Isolated left ventricular non-compaction: Clinical characterisation of a teenage male.

Isolated Left Ventricular Non-compaction (LVNC) is a type of cardiomyopathy that usually has a genetic origin. Its diagnosis is based on finding such as deep intertrabecular recesses or sinusoids and ventricular trabeculations communicating with the left ventricular cavity. LVNC was first clinically recognised almost four decades ago, yet its diagnostic and management challenges persist. In this report, we present the case of an 18-year-old boy, who presented at the National Institute of Cardiovascular Diseases, Karachi, in March 2023, with complaints of dizziness, pedal oedema, and shortness of breath. Echocardiography revealed signs suggestive of LVNC, which were confirmed conclusively on Cardiovascular Magnetic Resonance (CMR) (NC/C ratio>2.4). The patient underwent implantable cardioverter defibrillator (ICD) placement, was discharged after a smooth post-procedure recovery, and is doing well on follow-ups. Hence, ICD and guideline-directed medical therapy as a combination have turned out to have satisfactory outcomes in decreasing morbidity and providing mortality benefits for such patients.

Cultural hierarchies in health: Does inherited sociocultural position (biraderi) shape diet and nutrition among British Pakistani children? Protocol for a mixed-methods study.

This study aims to explore links between biraderi-a form of identity-based social grouping and stratification which cuts across religions among South Asians-and infant and child nutrition among British Pakistanis using data from the Born in Bradford cohort study. The study will entail a mixed-methods approach to (i) develop an operational framework of biraderi for epidemiologic analyses and apply it to longitudinal data from the Born in Bradford cohort study, (ii) quantify and describe child nutrition and dietary patterns for biraderi sub-groups, and (iii) investigate whether known mechanisms of identity-based segregation, graded inequality, and network effects operate through diet and nutrition in the UK. Using Krieger's ecosocial theory as an integrative framework we will (iv) re-conceptualise and interpret the role of biraderi / caste in the social construction and embodied experience of how infants and children eat in the UK. Following a literature review on biraderi and health, we will convene and consult a lay consultation group in Bradford through focus groups and academic experts through a Delphi study to guide planning, implementation, interpretation and dissemination of our secondary data analysis. In addition to being the first study to look at biraderi-based nutritional inequalities in the UK, our study is innovative in that we will formally involve experts and users in the design and interpretation of our quantitative analyses. Findings will be applicable in any part of the world where children experience disadvantage linked to sociocultural hierarchy and identity. Our findings will be of particular use in (i) identifying women and children at particular risk of suboptimal breastfeeding practices, poor complementary feeding, and unhealthy diets in primary school in the UK, and (ii) elucidating the sociocultural pathways through which inequalities in population health nutrition outcomes are expressed.

Inhomogeneous energy transfer dynamics from iron-stress-induced protein A to photosystem I.

Cyanobacteria respond to iron limitation by producing the pigment-protein complex IsiA, forming rings associated with photosystem I (PSI). Initially considered a chlorophyll-storage protein, IsiA is known to act as an auxiliary light-harvesting antenna of PSI, increasing its absorption cross-section and reducing the need for iron-rich PSI core complexes. Spectroscopic studies have demonstrated efficient energy transfer from IsiA to PSI. Here we investigate the room-temperature excitation dynamics in isolated PSI-IsiA, PSI, IsiA monomer complexes and IsiA aggregates using two-dimensional electronic spectroscopy. Cross analyses of the data from these three samples allow us to resolve components of energy transfer between IsiA and PSI with lifetimes of 2-3 ps and around 20 ps. Structure-based Förster theory calculations predict a single major timescale of IsiA-PSI equilibration, that depends on multiple energy transfer routes between different IsiA subunits in the ring. Despite the experimentally observed lifetime heterogeneity, which is attributed to structural heterogeneity of the supercomplexes, IsiA is found to be a unique, highly efficient, membrane antenna complex in cyanobacteria.

