Sc aggregates, has provided a very promising tool to improve the early diagnosis of human prion diseases. Over the decade since RT–QuIC was introduced, the diagnosis of not only prion diseases but also synucleinopathies and tauopathies has greatly improved. Therefore, in our study, we summarize the current trends and knowledge of RT–QuIC assays, as well as discuss the diagnosis of neurodegenerative diseases using RT–QuIC assays, which have been updated in recent years.The misfolding of proteins such as the prion protein, α-synuclein, and tau represents a key initiating event for pathogenesis of most common neurodegenerative disorders, and its presence correlates with infectivity. To date, the diagnosis of these disorders mainly relied on the recognition of clinical symptoms when neurodegeneration was already at an advanced phase. In recent years, several efforts have been made to develop new diagnostic tools for the early diagnosis of prion diseases. The real-time quaking-induced conversion (RT–QuIC) assay, an in vitro assay that can indirectly detect very low amounts of PrP Neurodegenerative diseases are characterized by the accumulation of disease-related misfolded proteins. Protein misfolding diseases such as prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and related misfolded prion protein (PrP), tauopathies, and synucleinopathies represent a major disease burden on society.Sc). It is accepted that PrPSc formation is the key initiating event in prion disease pathogenesis. As such, PrPSc is also the most widely used diagnostic surrogate marker for affected individuals and animals.Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of progressive neurodegenerative disorders. Human prion diseases (HBD) include Creutzfeldt-Jakob disease (CJD), fatal insomnia, Gerstmann-Sträussler-Scheinker syndrome, kuru, and variably protease-sensitive prionopath. The hallmark event in prion disorders associated with the deposition of misfolded forms of the prion protein  assays which can detect a small of prion seeding activity to exponentially amplify from various biopsies with high sensitivity and specificity. After more than a decade of the advent and development of the RT–QuIC assays ,9, it haIn our review, we summarize the trends in the development of RT–QuIC assays in recent years, applying RT–QuIC assays not only for the diagnosis of prion disease but also for other neurodegenerative diseases.Sc). Thus, the gold standard of diagnosis for prion disease is detected proteinase K-resistant prion protein (PrPSc). Like amyloid fibers found in Alzheimer’s and other amyloid-related disorders or tau aggregation in tauopathies, PrPSc is a variable polymer that can aggregate large fiber. The immune assay cannot distinguish between PrP and PrPSc because the distinguishing antibodies are not available. Western blotting (WB) can provide valuable information about the biochemical properties of PrPSc, but its detection range is narrow and unsuitable for evaluating the decontamination of prion seeds [Resistance to proteinase K (PK) digestion is considered a definition of the transmissible isoform of the prion protein  and RT–QuIC are the two most commonly used PrPC. These methods could successfully diagnose variant Creutzfeldt–Jakob disease (vCJD) using samples from the brain and peripheral tissues such as the spleen and tonsil [C, and even recombinant PrP produced in bacteria [PMCA was first described in 2001 , in whicd tonsil  and biold tonsil . PMCA cabacteria . Sc in the brains of sporadic CJD (sCJD) patients [However, the PMCA method only detects the prion seeding activity in the variant in CJD. About 10 years later, a new technique was introduced, the “quaking-induced conversion” (QuIC), which improves the speed and practicality by using recombinant bacterial-expressed PrPC (rPrPc) and by replacing shake for sonication . Moreovepatients ,23, PMCART–QuIC detects limited amounts of abnormal proteins. It is highly sensitive and specific in various specimens in the central and peripheral nervous systems but is not successful in samples containing blood, including whole blood, blood plasma, or blood-contaminated tissues. Previous studies have suggested that red blood cells in the Cerebrospinal fluid (CSF) sample inhibit the RT–QuIC response ,25. A cu14-fold dilutions and contains less than ~1 ag of PrPRes vCJD brain homogenates in human plasma, so it was around 104 times more sensitive than in the previous study. However, the assay was difficult to standardize and less reproducible than the standard RT–QuIC (given that eQuIC is significantly more sensitive than the RT–QuIC). Therefore, an adaptation of RT–QuIC, called e-QuIC, was developed . The stuAlthough there have been significant advances in recent years, the sensitivity and speed of first-generation RT–QuIC assays need to improve. One major advance has been developing a second-generation RT–QuIC assay using the N-terminally truncated Syrian hamster rPrP (SHarPrP (90–231)), comprising 0.002% sodium dodecyl sulfate (SDS) in the buffer solution and using a reaction temperature increased to 55 °C . The iniNeurodegenerative diseases are complex, multifactorial, and heterogeneous diseases that are identified by the accumulation of misfolded proteins in the brain. Many neurodegenerative diseases are associated with the accumulation of specific misfolded proteins.RT–QuIC was first successful in the diagnosis of human prion disease. It is highly accurate in identifying misfolded forms of prion proteins from the CSF of patients with CJD and has already been included in the diagnostic criteria of sporadic CJD, the most common human prion disease . The larUsing these first-generation assays, RT–QuIC was shown to have a sensitivity of 77–89% and a specificity around 100% ,34,35,36The presence of PrPSc in olfactory mucosa (OM)has been mentioned by many previous studies. 50 of digestive tissues reaching >106–8/g [A previous study showed that second-generation RT–QuIC helped to increase the diagnositic sensitivity and speed. These results were confirmed in a large study , which s>106–8/g .PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), or Lewy body dementia, are synucleinopathies caused by the abnormal accumulation of protein aggregates called α-synuclein in the brain. Outside prion RT–QuIC assays, α-synuclein RT–QuIC is the most developed RT–QuIC (α-synuclein RT–QuIC) seed amplification platform to aid in premortem diagnosis, largely using CSF specimens.Despite being developed in the last five years, αSyn RT–QuIC assays have been adapted for a range of diagnostically relevant human biospecimens, including the brain and CSF, olfactory mucosa, submandibular gland, and skin. It has previously been shown that α-synuclein can be detected in the brain and biological fluids such as CSF and serum ,53,54,55The first successful use of α-syn RT–QuIC was applied to detect α-synuclein aggregation in the brain and CSF from dementia with LB and PD patients. The results gave the sensitivities of 92% and 95%, with an overall specificity of 100%. Patients with tauopathies showed negative results. In particular, they found that three iRBD patients also had a positive RT–QuIC response, suggesting that the method could be used as an early diagnostic of synucleinopathy .A comparably more rapid α-syn RT–QuIC was developed, which demonstrated assay times of 1–2 days  comparedRT–QuIC assay application to the largest cohort of CSF samples has been examined. The method accurately detected α-synuclein seeding activity, including DLB, PD, iRBD, and PAF, with a sensitivity of 95.3%. In contrast, in samples of MSA patients, the assays gave no α-synuclein seeding activity, showing that MSA and LBD are associated with different conformational strains of α-synuclein. The study also showed 98% specificity in a neuropathological cohort of 101 cases lacking LB pathology .A recent study applied the RT–QuIC assays to detect CSF α-synuclein with the isolated rapid-eye-movement sleep behavior disorder. With 52 isolate REM sleep behavior disorder (iRBD) and 9 controls, the results showed that the sensitivity was 90% and the specificity was 78%. During follow-up, 32 (61.5%) patients were diagnosed with PD or DLB 3.4 ± 2.6 years after LP, and 31 (96.9%) of these were positive for CSF α-synuclein in the RT–QuIC, while none of the controls developed synucleinopathy .Some studies using the RT–QuIC assays to detect α-syn on peripheral tissues ,50,56,57Diseases involving tau pathology include those with preferential aggregation of 3 microtubule binding-repeat (3R), 4-repeat (4R), or both 3R and 4R (3R/4R) tau isoforms. The predominant 3R tau isoforms can be seen in In Pick disease (PiD). The 3R and 4R isoforms are deposited in AD. 4R tauopathies include corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), globular glial tauopathy (GGT), and argyrophilic grain disease (AGD).It has previously been shown that the Aβ and tau PMCA/RT–QuIC may work in diagnosing AD by distinguising between AD patients and other neurodegenerative disorders or controls by protein misfolding cyclic amplification assay (Ab-PMCA) with more than 90% of sensitivity and specificity using cerebrospinal fluid . AD RT–Q−7–10−9; PiD seeding activities were 100-fold higher in the frontal and temporal lobes than in the cerebellar cortex [The main success of tau RT–QuIC assay based on the seeded polymerization is that it can detect and distinguish PiD from other tauopathies, neurological diseases, and healthy controls. This method could detect the tau of seeding activity in 2 µL aliquots of PiD brain dilutions down to 10r cortex .Further developments in tau assay have resulted from the advent of AD RT–QuIC, which is the first RT–QuIC 3R/4R tau test to detect tau fibers in AD and chronic traumatic encephalopathy (CTE) from brain tissue, known as AD RT–QuIC . The met3–106-fold sensitivity. 4R RT–QuIC analysis of postmortem CSF of the PSP and CBD CSFs each had sensitivities of 100%, while 0/7-unaffected controls were positive, giving a diagnostic specificity of 100%. However, 4R RT–QuIC analysis of CSF had 69% and 50% of positive reactions for PSP and CBD/CBS, respectively [In the latest study, a group of a tau RT–QuIC for 4R tauopathies have been developed, specifically PSP, CBD, and FTDP-17 MAPT. This assay could detect disease-associated subtypes of 4R tau seeds as indicated by differences in their conformational templating of the fibrillar tau products of 4R RT–QuIC. Moreover, this study showed that the tau RT–QuIC assay can detect tau seeding activity in CSF collected from living patients. 4R RT–QuIC can detect 4R seeds in the brain tissue with up to 10ectively .Although only a short development, tau RT–QuIC has also had considerable success in diagnosing different types of taupathies with high sensitivity and specificity .Over the last 10 years, the RT–QuIC assay has gained significant attention among the available laboratory aids for the clinical diagnosis of neurodegenerative disorders. Although there are still certain limitations, RT–QuIC has become the most effective tool for the in vivo diagnosis of not only prion diseases but also synucleinopathies and tauopathies. Moreover, the advances in RT–QuIC also help direct valuable research for the early diagnosis and treatment of most of these devastating disorders.


