To compare the influence of posterior capsule opacification (PCO) morphology and severity on intraocular stray light and visual function with different levels of contrast.Forty-five patients diagnosed with PCO were included in this prospective consecutive case series. The Optical Quality Analysis System II (OQAS II) was adopted to assess the objective visual function including objective scatter index (OSI) and optical quality analysis system values (OVs) with 100, 20, and 9% contrast. RTVue-100 OCT was used to evaluate the PCO morphology and severity. Comparisons among visual function, morphology, and severity between pear type and fibrosis PCO were performed. The correlations among the PCO morphology, severity, OSI, and OVs were also determined.p = 0.02). The OSI was significantly higher in pear type PCO when compared with fibrosis PCO . In addition, the increased OSI in pear type PCO was significantly correlated with the 100% OVs and the 20% OVs but not with the 9% OVs. In fibrosis PCO, OSI was only correlated with the 100% OVs and the 20% OVs pre-YAG.There was a significant correlation between increased OSI and decreased visual acuity in PCO patients before laser capsulotomy. The changes of OSI were also correlated with the PCO area for the 3 mm IOL optic region (r = 0.43, OSI and OVs could objectively indicate the visual function impairment in PCO patients. Effects of PCO on light scattering and on objective visual function might be explained by the variations of morphology and severity. Posterior capsule opacification is still the major complication after cataract surgery, which impairs the visual function of 28% of patients 5 years after IOL implantation . Laser cIn previous studies, C-quant was used to assess the forward light scatter. However, this approach was based on the subjective compensation comparison method –7 and waSince previous studies have emphasized the influence of PCO morphology and severity on visual function, pear type and fibrosis PCO affect visual function, including visual acuity and contrast sensitivity, differently , 11, 15.Therefore, we combined the forward scatter method, OQAS-II, to assess the objective visual function and the backward scatter method, OCT, to assess the morphology of PCO. We aimed to compare the influence of different kinds of PCO morphology and severity on intraocular stray light and on visual function with different levels of contrast. We believe that objective visual function evaluation combined with morphology assessment plays an important role in PCO prevention and treatment.This prospective study recruited posterior capsule patients in Tianjin Eye Hospital. The study was reviewed and approved by the Research Review Broad of Tianjin Eye Hospital. Informed consent from each patient was collected before the examination and surgery, and the study strictly adhered to the tenets of the Declaration of Helsinki (1989). Patients with corneal opacity, glaucoma, trauma, complicated ocular surgery, and severe systemic disease were excluded from the study. All the surgeries were performed by one expert doctor. Routine ocular examinations including visual acuity VA , intraocular pressure, auto-refractometer examination, slip lamp examination and fundus examination were done before surgery.VA measured with the logarithmic visual acuity chart and converted to the logarithm of the minimum angle of resolution (logMAR) values for analysis.OQAS II  was adopted to access the quality of the visual system, the measurements including objective scatter index (OSI) and the optical quality analysis system values (OVs). The pupil diameter setting was 4 mm. Patients’ refractive errors were corrected by setting the real refractive state in the equipment before measurement. Patients were told to blink before measurement to reduce the influence of tear film. OSI was an objective quantification of the intraocular scattered light, which was defined as the ratio between the integrated light in the periphery and in the surroundings of the central peak of the double pass image. The central area was a circle with a radius of 1 min of arc, and the peripheral was a ring set between 12 and 20 min of arc. The OSI for normal eyes is approximately 1, and values over 5 represent highly scattered systems . OVs refRTVue-100 OCT  was used to evaluate the area, thickness and density of PCO with cross sectional images on the horizontal and vertical meridian at 3 mm IOL optic region. After pupil dilation, the corneal anterior module long adaptor lens was installed to the detecting probe. Patients fixated on the front red indicator light using the other eye. The cornea cross line mode was used to take the images of the PCO on the vertical and horizontal meridians. The images were then transferred to a personal computer for further analysis using Image-Pro Plus software 6.0. The area, thickness and density of the opacification at the 3 mm optic zone were measured. Similar method was used to value opacification area, thickness and density at 5 mm optic zone. Values of the vertical and horizontal meridians were then averaged for further analysis  OQASII measurement, and 34 eyes completed the post-YAG OQASII measurement (26 eyes with pear type PCO and 8 eyes with fibrosis PCO). The average age was 69.17 + 10.93 years. PCO time was 43.24 + 30.67 months (ranges: 10–132 months).p = 0.001). The VA improvement was also positively related to the OSI decrease, described in Fig. p ≤ 0.001).The LogMAR VA and OSI of PCO patients before and after laser capsulotomy are shown in Table The arc shaped PCO region ‘DFHIGE’, as described in Fig. 2, 0.12 ± 0.06 (0.03–0.24) mm and 44.14 ± 11.09 (27.49–68.26) at 3 mm optic zone, respectively. At 5 mm optic zone, PCO area was area, thickness and density were 0.59 ± 0.31 (0.08–1.23) mm2, 0.10 ± 0.05 (0.01–0.20) mm and 39.22 ± 10.61 (22.13–65.3), respectively. PCO area at 3 mm optic zone was significantly correlated with the OSI reduction after laser capsulotomy  as described in Fig. p = 0.76). The density and thickness were not statistically correlated.The severity of PCO was evaluated with PCO area, thickness and density, which were 0.48 ± 0.24 (0.07–1.04) mmp = 0.05 at 3 mm optic zone; Z = − 3.14, p = 0.002 at 5 mm optic zone; Z = − 2.71, p = 0.007 at 6 mm optic zone) and was thicker than the fibrosis PCO . The density of these two kinds of PCO was not significantly different . In addition, the area of pear type PCO at 3 mm optic region was correlated with the OSI reduction after laser capsulotomy ; for fibrosis PCO, the correlation decreased .The differences between pear type PCO and fibrosis PCO are shown in Fig. p = 0.001). After laser capsulotomy, VA increased, and there was no significant difference between the fibrosis PCO and the pear type PCO  . Laser capsulotomy significantly decreased the OSI of pear type PCO. The OSI of fibrosis PCO also decreased, though it was not statistically significant. After laser capsulotomy, there was no significant difference in OSI between fibrosis PCO and pear type PCO   Table .p ≤ 0.001; Z = − 3.9, p ≤ 0.001; Z = − 3.96, p ≤ 0.001).Before laser capsulotomy, the 100% OVs, 20% OVs and 9% OVs were 0.24 ± 0.20, 0.18 ± 0.13, and 0.12 ± 0.09, respectively, which significantly improved after laser capsulotomy: 0.62 ± 0.36, 0.39 ± 0.28 and 0.25 ± 0.15, respectively . After laser capsulotomy, the differences were not statistically significant.Comparing the OVs of fibrosis and pear type PCO, similar improvements were observed in Fig. b, c. HowThe OVs evaluated the objective visual acuity under three contrast conditions, as described in Table 3 and doubles by the age of 65 years, tripling by the age of 77 years [Visual function does not decline substantially until 50 years of age, but especially declines in the age range of 61–70 years . Stray l77 years . PCO is 77 years .In our study, OQAS-II was used to objectively evaluate the intraocular stay light. What we found was that pre-YAG OSI was 9.87 ± 4.73 and that LogMAR VA was 0.50 ± 0.27. It was reported that in the pseudophakic eye, OSI was 1.06 ± 0.48 and LogMAR VA was − 0.26 ± 0.06; in normal eyes, OSI was 1.03 ± 0.65 and LogMAR VA was − 0.25 ± 0.06 . Our finp = 0.07) [After laser capsulotomy, OSI decreased obviously, accompanied by significant VA improvement. The changes in OSI were well correlated with those of VA. These findings are supported by previous studies showing that laser capsulotomy removed the opacified posterior capsule and increased VA, CS –27 and i = 0.07) . Similar = 0.07) .To assess the effect of PCO morphology and severity on visual function, we classified the fibrosis and pear type PCO and analyzed the area, thickness and density  of theseWe found a positive correlation between the 3-mm PCO area and the OSI difference, which suggests that the larger opacification area might be paralleled by higher scatter light. We define PCO severity by multiplying the PCO area by density and found that it was also related with the OSI but not with the VA. This finding agreed with the previous finding that in PCO patients, stray light increased with good visual acuity . PCO sevWhen comparing the pear type PCO with fibrosis PCO, we found a larger area and a thicker sub-capsular opacification but a higher density of fibrosis PCO than pear type PCO. As reported, fibrosis PCO originated from cuboidal epithelial cells that lined the anterior capsule and resulted in wrinkling and thickening of the adjacent posterior capsule. It was reported that EPCO scores and PCO refractions evaluated with retro-illuminations in pear type PCO were significantly higher than those of the fibrosis PCO . Pear tyIn addition, Romina et al correlated the PCO severity with visual function and suggested that clinically considered high density fibrosis PCO might have a less deleterious effect on visual function compared with less severe pear PCO because light may be attenuated by the dense fibrosis PCO but may be scattered more in the pear PCO . Our resSince the daily optical environment varied in the light contrast, VA did not reflect visual function comprehensively. We evaluated the VA under three contrast conditions, 100, 20, and 9%. The OVs in our study were lower than those of the pseudophakic eyes , and theOur study has some limitations. The number of fibrosis PCOs was small, which may have limited the fibrosis PCO results. However, the results of fibrosis PCO in our study were consistent with previous results as we discussed above. Another limitation was that we used RTVue-100 OCT to assess the PCO severity on two cross-sectional images of the anterior segment using the opacification area, thickness and density. We found differences between fibrosis PCO and pear type PCO, and the correlation between PCO area with OSI changed, but we could not ignore the fact that cross-sectional images cannot represent the complete opacification. Therefore, further study with a more comprehensive method may be needed.In summary, PCO caused visual function impairments including increased scattered light and decreased VA. The increased intraocular scattered light was significantly correlated with the decrease in VA and the decrease in OVs. Pear type PCO tended to result in more serious visual impairment compared with fibrosis PCO, such as the lower VA and OVs with the 100, 20, and 9% contrast levels, as well as the higher OSI. This result agreed with the morphology and severity of pear type PCO, which tended to show a thicker and wider opacification compared with the fibrosis type.PCO with different morphology and severity showed different degrees of light scattering and objective visual function impairment. Laser capsulotomy removed PCO and improved visual function. OQASII measured OSI and OVs could objectively indicate the visual function impairment caused by PCO.