Ultrafast Energy Transfer in a Diatom Photosystem II Supercomplex.

The light-harvesting complexes (LHCs) of diatoms, specifically fucoxanthin-Chl a/c binding proteins (FCPs), exhibit structural and functional diversity, as highlighted by recent structural studies of photosystem II-FCP (PSII-FCPII) supercomplexes from different diatom species. The excitation dynamics of PSII-FCPII supercomplexes isolated from the diatom Thalassiosira pseudonana was explored using time-resolved fluorescence spectroscopy and two-dimensional electronic spectroscopy at room temperature and 77 K. Energy transfer between FCPII and PSII occurred remarkably fast (<5 ps), emphasizing the efficiency of FCPII as a light-harvesting antenna. The presence of long-wavelength chlorophylls may further help concentrate excitations in the core complex and increase the efficiency of light harvesting. Structure-based calculations reveal remarkably strong excitonic couplings between chlorophylls in the FCP antenna and between FCP and the PSII core antenna that are the basis for the rapid energy transfer.

Effects of lipids on the rate-limiting steps in the dark-to-light transition of Photosystem II core complex of Thermostichus vulcanus.

In our earlier works, we have shown that the rate-limiting steps, associated with the dark-to-light transition of Photosystem II (PSII), reflecting the photochemical activity and structural dynamics of the reaction center complex, depend largely on the lipidic environment of the protein matrix. Using chlorophyll-a fluorescence transients (ChlF) elicited by single-turnover saturating flashes, it was shown that the half-waiting time (Δτ 1/2) between consecutive excitations, at which 50% of the fluorescence increment was reached, was considerably larger in isolated PSII complexes of Thermostichus (T.) vulcanus than in the native thylakoid membrane (TM). Further, it was shown that the addition of a TM lipid extract shortened Δτ 1/2 of isolated PSII, indicating that at least a fraction of the 'missing' lipid molecules, replaced by detergent molecules, caused the elongation of Δτ 1/2. Here, we performed systematic experiments to obtain information on the nature of TM lipids that are capable of decreasing Δτ 1/2. Our data show that while all lipid species shorten Δτ 1/2, the negatively charged lipid phosphatidylglycerol appears to be the most efficient species - suggesting its prominent role in determining the structural dynamics of PSII reaction center.

Inter-subunit energy transfer processes in a minimal plant photosystem II supercomplex.

Photosystem II (PSII) is an integral part of the photosynthesis machinery, in which several light-harvesting complexes rely on inter-complex excitonic energy transfer (EET) processes to channel energy to the reaction center. In this paper, we report on a direct observation of the inter-complex EET in a minimal PSII supercomplex from plants, containing the trimeric light-harvesting complex II (LHCII), the monomeric light-harvesting complex CP26, and the monomeric PSII core complex. Using two-dimensional (2D) electronic spectroscopy, we measure an inter-complex EET timescale of 50 picoseconds for excitations from the LHCII-CP26 peripheral antenna to the PSII core. The 2D electronic spectra also reveal that the transfer timescale is nearly constant over the pump spectrum of 600 to 700 nanometers. Structure-based calculations reveal the contribution of each antenna complex to the measured inter-complex EET time. These results provide a step in elucidating the full inter-complex energy transfer network of the PSII machinery.

Left atrial appendage thrombus with severe mitral stenosis: Responders and non-responders to anticoagulation.