Background: Loneliness has been associated with adverse health outcomes, including increased mortality risk. Interventions aimed at addressing maladaptive social cognition have documented efficacy in reducing loneliness among older adults. Purpose: The purpose of this study was to determine the feasibility and efficacy of a web-based wellness program in reducing loneliness and improving psychosocial health among older adults with an AARP® Medicare Supplement plan insured by UnitedHealthcare Insurance Company. Methods: Eligible individuals were 65 years and older, who self-identified as lonely on a prior survey, and indicated that they had access to the internet through a computer or smartphone. Participants completed up to eight online modules comprised of a short lesson on an aspect of maladaptive social cognition, followed by a comprehension quiz, selection of a short-term goal, and a phone or text chat with a program coach. Four surveys were administered to assess the effects of program participation: (1) prior to the start of the program, (2) after completion of four online modules, (3) after completion of all eight modules, and (4) 30-60 days later. Results: Attrition was high. Overall, 220 (42%) program participants completed both T1/T2 surveys, 193 also completed a T3 survey, and 177 also completed a T4 survey. Post-survey data indicated that loneliness and perceived stress decreased while mental wellbeing, resilience, and perception of aging improved. Conclusion: Digital interventions aimed at addressing maladaptive social cognition offer potential to reach lonely older adults and support psychosocial wellbeing through reduced loneliness.


Since the endobronchial ultrasound bronchoscope was introduced to clinical practice, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become the procedure of choice to sample hilar and mediastinal adenopathy. Multiple studies have been conducted in the last two decades to look at the different technical aspects of the procedure and their effects on the final cytopathological yield. In addition, newer modes of ultrasound scanning and newer tools with the potential to optimize the selection and sampling of the target lymph node have been introduced. These have the potential to reduce the number of passes, reduce the procedure time, and increase the diagnostic yield, especially in rare tumors and benign diseases. Herein, we review the latest updates related to the technical aspects of EBUS-TBNA and their effects on the final cytopathological yield in malignant and benign diseases. Over the last two decades, there have been major developments in our ability to sample mediastinal and peribronchial structures. We have come a long way from the initial use of transbronchial needle aspiration (TBNA) for sampling through a rigid bronchoscope in 1949, to Wang et al. introducing TBNA through flexible bronchoscopy in 1983. Endobronchial ultrasound (EBUS) with real-time visualization of mediastinal structures was first employed in 1992 [Multiple studies have evaluated different components of the EBUS-TBNA procedure to optimize the pathological yield and eliminate unnecessary steps while reducing the time and complications. Newer ultrasound modes and many bronchoscopic tools have been introduced to optimize the selection of the lymph node and the collection of cytological and histological material.In this article, we aim to review the latest updates related to the technical performance of EBUS-TBNA and describe how emergent data can affect its diagnostic yield in lung cancer. In addition, we discuss the utility of EBUS-TBNA in the diagnosis of lymphoma and sarcoidosis.EBUS-TBNA is usually performed in the endoscopy suite under moderate sedation (MS), deep sedation, or general anesthesia (GA) . The choThe optimal needle size has been a subject of interest for interventional pulmonologists since the introduction of EBUS-TBNA. The factors that need to be considered are the ability to acquire satisfactory specimens to establish the diagnosis without increasing the side effects. The current literature supports the use of 21 G or 22 G needles, as no difference in specimen adequacy or diagnostic yield was found between the two sizes .When compared with the 22 G needle in sampling the same LN, the 25 G needle had a similar diagnostic yield for malignancy. The histology specimens containing malignant cells and the number of malignant cells were significantly higher in the 22 G compared with the 25 G needle, and no difference in complications was seen ,8. OtherMoreover, when the 22 G was compared with the larger 19 G needle in sampling the same LN in an alternating manner, there was no improvement in the overall diagnostic yield. However, more bloody passes and lower sample adequacy were observed with the 19 G needle aspirates . Similar2, p = 0.02) [In a prospective analysis of 83 EBUS-TBNA samples obtained from 47 patients, sampling of the same LN with 19 G and 21 G needles showed more cellular material based on the cell area in the cell block obtained with the 19 G compared with the 21 G (7.34 vs. 5.23 mm = 0.02) . In a pr = 0.02) . HoweverConversely, in a retrospective single-center study, Jones et al. found a higher proportion of lymphoma  and benign disease  in LN sampled with the 19 G, 21 G, and 22 G, respectively. The 19 G needle was observed to be superior to both 21 G and 22 G in subclassifying malignant diseases, with lower rates of NSCLC-NOS , and it reduced the need for invasive mediastinoscopy .Although studies comparing different needle sizes did not show any statistically significant differences in diagnostic yield, we cannot exclude that a small difference may exist, especially as some of these studies were underpowered to detect a difference, had a retrospective design, and may not have tested different needles on the same lymph nodes .EBUS-TBNA has traditionally been performed with the needle advanced and with a stylet occluding the needle until the lymph node is accessed under EBUS guidance. A 20 cm suction is then applied, and aspiration is done by moving the needle in the lymph node 10 to 20 times. The addition of suction has not been shown to improve the diagnostic yield or sample adequacy when compared with lower suction of 10 cm or no suction at all ,17,18.In a randomized controlled trial, Lin et al. evaluated the diagnostic yield of malignancy and the specimen adequacy of using suction and a stylet, suction with no stylet, and stylet with no suction. Each LN was sampled with the three methods using a 22 G needle. There were no significant differences among the groups in specimen adequacy rate or diagnostic yield of malignancy, although using suction increased the tissue-core acquisition rate compared with the no suction group .Fanning is a technique employed by endoscopists to influence the diagnostic yield of a procedure. It consists of sampling multiple areas within a lymph node in each pass by altering the angle of the needle with each subsequent agitation during a pass. This was shown to be superior in EUS-FNA of pancreatic lesions , but no ® 22 G FNB needle, Boston Scientific Co., Natick, MA, USA) , FNB had better histological samples in fewer attempts [Core biopsy specimens can also be obtained via EBUS. These samples involve the use of a Franseen tip 22 G fine needle biopsy (FNB) device equipped with three cutting edges  A–C. In aattempts .® needle from Cook Medical  is designed to provide a core of histological tissue in contrast to the cytological specimens from standard fine needle aspirations. It comes in two sizes, 22 G and 25 G. It has a reverse bevel that aims to collect a core histological sample by shearing material from the lesion during retrograde motion . Additional sampling methods such as mediastinoscopy and CT-guided FNA were obtained in 30% of patients who underwent standard EBUS-TBNA versus 15% of those who had EBUS core biopsy (p = 0.006) [In a retrospective study comparing 110 patients who had an EBUS using a 22 G needle with 125 patients who had an EBUS using the ProCore= 0.006) .A histological sampling of the lymph node can be done via mini-biopsy forceps, which is introduced through the initial hole made by the TBNA needle A–D.p = 0.001) and lymphoma . No complications occurred [Herth et al. evaluated the role of transbronchial forceps biopsy (TBFB) in 75 patients without known or suspected NSCLC. Specimens were acquired from subcarinal lymph nodes larger than 2.5 cm. Sampling was done with a 22 G needle, 19 G needle, and a 1.15 mm  mini-forceps with a cup opening of 7.3 mm. A diagnosis was obtained in 36%, 49%, and 88% of the cases while using the 22 G needle, 19 G needle, and the mini-forceps, respectively. The mini-forceps diagnostic yield compared with the needle was the highest in patients with sarcoidosis , with no additional complications .In a retrospective study of 91 patients who had a forceps biopsy with EBUS-TBFB after a non-diagnostic rapid on-site evaluation (ROSE), no difference was seen in the overall diagnostic yield of TBNA versus TBFB. Out of the non-diagnostic TBNA samples on rapid on side evaluation (ROSE) and cell block, subsequent TBFB sampling resulted in additional pathological diagnosis in 16% of the cases; 67% of these were non-caseating granulomas. No complications were reported .p < 0.00001), the diagnostic yield for sarcoidosis was 93% vs. 58% (p < 0.00001), and the diagnostic yield for lymphoma was 86% vs. 30% (p = 0.03). Pneumomediastinum occurred in 1%, pneumothorax in 1%, and bleeding in 0.8% of the patients [A meta-analysis of six observational studies included 443 patients in whom TBFB was performed after the initial EBUS-TBNA. Comparing EBUS-TBNA + EBUS-TBFB vs. EBUS-TBNA alone, the pooled overall diagnostic yield was 92% vs. 67%  with an outer diameter of 1.15 mm and a cup opening of 7.3 mm , the BosIn summary, EBUS-TBFB appears to be complimentary to EBUS-TBNA and can be used when additional tissue is needed for molecular marker studies and in the diagnosis of lesions when the initial sampling with EBUS-TBNA is inadequate or non-diagnostic.p = 0.001) and benign disorders . The diagnostic yield was similar in malignant lymphadenopathy. Two cases of pneumothorax and one case of pneumomediastinum were reported [A histological sampling of the lymph node has been reported with the use of a 1.1 mm cryobiopsy probe placed in the same hole created by the TBNA with a 3 sec freeze time before pulling the probe out. The specimen is thawed in saline and fixed in formalin . In a prreported .Pathological processes make the tissue harder compared with the normal surrounding structure. Elastography is a recent modality that allows the calculation and visualization of tissue elasticity during EBUS. Data are converted into an RGB  color image where hard tissue is shown in blue, medium tissue in green, and