gene variations could trigger VPS16-associated early-onset dystonia and diabetes mellitus: clinical identification of a family with MEFV and VPS16 genetic variation association.

We describe the clinical pictures of an index case with dystonia and his family resulting from VPS16 and MEFV genetic variations based on previously published data and discuss the mechanisms that may have brought out the clinical findings. A 17-year-old male had generalized dystonia that started at age 6 years, non-febrile abdominal pain attacks and was diagnosed with type 1 diabetes at age 14 years. Meanwhile, his 13-year-old sister had the same clinical presentation. His father was diabetic and his mother was asymptomatic. There was no consanguinity between the parents. Genetic variations were detected with whole exome sequencing. VPS16 c.1513C>T/p.Arg505* (likely pathogenic), MEFV c.2080A>G p.Met694val (pathogenic) and MEFV c.1772T>C p.Ile591Thr (unknown significance) heterozygous variants were detected in his siblings. The father had VPS16 c.1513C>T/p.Arg505* and MEFV c.2080A>G p Met694val variations and the mother had MEFV c.1772T>C p.Ile591Thr variations. The occurrence of these diseases in siblings but their absence in the parents suggests the idea that the coexistence of two separate variations in the VPS16 and MEFV genes determines the phenotype. In addition, the increase in MEFV variation load in this family and the fact that DM occurs at an earlier age suggest that inflammation may cause an early diabetic clinical presentation.

A survey on the management practices of graves’ disease by Egyptian physicians and a comparison to similar reports from USA, Italy, China, and Brazil

BackgroundGraves’ disease is the commonest cause of hyperthyroidism in iodine replete areas. Following universal salt iodization, most Egyptians are considered iodine sufficient. The present study aims to report a survey of real-life practices in the management of graves’ disease among Egyptian physicians and compare them to other similar reports.MethodsAn online survey was sent to members and affiliates of Alexandria thyroid association. Egyptian physicians were surveyed about initial diagnostics workup, management of an index case of uncomplicated graves’ disease not desiring pregnancy. Two modified scenarios were proposed to the index case to survey the impact on treatment preferences. Anonymous responses were collected, analyzed, presented, and compared to other published similar reports.ResultsSixty-eight participated out of 120 invited physicians (56.67%). Initial workup included TSH receptor antibodies 46/68 (67. 6%), thyroid ultrasound 45/68 (66.2%), and thyroid scintigraphy 25/68 (36.8%). Treatment preferences in the index case were antithyroid drugs (ATD’s) 52/68 (76.5%), radioiodine 12/68 (17.5%), and surgery 4/68 (6%). Compared to other reports, treatment preferences were almost identical to Italian ones, ATD’s (77.1%), radioiodine (16.2%), and surgery (4.5%). If the patient is complicated with graves’ orbitopathy, treatment preferences would change into ATD’s 37/67 (55%), radioiodine 1/67 (2%), radioiodine with corticosteroids 14/67 (21%), and surgery 15/67 (22%). If the patient is desiring pregnancy, treatment preferences would be ATD’s 32/68 (47%), radioiodine 5/68 (7.4%), and surgery 31/68 (45.6%).ConclusionA high participation rate was observed. Similar to other reports, medical treatment is the preferred modality of treatment in graves’ disease and surgery is the least utilized modality. Similar treatment preferences to Italians were observed in the index case.

Tuberculosis infection among close contacts of patients with pulmonary tuberculosis in China: a population-based, multicentered study

