A randomized, active-controlled, multi-centric, phase-II clinical study to assess safety and immunogenicity of a fully liquid DTwP-HepB-IPV-Hib hexavalent vaccine (HEXASIIL®) in Indian toddlers.

BACKGROUND: Combination vaccines are effective in simplifying complex vaccination schedules involving multiple vaccines. A fully liquid hexavalent diphtheria (D)-tetanus (T)-whole-cell pertussis (wP)- hepatitis B (HepB)-inactivated poliovirus (IPV)-Haemophilus influenzae b (Hib) vaccine (HEXASIIL®), manufactured by Serum Institute of India Pvt. Ltd. was tested for safety and immunogenicity following booster vaccination. METHODS: This was a phase-II/III, open label, multicentric, controlled trial in toddlers (phase II) and infants (phase III) in India. This manuscript presents results of phase II. Healthy toddlers aged 12-24 months were randomized (1:1) to receive a 0.5 ml booster dose of HEXASIIL® or comparator Pentavac SD + Poliovac, intramuscularly and followed for 28 days for safety assessment. Blood samples were collected pre-vaccination and 28 days post-vaccination to assess immunogenicity. Descriptive summary statistics were provided for safety and immunogenecity analyses. RESULTS: A total of 223 subjects were randomized. One subject droped out prior to dosing, due to consent withdrawal. Thus, 222 subjects received study vaccine (110 HEXASIIL® and 112 comparator). Frequency of solicited adverse events was comparable between HEXASIIL® and comparator (85.5 % vs 90.2 %). Most local and systemic solicited AEs were mild to moderate in severity. All events resolved completely without any sequelae and none led to subject discontinuation. No vaccine related serious AE was reported. Post vaccination, seroprotection rates against tetanus, Hib and polio type 1 and 3 were 100 % in both the groups. Seroprotection rates for diphtheria (99.1 % vs 100 %) and polio type 2 (98.2 % vs 100 %) were observed in HEXASIIL® and comparator group, respectively. For Hepatitis B, seroprotection was >99 % in both groups. Seroconversion observed for Bordetella Pertussis (94.5 % vs 95.4 %) and Pertussis Toxin (77.1 % vs 87.2 %) in HEXASIIL® and comparator group, respectively. CONCLUSION: HEXASIIL® vaccine was found to be safe and immunogenic in toddlers and supported its further clinical development in infants. Clinical Trial Registration - CTRI/2019/11/022052.

Neural network analysis of pharyngeal sounds can detect obstructive upper respiratory disease in brachycephalic dogs.

Brachycephalic obstructive airway syndrome (BOAS) is a highly prevalent respiratory disease affecting popular short-faced dog breeds such as Pugs and French bulldogs. BOAS causes significant morbidity, leading to poor exercise tolerance, sleep disorders and a shortened lifespan. Despite its severity, the disease is commonly missed by owners or disregarded by veterinary practitioners. A key clinical sign of BOAS is stertor, a low-frequency snoring sound. In recent years, a functional grading scheme has been introduced to semi-objectively grade BOAS based on the presence of stertor and other abnormal signs. However, correctly grading stertor requires significant experience and adding an objective component would aid accuracy and repeatability. This study proposes a recurrent neural network model to automatically detect and grade stertor in laryngeal electronic stethoscope recordings. The model is developed using a novel dataset of 665 labelled recordings taken from 341 dogs with diverse BOAS clinical signs. Evaluated via nested cross validation, the neural network predicts the presence of clinically significant BOAS with an area under the receiving operating characteristic of 0.85, an operating sensitivity of 71% and a specificity of 86%. The algorithm could enable widespread screening for BOAS to be conducted by both owners and veterinarians, improving treatment and breeding decisions.

Isoniazid resistance in Rifampicin sensitive pulmonary tuberculosis in children and adolescents.

BACKGROUND: Isoniazid (INH) and Rifampicin (RIF) are two crucial drugs used in antitubercular therapy. INH is known for its potent bactericidal effects and has a relatively higher prevalence of resistance compared to RIF. However, RIF resistance has been the subject of more extensive research. On the other hand, Ethambutol (EMB) and Streptomycin (STR) resistance have not been thoroughly studied, particularly in the context of children and adolescents. To address this knowledge gap, a study was designed to investigate the resistance patterns of INH, EMB, and STR in RIF-sensitive pulmonary tuberculosis (PTB) cases among children and adolescents. METHODS: Seventy-five newly diagnosed RIF sensitive PTB cases up to 18 years of age were enrolled. Retreatment cases were excluded. Sputum/gastric aspirate sample of these patients were sent for culture in Mycobacterium Growth Indicator Tube (MGIT) followed by drug susceptibility testing and Line Probe Assay. RESULTS: INH, EMB and STR resistance among RIF sensitive PTB cases was found to be 5.7%, 0% and 0.7% respectively. RIF resistance detected by CBNAAT was found to be 8.4%. CONCLUSION: Detection of INH resistance is as important as detecting RIF resistance as prevalence of INH resistance in RIF sensitive PTB among children and adolescents up to 18 years is around 6%.