Few studies have documented the marketing of commercial foods and beverages for infants and young children in West Java, Indonesia. To assess the prevalence of promotions at points‐of‐sale for commercially produced products commonly fed to young children in Bandung City, 43 small and large stores were visited in 2017. Promotions for breastmilk substitutes (BMS), commercially produced complementary foods (CPCF), and select types of commercial snack products were photographed and information recorded on promotion characteristics. There were 402 and 206 promotions observed with BMS and CPCF products, respectively. Sixteen promotions with BMS products for infants under 12 months were found in 42.9% of stores selling BMS, violating national regulations. Almost all BMS promotions (98.3%) included BMS products for ages 1 year and above (“growing‐up milks”). Of all BMS products available for sale, half of all infant/follow‐up formula and 77.2% of growing‐up milks were promoted. CPCF were found in 97.7% of stores, and 81.0% of these stores had promotions; 70.5% of all available CPCF products were promoted. Of the 2,451 promotions observed for commercial snack products, 17.3% used promotional techniques targeting young children or caregivers. Joint‐promotions were common, with BMS and CPCF marketed in combination with commercial snack products; 49.0% of BMS promotions were joint BMS‐snack promotions, and 80.0% or more of infant/follow‐up formula promotions included a commercial snack. Revising and enforcing infant food and beverage marketing regulations to ensure consistency with global standards are necessary to protect and promote optimal infant and young child feeding in Indonesia. Promotions for commercial infant and young child feeding products were wide‐spread in points‐of‐sale in Bandung City, Indonesia.Violations were observed of Indonesian regulations and the International Code of Marketing of Breast‐milk Substitutes.Almost all BMS promotions included a growing‐up milk and 49.0% included a joint‐promotion with commercial snack products.Nearly one‐fifth of promotions for five categories of commercial snack products were targeted to children or caregivers.Enforcement of national regulations is necessary to prevent promotions that can negatively impact child feeding. Additional regulations should be considered to restrict promotion of BMS for older children, joint‐promotion of BMS with commercial snacks, inappropriate promotion of commercial complementary foods and child‐targeted advertising of unhealthy commercial snack products.1The World Health Organization (WHO) and United Nations International Children's Emergency Fund (UNICEF) recommendations for optimal infant and young child feeding include exclusive breastfeeding for the first 6 months of life, at which point safe and appropriate complementary foods should be gradually introduced to a child's diet alongside continued breastfeeding up to 2 years and beyond , stating that CPCF may be promoted if they meet relevant guidelines for “composition, safety, quality and nutrient levels”  Protocol for Periodic Assessments , neighbourhood cooperative grocery stores (koperasi), minimarts and pharmacies (apotiks). Small stores were sampled for their proximity to public sector health facilities offering child health services ;infant cereal, including instant grain snacks/finger foods, including products such as biscuits/cookies, puffs or rusks;pureed foods and infant meals, which may include cereal, pasta, meat, poultry, fish, eggs, fruits and/or vegetables;infant pudding (instant milk/gelatine pudding); andabon (finely shredded meat).other CPCF products, including tea, juice, olive oil or CPCF were foods marketed as suitable for feeding young children if they met at least one of the following criteria: (1) recommended for introduction at an age of less than 3 years; (2) labelled with the words “baby”, “toddler,” “young child,” or synonym; or (3) in any other way were presented as being suitable for children under the age of 3 years ;savoury/salty snacks such as chips/crisps, crackers and agar‐agar;candy, chocolate and jellies/sweetened milks, defined as milks marketed for general consumption, with added sugar and flavour, excluding sweetened condensed milk; andmalt‐based beverages (e.g. Milo) and non‐dairy milks.Commercial snacks were defined as manufactured, packaged products marketed for consumption by all ages , online research and informal visits to seven stores. The final master lists included product brand, flavour, product description, age of use and manufacturer. Different flavours of a product were listed as different products. Products with varying package sizes  and different types of packaging  were listed as one product. Each product was assigned a unique identification code for data collection and analysis. Master lists for the commercial snack products were not generated because the large number of products on the market made this logistically unfeasible.To guide data collection on product availability, comprehensive master lists of all BMS and CPCF products for sale in Bandung City were generated through a review of the In each store, data on product availability were captured first. All areas inside a store were thoroughly surveyed  to identify all products for sale. Enumerators systematically matched each BMS and CPCF product found throughout the store to a paper copy of the master lists, checking off each individual product identified for sale. Any products not found on the master lists were added to the list for all subsequent points‐of‐sale to be visited.price‐related, such as coupons, discounts or buy‐one‐get‐one;displays, including brand shelves/counters/tables, special shop windows, posters/banners or shelf tags/talkers/wobblers;information materials, like leaflets, pamphlets/brochures or catalogues;free gifts to customers, such as toys, baby items or plastic food‐storage containers;product samples;company representatives in store;store banners/signs with store name/logo and product logo/brand; andany other promotions, such as contests, store bonus‐points or holiday baskets.Once all information on product availability was recorded, enumerators captured information on each promotion observed throughout the store. A promotion was defined as an individual occurrence of promotional activity in a store for one or more BMS, CPCF or commercial snack product, such as a shelf display, price discount or an informational brochure . If BMS or CPCF were promoted, the unique product codes from the master lists were recorded for each product observed in the promotion. Promotions for BMS and CPCF without distinct product sub‐categories  were captured as “sub‐category cannot be identified.” For each snack product promoted, the snack sub‐category (e.g. sweet biscuit), brand and manufacturer were recorded. Promotion data were collected on electronic tablets using the Android application Open Data Kit (ODK), and uploaded to ONA, an open‐source online platform ONA, . Each pr2.4After data collection was complete, photographs of the commercial snack promotions were reviewed for caregiver‐ or child‐targeting based on seven criteria adapted from previous research . Data were cleaned in Excel and all analyses were run in Stata.The number of unique BMS and CPCF products observed across all stores was summed to calculate overall product availability. Availability was also disaggregated by sub‐category of BMS and CPCF, manufacturer and location of production (domestic or imported). The number of stores selling at least one type of product or one product sub‐category was calculated to report availability by store.The number of stores with at least one promotion observed for each product type was determined. Percentage of stores with promotions was calculated by dividing the number of stores with promotions by the number of stores selling the product. Data on the availability of commercial snack products were not collected due to the overwhelming number of items available, so the percentage of stores selling snack products is reported out of all 43 stores in the study. Promotion data by store are also presented by small or large store size.The number and percentage of available BMS and CPCF products that were found promoted across all stores were calculated by dividing the number of products promoted by the number of products found available for sale. If a product was documented in at least one promotion, it was counted as promoted. Promotion by availability was also calculated for each BMS and CPCF sub‐category.The number and percentage of all promotions found across the 43 stores were calculated by type of product and sub‐category. If a promotion had at least one product type/sub‐category, it was included in the count of promotions. Promotions including multiple categories of products were classified as joint‐promotions, and the different combinations of product types were examined. The total numbers of BMS, CPCF and snack promotions were also disaggregated by type of promotion (e.g. price or display). Snack promotions were considered child‐targeted if they included at least one of the two criteria, and caregiver‐targeted if they included at least one of the five criteria.33.1n = 46), Nestle  and Kalbe . Sixty‐nine percent (n = 101) of all BMS products were domestically produced: 56.8% of infant formula products (n = 25), 70.8% of follow‐up formula products (n = 17) and 74.7% of growing‐up milk products (n = 59).In the 43 stores surveyed, 147 unique BMS products were found: 44 infant formulas, 24 follow‐up formulas and 79 growing‐up milks. The BMS products were from 13 different manufacturers, with three producing over 60% of those observed: Nutricia , in all 10 of the large stores and 18 of the 33 small stores (54.5%). The number of stores carrying the sub‐categories of BMS was similar, with 26 selling infant formula (60.5%), 25 selling follow‐up formula (58.1%) and 28 selling growing‐up milk (65.1%).n = 97), followed by snacks/finger foods , purees and infant meals , puddings  and other CPCF , which included thee olive oils, two teas and one abon. These items were produced by 20 different manufacturers, with three producing over half of all CPCF products: Indofood , Kraft Heinz  and Kalbe . Half of the 220 CPCF  were manufactured outside of Indonesia. The majority of infant cereal products  and all puddings (n = 7) were domestically produced, and most snacks/finger food products , purees and infant meals  and other CPCF products were imported .A total of 220 unique CPCF products were found. Infant cereal was the most common sub‐category of CPCF found . Nearly all stores sold an infant cereal product  and half had snacks/finger foods . Purees and infant meals, puddings and other CPCF products were observed less frequently .CPCF were almost universally available across all 43 stores  had promotions for infant and/or follow‐up formula. Nearly all stores in the study (95.3%) promoted the study's subset of commercial snack products commonly fed to children.BMS and CPCF products were promoted in the majority of the stores they were sold in . Promotions were more prevalent for BMS and CPCF in large stores  than small stores (77.8% and 75.0%). Almost half of