soft tissue in red . The imaQuantitative elastography data can also be produced by measuring the strain ratio (SR) of the lesion compared with the normal surrounding tissue. Malignant lymph nodes have a higher SR. An SR > 2.5 had a 100% sensitivity for predicting malignant lymph nodes .A meta-analysis of 17 studies for differentiating benign versus malignant adenopathy found a pooled sensitivity of 0.90 , 0.84–0.94) and specificity of 0.78  , suggestp = 0.003) and the rate of a suspicious specimen on cytology and non-diagnostic specimen in pathology was significantly lower compared with the non-ROSE group [ROSE of EBUS-TBNA samples allows for the rapid evaluation of the adequacy of the sample and a preliminary diagnosis before the specimen is completely evaluated. ROSE helps in assessing the adequacy of the sample, determining the need for additional molecular testing, and potentially decreasing the number of procedural sites. Multiple studies have been performed to compare the utility of ROSE for EBUS-TBNA samples ,40,41,42SE group . AnotherSE group .Overall, ROSE is a helpful tool to optimize the preparation of the specimen and evaluate the adequacy of lymph node sampling. It may help in increasing the diagnostic yield and avoiding repeated procedures  without affecting the total time of the procedure .Currently, there are no defined standardized criteria to determine the adequacy of a sample obtained with EBUS. In general, a sample is considered adequate when a diagnosis is made, such as granuloma or malignancy even in the absence of lymphoid tissue, or if sufficient benign lymphoid tissue is present .Nayak et al. defined an adequate sample as any smear that contains more than 5 fields with at least 100 lymphocytes per low-power field (×100) in a smear PLUS less than 2 groups of bronchial cells per low-power field (×100), or the presence of germinal center fragments, irrespective of the above-mentioned criteria . In addiCell block is a technique to preserve gross pathological specimens using paraffin blocks for histopathological analysis. It allows for the evaluation of cytological architecture and immunochemical staining, thereby allowing for better characterization of the malignancy . Cell blThe identification of predictive malignant cell biomarkers in NSCLC has enabled targeted therapies to be utilized for better patient outcomes . TestingALK fluorescence in situ hybridization [In a retrospective study from 2013 of 85 patients who underwent EBUS-TBNA, Yarmus et al. showed that a minimum of four passes per lymph node station is required to provide an adequate amount of specimen when advanced molecular marker analysis is limited to EGFR, KRAS sequencing, and dization . With thdization .EBUS-TBNA can provide adequate DNA sampling for next-generation sequencing (NGS). The amount of DNA needed for this modality depends on the NGS technique used. Cho et al. found the average total DNA amount from EBUS sampling to be 1971 ng with a range of 100 ng to 10,340 ng .In general, the adequacy of EBUS-TBNA for molecular analysis depends on the sample size, cellularity, tumor cell fraction in the samples, the presence of contaminants such as blood or bronchial cells, and the sensitivity of the molecular testing platform ,55. TrisOverall, the recent literature shows that lymph node sampling via EBUS-TBNA can provide enough material at least 92% of the time for a complete genomic test, which included several biomarkers by NGS and nCounter , and morEBUS-TBNA is a relatively safe procedure for the evaluation of mediastinal/hilar lymphadenopathy, with a reported diagnostic yield of up to 90% . That yiIn one of the largest studies, which included 75 patients with a final diagnosis of lymphoma, EBUS-TBNA was able to establish a diagnosis in 84% of the patients and was able to subtype lymphoma in 67% of de novo cases and in 81% of the relapsed cases . The lowp = 0.03) [While EBUS-TBNA can be the first diagnostic modality, EBUS-TBFB and EBUS core biopsies might be able to provide larger histopathological tissue to help in subtyping lymphoma ,28. In o = 0.03) .Flow cytometry is of particular importance in the immunological phenotyping of lymphomas . Since dEBUS-TBNA is the first choice for pathological confirmation of sarcoidosis . It has In a prospective study of 109 patients who underwent EBUS-TBNA for suspected stages I and II sarcoidosis, the cumulative yields for detecting non-caseating granulomas through the first, second, third, fourth, fifth, and sixth passes for the main target lesion were 63%, 75%, 82%, 85%, 86%, and 88%, respectively. The increase was statistically significant up to pass #4 . A higheProcedurally, the most common endosonographic findings from sarcoidosis lymph nodes include the presence of a homogeneous texture, oval shape, a conglomeration of lymph nodes ,76, distp < 0.00001) in one meta-analysis of 443 patients [There was no difference in the diagnostic yield in relation to needle size (22 G vs. 25 G , or 21 Gpatients .EBUS-TBNA remains the first-line minimally invasive test to evaluate mediastinal and hilar adenopathy. Since its introduction, the procedure has been refined to eliminate unnecessary steps and reduce the procedure time while optimizing the diagnostic yield. In areas where no difference between the different techniques was found, larger high-quality randomized controlled trials are recommended. In addition to providing nodal staging, EBUS-TBNA allows the acquisition of molecular markers that are essential in guiding the choice of therapy in patients with non-small cell lung cancer. It also provides an excellent diagnostic yield in stages I and II sarcoidosis. Newer tools such as core needles and mini-forceps are now available, and they appear to increase the histopathological specimen size and possibly the diagnostic yield in patients with lymphoma and benign diseases, therefore reducing the need for more invasive interventions such as mediastinoscopy.


N-glycosylation on these molecules are also summarized. With the increasing information of structure–function relationships, IgA- and IgM-based monoclonal antibodies will be an effective option in the therapeutic field.Immunoglobulin G (IgG) is currently the most studied immunoglobin class and is frequently used in antibody therapeutics in which its beneficial effector functions are exploited. IgG is composed of two heavy chains and two light chains, forming the basic antibody monomeric unit. In contrast, immunoglobulin A (IgA) and immunoglobulin M (IgM) are usually assembled into dimers or pentamers with the contribution of joining (J)-chains, which bind to the secretory component (SC) of the polymeric Ig receptor (pIgR) and are transported to the mucosal surface. IgA and IgM play a pivotal role in various immune responses, especially in mucosal immunity. Due to their structural complexity, 3D structural study of these molecules at atomic scale has been slow. With the emergence of cryo-EM and X-ray crystallographic techniques and the growing interest in the structure-function relationships of IgA and IgM, atomic-scale structural information on IgA-Fc and IgM-Fc has been accumulating. Here, we examine the 3D structures of IgA and IgM, including the J-chain and SC. Disulfide bridging and  N-linked glycans have been partially solved, and these should help gain a greater understanding of the role of N-glycan modifications in the functions of IgM and IgA.Immunoglobulins (Igs) are categorized into several classes , and all play an invaluable role in the immune response to pathogens. Natural IgG is a monomer composed of two heavy chains and two light chains. This simple structure allows relatively easy expression and purification. IgG is the most studied immunoglobin class and is frequently used in antibody therapeutics. In contrast, IgA was initially considered to be a non-inflammatory antibody for the maintenance of mucosal homeostasis . It has H, Cα1, Cα2, and Cα3), while the light chains are divided into two domains (VL and CL) .,22.α aremultimer ,24,25.N-linked glycosylation sites of the tailpiece are well conserved [N-linked glycosylation sites, Asn263 in Cα2 and Asn459 in the tail piece. Asn263 has mostly biantennary complex-type glycan with α2-6-linked sialic acids, while Asn459 is dominated by triantennary glycan with α2-6 and α2-3-linked sialic acids [N-linked glycans at Asn263 in Cα2 are located on the outer surface of Fc to avoid potential instability caused by considerable surface exposure of the unpaired Cα2 structural domain [N-glycan attached on Asn263 does not impact IgA binding to FcαR1 [N-linked glycan mediate antiviral activity [N-glycosylation sites (Asn166 in the Cα1 and Asn337 in the Cα2), and IgA2m(2) has an additional N-linked glycan at Asn211 in the Cα1 domain. These additional sites attach more neutralizing glycans, which creates a greater proinflammatory response of neutrophils and macrophages [Amino acid sequences of IgA show significant species differences in mammals and birds; however, onserved . Both isic acids ,28. N-lil domain ,29. Receto FcαR1 , consistto FcαR1 ,32. Asn4to FcαR1 . The glyactivity ,33. The activity . Human Irophages ,34,35,36H, Cμ1, Cμ2, Cμ3, and Cμ4) and two light chains with two domains . The heavy chains are covalently linked with an inter-chain disulfide bond Cys337–Cys337, and each light chain is bonded to Cys136 in the heavy chain (μ3) and Cys474–Cys536 (Cμ4). According to the sequence alignment, Cμ1, Cμ3, and Cμ4 of IgM are equivalent to the Cγ1, Cγ2, and Cγ3 of IgG. Cμ2 of IgM is an additional constant domain that corresponds to the hinge region of IgG, providing the flexibility necessary for binding to antigens on cell surfaces. Cys414 of the Cμ3 domain is essential for IgM polymerization and can form an inter-monomeric disulfide bond with the Cys414 of an adjacent monomer. Like IgA, there is a tailpiece with a short 18 amino acid peptide sequence at the C-terminus of the heavy chain. The Cys575–Cys575 disulfide bond in the tailpieces is critical for IgM polymerization. Five IgM monomers are linked by disulfide bonds to each other and to the J-chain to form a pentamer, while the J-chain is absent in the IgM hexamer [Immunoglobulin M (IgM) is another abundant antibody subclass active in human mucosal immunity, providing the first line of defense against pathogens ,37. The vy chain . Every F hexamer ,41,42,43μ units are arranged in almost perfect hexagonal symmetry with a 61° gap occupied by the J-chain, and a triangular SC perpendicularly docked to the Fcμ-J near-planar structure to form secretory IgM (sIgM) [μ3–Cμ4 and the tailpiece play important roles in the formation of IgM pentamers. Two neighboring Cμ3–Cys414 form interchain disulfide bonds, and two neighboring IgM-Cμ4 domains interact with each other by their FG loops (a loop between F and G strands). Ten tailpieces are arranged into two five-stranded parallel β-sheets. The two β-sheets stack together in an antiparallel fashion, which is critical for IgM pentamer stability. Cys575 residues of two adjacent Fcμ form a disulfide bond and Cys575 on the side of the hexagonal gap is linked to the J-chain, which is essential for IgM oligomerization [The molecular size of a fully assembled IgM complex is nearly a million Daltons; hence, determination of its detailed structure is challenging. Earlier studies suggested that the pentamer in the presence of the J-chain has a star-like appearance with five-fold symmetry ,45. HoweM (sIgM)  , Asn332 (Cμ2), Asn395 (Cμ3), Asn402 (Cμ3), and Asn563 (tailpiece): Asn171, Asn332, and Asn395 are exposed to solvent with complex-type glycans  attached. These glycans are vulnerable to enzymatic processing and involved in the binding of IgM to T-cell surface receptors  [There are five conserved nalized) . The glynalized) ,50.