INTRODUCTION AND OBJECTIVE: Mitral stenosis (MS) is one of the most frequently observed valvular heart lesions in developing countries and is due to different etiologies. The effects of anticoagulation in different types of left atrial appendage (LAA) are unknown. The current study aimed to determine the resolution of LAA thrombus on transesophageal echocardiography (TEE) after three months of optimal anticoagulation in patients with different types of LAA at baseline cardiac computed tomography of patients with severe MS. METHODS: This prospective cohort study observed the frequency of LAA thrombus resolution after three months of anticoagulation therapy in patients with severe MS. The response rate in different morphologies of LAA and locations was also assessed. Thrombus resolution after three months of warfarin therapy was assessed on repeat TEE. RESULTS: A total of 88 patients were included, mean age 37.95±11.87 years. Repeat TEE showed thrombus resolution in only 27.3% of patients. The rate of thrombus resolution was 8/12 (66.7%), 4/28 (14.3%), 8/36 (22.2%), and 4/12 (33.3%) for patients with cactus, cauliflower, chicken wing, and windsock LAA type, respectively. The resolution rate was 0/12 (0%), 4/44 (9.1%), and 20/32 (62.5%) for patients with thrombus in the base, body, and tip of the LAA, respectively. CONCLUSION: The cactus type of LAA morphology and thrombus at the LAA tip responded well to three months of anticoagulation, however, patients with thrombus in the LAA base and body and cauliflower and chicken wing morphology were non-responders and could benefit from early referral for surgical management.

Quantifying the Energy Spillover between Photosystems II and I in Cyanobacterial Thylakoid Membranes and Cells.

The spatial separation of photosystems I and II (PSI and PSII) is thought to be essential for efficient photosynthesis by maintaining a balanced flow of excitation energy between them. Unlike the thylakoid membranes of plant chloroplasts, cyanobacterial thylakoids do not form tightly appressed grana stacks that enforce strict lateral separation. The coexistence of the two photosystems provides a ground for spillover-excitation energy transfer from PSII to PSI. Spillover has been considered as a pathway of energy transfer from the phycobilisomes to PSI and may also play a role in state transitions as means to avoid overexcitation of PSII. Here, we demonstrate a significant degree of energy spillover from PSII to PSI in reconstituted membranes and isolated thylakoid membranes of Thermosynechococcus (Thermostichus) vulcanus and Synechocystis sp. PCC 6803 by steady-state and time-resolved fluorescence spectroscopy. The quantum yield of spillover in these systems was determined to be up to 40%. Spillover was also found in intact cells but to a considerably lower degree (20%) than in isolated thylakoid membranes. The findings support a model of coexistence of laterally separated microdomains of PSI and PSII in the cyanobacterial cells as well as domains where the two photosystems are energetically connected. The methodology presented here can be applied to probe spillover in other photosynthetic organisms.

Function of iron-stress-induced protein A in cyanobacterial cells with monomeric and trimeric photosystem I.

The acclimation of cyanobacteria to iron deficiency is crucial for their survival in natural environments. In response to iron deficiency, many cyanobacterial species induce the production of a pigment-protein complex called iron-stress-induced protein A (IsiA). IsiA proteins associate with photosystem I (PSI) and can function as light-harvesting antennas or dissipate excess energy. They may also serve as chlorophyll storage during iron limitation. In this study, we examined the functional role of IsiA in cells of Synechocystis sp. PCC 6803 grown under iron limitation conditions by measuring the cellular IsiA content and its capability to transfer energy to PSI. We specifically tested the effect of the oligomeric state of PSI by comparing wild-type (WT) Synechocystis sp. PCC 6803 with mutants lacking specific subunits of PSI, namely PsaL/PsaI (PSI subunits XI/VIII) and PsaF/PsaJ (PSI subunits III/IX). Time-resolved fluorescence spectroscopy revealed that IsiA formed functional PSI3-IsiA18 supercomplexes, wherein IsiA effectively transfers energy to PSI on a timescale of 10 ps at room temperature-measured in isolated complexes and in vivo-confirming the primary role of IsiA as an accessory light-harvesting antenna to PSI. However, a notable fraction (40%) remained unconnected to PSI, supporting the notion of a dual functional role of IsiA. Cells with monomeric PSI under iron deficiency contained, on average, only 3 to 4 IsiA complexes bound to PSI. These results show that IsiA can transfer energy to trimeric and monomeric PSI but to varying degrees and that the acclimatory production of IsiA under iron stress is controlled by its ability to perform its light-harvesting function.