stores selling BMS  included sweetened milk, followed by 71.4% (n = 15) with savoury snacks, 61.9% (n = 13) with malt‐beverages/non‐dairy milks, 57.1% (n = 12) with sweet biscuits and 38.1% (n = 8) with candy/chocolate/jellies.BMS products were jointly promoted with CPCF products in eight promotions Table , althougPrice‐related promotions were the most common method of promotion, accounting for 44.8% of all BMS promotions, 60.7% of CPCF promotions and 58.1% of commercial snack promotions Figure . DisplayTable n = 32), infant cereal  and puddings . Gift promotions were highly prevalent for purees and infant meals  and puddings . Price promotion was also the most frequently observed promotion method for all commercial snack product sub‐categories, followed by display promotions.Although overall the most common type of CPCF promotion was price promotion, the type of promotion varied by sub‐category of CPCF. Price promotions continued to be common for promotions with snacks/finger foods  met at least one of the criterion for child‐ or caregiver‐targeting. In total, 214 (8.7%) were child‐targeted, 119 (4.9%) were caregiver‐targeted and 92 (3.8%) were both child‐ and caregiver‐targeted. Figure In the review of 2,451 promotions with commercial snack products, 17.3%  violates the Code and subsequent resolutions. In addition, Indonesian law prohibits promotion of BMS products for children under 12 months of age. Although only 4.0% of all BMS promotions were in violation of national regulations, these were not isolated promotions. They were observed in 42.8% of all stores selling BMS and promoted half of all the infant and follow‐up formula products for sale. Moreover, these products were frequently found in joint‐promotion with commercial snack products.The promotion of growing‐up milks was rampant—98.3% of all BMS promotions, showcasing three‐quarters of all growing‐up milk products available for sale—and strongly reinforces the need to expand the scope of age covered in national regulations. Recent research in Bandung City found that 47.0% of children 12–23 months and 55.1% of children 24–35 months consumed a BMS in the prior day , promoting excess sugar consumption. A recent multi‐country study documented other instances of placement of BMS and CPCF in the same promotion at points‐of‐sale  were local or national chain stores, so promotions observed were likely to be found throughout the city and country. For commercial snack products, only a subset of categories was examined, which does not represent the totality of snack promotions or totality of promotions for commercial foods high in fat, sugar or salt in these stores. Additionally, we did not assess purchase or consumption of products so it is not known if promotion in this research led to greater consumption of these products. This assessment was carried out with assumptions about store characteristics and retail behaviour, which could have introduced bias: different store types were visited at different times/days of the week, which could have led to differentials in promotion observation, and the store sampling methodology differed between small and large store types.This study has several limitations. Stores sampled for this study were not representative of all vendors in the city; however, WHO's recommended NetCode protocol was followed and 44.2% of the stores (5International Code of Marketing of Breast‐Milk Substitutes and subsequent WHA resolutions, with significant repercussions for violators, would be useful in curbing industry violations. Expansion of current national laws to align with WHO guidance and protection of young children from the harmful effects of unhealthy consumption is urgently needed.This research conducted in large and small stores across Bandung City, West Java, Indonesia, has revealed numerous promotions for BMS, CPCF and commercially produced snack products, with several BMS promotions illegal under Indonesia law. A high prevalence of child‐ and caregiver‐targeted snack promotions was found, along with frequent joint‐promotion of BMS, CPCF and commercial snacks. Overall, these promotions may be contributing to decreased breastmilk intake and/or increased consumption of trans‐fats, sugar and salt among young children, ultimately leading to long‐term health consequences. A national system for monitoring and reporting violations of the The authors declare that they have no conflicts of interest.DH, MG, AS and MC prepared the manuscript, with input from DI. DH, A and MG collected the data, A coded data and MG oversaw data collection and coding. MG cleaned and analysed the data. AS guided data interpretation and provided technical insight. All authors reviewed and provided input on the final article.


Cochlear implant (CI) programming is similar for all CI users despite limited understanding of the electrode-neuron interface (ENI). The ENI refers to the ability of each CI electrode to effectively stimulate target auditory neurons and is influenced by electrode position, neural health, cochlear geometry, and bone and tissue growth in the cochlea. Hearing history likely affects these variables, suggesting that the efficacy of each channel of stimulation differs between children who were implanted at young ages and adults who lost hearing and received a CI later in life. This study examined whether ENI quality differed between early-implanted children and late-implanted adults. Auditory detection thresholds and most comfortable levels (MCLs) were obtained with monopolar and focused electrode configurations. Channel-to-channel variability and dynamic range were calculated for both types of stimulation. Electrical field imaging data were also acquired to estimate levels of intracochlear resistance. Children exhibited lower average auditory perception thresholds and MCLs compared with adults, particularly with focused stimulation. However, neither dynamic range nor channel-to-channel threshold variability differed between groups, suggesting that children’s range of perceptible current was shifted downward. Children also demonstrated increased intracochlear resistance levels relative to the adult group, possibly reflecting greater ossification or tissue growth after CI surgery. These results illustrate physical and perceptual differences related to the ENI of early-implanted children compared with late-implanted adults. Evidence from this study demonstrates a need for further investigation of the ENI in CI users with varying hearing histories. Newborn hearing screening has led to earlier detection of hearing impairments, allowing more children with severe-to-profound hearing loss to receive cochlear implants (CIs) at young ages  refers to the effectiveness with which each electrode stimulates its target spiral ganglion neurons. Suboptimal interfaces can result from electrodes positioned distant from target neurons  is another technique that could provide information about the effect of hearing demographics on the cochlear environment. EFI uses the built-in telemetry systems of modern CIs to measure how intracochlear potential is distributed in the cochlea  and eleven adults aged 48 to 84  with CIs participated in this study. Half of the children  failed a newborn hearing screening. The other children were diagnosed with severe-to-profound hearing loss prior to age four . All children received their first implant before age 5 . All adults were born with acoustic hearing, were diagnosed with severe-to-profound hearing loss in adulthood , and received their first CI at much older ages compared with the children . Ten children and three adults were bilaterally implanted; however, due to the large difference in number of bilaterally implanted individuals between the groups, only first-implanted CIs were included in this study. Participant demographics and speech identification scores are in Table Pediatric and adult CI users were recruited from hospitals and audiology clinics in the greater Seattle area. All participants used oral communication and were native speakers of American English. To minimize potential sources of variability, all participants utilized Advanced Bionics HiRes 90K devices and HiFocus 1J electrode arrays. In addition, individuals with electrode positioners were excluded from this study because (1) positioners are designed to place the electrodes closer to target neurons, and distance could affect auditory detection thresholds  is the steering coefficient: when ɑ = 0, all steered current passes through the more apical active electrode; when ɑ = 1, all steered current passes through the more basal active electrode. Electrode channel number  is typically defined by the basal active electrode. However, because the sQP configuration requires four electrodes, this arrangement is not possible to steer current for electrode 2. Instead, the same set of electrodes as steering for channel 3 are used, and an α value of 0 is set to center the current on electrode 2. This arrangement is “channel 2” despite electrode 2’s position as the apical active electrode.Thresholds were obtained with σ = 0 (monopolar) and σ = 0.9 (focused) electrode configurations. The sigma value for focused thresholds was chosen because it allowed for the presentation of current levels that were perceptible but below voltage compliance limits. These limits, defined as the maximum voltage supported by the device divided by the impedance of that electrode channel, were calculated for each subject at the beginning of the test session. For one participant (P08), however, a sigma value of 0.8 was used because this subject’s thresholds with σ = 0.9 could not be obtained without reaching voltage compliance limits. As the sigma value affects threshold levels, sensitivity analyses were performed by removing this subject’s data. The overall findings of this study were unaffected.Stimuli were biphasic, charge-balanced pulse trains with the cathodic phase leading. Pulses were 97 microseconds (μs) in duration and were presented at a rate of 997.9 pulses per second. Each pulse train was 200.4 milliseconds (ms) long. The Bionic Ear Data Collection System  and custom software in MATLAB  were used to present stimuli and record participant responses.MCL was first determined behaviorally for each channel using the Advanced Bionics clinical loudness scale . This scale ranges from “1” (“Just Noticeable”) to “10” (“Too Loud”). Current level was increased manually until subjects reported a loudness rating of “6” . MCL was then set as the upper limit for stimulation, ensuring that presented current levels for each participant would not exceed comfortable levels.For each electrode configuration, participants performed threshold sweeps of electrodes 2 through 15 in which ɑ was changed in steps of 0.1. Thresholds for electrodes 1 and 16 were not acquired because the focused electrode configuration necessitates flanking electrodes. Participants performed one forward sweep  and one backward sweep . Each sweep utilized a Békésy-like tracking procedure Békésy : the lisCurrent level requirements varied greatly between the electrode configurations as well as subjects’ individual electrode channels, and thus the logarithmic decibel scale was used. This scale is considered to be more