α2. Strand β4 is packed onto the tailpieces of Fcα1 to form another β-sheet. These two β-sheets fold into a single β-sandwich-like domain through strong hydrophobic interactions. β-hairpins 1 and 2 interact with the top surface of Fc2, while the bottom surface of Fc1 interacts with β-hairpin 3. β-hairpin 1, β3–β4 loop, β-hairpin 2, and C-terminal β-hairpin 3 form four lassos to further interact with the Fcα. Cys69 and Cys15 of the J-chain form disulfide bonds with the penultimate cysteine residues Cys471 of Fcα1 and Fcα2, which are the foundation for the locking of two IgA monomers to the J-chain [N-glycosylation site at Asn49 of the human J-chain. The attached oligosaccharides are represented in three forms, each differing in the amount of sialic acid, 30% contain two sialic acid residues, 55% contain a sialic acid residue on the α l,3-linked mannose branch, and 15% have no sialic acid but two terminal galactose residues [N-glycosylation site of the J-chain is distant from any SC-pIgA interaction interface in sIgA, which may be relevant for promoting host and pathogen lectin binding [The J-chain was identified in 1971 in fractions from sIgA and sIgM, but not in those from IgG, IgE, and IgD . It is h J-chain ,22,25. A J-chain . The big J-chain . The strresidues . The N-g binding .N-glycosylation sites , with fucosylated and sialylated N-glycans [N-linked glycosylation sites  and are mostly exposed on surfaces of the molecule. [Human pIgR plays a dominant role in mucosal immunity. The extracellular ligand-binding portion (known as SC) of pIgR is proteolytically cleaved and transported into mucosal secretions along with dimeric IgA (dIgA) or pentameric IgM (pIgM) . SCs bin-glycans . The ordolecule. ,60 They olecule. . Each doolecule. ,60,61. Wolecule. ,46. Noncolecule. ,25,46,54olecule. ,63.α/μR, FcαRI, complement receptor, FcμR, etc. Under homeostatic conditions, IgA complexed with pIgR inhibits bacterial adherence to the mucosal wall, which functions as the first line of defense of the body. Interactions with pIgR have been discussed in the SC section. Once pathogens enter the bloodstream, serum monomeric IgA initiates the third line of immune defense as a proinflammatory antibody interacting with the IgA-specific receptor FcαRI. Here, we elaborate on the interactions with human Fcα/μR and the IgA-specific receptor FcαRI, and IgM with the apoptosis inhibitor of macrophages (AIM). IgA interacts with FcαRI to trigger clearance of IgA-bound aggressive pathogens. Most IgA-dependent immune responses are mediated through FcαRI, inducing phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst, and cytokine release [αRI complex with IgA1 Fc have greatly facilitated our understanding of their interactions with IgA. Like most Ig receptors, FcαRI is a transmembrane glycoprotein comprising two extracellular Ig-like structural domains (EC1 and EC2), a transmembrane region, and a short cytoplasmic tail. The two extracellular structural domains are folded together at an angle of approximately 90° [N-glycosylation sites  and several O-glycosylation sites in free FcαRI. A recent study shows that Asn177 may not be glycosylated [αRI. The crystal structure of the FcαRI/Fcα complex shows that a single Fc dimer binds two FcαRI receptors. The interaction between FcαRI and IgA occurs at the Cα2-Cα3 interface, consisting of a central hydrophobic core and two sides of charged residues [αRI receptor binds to Fcα with a conformational change in two loops and a strand in EC1 [αRI is closest to the IgA interaction surface, and deglycosylation at Asn58 results in increased IgA binding [IgA and IgM Fcs are known to interact with a variety of receptors to mediate multiple effector functions, such as pIgR, Fc release . Crystaltely 90° ,32,65. Itely 90° . There aosylated ,67. IgA residues ,66,68,69d in EC1 . Asn58 o binding . The gly binding .α/μR, the only IgM Fc receptor on hematopoietic cells, plays a significant role in triggering IgA- and IgM-mediated immune responses [α/μR gene is located adjacent to pIgR on chromosome 1. Amino acid sequence alignment shows that there is a conserved motif in SC D1 that is crucial for interacting with sIgA and pIgM [α/μR and 3D homology modeling suggest the presence of a conserved peptide sequence  that interacts with IgA or IgM [α/μR has three CDR-like loops in EC2, and the CDR1-like loop lies exactly at the position of the conserved peptide sequence (TIHCHYAPSSVNRHQRKYW). Substitution experiments indicate that the CDR1- and CDR2-like loops together play a more essential role than the CDR3-like loop in binding to IgA and IgM, where positively charged Arg31 and the hydrophobic side chain of Val29 of the CDR1-like loop and Asn54-Gln55 of the CDR2-like loop contribute to ligand binding, while the CDR3-like loop assists in stabilizing the structure. Fcα/μR has a higher affinity for IgM than IgA and only binds to IgM and IgA polymers [N-glycosylation sites at Asn167 and Asn276, but the function of putative N-glycans in binding to IgA and IgM is unclear [Another novel Fc receptor Fcesponses ,72,73. Tand pIgM ,75. Thisand pIgM . StudiesA or IgM ,78. Likepolymers ,80. Ther unclear ,81.α/μR on antigen-presenting cells, including macrophages and follicular dendritic cells (FDC) [α/μR and are processed and present on MHC class II after internalization [Apoptosis inhibitor of macrophages (AIM) is a member of a scavenger receptor cysteine-rich (SRCR) superfamily and is expressed on the surface of macrophages . Recent ls (FDC) . AIM-conlization .μ3 domain at one edge, and the positively charged amino acid cluster  of SRCR3 interacts with the negatively charged cluster of the Fc-Cμ4 domain on the opposite edge [N-glycosylation sites  in murine AIM and these N-glycans affect the secretion and lipolytic functions. It is unclear whether the N-glycans play a role in IgM interactions [N-glycosylation sites of human AIM do not appear to possess any glycans.Single-particle negative-stain EM of a pIgM-AIM complex has shown how pIgM associates with AIM . There aite edge ,89,90. Tractions . PotentiαRI (against both HER2 and FcαRI) effectively clears breast cancer cells through neutrophil accumulation, but anti-HER2 × FcγRI does not [αRI is also a powerful candidate in recruiting polymorphonuclear cells against human B cell malignancies [Although IgA and IgM play an essential role in human mucosal immunity, conventional vaccinations usually do not induce mucosal immunity unless administrated to the mucosal surface. The progress in determining their structure and interaction with receptors suggests that IgA and IgM-based immunotherapy is an important field for the development of vaccinations and therapeutics. More than 90 therapeutic IgG antibody products have FDA approval, whereas almost no IgA and IgM antibodies have been tested in humans . The supdoes not . Anothergnancies . In addignancies ,99.αRI in the mouse. Many of these issues are now being addressed. For instance, modification of terminal N-glycans successfully lengthened the half-life of asialoglycoprotein receptor-mediated clearance [While there are many possible advantages of IgA and IgM in antibody therapy, there are several issues that need to be overcome. For example, how does IgA mediate both pro- and anti-inflammatory functions via FcαRI in order to exert a therapeutic effect. The short half-life makes use of IgA potentially expensive, and the need for the high frequency of administration is inconvenient for patients. Another issue is the efficiency of expression, production, purification, and complete assembly of recombinant IgA and IgM monoclonal antibodies with appropriate homogeneity. A more critical limitation is the lack of suitable animal models, one example being the differences in the polymerization state of serum IgA and the lack of Fclearance ,101. Syslearance ,101,102.learance ,104.The recently resolved three-dimensional structures of IgM Fc pentamers and IgA Fc multimers have provided us with an excellent base to help understand and modify these complex macromolecules. We hope that this review provides some ideas for the engineering of bispecific IgA and IgM antibodies and the development of more effective therapeutics.


Introduction: Social isolation disproportionately affected older adults prior to and especially during the COVID-19 pandemic. To help older adults cope with social isolation, a new program “Big and Mini” was created in April 2020 to link young and older adults together (matched through a custom website developed for this program) and to help increase social connectivity through weekly phone calls. Using a survey with both closed and open questions, this study evaluated participant feedback three months after the program was launched. Methods: 63 Bigs (age 50+) and 53 Minis (age 18+) completed the survey. Stress compared to before COVID-19, social isolation, life satisfaction, intergenerational solidarity, and satisfaction with the program were measured for both the Big and Mini participants. Descriptive, bivariate correlation, group comparison and conventional content analyses were conducted. Results: Results showed that 38.1% of Bigs and 37.7% of Minis felt higher levels of stress than before COVID-19. Both Bigs and Minis had medium levels of social isolation. They also reported high levels of satisfaction with life, satisfaction with the program, and intergenerational solidarity. Content analysis suggested that the reasons to join or expectations of the program were curiosity, friendship, mutually beneficial intergenerational connections, and coping with loneliness. Both Bigs and Minis reported benefits from the learning and sharing opportunities that the program offered. Conclusions: The Big and Mini program offers a promising approach with mutual benefits for both Bigs and Minis. Strategies to improve the program and implications for other phone-based intergenerational programs are presented.