Energy transfer from phycobilisomes to photosystem I at 77 K.

Phycobilisomes serve as a light-harvesting antenna of both photosystem I (PSI) and II (PSII) in cyanobacteria, yet direct energy transfer from phycobilisomes to PSI is not well documented. Here we recorded picosecond time-resolved fluorescence at wavelengths of 605-760 nm in isolated photosystem I (PSI), phycobilisomes and intact cells of a PSII-deficient mutant of Synechocystis sp. PCC 6803 at 77 K to study excitation energy transfer and trapping. By means of a simultaneous target analysis of the kinetics of isolated complexes and whole cells, the pathways and dynamics of energy transfer in vitro and in vivo were established. We establish that the timescale of the slowest equilibration between different terminal emitters in the phycobilisome is ≈800 ps. It was estimated that the terminal emitter in about 40% of the phycobilisomes transfers its energy with a rate constant of 42 ns-1 to PSI. This energy transfer rate is higher than the rates of equilibration within the phycobilisome - between the rods and the core or between the core cylinders - and is evidence for the existence of specific phycobilisome-PSI interactions. The rest of the phycobilisomes remain unconnected or slowly transferring energy to PSI.

Optimizing cognitive and behavioral approaches for perinatal depression: A systematic review and meta-regression analysis.

Cognitive behavioral therapies (CBT) have been demonstrated efficacious in treating perinatal depression (PND). This has been demonstrated in several meta-analyses of randomized controlled trials and quasi-experimental studies. However, there is a need for up-to-date meta-analytical evidence providing reliable estimates for CBT's effectiveness in treating and preventing PND. Furthermore, with the world moving toward precision medicine, approaches require a critical synthesis of psychotherapies, especially to unpack their mechanisms of action and to understand what approaches work best for whom. Therefore, the present systematic review and meta-regression analyses aim to answer these research questions. We searched six academic databases through February 2022 and identified 56 studies for an in-depth review. Using pretested data extraction sheets, we extracted patient-level and intervention-level characteristics and effect size data from each study. Random-effects meta-analyses and mixed-effect subgroup analyses were run to delineate the effectiveness and moderators of CBT interventions for PND, respectively. CBT-based interventions yielded a strong effect size (SMD = -0.74, 95% confidence interval [CI]: -0.91 to -0.56, n = 9,722) in alleviating depressive symptoms. These interventions were effective across different delivery formats (individual, group, and electronic) and could be delivered effectively by specialists and nonspecialists. Longer duration CBT interventions may not necessarily be more effective than shorter ones. Moreover, CBT-based interventions should consider including various behavioral ingredients to maximize intervention benefits.

Therapeutic Outcomes Following Isolated Transcatheter Tricuspid Valve Repair: A Systematic Review and Meta-analysis.

Tricuspid regurgitation (TR) is traditionally treated surgically, but isolated transcatheter tricuspid valve repair (ITTVR) offers a less invasive option. This study conducts a meta-analysis and systematic review to evaluate ITTVR outcomes in patients with TR. Database searches until March 2023 identified studies assessing ITTVR safety and efficacy in moderate/severe TR patients. Primary outcomes analyzed were severe TR, NYHA functional class improvement, and 6-minute walking distance. Meta-analyses used Risk ratio (RR) or mean difference with a random effects model. The review included 25 studies with 2421 patients. ITTVR improved NYHA functional class (RR: 3.262), reduced TR severity (RR: 0.303), and enhanced 6-minute walking distance (MD: +47.077 m). Echocardiographic parameters improved, including reductions in TR vena contracta, TR EROA, septolateral tricuspid annular diameter, RVEDD, RV FAC, and TAPSE. LVEF and PASP showed no significant changes. ITTVR improves functional outcomes and echocardiographic parameters in TR patients.

Long- and short-term acclimation of the photosynthetic apparatus to salinity in Chlamydomonas reinhardtii. The role of Stt7 protein kinase.