ObjectivesLimited information is currently available on the prevalence of and risk factors for tuberculosis infection (TBI) among close contacts of patients with pulmonary TB (PTB) in China. In this study, we estimated the burden of TBI among close contacts using QuantiFERON-TB Gold In-Tube assay (QFT) and identified factors associated with TB transmission among this high-risk population. MethodsFrom January 1, 2018 to August 31, 2020, we identified laboratory-confirmed patients with PTB from a population-based, multicentered, cluster-randomized control trial for tuberculosis preventive treatment. Close contacts of these patients were identified, interviewed, and tested using the QFT assay. We estimated TBI prevalence and calculated ORs and 95% CIs for TBI risk factors. ResultsA total of 3138 index cases and 8117 close contacts were identified. Of these contacts, 36 had PTB (a prevalence of 443.51 cases/100 000 population). Among the remaining 7986 close contacts; 3124 (39.12%) reported a positive QFT result. QFT positivity was significantly associated with older age (adjusted OR, 1.77; [95% CI, 1.27–2.47], 2.20; [95% CI, 1.59–3.05], and 2.74; [95% CI, 1.96–3.82]) for age groups: 35–44, 45–54, and 55–64, respectively) when compared with a younger age group: 5–14; longer contact duration (adjusted OR, 1.44; 95% CI, 1.22–1.69); and sharing of a bedroom (adjusted OR, 1.39; 95% CI, 1.18–1.65). DiscussionOur findings indicate a high TBI burden among the close contacts of PTB. The results also highlighted that contact tracing and investigation for TBI are necessary and beneficial, particularly for those who are older, have had a longer contact duration, and share a bedroom.

How effective is the BNT162b2 mRNA vaccine against SARS-CoV-2 transmission and infection? A national programme analysis in Monaco, July 2021 to September 2022

BackgroundWe quantified SARS-CoV-2 dynamics in different community settings and the direct and indirect effect of the BNT162b2 mRNA vaccine in Monaco for different variants of concern (VOC).MethodsBetween July 2021 and September 2022, we prospectively investigated 20,443 contacts from 6320 index cases using data from the Monaco COVID-19 Public Health Programme. We calculated secondary attack rates (SARs) in households (n = 13,877), schools (n = 2508) and occupational (n = 6499) settings. We used binomial regression with a complementary log–log link function to measure adjusted hazard ratios (aHR) and vaccine effectiveness (aVE) for index cases to infect contacts and contacts to be infected in households.ResultsIn households, the SAR was 55% (95% CI 54–57) and 50% (48–51) among unvaccinated and vaccinated contacts, respectively. The SAR was 32% (28–36) and 12% (10–13) in workplaces, and 7% (6–9) and 6% (3–10) in schools, among unvaccinated and vaccinated contacts respectively. In household, the aHR was lower in contacts than in index cases (aHR 0.68 [0.55–0.83] and 0.93 [0.74–1.1] for delta; aHR 0.73 [0.66–0.81] and 0.89 [0.80–0.99] for omicron BA.1&2, respectively). Vaccination had no significant effect on either direct or indirect aVE for omicron BA.4&5. The direct aVE in contacts was 32% (17, 45) and 27% (19, 34), and for index cases the indirect aVE was 7% (− 17, 26) and 11% (1, 20) for delta and omicron BA.1&2, respectively. The greatest aVE was in contacts with a previous SARS-CoV-2 infection and a single vaccine dose during the omicron BA.1&2 period (45% [27, 59]), while the lowest were found in contacts with either three vaccine doses (aVE − 24% [− 63, 6]) or one single dose and a previous SARS-CoV-2 infection (aVE − 36% [− 198, 38]) during the omicron BA.4&5 period.ConclusionsProtection conferred by the BNT162b2 mRNA vaccine against transmission and infection was low for delta and omicron BA.1&2, regardless of the number of vaccine doses and previous SARS-CoV-2 infection. There was no significant vaccine effect for omicron BA.4&5. Health authorities carrying out vaccination campaigns should bear in mind that the current generation of COVID-19 vaccines may not represent an effective tool in protecting individuals from either transmitting or acquiring SARS-CoV-2 infection.

POT1 tumour predisposition: a broader spectrum of associated malignancies and proposal for additional screening program