Aging Strong 2020 was developed to promote health and well-being and increase resilience by focusing on the pillars of enhanced purpose in life, social connectedness, and optimism. A series of eight interventions over three years tested the feasibility of enhancing these pillars. Interventions included: 1) An expressive writing program, 2) Animatronic pets, 3) A telephonic reminiscent program, 4) An online self-compassion mindfulness program, 5) A technology-based behavior change tool, 6) An online and workbook tool for purpose, 7) An online happiness program, and 8) A peer-to-peer support program. Each program demonstrated efficacy dependent on the pillar targeted and the population sampled. Overall, some improvement was found among participants in resilience (47%), purpose (49%), optimism (44%), and loneliness (48%). Further, participant satisfaction improved in each program with Net Promoter Scores increasing between 7-19 points. Results demonstrate that Aging Strong 2020 was successful, contributing to a holistic model of healthy aging.


Participants reported the benefits of enhanced SEWB and reduced psychological distress. This research reaffirms the need for culturally safe programs that acknowledge social determinants of health and are guided by the SEWB framework. Long-term commitment from the government is needed to support such programs.Culturally safe and responsive interventions that acknowledge Aboriginal models of selfhood are needed. Such interventions empower Aboriginal peoples and communities by increasing self-determination over individual and community social and emotional wellbeing (SEWB). In response to this need, the National Empowerment Project developed the Cultural, Social, and Emotional Wellbeing Program (CSEWB). The CSEWB aims to strengthen SEWB and cultural identity and subsequently reduce psychological distress in Aboriginal peoples. An Aboriginal Participatory Action Research approach ensured community ownership and engagement. Seven research questions and a culturally modified adaption of the Most Significant Change technique informed a thematic analysis of the evaluation content. Aboriginal adults ( Truth-telling about colonisation, community empowerment, and reclaiming cultural identity all play a critical role in strengthening the social and emotional wellbeing (SEWB) of Indigenous peoples . A lack Suicide has been described as the greatest public health challenge of our time. The age-standardised rate of suicide for Aboriginal and Torres Strait Islander peoples in Australia is two to three times the rate of non-Indigenous peoples . ReducinIn 2009, the Australian government formally endorsed the United Nations (UN) Declaration of the Rights of Indigenous Peoples . Yet, thIndigenous and mainstream understandings of health and wellbeing differ in important ways. The National Strategic Framework for Aboriginal and Torres Strait Islander Peoples’ Mental Health and Social and Emotional Wellbeing ,28 contaIn response to suicide rates in the Kimberely, Bardi woman Professor Pat Dudgeon led a community consultation that culminated in the landmark Hear Our Voices report as a part of the Kimberley Empowerment Project . In 2012The SEWB model  in FigurThe CSEWB program aims to empower Aboriginal and Torres Strait Islander peoples and strengthen family and community connections and cultural identity. Empowerment is achieved by educating program participants on SEWB and teaching life skills to support positive change . Connection to community groups, mentorship, and leadership are also emphasised to strengthen relational networks. Throughout the program, participants are reconnected with family, community, history, and culture using yarning and story-telling techniques. There is also education on positive parenting, family structures, and local and national Aboriginal and Torres Strait Islander history. The first CSEWB programs were delivered and evaluated between 2014 and 2016 in Kuranda and Cherbourg, two Queensland communities that participated in the NEP consultations . To ensuIn addition to SMSC, open-ended interviews informed six case studies. These case studies provided evidence of lived experiences of positive change in the program participants’ aspirations and abilities, as well as increased motivation to overcome the significant challenges and disadvantages endured over their lives. The case studies demonstrated that by strengthening cultural identity through a framework of SEWB, participants experienced an increased sense of belonging and connection to Country and a renewed focus on family and community connections. The key aim of the program was to reduce experiences of psychological distress and hopelessness that may contribute to suicide behaviours and to facilitate a sense of empowerment and agency for participants. Participants’ perceptions of distress (measured through SMSC) were reduced, despite unexpected events that contributed to widespread community grief and loss during the program delivery. The CSEWB program had a strong, positive impact on the Queensland communities. However, more research is needed to (1) investigate the efficacy of the CSEWB program in diverse Aboriginal communities across Australia, (2) investigate the underlying structure of Aboriginal and Torres Strait Islander wellbeing, and (3) explore culturally appropriate techniques to measure change in relation to Aboriginal SEWB, including both qualitative and quantitative measures. The current study aims to further validate and develop understandings of SEWB and to measure the impact of the CSEWB. Participants from three communities in Western Australia (WA) were engaged in post-program evaluation workshops. It was hypothesised that participation in the CSEWB program improves participant SEWB, reducing psychological distress and improving agency. It was also hypothesised that thematic analysis of the workshop content would provide further insight into the underlying structure of SEWB and potential mechanisms of change.Consistent with best practices in research with Aboriginal peoples, APAR was utilised in this study. APAR is a culturally safe and strengths-based research method. By implementing the right to self-determination in research, APAR empowers Aboriginal peoples to describe and share their own reality and to have community ownership of research processes and outcomes ,35. CommThree Aboriginal community centres were engaged as partners to host the workshops. The community centres and associated regions were (1) Langford Aboriginal Association ; (2) Darius Wells Centre ; and (3) Miya Kaadadjiny . These three centres are spread across the Perth metropolitan region  to maximise engagement and access. Each region has a community reference group (CRG) and recruited co-facilitators from the local area who had either participated in the program or were respected people within that community. Endorsement and recruitment were facilitated through the CRG membership and Aboriginal community-controlled organisations in the local area. The evaluation workshop facilitators were experienced co-facilitators from the program delivery. Author 4 was one of the community researchers during the initial NEP and has continued this role in managing and facilitating the delivery of the CSEWB program in Perth in partnership with Author 1 at the University of Western Australia.n = 8 Kwinana 2019; n = 5 Girrawheen 2019; n = 9 Langford 2019; n = 10 Kwinana 2020; n = 8 Langford 2020; n = 9 Langford 2021). All workshop participants identified as Aboriginal peoples. None of the program participants in this research identified as Torres Strait Islander. Written informed consent for the use of de-identified data for research and evaluation purposes was obtained from all participants prior to the commencement of each workshop. Participants who had completed the CSEWB program in Perth were the focus of this research. These participants were recruited to the CSEWB program from the NEP or were referred to the CRG by local service providers. Following the CSEWB graduations, the 82 program graduates were invited to attend the evaluation workshop. In total, 49 adults  participated in 1 of 6 workshops . The questions are shown below.What does social and emotional wellbeing mean to you?What increases your social and emotional wellbeing?How do you gain a greater understanding of social and emotional wellbeing?How do you get others to understand and strengthen social and emotional wellbeing?How do we engage Aboriginal youth in understanding social and emotional wellbeing?What contributes to Aboriginal people’s social and emotional wellbeing?Davies and Dart’s  Most SigA post-program evaluation form asking about the purpose and perceptions of the workshop and requesting details for changes to improve program content was collected to measure participants’ satisfaction with the service delivery and content.The CSEWB program ran for approximately 6.5 h one day per week for 12 weeks and concluded with a 1-day evaluation workshop. Complimentary childcare facilities, meals, and transport were provided for participants during program hours in order to maximise engagement and minimise dropout. The program followed the structure outlined in the NEP CSEWB Facilitators Guide. Each group was facilitated by two co-facilitators who were local community members and undertook facilitation training prior to workshop commencement. If participants did not attend, they were able to catch up on the work in their own time or attend a one-on-one session with a facilitator. Culturally responsive counsellors were available to contact during or outside program hours. A community project, determined by participants, was undertaken at the end of the program and before the evaluation workshop. This paper reports on the evaluation workshop following completion of the program. Participants who completed all program content were graduates. A thematic analysis  was usedIn this study, multiple methods were used to enhance the reliability and validity of the thematic analysis. First, two research teams  conducted an independent thematic analysis of the workshop data. Consistent with , the anaAnalysis of the responses from the semi-structured interviews and SMSC showed the emergence of six key themes and fifteen subthemes that characterise SEWB. Each theme and associated subthemes are described in turn below. The importance of culture in strengthening the understanding and experience of SEWB was the most prominent theme in the participants’ interviews and one of the strongest themes in the SMSC. Participants described that participation in the program gave them an understanding of cultural identity and its role in strengthening SEWB. Culture was separable into four subthemes: (a) cultural knowledge, (b) cultural practices, (c) connection to Country, and d) spirituality. Cultural knowledge included a commitment to learning about culture  as well as participating in cultural traditions and cultural forms of healing . The importance of ‘yarning’ or ‘story-telling’ was emphasised and linked to respecting Elders and connecting to culture, community, and family. Spending time in the bush or on traditional homelands was important. ‘Shoes off, on boodja (Country)’, ‘going out bush with Elders’, ‘going back to Country’, ‘gatherings on Country’, and ‘acknowledging Country’ facilitated (re)connecting with Aboriginal culture through land and place. Participants shared a sense of empowerment in embracing cultural practices and connection to Country that could be expressed through activities such as Welcome to Country ceremonies.Connecting to spirituality was generally described indirectly, as ‘what I believe’, or through mindful practices , or ‘time out’ . These quiet practices were described as ‘relaxing’, ‘spiritual’, or ‘connecting to spirit’ when questioned how they are associated with enhanced wellbeing . SMSC described that as a result of remembering history, a new appreciation of culture and how it impacts Aboriginal wellbeing was found . This included ‘recognising,’ ‘respecting,’ and ‘trusting Elders and listening to their stories’. In the words of one individual, ‘I have learnt a great deal about how important it is to carry on our culture, traditions and language to our younger generations and not let it disappear’. This