suitable than a linear scale for reporting such values because CI loudness growth functions are typically nonlinear  was utilized to assess the variation in monopolar and focused thresholds across the electrode array. The standard deviation of the signed differences in thresholds between each adjacent electrode was calculated from the threshold profiles of each participant. Use of the standard deviation instead of the mean difference between channels provides a measurement of the local variability, as opposed to the absolute magnitude of variability of all channels  or maximum acceptable levels (MALs), so that children would not be exposed to sounds that were louder than “comfortable.” The differences between MCL and threshold in dB for each electrode were calculated for each participant for both the monopolar and the focused electrode configurations. For a subset of channels for one child and for several adult subjects , voltage compliance limits of the device were reached at current levels below MCL with focused stimulation. The level of current at compliance limit was not the true MCL for such channels, and therefore focused MCL and dynamic range values for those channels were not included in the analyses.A one-way MANCOVA was conducted to compare dynamic range between early-implanted children and late-implanted adults. Monopolar and focused dynamic range were dependent variables, “Group” was the independent variable of interest, and “Electrode” was included as a covariate to account for variance in dynamic range due to electrode site.The level of current used to define the upper limit of the dynamic range, the MCL, is also a measure related to the ENI and could potentially differ between early-implanted children and late-implanted adults. Therefore, an additional one-way MANCOVA testing a separate hypothesis was performed with focused and monopolar MCLs as the dependent variables. “Group” was set as the independent variable and “Electrode” was again included as a covariate to control for site-specific effects on MCL. A Bonferroni correction for multiple comparisons for each analysis was performed at ɑ = 0.025.Electrical field imaging (EFI) data were collected using BEDCS . The stimuli were biphasic monopolar pulses  delivered at a rate of 16.6/s. Ten pulses were presented consecutively on each electrode site, while the voltage on every electrode was recorded sequentially at a 56 kHz sampling rate.long; resistance to current flow from the electrode along the length of the cochlea), transverse , and total  resistances. The resistor components of the network were labeled Rlong and Rtrans for each electrode position. The values were estimated using least squares optimization, with a localized weighting scheme to improve fitting of the EFI profiles and a regularization constraint to impose some degree of smoothness on the Rlong and Rtrans values across electrodes. One additional resistor value was defined for each stimulating electrode, as the peak of the reconstructed EFI profile (based on the solution to the ladder network). This value was termed Rtotal, as it represented the total resistance encountered by the stimulation electrode, incorporating all possible current pathways in the resistor network model.The data were analyzed offline using MATLAB . After averaging, signal amplitude at each recording electrode was calculated as half the difference between the positive and negative voltage excursions, then scaled to units of resistance. Following the approach of Vanpoucke et al. , the 16 long, Rtrans, and Rtotal for each electrode of a subject’s array. A one-way MANCOVA was performed to examine potential differences in these intracochlear resistance values between children and adults. Rtrans, Rlong, and Rtotal were dependent variables and “Group” was the independent variable. “Electrode” was included as a covariate to control for site-specific effects on intracochlear resistance. A Bonferroni correction for multiple comparisons was performed at ɑ = 0.017.This analysis resulted in estimates for RClinical electrode impedance measurements for each electrode in each participant’s array were collected via SoundWave software  at the beginning of the testing session in which EFI data were collected. A one-way univariate analysis of covariance (ANCOVA) was conducted to determine whether electrode impedance differed significantly between early-implanted children and late-implanted adults. “Electrode” was included as a covariate to account for any site-specific changes in electrode impedance.long was set as the independent variable in this model. This EFI component assesses resistance to current within the cochlea instead of resistance to current flowing out of the cochlea  = 9.5, p < 0.001, Wilk’s ƛ = 0.941, partial η2 = 0.059) when controlling for electrode site. Focused thresholds were significantly different between the children and adults  = 16.1, p < 0.001, partial η2 = 0.051). Significant differences were not observed between groups for monopolar thresholds  = 1.9, p = 0.17, partial η2 = 0.006). No significant effects of electrode site on threshold profiles were found  = 2.5, p = 0.08, Wilk’s ƛ = 0.983) suggesting that group means were not significantly driven by thresholds from specific electrodes.Focused thresholds across the electrode array were higher than monopolar thresholds in early-implanted children as well as in late-implanted adults, consistent with previous studies conducted in adults with CIs  = 0.6, p = 0.943, Wilk’s ƛ = 0.994). Channel-to-channel variability did not differ significantly between children and adults for either electrode configuration  = 0.07, p = 0.80; monopolar: F = 0.10, p = 0.76).Channel-to-channel variability was defined as the standard deviation of the signed differences in threshold between neighboring electrodes. For the monopolar electrode configuration, channel-to-channel variability ranged from 0.29 to 3.91 dB in children and from 0.8 to 4.16 dB in adults  = 0.30, p = 0.74, Wilk’s ƛ = 0.998). Average values were very similar between groups  = 3.9, p = 0.051, Wilk’s ƛ = 0.977).Similarly, as shown in Fig. F,259 = 0.F = 15.9, p < 0.001, Wilk’s ƛ = 0.891, partial η2 = 0.109). Children had significantly lower MCLs for the focused  = 31.9, p < 0.001, partial η2 = 0.1099) and monopolar  = 11.7, p = 0.001, partial η2 = 0.043) electrode configurations. Uncorrected means and standard deviations are in Table F = 6.7, p = 0.001, Wilk’s ƛ = 0.951, partial η2 = 0.049). This finding was significant for MCLs obtained with the monopolar configuration only  = 9.2, p = 0.003, partial η2 = 0.034; focused  = 0.01, p = 0.93). MCLs obtained with monopolar stimulation demonstrated a consistent increase from the most apical (electrode 2) to the most basal (electrode 15) channel. This observation is akin to that of Baudhuin et al. While dynamic range itself did not significantly differ between early-implanted children and late-implanted adults, a significant effect of group was found for the upper limit of the dynamic range  = 9.4, p < 0.001, Wilk’s ƛ = 0.920, partial η2 = 0.080) as well as electrode site  = 10.4, p < 0.001, Wilk’s ƛ = 0.912, partial η2 = 0.088) after correcting for multiple comparisons (ɑ = 0.017). Children demonstrated significantly higher Rtrans  = 20.9, p < 0.001, partial η2 = 0.060) and Rtotal  = 9.9, p = 0.002, partial η2 = 0.030) compared with adults. No significant differences between groups were observed for Rlong  = 2.7, p = 0.097), although on average, children did exhibit higher Rlong values, as shown in Fig. long values of children and adults  = 6.6, p = 0.010, partial η2 = 0.020) and Rlong  = 19.0, p < 0.001, partial η2 = 0.055). The location of the electrode in the array influenced the mean values for both groups: on average, both types of resistance were greater for basal electrodes compared with apical electrodes. Electrode site was not found to significantly influence Rtrans  = 2.2, p = 0.135).Analysis of EFI intracochlear resistance values between early-implanted children and late-implanted adults revealed a significant effect of group  = 0.05, p = 0.82, partial η2 = 0; see Table F = 74.7, p < 0.001, partial η2 = 0.176). Basal electrodes exhibited higher impedance levels than apical electrodes, similar to the results found for Rlong and Rtotal, and consistent with findings from previous studies in adults and children with CIs that controlled for physical characteristics of the electrode array  = 80.0, p < 0.001). This result suggests that these measures are related, and perhaps similarly affected by the degree of ossification and tissue growth in the cochlea.Despite demonstrating significantly higher EFI component values, early-implanted children’s clinical electrode impedance values were similar to those of late-implanted adults . Increased intracochlear resistance (R) in children would lead to less current flow (I) along the cochlea and away from the neural targets to equal the same driving voltage gradient (V) at the spiral ganglion as in the late-implanted adults. Less current (I) would therefore be required to achieve threshold in individuals with higher intracochlear resistance (R). Continued study is needed to better understand how the complex geometry of the cochlea affects the spread of excitation with CI stimulation.long, which reflects global current flow within the cochlea, to thresholds of participants . A significant interaction between “Group” and “Stimulus Type” was also found , demonstrating that thresholds were significantly different between groups even when intracochlear resistance was taken into account. Altogether, these results indicate that hearing demographics can alter physical characteristics of the cochlea that influence auditory signal transmission.An exploratory regression analysis was performed to investigate whether intracochlear resistance levels of the participants in this study affected auditory detection thresholds. A linear mixed-effects model was performed in R using the lme4 package (Bates et al. Consistent with previous studies in adults (e.g., Bierer Examinations of individual participant data revealed that children had regions of relatively elevated focused thresholds within their threshold profiles, akin to late-implanted adults. Although early implantation has been associated with better outcomes for children (e.g., Wang et al. Further, although the relation between spectral discrimination and speech identification scores in pediatric CI users may depend on the tests utilized (e.g., DiNino & Arenberg, 2018; Gifford et al. In conclusion, the differences related to the ENI between early-implanted children and late-implanted adults may be explained by neuronal survival, etiology of deafness, or other factors related to intracochlear characteristics. Future studies should investigate the physiological mechanisms that contribute to ENI quality in these groups. Investigations similar to the present study could also be extended to other CI user populations, such as children who had progressive hearing loss or adults who lost their hearing as children. Such studies could provide valuable information about the effect of hearing demographics on auditory signal transmission and perception of individuals with CIs.


