Search

An earthquake of moderate magnitude 5.9 occurred northeast of Harnai (Baluchistan), Pakistan, on 07 October 2021. This event caused several deaths and injuries due to the collapse of many mud houses in the epicentral area according to the Provincial Disaster Management Authority (PDMA). The event occurred along the Quetta syntaxis, which is one of the most seismically active zones of the country. The source mechanism of the mainshock based on the moment tensor inversion technique was determined using seismic data from the local network. Stress patterns and active tectonics within the Harnai area were investigated on the basis of recent event and previously available focal mechanism solutions. The 2021 earthquake source mechanism was oblique slip with 12 km focal depth and appears to be associated with the Harnai–Karahi fault zone. Interestingly, the nodal plane oriented in the east–west direction having a high dip corresponds to reverse faulting, whereas the low dip nodal plane trending northwest–southeast-depicts a strike-slip mechanism. The upper crustal stress field and current tectonic deformation in this region are governed by the oblique convergence between the Indian and Eurasian plates along the Chaman fault zone marking the transform plate boundary. The local tectonic stress pattern anomalously supports the low dip nodal plane of the determined fault plane solution representing transpressional environment in which originally produced reverse fault is being reactivated with a dominantly strike-slip sense of movement. In this area, two stress regimes, strike-slip and thrust mechanism, were identified based on homogenous stress patterns. The recent Harnai earthquake occurred in a region where thrust-faulting environment due to horizontal principal compression (SHmax) directed in north-northwest–south-southeast act as first order stress owing to the collision of the Indian and Eurasian plates. The SHmax direction of other subset areas has a similar orientation but different stress ratio (R′), which depicts strike-slip faulting. The presence of a rigid (Katawaz) block along the plate boundary, which impedes the Indian plate motion, causes the second-order stresses that result in strike-slip sense of movement in the pre-existing reverse faults. The same stress seems to be responsible for bending of the existing faults to produce en echelon structures within the Sulaiman range and generates connecting faults in the form of a bookshelf model.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

On 24 September 2019, an Mw 5.9 earthquake struck near the Mangla reservoir in northeastern Pakistan and resulted in 39 fatalities and 746 serious injuries, making it the deadliest earthquake in the region since the 2005 Mw 7.6 Kashmir earthquake. Here, we integrate geodetic, seismic, and field observations to characterize the source properties and impact of the Mirpur earthquake as well as investigate whether it might be a reservoir-induced event. From inverting Interferometric Synthetic Aperture Radar data, we find that a fault with strike ∼310°, dip ∼6°, and rake ∼117° is the optimal source, with slip concentrated between 5 and 6 km depth. This is consistent with our relocated aftershocks depth distribution and the lack of surface rupture observed in the field. Therefore, we infer that the earthquake ruptured the Main Himalayan Thrust (MHT). The event’s shallow depth might explain the extensive damage caused despite its moderate magnitude, with a maximum shaking intensity of VIII based on our field survey. The survey also revealed extensive damages associated with earthquake-induced liquefaction. Our modeling shows that loading due to increased reservoir water level in the three months before the Mirpur earthquake led to Coulomb stress increase of ∼7–10 kPa on the rupture plane. However, this effect is ∼10 times smaller than the Coulomb stress increase due to the 2006 Mangla earthquake, and the Mirpur earthquake only occurred ∼1–2 weeks after peak water level. These suggest that pore pressure diffusion contributed to promoting the fault rupture at a time when it is close to failure due to accumulated stress from inter-seismic loading. Because the Mirpur earthquake resulted in a stress increase of >0.2 MPa on the surrounding sections of the MHT and nearby faults, future rupture of these faults is a significant hazard and proper management of reservoir operations is necessary to prevent further elevating the seismic risk.