new knowledge and responsibility bolstered self-esteem, ‘I have more insight into my cultural learnings about cultural stories and more confidence into every aspect of my life’. This seemed to some to be something that was not consciously expressed prior to the program . Even if connection to kinship had been thwarted due to Stolen Generations membership and forced child removals, wellbeing could be nourished through a sense of attachment to Country, as described by one participant, ‘while Country still accepted me, I was forever rejected by those I was meant to belong to, continually crushing my spirit, learning that Country accepts unconditionally’. Similarly, there was an appreciation of ancestors as an important form of attachment and comfort, ‘Family inspiration through time’; ‘acknowledgement through your old ones.’Community was also a prominent theme in the interviews. Participants described that completing the program significantly contributed to their interest in and perceived benefits of participating in and engaging with their communities. For many participants, sharing and promoting information about the program was central to building community support. The opportunity to participate in a community project reinforced a sense of connectedness and belonging to others, asserting themselves as a proud member of their community. The sense of belonging and connection to community was clearly linked to an increased sense of wellbeing.Community involved two subthemes: (a) seeking support from others and (b) giving support to others. Seeking support involves being actively engaged in the community as well as looking for and accessing support services . Participants described an increased awareness of culturally appropriate services where they felt comfortable. This resulted in stronger community connection and confidence in reaching out. Communication was integral to this process , as was active participation . Social and sporting activities  allowed participants to feel connected and an increased sense of belonging. Giving support was even more important, as participants felt a new responsibility to ‘encourage’ and ‘motivate’ others , and be a positive role model within their communities .In the SMSC, many participants described that participating in the community, rather than being isolated, was a significant change for them . The importance of community strength in cultural and personal wellbeing was also described  but had walked away with more knowledge of my culture and connection and how that feels in the community’; ‘I have enhanced my association of togetherness and will continue to highlight this in my life.’).Participants commonly described the importance of kinship and connectedness with family and friends. Knowing who their mob is and where they come from empowered people to feel more confident in their cultural identity. The intricate knowledge of complex family lines helped to strengthen participants’ sense of belonging and was linked to reduced feelings of isolation and increased wellbeing. This theme was separable into two subthemes: (a) family connections and (b) developing positive relationships. Spending time with family was commonly mentioned as integral to wellbeing. Often, this involved increasing the amount of time spent with family , but also having a deeper understanding of family . Distinctions were made around the influence of different family members. Participants identified that seeking out positive family members was critical to maintaining a sense of wellbeing. Positive relationships included developing positive relationships  and developing interpersonal skills . Positive relationships also included positive parenting practices  and positive intimate relationships ‘healthy sexual relationships’.The negative impact of unhealthy relationships and a lack of effective interpersonal skills prior to the program was described in SMSC. Participants described ‘internal issues of identity and belonging’ and the negative impact of feeling a thwarted sense of belonging in their communities ‘being rejected by those I was meant to belong to was crushing my spirit’. By increasing interpersonal skills during the program, participants felt more empowered to deal with conflicts . Further, participants often described the significant change of learning more about their family history . The negative impact of government assimilation and removal policies on family and the motivation to be a better parent were also commonly described .Learning about and accepting Aboriginal history and the continued impact of social determinants was a strong theme in participants SMSC. History was separable into two subthemes: (a) accepting the past and (b) understanding the present. Being able to understand one’s history  and current social determinants  were not necessarily considered to be core dimensions of the wellbeing construct, rather they were described as a catalyst for change and a necessary component to ‘accept’, ‘heal’, and ‘move forward’. Participants commonly described having a prior awareness of historical context , yet the program was able to ‘put it all together’ and show ‘the connections’ in regard to ‘how the past effects the future’ and identify reasons for contemporary disadvantage . The SMSC described that the program allowed them to ‘remember the past’ and ‘overcome the fear of asking family questions about the Stolen Generation’ and ‘not be shame’. The stories commonly described the necessity of ‘looking back to move forward’ and ‘learning from the past to strive for tomorrow’. Understanding the impact of the past in their present lives allowed for a greater understanding of self , tolerance and empathy towards others , and a renewed determination towards a better future . The importance of maintaining one’s health was another key theme, although relatively minor in strength. Many participants highlighted how completing the course equipped them with insight into and education around their health. The program provided a holistic perspective on health; thus, connection to the other themes was critical to maintaining good health and wellbeing. Participants also expressed that the program helped them to identify with healthier lifestyles.The health theme was separable into two subthemes: a) healthy body and behaviours and b) healthy mind and emotions. Healthy body and behaviours involved being active , healthy lifestyles , and accessing healthcare providers . Mental or emotional wellbeing included mental health  and positive lifestyle practices . SMSC revealed that participants often experienced poor mental health prior to the program . Participants often described positive ways that personal health practices changed during the program and demonstrated an increased sense of control over their health and wellbeing  and how personal health became of greater value . Self was a strong theme in participants SMSC, but was a weaker theme in the interviews. Participants commonly described a positive change in their sense of self and described that the program had renewed their interest in living a happy life and achieving self-development. Completing the program provided many participants with strategies to increase their daily happiness and achieve their longer-term goals. This theme was separable into three subthemes: (a) self-confidence, (b) experiencing joy, and (c) personal development. The increase in self-esteem was emphasised by participants, most often described as increased ‘confidence’, and similarly as ‘empowerment’, ‘pride’, and a ‘sense of identity’ and ‘feeling complete’ or ‘whole’. In addition, participants described a renewed sense of joy; this could be emotionally through ‘being happy’, ‘laughter’, and ‘positivity’, and enjoying hobbies . The theme of self was less prominent in the interviews than in SMSC. Participants commonly described becoming a changed person through the course , in that they developed a sense of self-love, empowerment, and pride, and an improved capacity for self-care. Although many described the sense of ‘a new beginning’, this did not necessarily imply smooth sailing ahead. Indeed, many also acknowledged circumstances of hardship that would persist, yet expressed optimism in facing challenges . The new confidence was often described as ‘finding a voice’ and being able to speak out, speak up, or stand up. ‘Being strong in myself’ was seen as necessary to lead others and teach others and fulfil responsibilities to family; in the words of one participant, ‘I constantly left myself to last and it wasn’t until it was too late that I realised that if I don’t look after myself first I can’t look after my own family’. Intertwined with this new confidence was a determination to overcome the negative impact of social determinants through personal development. Personal development involved a more holistic view of relational success (vs. Western ideas of success), education , employment (both paid and volunteering), and incorporated other examples of motivation and life skills . Willingness to engage in future training demonstrates the value participants put on self-development and life skills and their confidence in pursuing their goals ’). The program played a critical role in facilitating these changes. A feedback form was also administered to participants at the end of the workshop. The content of the evaluation feedback is reported in Novel approaches to suicide prevention are needed in Aboriginal and Torres Strait Islander communities. To be effective, these approaches must work within a decolonial SEWB framework . This prIn addition to participant empowerment, the SEWB construct was explored using a thematic analysis of six interview questions answered collectively by the workshop groups. Using thematic analysis, 6 themes and 15 subthemes emerged that describe SEWB. The six overarching themes  reflect the domains and determinants described in the SEWB model . The 15 The CSEWB program is a successful, Aboriginal-led community initiative that builds on the strong community-based foundation of the NEP ,4,23. ThFuture research should aim to develop and validate culturally appropriate scales that are governed by and developed using appropriate research methodologies and directly contribute to an Aboriginal understanding of SEWB. For example, these scales could ask, over the last four weeks, how much had they had connected with culture, connected with spirituality, sought or provided community support, or felt kinship in positive relationships. Community-based APAR research from Aboriginal-led research teams partnering with the community would be integral in understanding the best ways to frame these questions, the mode of delivery for such questions, and a meaningful scale on which to assess these factors .This research must also be viewed in light of its limitations. This paper reports on a sample of 49 interviews and SMSC. This sample provides considerable detail about these individuals’ experiences. From this information, details on the relative importance of the emerging themes to an Aboriginal sense of wellbeing was provided. Larger samples could provide further detail on the strength of relative importance of each theme to wellbeing. Further, longitudinal data collected on these themes and the timing of related factors, such as traumatic life events, stress, and use of coping skills, could elucidate the trajectory of these needs.This research reaffirms the utility of culturally appropriate programs that acknowledge social, historical, political, and cultural determinants of mental health in Aboriginal peoples and supports the utility of the SEWB framework and APAR methods to guide the development of these programs and assess their efficacy. Beyond the Australian context, this research also aligns with the UN 2030 Sustainable Development Goal 3: good health and wellbeing and the UN Declaration on the Rights of Indigenous Peoples 2007). Future research would be well placed to develop an instrument or method for assessing SEWB domains and determinants of health from an Aboriginal lens, incorporating themes from the CSEWB program evaluation alongside the SEWB model . Future . Social This section is not mandatory but may be added if there are patents resulting from the work reported in this manuscript.