Salt stress triggers an Stt7-mediated LHCII-phosphorylation signaling mechanism similar to light-induced state transitions. However, phosphorylated LHCII, after detaching from PSII, does not attach to PSI but self-aggregates instead. Salt is a major stress factor in the growth of algae and plants. Here, our study mainly focuses on the organization of the photosynthetic apparatus to the long-term responses of Chlamydomonas reinhardtii to elevated NaCl concentrations. We analyzed the physiological effects of salt treatment at a cellular, membrane, and protein level by microscopy, protein profile analyses, transcripts, circular dichroism spectroscopy, chlorophyll fluorescence transients, and steady-state and time-resolved fluorescence spectroscopy. We have ascertained that cells that were grown in high-salinity medium form palmelloids sphere-shaped colonies, where daughter cells with curtailed flagella are enclosed within the mother cell walls. Palmelloid formation depends on the presence of a cell wall, as it was not observed in a cell-wall-less mutant CC-503. Using the stt7 mutant cells, we show Stt7 kinase-dependent phosphorylation of light-harvesting complex II (LHCII) in both short- and long-term treatments of various NaCl concentrations-demonstrating NaCl-induced state transitions that are similar to light-induced state transitions. The grana thylakoids were less appressed (with higher repeat distances), and cells grown in 150 mM NaCl showed disordered structures that formed diffuse boundaries with the flanking stroma lamellae. PSII core proteins were more prone to damage than PSI. At high salt concentrations (100-150 mM), LHCII aggregates accumulated in the thylakoid membranes. Low-temperature and time-resolved fluorescence spectroscopy indicated that the stt7 mutant was more sensitive to salt stress, suggesting that LHCII phosphorylation has a role in the acclimation and protection of the photosynthetic apparatus.

Fluorescence quenching in thylakoid membranes induced by single-walled carbon nanotubes.

The distinct photochemical and electrochemical properties of single-walled carbon nanotubes (SWCNTs) boosted the research interest in nanomaterial utilization in different in vivo and in vitro photosynthetic biohybrid setups. Aiming to unravel the yet not fully understood energetic interactions between the nanotubes and photosynthetic pigment-protein assemblies in an aqueous milieu, we studied SWCNT effects on the photochemical reactions of isolated thylakoid membranes (TMs), Photosystem II (PSII)-enriched membrane fragments and light-harvesting complexes (LHCII). The SWCNTs induced quenching of the steady-state chlorophyll fluorescence in the TM-biohybrid systems with a corresponding shortening of the average fluorescence lifetimes. The effect was not related to changes in the integrity and macroorganization of the photosynthetic membranes. Moreover, we found no evidence for direct excitation energy exchange between the SWCNTs and pigment-protein complexes, since neither the steady-state nor time-resolved fluorescence of LHCII-biohybrid systems differed from the corresponding controls. The attenuation of the fluorescence signal in the TM-biohybrid systems indicates possible leakage of photosynthetic electrons toward the nanotubes that most probably occurs at the level of the PSII acceptor site. Although it is too early to speculate on the nature of the involved electron donors and intermediate states, the observed energetic interaction could be exploited to increase the photoelectron capture efficiency of natural biohybrid systems for solar energy conversion.

Energy transfer from phycobilisomes to photosystem I at room temperature.

The phycobilisomes function as the primary light-harvesting antennae in cyanobacteria and red algae, effectively harvesting and transferring excitation energy to both photosystems. Here we investigate the direct energy transfer route from the phycobilisomes to photosystem I at room temperature in a mutant of the cyanobacterium Synechocystis sp. PCC 6803 that lacks photosystem II. The excitation dynamics are studied by picosecond time-resolved fluorescence measurements in combination with global and target analysis. Global analysis revealed several fast equilibration time scales and a decay of the equilibrated system with a time constant of ≈220 ps. From simultaneous target analysis of measurements with two different excitations of 400 nm (chlorophyll a) and 580 nm (phycobilisomes) a transfer rate of 42 ns-1 from the terminal emitter of the phycobilisome to photosystem I was estimated.