From February 2015 through October 2017, 25 patients  underwent 637 telephone interventions. In 57.5% of the calls no problems were identified, 3.9% were recalled on the next day because of alarms. In 26.5% (n = 169), the VAD Coordinator had to refer to the physician due to elevated blood pressure , INR < 2.0 or > 4.0 (n = 24) or edema (n = 10), 11.9% of the calls led to a follow‐up because of equipment or exit‐site problems. Propensity‐adjusted 2‐year survival  was significantly higher for the telephone intervention group. Continuous, standardized communication with VAD outpatients is important for early detection of upcoming problems and leads to significantly improved survival.Ventricular assist devices (VADs) are an established therapeutic option for patients with chronic heart failure. Continuous monitoring of VAD parameters and their adherence to guidelines are crucial to detect problems in an early stage to optimize outcomes. A telephone intervention algorithm for VAD outpatients was developed, clinically implemented and evaluated. During the phone calls, a structured inquiry of pump parameters, alarms, blood pressure, INR, body weight and temperature, exit‐site status and heart failure symptoms was performed and electronically categorized by an algorithm into 5 levels of severity. VAD outpatient outcomes without ( Ventricular assist devices (VADs) are an established therapeutic option for patients with end‐stage heart failure With the establishment of destination therapy (DT) in patients with advanced heart failure, VAD clinicians are faced with the aspect of longer support duration extending into years. While the application of mechanical circulatory support (MCS) as DT has evolved, international experts remain uncertain about the intensity of follow‐up care needed to achieve optimal outcomes To further this reduction, a telephone intervention algorithm for constant communication with VAD outpatients was developed, clinically implemented, and evaluated. The particular aim of this single center study was to test the hypothesis that telephone interventions of left ventricular assist device (LVAD) patients, performed by VAD Coordinators, could aid early identification of potential adverse events and allow earlier interventions leading to a significant reduction in mortality when compared to usual care.n = 25 patients implanted after the clinical telephone intervention implementation were assigned to the study cohort. Freedom to decline and anonymity in all reported data were guaranteed.The study compared usual care (control group) to VAD outpatients who received bi‐weekly standardized telephone interventions Fig.  additionSubjects in the usual care (UC) group continued treatment with the VAD team in the same manner as in the telephone intervention (TI) group, except for bi‐weekly phone calls. In both groups, frequency of outpatient clinic visits  and medical therapy postdischarge was comparable, including phenprocoumon anticoagulation therapy  target range: 2.0–3.0), acetylsalicylic acid (ASA) antiplatelet monotherapy (daily dose: 100–200 mg), and MAP target < 90 mm Hg. The adherence to the INR target range was assessed by the percent of time in therapeutic range (TTR) based on the Rosendaal method Patients assigned to the TI group were followed with a telephone intervention by a VAD Coordinator. No calls were placed if the patient was either currently admitted into hospital, or was seen in the clinic that week, or had already phone contact with the VAD team that week. During the telephone interventions, patients were initially asked an open‐ended question, followed by a structured inquiry about VAD parameters , alarms, MAP, INR, body weight and temperature, driveline exit‐site status, and symptoms of dyspnea and/or edema. The content of the intervention was documented electronically with a graphical user interface Fig.  in the Vn = 4), were pediatric patients (n = 13), follow‐up was performed in another center (n = 4) or for patients recently placed on device, their follow‐up period post discharge lasted less than 12 months (n = 6). This triage resulted in 107 eligible patients (71 UC and 36 TI group) from which 11 patients were excluded because the first telephone intervention was not performed within 1 week following hospital discharge  as Bridge to Transplant (BTT), DT or Bridge to Candidacy (BTC) were included in the study. The maximum follow‐up for each patient was 24 months post discharge.n = 71 UC and n = 25 TI). Demographics and risk factors (only one variable was picked from among a closely related cluster of variables to represent the cluster) were included in the model, using the variables and categories described in Table The UC and TI group showed differences in their demographics, risk factors and operative variables Table . To minin = 22) versus UC (n = 22) group comparison of (i) 2‐year post discharge survival, (ii) 2‐year post discharge freedom from any readmission, (iii) reasons for readmission including total length of hospital stay following 2 years after discharge, and (iv) mean arterial blood pressure (MAP) during regular outpatient follow‐up.This propensity score was used in four complementary analyses: propensity–adjusted TI  or Mann‐Whitney U test  for continuous variables, respectively. Normal distribution was assessed by the Shapiro‐Wilk test. Propensity‐adjusted survival and freedom from any readmission was analyzed using Kaplan‐Meier curves and compared with the log‐rank test. In all analyses, a value of P < 0.05 was considered as statistically significant.Statistical Analysis was performed using SPSS for Windows Release 23.0.0  and R statistical software for Windows, version 3.3.0 . Characteristics of patients with and without telephone intervention are reported as mean ± SD, compared with the Fisher exact test for categorical and the Student's n = 96 outpatients who had undergone LVAD implantation between January 2012 and November 2015 were retrospectively analyzed. Of these, n = 71 received UC and n = 25 bi‐weekly telephone interventions additionally to their UC. Baseline characteristics of the two groups were significantly different. Therefore, a propensity score was derived and applied to all includable VAD outpatients to match the two groups of patients. This PSM resulted in a risk adjusted matched dataset of n = 22 UC and n = 22 TI patients  were implanted. Surgical access was a full sternotomy (34%) or bilateral mini‐thoracotomy (66%). Following discharge, postoperative medical therapy included oral phenprocoumon (vitamin K‐antagonist) anticoagulation therapy, with an INR target range of 2.0–2.5 in 82% of the patients and acetylsalicylic acid (ASA) antiplatelet monotherapy with an average daily dose of 135.2 ± 66.1 mg.Of the 44 patients included in the risk adjusted cohort, 15 (34%) received a VAD as BTT, 15 (34%) as DT and 14 (32%) as BTC. Mean age of the patients was 59.6 ± 11.34 years (range 19–77 years), and 16% were female. The cause of cardiomyopathy was dilated in 19 patients (43%). Three different devices (n = 366) of the calls revealed no problems as patients adhered well to institutional guidelines of blood pressure, INR, and pump parameters were within normal operation. Thus, all calls resulted in scheduling the next call in 2 weeks. In 3.9% (n = 25) of the cases, patients were recalled by the VAD Coordinator on the next day to reassess the patient status because of alarms  or minor changes in pump parameters. In 26.5% (n = 169), the VAD Coordinator had to refer to the physician due to elevated MAP or body temperature > 38°C, INR out of range, or a body weight increase of more than +5 kg over the preceding 2 weeks. The most common reasons for assigning the 26.5% calls entering category C were a MAP > 85 mm Hg (n = 125), INR <2.0 or >4.0 (n = 24), or new symptoms of heart failure, for example, peripheral edema and/or dyspnea (n = 10). Overall, 11.9% (n = 76) of the telephone interventions resulted in a follow‐up visit in the following week because of peripheral device problems  or driveline exit‐site infections. Only 0.2% (n = 1) of the calls were assigned to category A and resulted in an immediate readmission. Most of the calls (95.6%) lead to a single severity classification and 4.4% (n = 28) to multiple categories . 