Jeevika – the Bihar Rural Livelihoods Promotion Society – and find that a 1% increase in program membership was associated with a 0.6% increase in annual program expenditures, indicating large economies of scale. Predicted costs from regressions suggest that the annual per capita program expenditures declined from $29 when the program covered 100,000 members to $5 when it reached 10 million members. Previous impact evaluations of Jeevika showed sizeable but smaller substitutions away from high-cost debt after scale-up than during the pilot, but we found that economies of scale led to similar cost-effectiveness ratios for this outcome. We also found that formation of higher-level federations is associated with lower marginal costs than setting up SHGs. However, previous evidence suggests that Jeevika did not generate average impacts on women’s agency and asset ownership after scale-up. Building on a rich history of research on Jeevika, we argue that program implementers must identify key success factors in pilot programs to minimize tradeoffs between cost savings and potentially reduced impacts after scale-up. Further, we suggest investments in linking SHGs to federations to improve the cost-effectiveness of SHGs.Livelihoods and microfinance programs for women often show reduced impacts after scale-up. Yet, program scale-up may reduce average per capita costs and maintain cost-effectiveness despite lower impact. This paper presents evidence on the association between program scale, costs, and cost-effectiveness by analyzing how the costs of a large-scale Self-Help Group (SHG) program in India changed from its inception in 2007 to its scale-up in 2019. We use expenditure data from program’s audit statements of  These interventions include self-help groups (SHGs), savings groups, mothers’ groups, health groups and community mobilization groups . While iTo some extent, these decisions to scale are justified by evidence on the impact of women’s groups. A systematic review showed that SHGs have positive effects on several domains of women’s empowerment—including economic, reproductive, social, and political domains—although impacts depend substantially on program design and implementation context . Apart fGiven the growing interest in expanding the outreach of women’s groups with economic objectives, it is imperative to study the potential role of scale in influencing program impact, implementation, and costs of these groups. Without such information, the policy implications of studies examining the impact of women’s groups operating at scale will remain unclear. While various studies examine the costs and cost-effectiveness of women’s groups aiming to improve health outcomes , somewhaJeevika – changed over time since its inception in 2007 when it mobilized 8,000 women into SHGs, to its current reach where it has mobilized over 11 million women into 0.9 million SHGs. Jeevika has operated the Bihar Rural Livelihoods Project (BRLP) since 2007, and currently implements India’s NRLM through Bihar’s State Rural Livelihoods Mission (SRLM). The NRLM, which was launched in 2011, operates in 28 states through the SRLMs, which create and work with women’s SHGs to facilitate institutional and capacity building, financial inclusion, livelihoods promotion, social inclusion, and development. SHGs under NRLM (and BRLP) usually start with a period of collective savings to facilitate intragroup lending, after which members can gradually take larger loans . Additionally, to facilitate collective capacity, Jeevika created a federation of community institutions, under which SHGs were linked to Village Organizations (VOs) and VOs were linked to Cluster-Level Federations (CLFs). Among other activities, these federations provide training to improve agricultural and non-agricultural livelihoods and health outcomes, including training for some of the most disadvantaged groups.This paper addresses this evidence-gap by examining how the costs and cost-effectiveness of an SHG program in India changed with respect to program scale. We study how the costs of a large-scale SHG program in the state of Bihar – meta-analysis of development programs, including those that focus on microfinance, financial literacy and women’s empowerment, concluded that larger programs and programs that were implemented by governments had lower effects  for benefits from reduced dependence on high-cost loans after an initial pilot of Jeevika with an estimate of the CER after the scale up of the program. While the scaled-up program may be equally cost-effective as the pilot in achieving benefits from reduced dependence on high-cost loans, the scaled-up program is less cost-effective than the pilot in achieving positive effects on women’s empowerment and asset ownership. As in the previous impact evaluations, this paper treats reduced dependency on formal loans as the primary outcome, but we also examined costs of producing potential downstream effects on women’s empowerment and ownership of consumption and productive assets. Unlike during the pilot, the evaluation of the scaled-up Jeevika program did not find statistically significant average effects on women’s asset ownership and intra-household decision-making . The structure and goals of the BRLP were defined along similar poverty alleviation projects as in other states, with an initial goal of improving livelihoods of the rural poor by developing institutional capacity through women’s SHGs and linking them to formal financial institutions and other agencies to negotiate better services. In 2007, the Government of Bihar established the Jeevika facilitates collective action, adoption of livelihoods enhancement and income generating activities, and development of linkages with market institutions , Special Technical Assistance Fund (STAF), Project Management (PM), and the Community Investment Fund (CIF). The CID fund provides all expenses for institution building, including the costs of mobilizing groups, developing direct linkages to the formal finance services providers, formation of federations, and capacity building of staff at the district, block, and cluster level. The STAF provides technical assistance to the formal financial sector and other partners to support microfinance initiatives and pro-poor banking and promote public–private partnerships to improve the quality and quantity of public services delivered to communities. Overall coordination, project implementation, financial management and monitoring and evaluation at the state and district levels are supported through resources under the PM component. Finally, the CIF component provides direct grants to the community through the Revolving Funds (RFs), as well as through Vulnerability Reduction Funds (VRFs). The RF aims to meet the credit need of group members and is considered “catalytic capital” for leveraging repeat bank finance, thus promoting income generating activities, for example through investments in livelihood skills development. The VRF is usually provided to VOs to address food security risks, health risks, and natural disasters through the Food Security Fund or Health Security Fund. Jeevika disburses CIF to SHGs and federations as a grant on a demand-driven basis through a participatory micro-planning process.Program expenditures under 44.1Jeevika annual reports and audited financial statements from 2007–08 to 2018–19. These data provide information on annual program outreach and scale, including the number of households mobilized into SHGs, number of SHGs promoted, number of VOs and CLFs formed, and the number of SHGs linked to a bank account. We collected data on program expenditures from annual audit statements of Jeevika and World Bank project documents. It is important to note that our analyses are only based on reported program expenditures. Ideally, a costing analysis should include costs of resources that were utilized but not directly paid for – for example, the time spent by volunteer staff, or use of buildings and resources for BRLP-specific activities that may have been already in use and paid for by another government entity. All costs presented in this study should therefore be considered as an underestimate of true program costs and should be regarded as program accounting costs only. For this reason, we should also exercise some caution in the interpretation of the cost-effectiveness estimates. We use the terms “costs” and “expenditures” interchangeably in the rest of this paper.We obtained data on program implementation, components, outreach, and expenditures from 4.2Jeevika program to complement our costing analysis and generate evidence on cost-effectiveness. We accessed and analyzed data from two impact evaluations of the Jeevika program – the first focusing on the pilot phase of the project pre-2012 , and expenditures related to overall operations and management. We also study the changes in total program costs in relationship to core program activities, including the federation of SHGs, such as the formation of SHGs, VOs, CLFs, and bank linkages.We examine the costs of increasing both the scope as well as the scale of services related to expanding Jeevika program, treating each Jeevika member added as an additional program output. While not all women received the same level of services with the same intensity, we estimate an average cost equivalent to an “Intent to Treat” cost – that is, expenditure per woman SHG member with access to potential program services. From Jeevika’s expenditure components discussed earlier, we consider three expenditure components – Community Institution Development, Special Technical Assistance Fund, and Project Management. We do not include Community Investment Funds when studying the relationship of costs with scale because it is disbursed to SHGs or their federations as a one-time grant or capital based on need and is usually a fixed amount .3Jeevika aims to form SHGs that will eventually become self-reliant and self-managed by gradually adopting income generating activities and profits for the federations. In 2017, the World Bank conducted an implementation assessment of the program, and through a random stratified sample, found that 89% of older SHGs (formed prior to 2012) had become self-reliant by 2017  Model 1 – Cumulative Participation, under which we assume that every SHG member under Jeevika is eligible for all services, irrespective of when they joined the program; and (2) Model 2 – Fixed-Period Participation, under which we assume that Jeevika supports all SHGs and related-activities for a period of three years, after which SHGs become self-sustainable. For Model 2, we divide all expenditure components in each year among women who have been a member of Jeevika for no longer than three years. In our conversations with the program implementation team, we were informed that Jeevika continues to support participants throughout their membership, and therefore the first assumption is more plausible. The nature of support is likely to vary over time, however, with older groups receiving more support with economic livelihoods and newer groups receiving support with bank and credit linkages. by 2017 . AlthougWe extracted all program expenditure data in local currency (INR) and converted to 2018 USD by first converting annual expenses to 2018 prices by adjusting for INR inflation using the Consumer Price Index (CPI) method, and then converting to 2018 USD by adjusting for 2018 market exchange rate. We then used the production function to test the possibility of increasing, decreasing or constant returns to scale, for the same program over time. We estimated the time-varying growth in logged costs as a function of logged scale as shown in Eq. (1):In Eq. (1),  at hand  and help at hand . The goaJeevika, focusing on the primary program outcomes – (1) annual SHG formation; (2) annual VO formation; (3) annual CLF formation; and (4) annual number of SHGs linked to the bank. The first three activities directly address the key output of Jeevika – formation of women-led community institutions at different levels. The fourth activity denotes the financial inclusion goal of the program. Our data do not allow for disaggregating costs beyond the three categories of CID, PM, and STAF, implying that we cannot reliably estimate the cost of each specific activity. Yet, following the same specification as in Eq. (1), we can estimate how the total annual expenditure of program changes with respect to each of the four indicators. To do this, we replace Next, we investigate how total program expenditures change with respect to specific economic activities. We use four different indicators of economic activities under We estimate four different specifications of Eq. (2) for each economic activity as input for channels for ultimate program impacts, the key advantage of analyzing these data is that, unlike impact evaluation data, data on performance indicators are available annually and therefore provide more data points to create a time-series dataset.Finally, we examine whether the pace of achieving program outputs and likelihood of impacts changes with scale using two different approaches. We start by leveraging the data on program activities to analyze two key channels through which the program aims to improve women’s economic outcomes – financial inclusion and federation formation. Financial inclusion, including access to and use of formal banking services, is the first program focus after group mobilization. If scaling up adversely impacts implementation quality, many SHGs may become defunct, women may stop attending group meetings, and the pace of linking SHGs to formal bank accounts may slow down. Further, formation of higher-level federations depends on additional program capacity on the implementation side, and a certain ‘grade’ of performance on the SHG side . FederatJeevika resulted in a statistically significant and sizeable reduction in interest rates on loans taken by households, primarily due to reduced dependence on informal moneylenders , project management (PM), and technical assistance (STAF). Jeevika membership was associated with a <1% increase in program costs, suggesting strong economies of scale. Specifically, a 1% increase in scale was associated with a 0.6% increase in expenditures in Model 1, and a 0.7% increase in expenditures in Model 2. Additionally, the marginal change in costs decreases with increases in outreach. Specifically, the estimates suggest that annual per capita expenditure