A massive snow avalanche occurred on April, 2012 at Gayari, located in NE part of Pakistan, close to India and China Border. The catastrophic avalanche killed nearly 148 people, majority of which were Pakistan army personnel destroying army base camp. To mitigate its future hazard, different triggering mechanisms have been investigated in this study. We contemplate that the avalanche was triggered due to snow pack existence on favorable slope in combination with different meteorological conditions and anomalous ground vibration. The avalanche occurrence clock was advanced by two earthquakes: M4.1 at a distance ∼ 125 km that occurred about 21 hours before and another comparatively larger (M5.6) earthquake that occurred comparatively at larger distance (∼ 370 km) and longer time (∼ 25 days) before which have significantly changed the loading conditions. The latter event (M 5.6) has imparted maximum peak dynamic stress and cumulative seismic moment a month before the avalanche. Interestingly the avalanche occurred within the seismic coda of M2.8 earthquake from Hindu Kush region, located at 560 km distance. Although the size and its expected impact on avalanche might be minor but its role in instantaneous triggering cannot be ruled out. Even smaller events at larger distance have been reported to cause snow avalanches in same environments. The presence of cracks within the avalanche, were further weaken by persistence of extremely low temperature (lowest in the past decade), causing high precipitation rate along with altering the mechanical properties of the weak layer within the snow pack. Robust wind pressure pattern highest and lowest in March and April, 2012 respectively might be responsible for abrupt changes in loading conditions.

IntroductionEnvironmental enteropathy is an important contributor to childhood malnutrition in the developing world. Chronic exposure to fecal pathogens leads to alteration in intestinal structure and function, resulting in impaired gut immune function, malabsorption, and growth faltering leading to environmental enteropathy.MethodsA community-based intervention study was carried out on children till 24 months of age in Matiari district, Pakistan. Blood and fecal specimens were collected from the enrolled children aged 3–6 and 9 months. A real-time PCR-based TaqMan array card (TAC) was used to detect enteropathogens.ResultsGiardia, Campylobacter spp., enteroaggregative Escherichia coli (EAEC), Enteropathogenic Escherichia coli (EPEC), Enterotoxigenic Escherichia coli (ETEC), and Cryptosporidium spp. were the most prevailing enteropathogens in terms of overall positivity at both time points. Detection of protozoa at enrollment and 9 months was negatively correlated with rate of change in height-for-age Z (ΔHAZ) scores during the first and second years of life. A positive association was found between Giardia, fecal lipocalin (LCN), and alpha 1-Acid Glycoprotein (AGP), while Campylobacter spp. showed positive associations with neopterin (NEO) and myeloperoxidase (MPO).ConclusionProtozoal colonization is associated with a decline in linear growth velocity during the first 2 years of life in children living in Environmental enteric dysfunction (EED) endemic settings. Mechanistic studies exploring the role of cumulative microbial colonization, their adaptations to undernutrition, and their influence on gut homeostasis are required to understand symptomatic enteropathogen-induced growth faltering.

Numerous safe and effective coronavirus disease 2019 vaccines have been developed worldwide that use various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S as compared with vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity, and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by receptor binding domain–specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies., Science Immunology, 7 (78), ISSN:2470-9468

Aim: To determine Leptin/Adiponectin ratio, LDL/HDL ratio and AdipoR1 in obese and healthy subjects along with their respective lipid status. Methods: This cross-sectional comparative study was conducted in Sialkot city. One hundred and thirty-two participants took part in this research. Participants were equally divided into two groups containing non-obese and obese subjects. Mean age was 39.6±0.97 years. Mean BMI for obese subjects was 31.55±0.6 while non-obese group BMI was 20.5±0.2. Individuals with conditions and history of drugs were excluded. Informed and written consent was obtained prior to fasting blood sampling. Serum extraction and proper storage for later testing was carried out. ELISA method used for Adiponectin, AdiopR1 and leptin estimations while lipid profile was determined by Randox Diagnostics kits, using micro lab. SPSS v. 26. was used for comparison between by Mann-Whitney U tes. Results: Higher levels of Leptin/Adiponectin ratio(0.85±0.1) and LDL/HDL ratio (3.39 ± 0.1), serum Adiponectin (545± 73.3 ug/L), leptin (320.7±50.3 pg/mL) and AdipoR1 (28.9± 2.8 ng/mL) in obese when compared with healthy individuals, Leptin/Adiponectin ratio (0.44 ± 0.07 ) and LDL/HDL ratio (2.56 ± 0.08) Adiponectin (834± 70.6 ug/L), AdiopoR1 (17.8± 1.97 ng/mL), leptin (224.4±168.7 pg/mL). Correlation of adiponectin found positive for AdipoR1(r=0.336,p