Ultrafast Excitation Energy Transfer Dynamics in the LHCII-CP29-CP24 Subdomain of Plant Photosystem II.

We measure the two-dimensional electronic spectra of the LHCII(M)-CP29-CP24 complex in photosystem II (PSII) and provide the first study of the ultrafast excitation energy transfer (EET) processes of an asymmetric and native light-harvesting assembly of the antenna of PSII. With comparisons to LHCII, we observe faster energy equilibrations in the intermediate levels of the LHCII(M)-CP29-CP24 complex at 662 and 670 nm. Notably, the putative "bottleneck" states in LHCII exhibit faster effective dynamics in the LHCII(M)-CP24-CP29 complex, with the average lifetime shortening from 2.5 ps in LHCII to 1.2 ps in the bigger assembly. The observations are supported by high-level structure-based calculations, and the accelerated dynamics can be attributed to the structural change of LHCII(M) in the bigger complex. This study shows that the biological functioning structures of the complexes are important to understand the overall EET dynamics of the PSII supercomplex.

Ultrafast excitation quenching by the oxidized photosystem II reaction center.

Photosystem II (PSII) is the pigment-protein complex driving the photoinduced oxidation of water and reduction of plastoquinone in all oxygenic photosynthetic organisms. Excitations in the antenna chlorophylls are photochemically trapped in the reaction center (RC) producing the chlorophyll-pheophytin radical ion pair P+ Pheo-. When electron donation from water is inhibited, the oxidized RC chlorophyll P+ acts as an excitation quencher, but knowledge on the kinetics of quenching is limited. Here, we used femtosecond transient absorption spectroscopy to compare the excitation dynamics of PSII with neutral and oxidized RC (P+). We find that equilibration in the core antenna has a major lifetime of about 300 fs, irrespective of the RC redox state. Two-dimensional electronic spectroscopy revealed additional slower energy equilibration occurring on timescales of 3-5 ps, concurrent with excitation trapping. The kinetics of PSII with open RC can be described well with previously proposed models according to which the radical pair P+ Pheo- is populated with a main lifetime of about 40 ps, which is primarily determined by energy transfer between the core antenna and the RC chlorophylls. Yet, in PSII with oxidized RC (P+), fast excitation quenching was observed with decay lifetimes as short as 3 ps and an average decay lifetime of about 90 ps, which is shorter than the excited-state lifetime of PSII with open RC. The underlying mechanism of this extremely fast quenching prompts further investigation.

Trimeric photosystem I facilitates energy transfer from phycobilisomes in Synechocystis sp. PCC 6803.

In cyanobacteria, phycobilisomes (PBS) serve as peripheral light-harvesting complexes of the two photosystems, extending their antenna size and the wavelength range of photons available for photosynthesis. The abundance of PBS, the number of phycobiliproteins they contain, and their light-harvesting function are dynamically adjusted in response to the physiological conditions. PBS are also thought to be involved in state transitions that maintain the excitation balance between the two photosystems. Unlike its eukaryotic counterpart, PSI is trimeric in many cyanobacterial species and the physiological significance of this is not well understood. Here, we compared the composition and light-harvesting function of PBS in cells of Synechocystis sp. PCC 6803, which has primarily trimeric PSI, and the ΔpsaL mutant, which lacks the PsaL subunit of PSI and is unable to form trimers. We also investigated a mutant additionally lacking the PsaJ and PsaF subunits of PSI. Both strains with monomeric PSI accumulated significantly more allophycocyanin per chlorophyll, indicating higher abundance of PBS. On the other hand, a higher phycocyanin:allophycocyanin ratio in the wild type suggests larger PBS or the presence of APC-less PBS (CpcL-type) that are not assembled in cells with monomeric PSI. Steady-state and time-resolved fluorescence spectroscopy at room temperature and 77 K revealed that PSII receives more energy from the PBS at the expense of PSI in cells with monomeric PSI, regardless of the presence of PsaF. Taken together, these results show that the oligomeric state of PSI impacts the excitation energy flow in Synechocystis.