Demonstration of a Transparent and Adhesive Sealing Top for Microfluidic Lab-Chip Applications.

A transparent and adhesive film-based enclosing and sealing method is here presented for out-of-cleanroom-based open-form microfluidic devices. The commercially available polyester flexible film known as Microseal 'B' is presented in this paper as a cover seal for open-form microfluidic devices. This film is adaptable to high working temperatures and is biocompatible. The quality of the sealing film was investigated by leak tests, fluorescence tests, and contact angle measurements. The investigations revealed its sealing strength, fluorescence detection compatibility, and surface wettability. It was found that the proposed sealing polyester film on the 3D-printed device could sustain a gauge pressure of 2.7 atm at a flow rate of 4 mL/min without any leaks. It also provided fluorescence detection compatibility and an intensity-to-background ratio in the range of 2.3 to 4.5 for particle sizes of 5 µm and 15 µm, respectively, which is comparable with the performances of other sealing materials. The film's hydrophobicity is comparable to other polymers used in microfluidics. This paper concludes by showcasing some applications of such transparent tops in classical microfluidic devices used for droplet generation and fluid mixing, in order to demonstrate the prospects of this fabrication technique in lab-on-a-chip devices.

A phase III randomized-controlled study of safety and immunogenicity of DTwP-HepB-IPV-Hib vaccine (HEXASIIL®) in infants.

A fully liquid hexavalent containing Diphtheria (D), Tetanus (T) toxoids, whole cell Pertussis (wP), Hepatitis B (Hep B), type 1, 2, 3 of inactivated poliovirus (IPV) and Haemophilus influenzae type b (Hib) conjugate vaccine (DTwP-HepB-IPV-Hib vaccine, HEXASIIL®) was tested for lot-to-lot consistency and non-inferiority against licensed DTwP-HepB-Hib + IPV in an open label, randomized Phase II/III study. In Phase III part, healthy infants received DTwP-HepB-IPV-Hib or DTwP-HepB-Hib + IPV vaccines at 6, 10 and 14 weeks of age. Blood samples were collected prior to the first dose and 28 days, post dose 3. Non inferiority versus DTwP-HepB-Hib + IPV was demonstrated with 95% CIs for the treatment difference for seroprotection/seroconversion rates. For DTwP-HepB-IPV-Hib lots, limits of 95% CI for post-vaccination geometric mean concentration ratios were within equivalence limits (0.5 and 2). Vaccine was well-tolerated and no safety concerns observed.Clinical Trial Registration - CTRI/2019/11/022052.

Non-thyroidal Illness in Children with Congestive Heart Failure

Objective: To estimate the proportion and risk factors of non-thyroidal illness (NTI) in children with congenital heart disease (CHD) with congestive heart failure (CHF). Methods: This study enrolled children (6 weeks to 60 months age) with CHD and CHF. The clinical profile and disease severity, derived from the Pediatric Early Warning Score (PEWS) was recorded. Baseline blood samples were taken within 24 hours of hospitalization and evaluated for free tri-iodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), N-terminal pro-brain natriuretic peptide (NT pro-BNP) and reverse T3. Results: A total of 80 (64 acyanotic CHD) children of median (interquartile range) age 5 (2.5, 8.0) months were enrolled. NTI was seen in 37 (46%) of whom 27 had low fT3 levels. The proportion of NTI was highest in children with severe disease (20/30), than moderate (4/9) or mild disease (13/41) (p=0.018). Ten (27%) patients with NTI died compared to 2 (4.7%) without NTI with unadjusted odds ratio (OR) [95% confidence interval (CI)] 7.593 (1.54, 37.38); p=0.006. After adjusting for NTI, shock and NT-pro-BNP levels, PEWS was the only significant predictor of mortality (OR: 1.41, 95% CI: 1.03, 1.92; p=0.032). Linear regression for fT3 identified a significant relationship with log NT-BNP [beta -3.541, (95% CI: -1.387, -0.388)] and with TSH [beta 2.652 (95% CI: 0.054, 0.383)]. The cutoff (area under the curve, 95% CI) that predicted mortality were fT4 <14.5 pmol/L (0.737, 0.60, 0.88), fT3/rT3 index <1.86 pg/ng (0.284, 0.129, 0.438) and NT pro-BNP >3725 pg/mL (0.702; 0.53, 0.88). Conclusion: NTI was present in a significant proportion of children with CHD and CHF. fT3 level was significantly associated with NTBNP levels and thus severity of CHF.