On May 06, 2022 an earthquake of M5.4 occurred in NW of Khuzdar (Baluchistan), Pakistan. This event caused damages to infrastructure and collapsed several mud houses, according to local news agencies. On the same day, an earthquake of a similar size (M5.4) which is 230km away from the Khuzdar earthquake occurred in Dalbandin, Baluchistan. Both of these earthquakes were independent and have not appeared to be related with each other. The 2013 Awaran earthquake of magnitude 7.7 has been the largest event within this region, located 70 km away from a recent event. The recent seismicity within the Khuzdar area might be the post viscoelastic relaxation the of Awaran earthquake having the NE-SW nodal plane as the fault plane. To understand the faulting style and tectonic setting, moment tensor inversion was performed using local seismic data. The mechanism of this event was strike-slip (sinisteral faulting style) and associated with Ornach-Nal strike-slip fault. Based on 38 events focal mechanism solutions from the global Harvard Centroid Moment Tensor (CMT) of the Khuzdar region depict NW-SE orientation of SHmax direction. Reduced stress tensors obtained from formal stress inversion are then divided into two subsets (thrust and strike-slip) on basis of their stress homogeneity. The present-day stress state confirms, the oblique convergence of Indian and Arabian Plates beneath Eurasian which is subjected to a transpressional tectonic environment. A lower b-value (0.7) and accelerated earthquake sequence were observed in the Khuzdar region before this event. The spatial distribution of b-value depicts the lowest value in this region, before the occurrence of the Awaran earthquake. Although high differential stress was exhibited in this region but large has not occurred. These stresses were transferred to the western part, where the Awaran earthquake has been occurred.

This study presents the coherently stacked P-wave receiver functions and bouguer anomaly mapping ofWestern Himalayas (longitude 71◦ -74◦ E and latitude 31◦ -34◦ N ) to estimate crustal thickness. Data used for P-wave receiver function is from a local seismic network of Pakistan whereas, gravity data is extracted from Topex and available in the public domain for research. The crust thickness and average crust Vp/Vs ratio at each station of the network are obtained by coherently stacking the Ps, PpPs, PpSs + PsPs phases of 15seismic stations. The data used in this study was collected from 2012 to 2019, events with magnitudes mb ≥ 6 and epicentral distances 30◦ to 95◦ were chosen. There is a significant difference in Moho depth beneath the broadband seismic stations used for the investigations. Moho depth is 36 km in the south, on average 46 km in the center, and 52 km at the northernmost seismic station of the study area. The crust is generally dipping from South to North for the study area. In order to support this interpreted argument of moho-depth variation from the P-wave receiver function, residual calculation of Bouguer anomaly data was carried out as well. The residuals showing a variation of anomalous data from -89 to 193 mGal in the study area have presented a good correlation and favored the argument of crustal dipping as suggested by the P-wave function from the seismic network. The trend confirms that the crustal thickening and shortening are caused by the collision of Indian and Asian plates.

Development and calibration of distance attenuation curve for local seismic data are requisite for better seismo-tectonic modeling and seismic hazard estimation. Local magnitude scale developed for Northern Punjab (Potwar Plateau and Salt Range) has been tested against different geometrical spreading values. Trade-off or linear inter dependence has been observed between local magnitude scale parameters. To address this issue, either nonparametric approach with proper smoothing factor or parametric approach with single parameter (a) as constant may be used. In this study, we fixed geometrical spreading parameter to eliminate parameters dependency and hence reduction in error was achieved. Geometrical spreading was observed to be distance-dependent factor rather than a constant parameter. A variance reduction of 11%, with zero error in anelsatic attenuation parameter was achieved by fixing geometrical parameter and performing parametric inversion. The new magnitude scale with distance correction factor is given by the expression; $$-{\mathrm{log}}A_o = {\mathrm{log}}(R)+0.0006(R)-1.7419$$ , where R is hypocentral distance, valid for $$R < 130$$ km and depth < 30 km. Lower attenuation (i.e., $$b = 0.0006$$ ) was observed in new magnitude scale as compared to previously developed magnitude scale (i.e., $$b = 0.00115$$ ) for the same area. The pronounced lower attenuation of seismic waves beneath the intraplate region of Northern Punjab is apparently owes to regional tectonics. Northern Punjab is relatively stable part of the Indian shield with Precambrian basement rock overlaid by varying thickness of salt diapirs and thick sedimentary cover.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to acute respiratory distress syndrome (ARDS). Understanding the evolution of the virus, and immune-pathogenic processes are critical for designing future therapeutic interventions. In this review, we collate information on the structure, genome, viral life cycle, and adult and pediatric host immune responses in response to SARS-CoV-2. The immunological responses are a prototype of the developmental origins of health and disease (DOHaD) hypothesis to explain the socio-geographic differences impacting the severity and mortality rates in SARS-CoV-2 infections. The DOHaD hypothesis identifies the relevance of trained innate immunity, age groups, and geography for effective vaccinations. As COVID-19 vaccines are being rolled out, it may be pertinent to assess population-based immunological responses to understand the effectiveness and safety across different populations and age groups.