42.0% (n = 110) of the detected and classified problems were emerging problems, whereas 58.0% (n = 152) were problems that were already known or under treatment, such as a INR < 2.0 in patients on low‐molecular‐weight heparin (Enoxaparin) therapy, driveline infection under medical treatment, or elevated MAP > 85 mm Hg consequent to elevated antihypertensive therapy by the VAD team within the last week.From February 2015 through October 2017, the 25 patients of the TI group underwent 637 telephone interventions Fig. . Within P = 0.02. Within 24 months post discharge, the frequency of elevated MAP (>90 mm Hg) during regular follow‐up was significant lower (P = 0.047) in TI patients: 22.7% (UC) versus 31.8% (TI) had no, 9.1% (UC) versus 31.8% (TI) one, 36.4% (UC) versus 27.3% (TI) two, and 31.8% (UC) versus 9.1% (TI) multiple (≥3) times elevated MAP during regular follow‐up.Telephone intervention was associated with a significantly reduced MAP measured during regular outpatient follow‐up in the hospital by the VAD Coordinator: 86.3 ± 12.4 mm Hg (UC) versus 82.8 ± 9.3 mm Hg (TI), n = 622 assessed INR measurements in the TI group, INR was 2.4 ± 0.4 with a mean time in therapeutic range (TTR) of 72.2 ± 13.6% and 72.4 ± 13.0% of tests in the target range.Patients in the TI group adhered well to the institutional anticoagulation therapy guidelines. Patient self‐testing of INR was performed with the CoaguCheck XS . Of P = 0.89, Fig. Within 2 years following initial discharge, 32% UC and 26% TI patients had one readmission, 53% UC and 45% TI patients had multiple readmissions (≥2), with no significant difference of the average time to any first readmission  within 2‐years post discharge was nonsignificantly higher in the UC versus TI group. Patients were supported for a total of 23 173 days of which 89.5% (UC) versus 96.3% (TI), P = 0.60, were spent out of hospital.Freedom from any readmission  and other causes  in 45.8% of the TI patients . Neurological dysfunction was comparable between groups , although no readmission due to hemorrhagic cerebral strokes occurred in the TI group , representing the second most frequent clinical readmission profile in the UC group. 33.3% device‐related driveline or pocket infections as the primary cause of readmission represented the second most frequent reason in the TI cohort and occurred significantly more often than in the UC group . Pump thrombus related admissions were comparable between the groups , where all thrombus events could be successfully treated by thrombolytic therapy in the TI group, but pump exchange was necessary in 50% of the UC group.At 24 months post discharge, the most common etiology for readmission was major bleeding  in 36.4% of the UC  was significantly higher in the telephone intervention group.Kaplan‐Meier curves for the UC and TI group 2‐years post initial hospital discharge, are presented in Fig. P = 0.44). Causes of death in the UC group included neurological dysfunction (n = 3), major infection (n = 3), major bleeding (n = 1), renal dysfunction (n = 1), and respiratory failure (n = 1). Only two patients in the TI group died after rehospitalization due to a neurological event  on and a major infection on postdischarge day 212 and 365, respectively.Of those patients who expired during the follow up period, in the UC cohort nonsignificant more patients died at home than in the hospital , all of them could be successfully treated by medical therapy in the TI group, but 50% of UC patients required a pump exchange as the pump thrombus was already manifested. Driveline infection as the primary cause of readmission occurred significantly more often in the TI group . Whereas UC and TI patients have the same potential risk for driveline infections, they were potentially undiagnosed in UC patients as they were unlikely to communicate their wound status to the VAD center if not actively asked for it. Thus, telephone intervention might lead to earlier detection of driveline infections allowing adequate treatment of them during an additional follow up in the next week (category B), in possible comparison to n = 3 UC patients who died at home due to sepsis following severe driveline infection. Other readmission causes which can be treated faster and easier, at less expense We suggest that enhanced monitoring based on telephone interventions contributes to the earlier detection and even avoidance of severe adverse events. This is evidenced first at 24 months post hospital discharge where we observed a significantly better survival in the TI outpatient cohort without any out‐of‐hospital death, whereas 44.6% of the UC patients died at home, where their problems were either not detected or were detected too late. A second potential benefit was a nonsignificantly higher freedom from any readmission in the TI group (15% vs. 29% UC), especially when considering the readmission clinical profiles at 24 months post discharge, it becomes evident that TI might lead to earlier adverse event detection. Although pump thrombus related admissions were comparable between the groups .Another possible contribution to improved survival in the TI group is better adherence to institutional guidelines for anticoagulation and hypertension management: Previous studies revealed that VAD patients spent only 50–60% of their TTR Finally, psychological factors may contribute to the better outcomes of TI patients. The routinely performed query of pump parameters during the telephone intervention could raise the patients' desire to know their normals  and to communicate abnormalities to the VAD team immediately. Based on these regular calls, the inhibition level of patients to call the 24/7 emergency hotline in case of alarms or problems may be lower, thus leading to more frequent readmissions but earlier detection of adverse events. Patient acceptance of this new treatment tool was high, as only one of 25 patients refused the frequent intervention after 11 months, but asked for resumption in the program after 2 months of suspension. As frequent follow‐up schedules are difficult to sustain with a large number of VAD‐supported patients potentially spread over a larger geographical area, this novel tool for VAD outpatient management may well be a useful additional approach to usual care.This retrospective study was performed at a single center; therefore, generalizability may be limited. The algorithm was applied nonrandomized to all VAD outpatients as this enhanced patient management strategy evolved as “best practices” in our center. Additionally, the rather small sample size limits interpretation and statistical power. A larger multicenter study might better characterize VAD outpatient management with and without telephone intervention than was possible in this study.Continuous, standardized telephone interventions with ventricular assist device outpatients enable a constant communication and fast information transfer, which allows an early detection of upcoming problems with an immediate benefit for survival and severity reduction of adverse events compared to usual oversight of VAD outpatients.TS, DZ and HS developed the concept and design, TS and FM performed the statistical analysis, funding was secured by DZ, GL and HS, TS drafted the article, TS, JH, ZH, GN, HS, JR, KD, PA and DW collected the data.None of the authors has any financial relationship related to this manuscript to disclose.


Although recent studies have shown that botulinum toxin‐A (BTX‐A) has a good analgesic effect on trigeminal neuralgia (TN) and peripheral neuropathic pain (PNP), the quality of evidence is low due to limited data. This meta‐analysis is used to synthesize existing evidence for the treatment of these conditions with BTX‐A.http://ClinicalTrials.gov). Data from included randomized controlled trials (RCTs) on the efficacy and safety of BTX‐A in treating TN and PNP were extracted for meta‐analysis.Relevant trials were accessed by using an electronic search in databases  were included in this meta‐analysis. The pooled effect of BTX‐A was superior to placebo based on pain intensity . Number needed to treat (NNT) for 50% pain intensity reduction showed better effect of BTX‐A on TN and postherpetic neuralgia (PN). Adverse events associated with BTX‐A were similar to placebo .Finally, 10 RCTs (Pooled data from our meta‐analysis suggest that BTX‐A is efficacious and safe in treating TN and PNP. However, due to the limited sample size and heterogeneity, further larger and well‐designed RCTs are imperative to validate these findings. In summary, our pooled results support the injection of botulinum toxin‐A as a promising alternative treatment for trigeminal neuralgia and peripheral neuropathic pain. Further larger and well‐designed randomized controlled trials are still needed to provide more in‐depth insight into current issues. Meta‐analysis method can pool the data from small studies to provide evidence with better power. Hence, we performed this meta‐analysis to synthesize all this evidence from the published RCTs on the efficacy and safety of BTX‐A in treating TN and PNP.22.1http://ClinicalTrials.gov) from 1988 to May 2018. The MeSH headings were as follows: “Neuralgia,” “Trigeminal Neuralgia,” “Peripheral Nervous System Diseases,” “Diabetic Neuropathies,” “Neuralgia, Postherpetic,” “Facial Neuralgia,” “Sciatica,” “Sciatic Neuropathy,” “Neuritis,” “Brachial Plexus Neuritis,” “Median Neuropathy,” “Botulinum Toxins.” Citations of included publications were identified additionally. Individual was restricted to humans, and language was restricted to English. Moreover, we searched for unpublished gray literature in http://ClinicalTrials.gov.We have confirmed that our study follows the recommendation of Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement  for selection. Two authors independently screened the references according to the predetermined inclusion and exclusion criteria. The inclusion criteria were as follows: (a) RCTs evaluating efficacy and safety of BTX‐A on TN and PNP; (b) no limitation to age of patients