Stool CBNAAT: Alternative tool in the diagnosis of pulmonary tuberculosis in children.

Tuberculosis (TB) remains a significant public health concern, especially in children. The World Health Organization now provides estimates on pediatric TB cases and deaths, underscoring the urgency of addressing this issue. In India, childhood TB contributes significantly to the global burden, with a notable gap between reported cases and estimated incidence. Diagnosing pulmonary TB in children presents challenges, primarily due to difficulties in obtaining suitable respiratory specimens. Rapid tests like Cartridge-Based Nucleic Acid Amplification Test (CBNAAT) have shown promise in enhancing diagnostic sensitivity. Recent research suggests that stool samples offer a non-invasive alternative for diagnosing pulmonary TB in children, with good diagnostic accuracy observed for stool CBNAAT. Furthermore, stool CBNAAT results demonstrate high agreement with gastric aspirate CBNAAT in TB diagnosis. Various stool processing methods, such as centrifugation, filtration, and sedimentation, have shown improved results for CBNAAT testing. However, it is crucial to standardize these methods to ensure consistent and comparable outcomes. Integrating stool CBNAAT into existing diagnostic algorithms for pediatric TB can enhance accuracy and efficiency in diagnosis. When implementing these algorithms, local resources, epidemiological context, and healthcare settings should be taken into account. Stool CBNAAT holds promise for microbiological confirmation of pediatric pulmonary TB, especially in resource-limited settings where obtaining representative respiratory specimens is challenging. Further comparative studies and standardization of stool processing methods are necessary to determine the most suitable approach in different contexts. By doing so, we can make significant strides in improving TB diagnosis and management in children.

Adverse drug reactions in children and adolescents on daily antitubercular regimen: An observational longitudinal study.

OBJECTIVES: Subsequent to introduction of daily fixed dose combination (FDC) regimen with increased dosages and inclusion of ethambutol in continuation phase of antitubercular therapy (ATT) in India, this study was done to evaluate adverse drug reactions (ADRs) in children and adolescents. METHODS: Longitudinal observational study conducted in tertiary teaching hospital. Children (1 month-18 year), with newly diagnosed drug sensitive tuberculosis, started on daily FDC regimen of ATT, were included. Participants were followed up at 2 weeks, 8 weeks and 6 months. Division of AIDS (DAIDS) severity grading and World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality assessment was done. RESULTS: In 99 participants, 29 experienced ADRs. Most commonly ADRs involved hepatobiliary (11.1%) and gastrointestinal (8.1%) systems. Grade 3 severity noted in 35.5% ADRs. Certain causality classified in 19.3%. Presence of ADRs was significantly higher in participants with vs without malnutrition [40.5% vs 21.1% (p = 0.036)]. Tendency for more severe ADRs noted in participants with vs without malnutrition [Grade 3 ADRs out of all ADRs: 64.7% vs 0% (p < 0.001)]. CONCLUSION: Incidence and severity of ADRs has increased after introduction of daily FDC of ATT. Most common ADR observed were hepatobiliary. Malnutrition and less weight for age were risk factors for occurrence and severity of ADRs.

Spirometry in Children at Six Months After SARS-CoV-2 Infection: A Single-Center Study.

OBJECTIVE: To study the spirometry parameters of children six months after severe acute coronavirus 2 (SARS-CoV-2) infection. METHODS: This single center descriptive study enrolled children aged 7-18 years after 6 months of SARS-CoV-2 infection. A detailed interval history and clinical examination was recorded. Spirometry was performed and best of the three attempts was taken into consideration to measure forced vital capacity (FVC) and forced expiratory volume 1 second (FEV1). RESULTS: A convenience sample of 40 (21 boys) children was enrolled, median (IQR) age 13 (10.75, 17) years. Twelve (30%) children had abnormal spirometry with low FVC (<80%); 10/12 (83.3%) had FEV1<80%. Children who were underweight had higher odds of having abnormal spirometry [OR (95% CI) 5.13 (1.19, 22.11); P=0.028]. There was no significant association of abnormal spirometry with age, sex, severity of initial infection and oxygen requirement during the initial infection (P>0.05). CONCLUSION: Abnormal spirometry results were observed in one-third children post-SARS-CoV-2 infection at six months follow-up.