In this research work, we have performed comparative diurnal variations of atmospheric Potential Gradient (PG) of fair-weather days by using the data of three stations installed in Northern, Pakistan for the year 2018. We investigated the impact of both local and global factors and meteorological parameters in the diurnal variation of atmospheric Potential Gradient on the annual and seasonal time scale. We observed two peaks, primary and secondary. This is because of the land-based measurements of annual and seasonal variations. The annual average curve of Potential Gradient of all three stations: Islamabad (CES), Muzaffarabad (MZF), and Balakot (BKT) demonstrated a notable deviation from the standard oceanic Carnegie curve. The atmospheric Potential Gradient variations are due to numerous meteorological factors e.g., air pollution, humidity, aerosol particles, fog, and temperature. Among three stations, the MZF station is located in highland (mountainous) and it demonstrated a higher atmospheric Potential Gradient. We further differentiate the results of our three stations with global results for authenticity and observed coherence between them. In addition, a positive correlation of fair-weather Potential Gradient is observed with temperature and a notable correlation between relative humidity and atmospheric Potential Gradient for all the three observatories.

Background Pakistan introduced Ten-valent pneumococcal-conjugate-vaccine PCV10 in 2012 as a 3 + 0 schedule without catch-up. Methods Children

Stunting is a global public health issue. We sought to train and evaluate machine learning (ML) classification algorithms on the Zambia Demographic Health Survey (ZDHS) dataset to predict stunting among children under the age of five in Zambia. We applied Logistic regression (LR), Random Forest (RF), SV classification (SVC), XG Boost (XgB) and Naïve Bayes (NB) algorithms to predict the probability of stunting among children under five years of age, on the 2018 ZDHS dataset. We calibrated predicted probabilities and plotted the calibration curves to compare model performance. We computed accuracy, recall, precision and F1 for each machine learning algorithm. About 2327 (34.2%) children were stunted. Thirteen of fifty-eight features were selected for inclusion in the model using random forest. Calibrating the predicted probabilities improved the performance of machine learning algorithms when evaluated using calibration curves. RF was the most accurate algorithm, with an accuracy score of 79% in the testing and 61.6% in the training data while Naïve Bayesian was the worst performing algorithm for predicting stunting among children under five in Zambia using the 2018 ZDHS dataset. ML models aids quick diagnosis of stunting and the timely development of interventions aimed at preventing stunting.

Measurement quality and analysis capability of infrasonic signals are both affected by background wind-noise. Physical filters, i.e., barriers and pipe arrays, are traditionally employed to reduce such noise. However, limited efficacy, site dependence, cost, requirement of space, non-portability, and frequent maintenance are some of their major drawbacks. This work proposes an adaptive filtering-based adaptive line enhancer (ALE) noise cancellation scheme as an alternative. Two infrasonic sensors (Chaparral Physics 50A), are adjacently deployed. One sensor is fitted with a conventional four-armed non-porous hose array (physical filter), while the ALE scheme is applied to the second sensor, sans physical filter. In high wind-noise conditions, the ALE scheme seems to behave as a lowpass filter (cutoff at 0.2 Hz), with a maximum attenuation of 26 dB at 8 Hz, while the physical filter provides significant attenuation only above 4 Hz with a maximum attenuation of 17 dB at 8 Hz. Generally, at other frequencies, the ALE scheme provides up to 20 dB superior noise attenuation as compared to the physical filter. The ALE also provides up to 6 dB gain in the signal-to-noise ratio as compared to the physical filter, due to non-attenuation of the infrasonic signal.

Background Shigella is a leading cause of childhood diarrhea and target for vaccine development. Microbiologic and clinical case definitions are needed for pediatric field vaccine efficacy trials. Methods We compared characteristics of moderate to severe diarrhea (MSD) cases in the Global Enteric Multicenter Study (GEMS) between children with culture positive Shigella to those with culture-negative, quantitative polymerase chain reaction (qPCR)-attributable Shigella (defined by an ipaH gene cycle threshold, Molecular methods identified Shigella more commonly than microbiologic culture in younger and stunted children. A simplified clinical score containing dehydration, hospitalization, and diarrhea duration could be used to stratify vaccine trial endpoints by severity based on its ability to predict death.