Protection of Telomeres Protein 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex, regulating telomere length. Some POT1 gene pathogenic variants (PV) lead to telomere elongation, genomic instability and higher risk of cancer. POT1 tumour predisposition syndrome (POT1-TPD) has autosomal dominant inheritance and unknown penetrance. It is associated with increased risk of cutaneous melanoma, chronic lymphocytic leukaemia, angiosarcoma and gliomas. In this work, we aim to describe a broader cancer phenotype related to POT1-TPD, in three families (two with a four generation pedigree, one with a five generation pedigree). The three index cases were referred to our oncogenetic centre for genetic counselling due to their personal history of cancer. Two underwent clinical exome sequencing of 4,867 genes associated with Mendelian genetic diseases, and another underwent gene panel sequencing including POT1, which identified three different POT1 PV: NC_000007.14(NM_015450.2):c.349C>T; NC_000007.14(NM_015450.2):c.233T>C and NC_000007.14(NM_015450.2):c.818G>A; already described in the literature. Referenced relatives, did a target genetic test (according to the POT1 PV identified in the family). In total, 37 individuals were tested (51.4% females), median age of 46 (22–81) years, with POT1 PV detected in 22. POT1-TPD was observed, but also a higher incidence of other cancers (other sarcomas, papillary thyroid cancer, early onset prostate cancer and leukaemia). These findings contribute to an increase in our knowledge about POT1 PV, and it can play a role in the definition of future POT1 PV screening criteria, POT1 carrier surveillance protocols (possibly considering screening for all types of sarcomas) and in genetic counselling.

Mycobacterium tuberculosis Infection in School Contacts of Tuberculosis Cases: A Systematic Review and Meta-Analysis.

Substantial tuberculosis transmission occurs outside of households, and tuberculosis surveillance in schools has recently been proposed. However, the yield of tuberculosis outcomes from school contacts is not well characterized. We assessed the prevalence of Mycobacterium tuberculosis infection among close school contacts by performing a systematic review. We searched PubMed, Elsevier, China National Knowledge Infrastructure, and Wanfang databases. Studies reporting the number of children who were tested overall and who tested positive were included. Subgroup analyses were performed by study location, index case bacteriological status, type of school, and other relevant factors. In total, 28 studies including 54,707 school contacts screened for M. tuberculosis infection were eligible and included in the analysis. Overall, the prevalence of M. tuberculosis infection determined by the QuantiFERON Gold in-tube test was 33.2% (95% CI, 0.0-73.0%). The prevalences of M. tuberculosis infection based on the tuberculin skin test (TST) using 5 mm, 10 mm, and 15 mm as cutoffs were 27.2% (95% CI, 15.1-39.3%), 24.3% (95% CI, 15.3-33.4%), and 12.7% (95% CI, 6.3-19.0%), respectively. The pooled prevalence of M. tuberculosis infection (using a TST ≥5-mm cutoff) was lower in studies from China (22.8%; 95% CI, 16.8-28.8%) than other regions (36.7%; 95% CI, 18.1-55.2%). The pooled prevalence of M. tuberculosis infection was higher when the index was bacteriologically positive (43.6% [95% CI, 16.5-70.8%] versus 23.8% [95% CI, 16.2-31.4%]). These results suggest that contact investigation and general surveillance in schools from high-burden settings merit consideration as means to improve early case detection in children.

Tracing household transmission of SARS-CoV-2 in New Zealand using genomics

By early 2022, the highly transmissible Omicron variant of SARS-CoV-2 had spread across most of the world. For the first time since the pandemic began, New Zealand was experiencing high levels of community transmission of SARS-CoV-2. We enroled a cohort of households to better understand differences in transmission dynamics among subvariants of Omicron. We enroled 71 households, comprising 289 participants, and aimed to use viral genomes to gain a clearer understanding of variant-specific differences in epidemiological parameters affecting transmission dynamics. Approximately 80% of the households enroled experienced transmission of BA.2, while most of the remaining households had infections with BA.1 or BA.5. Using a logistic regression generalised linear mixed model, we found no difference in household secondary infection rate between Omicron subvariants BA.1, BA.2 and BA.5. Of the households recruited, the vast majority (92%) experienced a single chain of transmission with one inferred introduction. Further, we found that in 48% of the households studied, all household participants became infected following an index case. Most household participants tested positive within a week following an introduction, supporting the seven-day isolation requirement for household contacts that was in place in New Zealand at the time. By integrating genomic and epidemiological data, we show that viral transmission dynamics can be investigated with a higher level of granularity than with epidemiological data alone. Overall, households are a high risk setting for viral transmission in New Zealand.