and study area. The exclusion criteria were as follows: (a) unreliably extracted data; (b) datasets from articles unable to extract; and (c) case reports, case series, reviews, commentaries, errata, notes, letters, and abstract articles only. All conflicts in screening step were discussed between two authors to reach an agreement, and supervisor adjudicated unresolved conflicts if necessary. The full texts of all included trials were downloaded for screening to identify available data for extraction.2.3Outcomes measures as follow were used to evaluate the efficacy and safety of BTX‐A in treating TN and PNP: (a) visual analog scale (VAS) score, neuropathy pain scale (NPS), and numeric rating scale (NRS) score; (b) NNT (with pain score reduced >50%); and (c) adverse events associated with BTX‐A injections.2.4The standardized template was developed for extraction. The relevant data were extracted into the template independently by two authors. Extracted data included: journal, author, publication year, sample size, population, patients' gender and age, injection route, duration of treatment, study design, follow‐up time, and main outcomes measures. Cochrane risk‐of‐bias tool was used to assess the methodological quality of the included trials based on sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias . Continuous variables were pooled as standard mean difference (SMD) using the generic inverse variance method, while dichotomous data were aggregated as odds ratio (OR) by Mantel–Haenszel (M‐H) method. All analyses were conducted using random‐effect and fixed‐effect model. The sensitivity analysis was used to assess the effect of the hypothetical model on the overall effect size, by comparing the analysis between the random‐effect model and fixed‐effect model. Heterogeneity analysis was performed with I‐square and chi‐square tests across the included trials. p‐value < .05 was identified as a statistically significant level.Statistical analysis was carried out with R3.4.3 , detecting no significant heterogeneity  mean visual analog scale (VAS) score, neuropathy pain scale (NPS), and numeric rating scale (NRS) at the end of follow‐up. The final analysis showed statistically significant reduction in pain score for BTX‐A group (SMD = −0.48, 95% CI −0.74, −0.23] at the first month, SMD = −0.58, 95% CI  at the 2nd month, and SMD = −0.55, 95% CI  at the 3rd month; Figure 4, −0.23 4In the present meta‐analysis, our pooled data showed that BTX‐A provides significant benefit in the treatment of patients with TN and PNP compared with placebo, improving the proportion of respondents and pain scores at follow‐up. The reported adverse reactions were mild, transient, and nonsystemic. No serious adverse reactions were presented in the treatment than placebo arms in these studies. All these evidence suggested that BTX‐A is efficacious and safe in treating TN and PNP compared with placebo. However, the evidence was moderate owing to limited studies and small sample size.As early as 2002, Micheli et al. reported that a 70‐year‐old man with hemifacial spasm associated with trigeminal neuralgia secondary to an ectatic basilar artery was treated with BTX‐A, and relief was gained not only from twitching but also from pain (Micheli, Scorticati, & Raina, Recently, three reviews have demonstrated that BTX‐A may provide a clinically significant benefit in treating TN (Morra et al., To our knowledge, this is the first meta‐analysis to assess the overall impact of BTX‐A on TN and PNP compared with placebo. However, several limitations associated with this meta‐analysis should be noted. First, because of the limited number of studies included in this meta‐analysis, type‐II errors owing to chance cannot be completely excluded (Thorlund et al., 5In summary, our pooled results support the injection of BTX‐A as a promising alternative treatment for TN and PNP. Further larger and well‐designed RCTs are still needed to provide more in‐depth insight into current issues.The authors declare no conflict of interest.


OGS)‐pathological targets and formononetin (FN)‐treated targets before the main core predictive biotargets were screened. In addition, all core targets were selected through a number of bioinformatic databases, followed by identification of predominant biological processes and signalling pathways of FN anti‐OGS. Further, top three core targets of FN anti‐OGS were determined as oestrogen receptor 1 (ESR1), tumour protein p53 (TP53), receptor tyrosine‐protein kinase erbB‐2 (ERBB2) respectively. In clinical biochemical data, the plasma samples of OGS showed the increased trends of alkaline phosphatase, triglyceride, blood glucose, lactate dehydrogenase, high‐sensitive C‐reactive protein and some immune cell counts when referenced to medical criteria. In clinicopathological examination, histological OGS sections resulted in increased positive cell counts of neoplastic ESR1, TP53, ERBB2. To further validate these corn proteins in experimental study in vivo, FN‐treated tumour‐bearing nude mice showed intracellular reductions of ESR1, TP53, ERBB2 positive expressions, accompanied with visibly reduced tumour weights. Collectively, our bioinformatic and experimental findings disclosed main core targets, biological processes and signalling pathways of FN anti‐OGS. Interestingly, the top core targets were representatively validated following FN treatment in vivo. Therefore, we reasoned that these predictive targets might be the potential biomarkers for screening and treating osteosarcoma.In current study, a bioinformatic‐based network pharmacology was used to identify the osteosarcoma ( In addition, treated targets of FN were predicted via two different databases of chemical association networks (STITCH) and Swiss TargetPrediction. Further, a database of gene‐disease associations (DisGeNET) was utilized to screen the OGS‐diseased genes, and the optimal genes were identified through the designed parameters and scoring index. Subsequently, the optimal targets of FN were pooled with the disease genes of OGS before producing pharmacological targets of FN anti‐OGS.2.2The pick‐up targets were re‐assay using a database of functional protein association networks (STRING) to further produce a PPI network of FN anti‐OGS. Following computerized setting, correlative proteins with a confidence score >0.9 were identified via a Cytoscape software for eliminating duplicates, mean degree of freedom and maximum degree of freedom. And a target‐associated protein network of FN anti‐OGS was produced. After collecting a target‐related protein network, core targets of FN anti‐OGS were produced through grading values in software parameters.2.3Following by Funrich software, the core targets of FN anti‐OGS were identified the correlative biological processes and signalling pathways via enrichment analyses. Among these data, top 20 biological processes and signalling pathways were isolated according to the degree of importance for further discussion.2.4In hospitalization cases, five adult patients were medically identified as OGS using biochemical test and pathological inspection during 2018. The biochemical data of OGS patients were harvested for analysis. In addition, histopathological sections of OGS were used for immunofluorescence staining. Further, some OGS and OGS‐free samples were surgically isolated and stored at liquid nitrogen before conducting western blot experiment. And the Hospital Ethics Committee has approved this human study. This human study was implemented according to the required principles of the Declaration of Helsinki.2.57. After being producing solid tumour, the tumour‐bearing mice were treated with different doses of FN for 14 days. At the end of the experiments, the tumour was removed and weighed. Some of the tumour samples were fixed with 4% paraformaldehyde for immunostaining.Commercially available BALB/c‐nu nude mice, aged 6 weeks, were purchased from Hunan Slack Jingda Experimental Animal Co., Ltd . After being acclimatized for 5 days, the mice were hypodermically injected with U2‐OS cells  at a cell density of 1 × 102.6As described previously,33.1As a result, total 200 genes from DisGeNET database were harvested widely. Meanwhile, other 189 diseased genes of OGS were pick‐up as potential targets for re‐analysis. In addition, 53 FN‐associated genes from the HIT database were identified. As a result, 12 therapeutic targets of FN anti‐OGS were finally identified through pooled data of diseased and pharmacological targets   years and the sexual proportion was Male:Female (4:1). As shown in Table 7.5 years3.4P < 0.05)   Figure B.4A primary osteosarcoma is a neoplastic growth in bone tissue, followed by malignant proliferation and metastasis.5Taken together, these bioinformatic findings from network pharmacology discolse the main biotargets and molecular mechanisms of FN anti‐OGS. In addition, further clinicopathological and experimental data are validated to characterize the top core targets. Therefore, the network pharmacology may be used for development of TCM‐isolated component.The authors declare no conflict of interest and are responsible for the contents of this study.