Background Prolonged enteropathogen shedding after diarrhea complicates the identification of etiology in subsequent episodes and is an important driver of pathogen transmission. A standardized approach has not been applied to estimate the duration of shedding for a wide range of pathogens. Methods We used a multisite birth cohort of children 0–24 months of age from whom diarrheal and monthly nondiarrheal stools were previously tested by quantitative polymerase chain reaction for 29 enteropathogens. We modeled the probability of detection of the etiologic pathogen before and after diarrhea using a log-normal accelerated failure time survival model and estimated the median duration of pathogen carriage as well as differences in subclinical pathogen carriage 60 days after diarrhea onset in comparison to a prediarrhea baseline. Results We analyzed 3247 etiologic episodes of diarrhea for the 9 pathogens with the highest attributable burdens of diarrhea. The median duration of postdiarrheal carriage varied widely by pathogen, from about 1 week for rotavirus (median, 8.1 days [95% confidence interval {CI}, 6.2–9.6]) to >1 month for Cryptosporidium (39.5 days [95% CI, 30.6–49.0]). The largest increases in subclinical pathogen carriage before and after diarrhea were seen for Cryptosporidium (prevalence difference between 30 days prior and 60 days after diarrhea onset, 0.30 [95% CI, .23–.39]) and Shigella (prevalence difference, 0.21 [95% CI, .16–.27]). Conclusions Postdiarrheal shedding was widely variable between pathogens, with strikingly prolonged shedding seen for Cryptosporidium and Shigella. Targeted antimicrobial therapy and vaccination for these pathogens may have a relatively large impact on transmission., In a multisite birth cohort study of children 0–24 months of age and with quantitative polymerase chain reaction detection of diarrheal pathogens, we estimate the duration of postdiarrheal carriage in low-resource settings, with strikingly prolonged shedding seen for Cryptosporidium and Shigella.

Pakistan and its surroundings are among the most seismically active regions in the world. Occurrence of major earthquakes in Pakistan is a real hazard for life. In this study, an attempt has been made to estimate the seismic hazard in terms of earthquake occurrence conditional probabilities in different zones of Pakistan. We assumed that the temporal data of earthquakes, that occurred in different regions of Pakistan follow a certain probability distribution. In present study, the 10 probability models that include the exponential, gamma, generalized Pareto, inverse Pareto, kappa, log-logistic, lognormal, Pareto, transformed gamma and Weibull are used to analyze the interevent times of the earthquakes with $$M_{w}\ge 5.5$$ in different regions of Pakistan. In current study, Pakistan territory has been divided into five different seismic zones based on their tectonic settings. Parameters of the considered distributions are estimated by using the maximum likelihood method using the reviewed earthquake catalogue compiled by Centre for Earthquake Studies (CES), Pakistan. The best suitable model in each seismic zone is selected through various model selection criteria. The results show that the log-logistic distribution provides the best representation of earthquake temporal data of plate convergence zones; while the gamma distribution best explains the temporal seismicity of other tectonic regimes including the transform plate boundary, fold and thrust belts and stable plains. The most suitable gamma and log-logistic models are used for the earthquake occurrence probabilities in different regions of Pakistan. The highest $$(>96\%)$$ and the least $$(>30\%)$$ earthquake occurrence conditional probabilities are respectively observed for Zones I and V among five seismic zones for different combinations of elapsed time $$(\tau )$$ and time interval $$(\upsilon )$$ . The estimated probability of $$M_{w}\ge 5.5$$ event reaches (60–98)% in next (3–9) years time interval without any elapsed time $$(\tau =0)$$ in Zones II to IV (the time periods corresponding to 3–9 years time interval are 2016–2022, 2020–2026 and 2019–2025 in Zones I, II and III respectively) since the last event occurrence time in each of these seismic zone. The mean values of the interevent time for an earthquake occurrence of $$M_{w}\ge 5.5$$ in Zone-I to Zone-V are respectively calculated as 0.90, 1.78, 4.52, 3.35 and 11.76 years, respectively. The results of the present study indicate that Zone-I has potential capability of producing an earthquake of magnitude 5.5 or higher in next 3 years (2019–2021) time interval since the last event occurrence in May 2018. The earthquake hazard curves associated with earthquake occurrence probabilities are also developed in order to understand the current and future earthquake mechanism in the study region.