was approximately $29.6 in Model 1 and $29.1 in Model 2 when the program served 100,000 women; around $11.8 in Model 1 and $13.3 in Model 2 when the program served one million women; and fell as low as $4.7 in Model 1 and $6.1 in Model 2 when the program served ten million women. These predicted costs suggest that the decline in costs per capita slows down with a large increase in scale. This is likely because as scale increases by a large number, existing inputs may reach their threshold of productivity and the program may require a large amount of new inputs, which drives up the operational costs.Next, we break down the overall non-CIF expenditure into its subcomponents – specifically, CID, STAF, and PM related expenditure. As shown in The CID component includes expenditures on project start-up, community mobilization, formation of higher-level federations, capacity management, and implementation of inclusive strategies to ensure that the project activities prioritize the most economically and socially deprived communities. Initially, as the program scaled and mobilized more households, a higher proportion of resources was devoted to CID (between years 2008 and 2011). STAF related costs were used to cover expenses related to program innovation, partnerships with government agencies and non-governmental organizations for financial inclusion and technical support on production and livelihoods activities. The project reported having spent lower amounts on the STAF component than initially estimated because of leveraging already established innovation linkages . The invMore formally, we find evidence for economies of scale across all three expenditure components, as shown in regression estimates in 6.3We next analyze how annual program expenditures change in response to changes in annual (1) SHG formation, (2) VO formation, (3) CLF formation, and (4) the number of SHGs linked to the bank. 6.4quality of project activities, however. As discussed below, these performance indicators likely present an incomplete picture of the change in full benefits, for example, in case linkages to federations are equally likely for all SHGs but new federations produce smaller impacts because of their weaker capacity.We next analyze how three key performance indicators changed with respect to scale. Our estimates suggest that the pace of project outputs increased significantly with program scale . Specifi7Our findings suggest that large scale implementation of women’s SHG programs has considerable potential to benefit from reduced costs due to economies of scale. These findings produce an important side to an often-told incomplete story where successful pilot interventions fail to produce similar impacts when scaled up  failed to see most of these individual-level and household-level effects. These changes in impacts likely result from the scale and complexity of the Jeevika program. The program includes multiple components, covers a wide geographical area, and as of 2021, covers over eleven million households. The implementation of the program also varies across contexts due to variation in local capacity, population needs, and other contextual factors. Further, as the program scaled up, several components of the program were implemented in collaboration with different organizations.Findings from two impact evaluations  – the fiAn ethnographic study attributed the failure to produce similar effects in the second phase to the pressure to scale up quickly . The stuJeevika program, more than twice the average impact of $33 in phase 2. However, it costed 91 cents to reduce each additional dollar of high-cost debt in phase 1 – only slightly different from 88 cents in phase 2. While program impact declined by almost 62% after scale-up, it was 3 cents less costly after scale-up to achieve an additional dollar of benefit in reducing high-cost debts than during the pilot.Combining our cost estimates with existing impact evaluation estimates, we find that despite the considerably lower impacts on high-cost loans of households after the scale-up than during the pilot phase, the differences fade away when we estimate cost-effectiveness ratios. For the cost-effectiveness analysis, we first focus on the costs of achieving benefits related to lower costs of borrowing, estimated as the ratio of costs to household change in high-cost debt. In Phase 1, the program led to a 46% decrease in total high-cost debt per household, while in phase 2, the decrease was approximately 15% .6 As shoJeevika to assess the uncertainty in cost-effectiveness estimates due to imprecision in the impact estimates. In line with Some caveats should be considered when interpreting these findings. First, the Phase 1 evaluation is less robust as it relied on propensity score matching on retrospective data, while the phase 2 evaluation used a randomized controlled trial. Therefore, impact estimates from Phase 1 evaluation may be an overestimate of the true program effect if motivated women were more likely to participate in the program. Second, the cost-effectiveness ratios shown here only apply to benefits caused by reduced costs of borrowing resulting from reduced interest rates. For this study, our primary aim is to demonstrate the consequences of ignoring cost data when interpreting findings of impact evaluations of scaled-up programs. Several other outcomes need to be considered in the estimation of a holistic benefit-to-cost ratio.However, the Phase 2 evaluation did show meaningful and statistically significant negative effects on interest rates charged by informal lenders, which resulted in a reduction in the difference in average borrowing rates faced by landholding and landless households by two-thirds . The redJeevika in achieving positive effects on women’s empowerment outcomes  is among the world’s largest non-profit organizations with a scale of over 120 million people across eleven countries . BRAC’s 8Jeevika program, suggesting that the results may well be externally valid.To analyze returns to scale, we examined how cost per borrower changed with the number of borrowers in each year (a proxy for microfinance outreach). Jeevika participation was $235 if the beneficiary joined the program in 2008 (first phase) and $90 if the beneficiary joined the program in 2013 (second phase). We also compare our findings with evidence from similar livelihoods programs implemented around the world. A recent study estimated the range of costs of economic inclusion programs implemented globally between $41 and $2,253 per beneficiary over an average of a little over 3 years of participation in 2011 PPP . Using tJeevika in Bihar. A breakdown of cost components suggested that Bihar spent more on providing specialized funds and market links, and less on targeting costs. These differences likely reflect differences in scale and the gains from early implementation experience of Jeevika that may have brought down targeting costs. Comparing earlier formed and later formed SHGs across seven states, Analyzing the National Rural Livelihoods Project (NRLP) implemented across India, 9This study brings together two seemingly disjoint streams of discourse in translating evidence from impact evaluations to policymakers – First, the past decade has seen an increasing emphasis, especially in international development, on incorporating cost estimates and cost-effectiveness and cost-benefit analyses into impact evaluations . Second,Jeevika on basic program activities increased less than proportionately as scale increased – average annual program expenditure was $29 when the program had 100,000 members, $11-$13 when the program had one million members and was as low as $4-$6 with 10 million members. Comparing our findings with similar programs across the world, we found that average cost per beneficiary for Jeevika falls within the range of costs reported for economic inclusion programs funded by the World Bank. However, it remains important to note that information on program costs is very rarely reported in impact evaluations. For example, out of 97 impact evaluations of financial inclusion programs that are currently funded by the World Bank, only 20 studies reported information on costs, with only 15 studies collecting cost information at a disaggregated level (Our analyses on economies of scale of SHG implementation in Bihar contribute to addressing this evidence gap through three key takeaways. First, we conducted a cost analysis to estimate the average costs of one of the largest SHG programs in the world over twelve years, showing per capita annual costs for each level of scale, and the extent to which the program can benefit from economies of scale. We found that annual per capita expenditure of ed level .Jeevika can improve the cost-effectiveness of its programming by continuing to place a large emphasis on the formation of higher-level federations.Second, we found that the extent of economies of scale varies considerably with program activities. Our findings indicate that formation of higher-level federations and SHG-bank linkages can be achieved at a relatively low marginal cost. Evidence from other studies shows marked improvements in the performance of SHGs after the formation of VOs and CLFs. Specifically, Jeevika did have positive effects on consumption and productive asset ownership for landless households after scaling up, the program had only modest average treatment effects on consumption asset ownership and no positive effects on productive asset ownership or women’s decision-making power (Jeevika could have been equally cost-effective on these outcomes in the scaled-up phase if impacts on these outcomes were about half the impacts during the pilot.Third, we found that although the average high-cost loan amounts decreased by lower amounts in phase 2 compared to the pilot, the difference in program impacts did not translate to large differences in cost-effectiveness, after combining our cost estimates with impact estimates from the pilot phase and the scaled-up phase. The differences in impact fade away in the cost-effectiveness analysis because the lower implementation costs of the scaled-up model were able to fully offset the lower benefits. However, it is important to emphasize that cost savings from scale-up are not meaningful if the program fails to generate any impact after scaling up. While ng power . Yet, beJeevika, for example, implementation research found that the program was less consistent in applying some of the ritualized processes of group activities after its scale-up, and coordinators spent less time on gathering contextual information and adapting their messaging for mobilization (The differences in costs, impacts, and cost-effectiveness between the pilot and the scale-up suggest a need for a more nuanced interpretation of our findings. Implementers and researchers must identify early on the factors that lead to better implementation quality and therefore higher impact. In the case of lization . Along wJeevika even with an increase in costs, as long as Jeevika maintains the elements that were critical for success during the pilot phase. Further, the costs of contextual information and mobilization are mostly one-time costs, which likely do not require long-term investments. Extrapolating the information presented in From a policy perspective, these findings suggest that SHG programming at scale could increase its cost-effectiveness by prioritizing program elements that evaluations of pilot programs identify as critical for achieving positive impacts on women’s empowerment and asset ownership. Qualitative evidence indicates that gathering contextual information and adapting messaging for mobilization was critical for achieving positive effects on women’s empowerment. Strengthening these program elements at scale could increase the cost-effectiveness of Minimizing tradeoffs between impacts and cost savings after scale-up also requires addressing factors that influence SHG dropout. Specifically, the leadership of higher-level federations plays an important role in conflict resolution , likely Jeevika’s SHG program faced similar challenges. Our study shows that it is critical to examine the costs and cost-effectiveness of development programs at different stages of program scale. Such analyses require longitudinal data on the program activities – specifically the components that are critical for program effectiveness, costs, and impact, and how these change with the number of program participants. These data are currently very scarce, including on SHG programs in other Indian states, which makes it challenging for decision makers to make evidence-based decisions about the scale-up of international development programs. For SHGs in particular it is critical to examine how changes in costs after scale-up are related to the group-based nature of SHGs. Recent studies indicate that training SHG members in a group setting could lead to more cost-effective outcomes than training SHG members individually (Jeevika data on specific cost categories did not include sufficient detail about group-based versus individual activities, but future studies should examine this question by collecting primary data on cost ingredients by economic activity, following existing guidelines and tools (Studies have shown that implementing development interventions at scale is challenging. In a recent note on insights from research in development economies, vidually . These dnd tools .Regardless, however, our results show that the current emphasis on the reduced effectiveness after program scale-up is not sufficient and may result in a biased view about the possibility of achieving positive impacts at scale when studies fail to account for the existence of economies of scale. While program effectiveness may reduce after scale-up for most international development programs , the preJeevika led to a reduction in interest rates charged by informal moneylenders (We recognize that the implementation and costs of large-scale SHG programs in India differs widely across contexts, showing the importance of studying women’s group implementation models . This stylenders , may impGarima Siwach: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing. Sohini Paul: Data curation, Investigation, Writing – original draft, Writing – review & editing. Thomas de Hoop: Conceptualization, Resources, Funding acquisition, Writing – original draft, Writing – review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.