Two-Dimensional Electronic Spectroscopy of a Minimal Photosystem I Complex Reveals the Rate of Primary Charge Separation.

Photosystem I (PSI), found in all oxygenic photosynthetic organisms, uses solar energy to drive electron transport with nearly 100% quantum efficiency, thanks to fast energy transfer among antenna chlorophylls and charge separation in the reaction center. There is no complete consensus regarding the kinetics of the elementary steps involved in the overall trapping, especially the rate of primary charge separation. In this work, we employed two-dimensional coherent electronic spectroscopy to follow the dynamics of energy and electron transfer in a monomeric PSI complex from Synechocystis PCC 6803, containing only subunits A-E, K, and M, at 77 K. We also determined the structure of the complex to 4.3 Å resolution by cryoelectron microscopy with refinements to 2.5 Å. We applied structure-based modeling using a combined Redfield-Förster theory to compute the excitation dynamics. The absorptive 2D electronic spectra revealed fast excitonic/vibronic relaxation on time scales of 50-100 fs from the high-energy side of the absorption spectrum. Antenna excitations were funneled within 1 ps to a small pool of chlorophylls absorbing around 687 nm, thereafter decaying with 4-20 ps lifetimes, independently of excitation wavelength. Redfield-Förster energy transfer computations showed that the kinetics is limited by transfer from these red-shifted pigments. The rate of primary charge separation, upon direct excitation of the reaction center, was determined to be 1.2-1.5 ps-1. This result implies activationless electron transfer in PSI.

Effectiveness of a technology-assisted, family volunteers delivered, brief, multicomponent parents' skills training intervention for children with developmental disorders in rural Pakistan: a cluster randomized controlled trial.

BACKGROUND: Globally, there is a large documented gap between needs of families and children with developmental disorders and available services. We adapted the World Health Organization's mental health Gap-Intervention Guidelines (mhGAP-IG) developmental disorders module into a tablet-based android application to train caregivers of children with developmental disorders. We aimed to evaluate the effectiveness of this technology-assisted, family volunteers delivered, parents' skills training intervention to improve functioning in children with developmental disorders in a rural community of Rawalpindi, Pakistan. METHODS: In a single-blinded, cluster randomized controlled trial, 30 clusters were randomised (1:1 ratio) to intervention (n = 15) or enhanced treatment as usual (ETAU) arm (n = 15). After screening, 540 children (18 participants per cluster) aged 2-12 years, with developmental disorders and their primary caregivers were recruited into the trial. Primary outcome was child's functioning, measured by Childhood Disability Assessment Schedule for Developmental Disorders (DD-CDAS) at 6-months post-intervention. Secondary outcomes were parents' health related quality of life, caregiver-child joint engagement, socio-emotional well-being of children, family empowerment and stigmatizing experiences. Intention-to-treat analyses were done using mixed-models adjusted for covariates and clusters. RESULTS: At 6-months post-intervention, no statistically significant mean difference was observed on DD-CDAS between intervention and ETAU (mean [SD], 47.65 [26.94] vs. 48.72 [28.37], Adjusted Mean Difference (AMD), - 2.63; 95% CI - 6.50 to 1.24). However, parents in the intervention arm, compared to ETAU reported improved health related quality of life (mean [SD] 65.56 [23.25] vs. 62.17 [22.63], AMD 5.28; 95% CI 0.44 to 10.11). The results were non-significant for other secondary outcomes. CONCLUSIONS: In the relatively short intervention period of 6 months, no improvement in child functioning was observed; but, there were significant improvements in caregivers' health related quality of life. Further trials with a longer follow-up are recommended to evaluate the impact of intervention. Trial registration Clinicaltrials.gov, NCT02792894. Registered April 4, 2016, https://clinicaltrials.gov/ct2/show/NCT02792894.