Objectives 1- To compare the effectiveness of 1% Hydrogen peroxide, 0.2% Povidone-Iodine, 2% hypertonic saline and a novel solution Neem extract (Azardirachta indica) in reducing intra-oral viral load in COVID-19 positive patients. 2- To determine the salivary cytokine profiles of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL- 17 among COVID-19 patients subjected to 1% Hydrogen peroxide, 0.2% Povidone-Iodine, 2% hypertonic saline or Neem extract (Azardirachta indica) based gargles. Trial design This will be a parallel group, quadruple blind-randomised controlled pilot trial with an add on laboratory based study. Participants A non-probability, purposive sampling technique will be followed to identify participants for this study. The clinical trial will be carried out at the Aga Khan University Hospital (AKUH), Karachi, Pakistan. The viral PCR tests will be done at main AKUH clinical laboratories whereas the immunological tests (cytokine analysis) will be done at the Juma research laboratory of AKUH. The inclusion criteria are laboratory-confirmed COVID-19 positive patients, male or female, in the age range of 18-65 years, with mild to moderate disease, already admitted to the AKUH. Subjects with low Glasgow coma score, with a history of radiotherapy or chemotherapy, who are more than 7 days past the onset of COVID- 19 symptoms, or intubated or edentulous patients will be excluded. Patients who are being treated with any form of oral or parenteral antiviral therapy will be excluded, as well as patients with known pre-existing chronic mucosal lesions such as lichen planus. Intervention and comparator Group A (n=10) patients on 10 ml gargle and nasal lavage using 0.2% Povidone-Iodine (Betadiene® by Aviro Health Inc./ Pyodine® by Brooks Pharma Inc.) for 20-30 seconds, thrice daily for 6 days. Group B (n=10) patients will be subjected to 10 ml gargle and nasal lavage using 1% Hydrogen peroxide (HP® by Karachi Chemicals Products Inc./ ActiveOxy® by Boumatic Inc.) for 20-30 seconds, thrice daily for 6 days. Group C will comprised of (n=10) subjects on 10ml gargle and nasal lavage using Neem extract solution (Azardirachta indica) formulated by Karachi University (chemistry department laboratories) for 20-30 seconds, thrice daily for 6 days. Group D (n=10) patients will use 2% hypertonic saline (Plabottle® by Otsuka Inc.) gargle and nasal lavage for a similar time period. Group E (n=10) will serve as positive controls. These will be given simple distilled water gargles and nasal lavage for 20-30 seconds, thrice daily for six days. For nasal lavage, a special douche syringe will be provided to each participant. Its use will be thoroughly explained by the data collection officer. After each use, the patient is asked not to eat, drink, or rinse their mouth for the next 30 minutes. Main outcomes The primary outcome is the reduction in the intra-oral viral load confirmed with real time quantitative PCR. Randomisation The assignment to the study group/ allocation will be done using the sealed envelope method under the supervision of Clinical Trial Unit (CTU) of Aga Khan University, Karachi, Pakistan. The patients will be randomised to their respective study group (1:1:1:1:1 allocation ratio) immediately after the eligibility assessment and consent administration is done. Blinding (masking) The study will be quadruple-blinded. Patients, intervention provider, outcome assessor and the data collection officer will be blinded. The groups will be labelled as A, B, C, D or E. The codes of the intervention will be kept in lock & key at the CTU and will only be revealed at the end of study or if the study is terminated prematurely. Numbers to be randomised (sample size) As there is no prior work on this research question, so no assumptions for the sample size calculation could be made. The present study will serve as a pilot trial. We intend to study 50 patients in five study groups with 10 patients in each study group. For details, please refer to Fig. 1 for details. Trial Status Protocol version is 7.0, approved by the department and institutional ethics committees and clinical trial unit of the university hospital. Recruitment is planned to start as soon as the funding is sanctioned. The total duration of the study is expected to be 6 months i.e. August 2020-January 2021. Trial registration This study protocol was registered at www.clinicaltrials.gov on 10 April 2020 NCT04341688. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

This study presents a detailed measurement of indoor and outdoor terrestrial gamma radiation levels in different cities of Pakistan. The measurements covered dwellings in 27 cities, covering all provinces and region of Azad Kashmir. Most of the houses were of attached type, made of brick walls and concrete roofs. The measurements were made by a handheld radiation survey meter containing Geiger–Muller tube. The average absorbed dose rate in air was 100 ± 32 nGy h−1 for indoor and 74 ± 30 nGy h−1 for outdoor. The population-weighted mean terrestrial dose rates were 90 nGy h−1 for indoor and 78 nGyh−1 for outdoor. The ratio of indoor to outdoor absorbed dose rate was 1.5 as compared to 1.3 for the world average. The estimated average annual effective dose rate was 0.58 ± 0.18 mSv a−1 and the mean excess life time cancer risk was 2.0 × 10−3.

The SARS-CoV-2 Omicron variant of concern comprises three sublineages designated BA.1, BA.2, and BA.3, with BA.2 steadily replacing the globally dominant BA.1. We show that the large number of BA.1 and BA.2 spike mutations severely dampen plasma neutralizing activity elicited by infection or seven clinical vaccines, with cross-neutralization of BA.2 being consistently more potent than that of BA.1, independent of the vaccine platform and number of doses. Although mRNA vaccines induced the greatest magnitude of Omicron BA.1 and BA.2 plasma neutralizing activity, administration of a booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1 and BA.2 across all vaccines evaluated. Our data suggest that although BA.1 and BA.2 evade polyclonal neutralizing antibody responses, current vaccine boosting regimens may provide sufficient protection against Omicron-induced disease.

Bifidobacterium longum subspecies detected in infant stool have been associated with numerous subsequent health outcomes and are potential early markers of deviation from healthy developmental trajectories. This analysis derived indicators of carriage and early colonization with B. infantis and B. longum and quantified their associations with a panel of early-life exposures and outcomes. In a sub-study nested within a multi-site birth cohort, extant stool samples from infants in Bangladesh, Pakistan and Tanzania were tested for presence and quantity of two Bifidobacterium longum subspecies. The results were matched to indicators of nutritional status, enteropathogen infection, histo-blood group antigens, vaccine response and feeding status and regression models were fitted to test for associations while adjusting for covariates. B. infantis was associated with lower quantity of and decreased odds of colonization with B. longum, and vice versa. Length at birth was associated with a 0.36 increase in log10B. infantis and a 0.28 decrease in B. longum quantity at 1 month of age. B. infantis colonization was associated with fewer viral infections and small reductions in the risk of rotavirus and sapovirus infections, but not reduced overall diarrheal disease risk. No associations with vaccine responses, HBGAs or later nutritional status were identified. Suboptimal intrauterine growth and a shorter duration of exclusive breastfeeding may predispose infants to early intestinal colonization with the B. longum subspecies at the expense of B. infantis, thus denying them potential benefits of reduced enteric virus episodes.

Numerous safe and effective COVID-19 vaccines have been developed that utilize various delivery technologies and engineering strategies. The influence of the SARS-CoV-2 spike (S) glycoprotein conformation on antibody responses induced by vaccination or infection in humans remains unknown. To address this question, we compared plasma antibodies elicited by six globally-distributed vaccines or infection and observed markedly higher binding titers for vaccines encoding a prefusion-stabilized S relative to other groups. Prefusion S binding titers positively correlated with plasma neutralizing activity, indicating that physical stabilization of the prefusion conformation enhances protection against SARS-CoV-2. We show that almost all plasma neutralizing activity is directed to prefusion S, in particular the S1 subunit, and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants and longer durability than current technologies.

SUMMARYThe recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb1, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab2, S2X2593 and S2H974, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

The underperformance of oral vaccines in children of low- and middle-income countries is partly attributable to underlying environmental enteric dysfunction (EED).We conducted a longitudinal, community-based study to evaluate the association of oral rotavirus vaccine (Rotarix®) seroconversion with growth anthropometrics, EED biomarkers and intestinal enteropathogens in Pakistani infants. Children were enrolled between three to six months of their age based on their nutritional status. We measured serum anti-rotavirus immunoglobulin A (IgA) at enrollment and nine months of age with EED biomarkers and intestinal enteropathogens.A total of 391 infants received two doses of rotavirus (RV) vaccine. 331/391 provided paired blood samples. Of these 331 children, 45% seroconverted at 9 months of age, 35% did not seroconvert and 20% were seropositive at baseline. Non-seroconverted children were more likely to be stunted, wasted and underweight at enrollment. In univariate analysis, insulin-like growth factor (IGF) concentration at 6 months were higher in seroconverters, median (25th, 75th percentile): 26.3 (16.5, 43.5) ng/ml vs. 22.5 (13.6, 36.3) ng/ml for non-seroconverters, p-value = 0.024. At nine months, fecal myeloperoxidase (MPO) concentrations were significantly lower in seroconverters, 3050(1250, 7587) ng/ml vs. 4623.3 (2189, 11650) ng/ml in non-seroconverted children, p-value = 0.017. In multivariable logistic regression analysis, alpha-1 acid glycoprotein (AGP) and IGF-1 concentrations were positively associated with seroconversion at six months. The presence of sapovirus and rotavirus in fecal samples at the time of rotavirus administration, was associated with non-seroconversion and seroconversion, respectively.We detected high baseline RV seropositivity and impaired RV vaccine immunogenicity in this high-risk group of children. Healthy growth, serum IGF-1 and AGP, and fecal shedding of rotavirus were positively associated with RV IgA seroconversion following immunization, whereas the presence of sapovirus was more common in non-seroconverters.Clinical Trials ID: NCT03588013.

To address the disproportionate burden of preterm birth (PTB) in low- and middle-income countries, this study aimed to (1) verify the performance of the United States-validated spontaneous PTB (sPTB) predictor, comprised of the IBP4/SHBG protein ratio, in subjects from Bangladesh, Pakistan and Tanzania enrolled in the Alliance for Maternal and Newborn Health Improvement (AMANHI) biorepository study, and (2) discover biomarkers that improve performance of IBP4/SHBG in the AMANHI cohort. The performance of the IBP4/SHBG biomarker was first evaluated in a nested case control validation study, then utilized in a follow-on discovery study performed on the same samples. Levels of serum proteins were measured by targeted mass spectrometry. Differences between the AMANHI and U.S. cohorts were adjusted using body mass index (BMI) and gestational age (GA) at blood draw as covariates. Prediction of sPTB < 37 weeks and < 34 weeks was assessed by area under the receiver operator curve (AUC). In the discovery phase, an artificial intelligence method selected additional protein biomarkers complementary to IBP4/SHBG in the AMANHI cohort. The IBP4/SHBG biomarker significantly predicted sPTB < 37 weeks (n = 88 vs. 171 terms ≥ 37 weeks) after adjusting for BMI and GA at blood draw (AUC= 0.64, 95% CI: 0.57–0.71, p < .001). Performance was similar for sPTB < 34 weeks (n = 17 vs. 184 ≥ 34 weeks): AUC = 0.66, 95% CI: 0.51–0.82, p = .012. The discovery phase of the study showed that the addition of endoglin, prolactin, and tetranectin to the above model resulted in the prediction of sPTB < 37 with an AUC= 0.72 (95% CI: 0.66–0.79, p-value < .001) and prediction of sPTB < 34 with an AUC of 0.78 (95% CI: 0.67–0.90, p < .001). A protein biomarker pair developed in the U.S. may have broader application in diverse non-U.S. populations.

The relationship between environmental factors and child health is not well understood in rural Pakistan. This study characterized the environmental factors related to the morbidity of acute respiratory infections (ARIs), diarrhea, and growth using geographical information systems (GIS) technology. Anthropometric, address and disease prevalence data were collected through the SEEM (Study of Environmental Enteropathy and Malnutrition) study in Matiari, Pakistan. Publicly available map data were used to compile coordinates of healthcare facilities. A Pearson correlation coefficient (r) was used to calculate the correlation between distance from healthcare facilities and participant growth and morbidity. Other continuous variables influencing these outcomes were analyzed using a random forest regression model. In this study of 416 children, we found that participants living closer to secondary hospitals had a lower prevalence of ARI (r = 0.154, p &lt, 0.010) and diarrhea (r = 0.228, p &lt, 0.001) as well as participants living closer to Maternal Health Centers (MHCs): ARI (r = 0.185, p &lt, 0.002) and diarrhea (r = 0.223, p &lt, 0.001) compared to those living near primary facilities. Our random forest model showed that distance has high variable importance in the context of disease prevalence. Our results indicated that participants closer to more basic healthcare facilities reported a higher prevalence of both diarrhea and ARI than those near more urban facilities, highlighting potential public policy gaps in ameliorating rural health.