ClC‐7 gene identified a known heterozygous mutation, c.643G>A in exon 7, encoding p.Gly215Arg. In vitro osteoclast differentiation from the ADOII patient's peripheral blood mononuclear cells (PBMCs) increased compared with control despite their dysfunctional bone resorbing capacity. Osteoclasts from the ADOII patient's PBMCs and ClC‐7 knockdown bone marrow monocytes (BMMs) showed an enhanced Ser‐71 phosphorylation of Rac1/Cdc42 and increase of the microphthalmia‐associated transcription factor (MITF) and receptor activator of NF‐κB (RANK) that can be responsible for the enhanced osteoclast differentiation. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.The autosomal dominant osteopetrosis type II (ADOII) caused by the mutation of chloride channel 7 (ClC‐7) gene is the most common form of adult‐onset osteopetrosis. Despite dysfunctional bone resorption, an augmented osteoclast differentiation was reported recently in ADOII patients. DNA sequencing analysis of the ADOII patient's  ClC‐7) gene in chromosome 16p13.Osteopetrosis is a group of inherited disorders in which the bones become harder and denser resulting from the dysfunction of osteoclasts.+ ATPase.The acidification under the osteoclast attached to the bone surface is necessary to dissolve the crystallized calcium phosphate.ClC‐7 gene. In spite of dysfunctional resorption capacity, in vitro osteoclast differentiation from peripheral blood mononuclear cells (PBMCs) was enhanced in the ADOII patient, and it was associated with enhanced phosphorylation of the small GTPases Rac1/Cdc42 and increase of the microphthalmia‐associated transcription factor (MITF) and receptor activator of NF‐κB (RANK).Here we present a case of ADOII with the missense mutation of c.643G>A encoding p.Gly215Arg in exon 7 of A 60‐year‐old Korean man was admitted complaining of right anterior chest pain after chest contusion, and radiographic evaluation revealed multiple fractures at the right 7th through 10th ribs. He had a number of past histories of fracture, including right distal radius, right humerus, right ankle, left 4th metatarsal, and ribs. He had hypertension and type 2 diabetes mellitus. His parents or children did not have a distinguished history of fracture. General examination revealed a normal stature of 170 cm, and he wore dentures because of dental caries and periodontitis.T‐score of +11.8 at L3 and +11.6 at L4 level, and BMD of femoral head also increased to T‐score +8.8. The bone resorption marker of serum type I collagen C‐telopeptide (CTX) level was 0.167 ng/mL, which was in a lower normal range.Initial laboratory investigation revealed serum calcium of 8.5 mg/dL (reference level 9.1–11.0), serum phosphorus 3.3 mg/dL (2.3–4.7), serum intact parathyroid hormone 32.0 pg/mL (12.0–88.0), bone‐specific alkaline phosphatase 11.8 µg/L (11.6–20.10), and 25‐hydroxy vitamin D 27.7 ng/mL (30.1–100.0). The rest of his laboratory results including complete blood count, liver function tests, urinalysis, and other serologic tests were within normal limits. The chest radiograph revealed a generalized symmetric increase in bone mass, which showed a stark visualization of the anterior ribs. The skull radiograph showed a thickening of the base of skull. Alternating sclerotic and lucent bands were found in the iliac crests and in vertebral bodies, called “sandwich spine.” The femoral bone shows cortical thickening and medullary encroachment  in exon 7 . This mutation results in the change of 215th amino acid of ClC‐7, Glycin into Arginin (p.Gly215Arg: NP_001278.1), which is located between transmembrane domain 2 and 3, where it is known to influence the channel's pore propertiesB). Multiple sequence alignment of ClC‐7 protein showed the phylogenetic conservation of Glycin at amino acid position 215 between different species .The DNA sequencing analysis of the patient's >A NM_00187.5 in eG>A NM_0087.5 in e>A NM_00187.5 in e>A NM_00187.5 in eA). Despite the increase in the number of osteoclasts, the osteoclasts from the ADOII patient created less resorption area than in controls .To investigate the osteoclast differentiation capacity in the ADOII patient, PBMCs were cultured with 30 ng/mL RANKL and 30 ng/mL M‐CSF for 21 days. The PBMCs from the ADOII patient gave rise to significantly increased numbers of TRAP‐positive multinuclear osteoclasts compared with controls , MMP9, and ITGB3 were increased in ADOII. On the other hand, the expression of OC‐STAMP was significantly decreased in ADOII osteoclasts compared with controls .To elucidate the mechanism of enhanced osteoclastogenesis in ADOII, we screened the expression of major genes regulating osteoclast differentiation. Among three major transcription factors of osteoclast, the RNA expression of D).Despite there being no difference in RNA level, the CDC42, a small GTPase of the Rho family, is known to be activated by increase of intracellular chloride in primary ciliogenesis.A). Knockdown of ClC‐7 in osteoclasts showed an enhanced mRNA expression of Mitf, Rank, DC‐stamp, and Atp6v0d2 and reduced c‐Fos compared with shControl. The RNA expression of Acp5, Mmp9, and Itgb3 that increased in the AODII patient's osteoclasts failed to show any difference in ClC‐7 knockdown osteoclasts . In protein level, the Ser‐71 phosphorylation of Rac1/Cdc42 was increased in the ClC‐7‐knockdowned osteoclasts compared with control shRNA. ClC‐7 knockdown showed the increased protein expression of MITF and Rank but decrease of Nfatc1, c‐Fos, OC‐stamp, and β3‐integrin compared with control shRNA . These results suggest the enhanced osteoclast differentiation in the ClC‐7‐mutated monocytes can be the result of an activation of Rac1/Cdc42 and expression of MITF and RANK.To validate whether the molecular changes shown in the ADOII patient are common phenomena associated with ClC‐7 loss‐of‐function, we then conducted an in vitro ClC‐7 knockdown experiment. Mouse BMMs transfected with lentiviral shRNA targeting ClC‐7 revealed an enhanced osteoclast formation compared with control shRNA Fig. A. Knocksts Fig. B. In prClC‐7 gene. The G215R mutation of ClC‐7 gene has been known as the most common cause of ADOII.In this study, we identified a patient with ADOII harboring a missense mutation, c.643G>A p.G215R) in exon 7 of R in exonIn lysosome, ClC‐7 has a function of a chloride‐proton antiporter that affects lysosomal acidification.In this study, we confirmed the enhanced Ser‐71 phosphorylation of Rac1/Cdc42 protein in the osteoclast from the ADOII patient and ClC‐7 knockdown BMMs. Ser‐71 phosphorylated Rac1/Cdc42 appear to be in their active conformation according to pull‐down assay with PAK CRIB‐domain and Rho‐GDI.Ctsk, Oscar, ClC‐7, and TRAP.A further interesting finding of this study is that an enhanced osteoclast differentiation in ADOII of G215R ClC‐7 is associated with augmented expression of MITF, a basic helix‐loop‐helix‐leucine zipper transcription factor.In conclusion, we provide a mechanical insight to understand how osteoclast differentiation can be enhanced in ADOII patients. Increased intracellular chloride by defective chloride channel can induce the activation of Cdc42 that can be associated with the enhanced activation of MITF and RANK signaling Fig. . These cAll authors state that they have no conflicts of interest.Supporting Data S1.Click here for additional data file.


ADIPOQ gene single‐nucleotide polymorphisms have been associated with NAFLD susceptibility, but with inconsistent results across the studies. This study aimed to investigate the association between ADIPOQ polymorphisms  and the risk of NAFLD.Nonalcoholic fatty liver disease (NAFLD) is a significant contributor to global hepatic disorders. PubMed, Embase, Wanfang, Web of Science, and China National Knowledge Infrastructure databases were used to identify the relevant published literature. Statistical analyses were calculated with STATA 11.0 software and RevMan 5.2. Summary odds ratios (OR) and 95% confidence intervals (CIs) were generated to assess the strength of the associations.ADIPOQ gene +276G>T polymorphism was not associated with NAFLD under various genetic models . Moreover, no statistical significant association was found between +276G>T and NAFLD risk in the subgroups. ADIPOQ gene −11377C>G polymorphism significantly increased the risk of NAFLD .Eleven relevant articles with a total of 3,644 participants  were included. Our meta‐analysis results revealed that ADIPOQ gene −11377C>G may be a risk factor for NAFLD, while there was no association between ADIPOQ gene +276G>T polymorphism and the risk of NAFLD. Further studies are needed to detect the relationship between these ADIPOQ polymorphisms and NAFLD. The search strategy was based on a combination of the following terms: adiponectin or ADIPOQ or adipose most abundant gene transcript 1 or APM1 or rs1501299 or rs266729 AND nonalcoholic fatty liver disease or NAFLD or nonalcoholic steatohepatitis AND single‐nucleotide polymorphism or genetic polymorphism. We performed a manual search of references included in pertinent articles and reviews. If there was duplication of published literature by the same research group, the study with the larger sample size was selected.We used PubMed, Embase, Wanfang, Web of Science, and China National Knowledge Infrastructure databases to search for potentially relevant studies published before November, 2018, which focused on the associations of the two polymorphisms in the 2.2ADIPOQ gene+276G>T (NM_001177800.1:c.214+62G>T) and −11377C>G (NG_021140.1:g.4012C>G) and NAFLD risk, (b) every patient selected have to base on diagnostic criteria for NAFLD: persistently (at least 6 months) abnormal levels of aspartate aminotransferase and alanine aminotransferase, or evidence of fatty liver using ultrasound or other imaging techniques, with a daily alcohol consumption <20 g/day in men and <10 g/day in women; patients with infectious (such as hepatitis B virus and hepatitis C virus and HIV), viral, drug‐induced, auto‐immune hepatitis, and other serious diseases  were excluded, (c) the genotype distribution in control group should accord with Hardy–Weinberg equilibrium (HWE), (d) published data of allele and genotype frequencies must be explicit or could be calculated from the article text. Excluded articles should have the following characteristics: (a) case‐control studies without control information, (b) existing duplicate publication of data, (c) not enough data information form articles.Potentially relevant studies in our meta‐analysis have to meet following inclusion criteria: (a) case‐control studies focused on the association between the 2.3Original data from published studies were independently extracted by two investigators into a standardized form. Contested issues in data extraction were resolved through discussions and re‐inspection with the third investigator. The following information was collected: the first author's surname, year of publication, country, ethnicity, source of controls, number of cases and controls, genotyping methods, frequency of allele and genotype, HWE and Newcastle–Ottawa Scale (NOS) score.2.4The methodological quality of each literature included in our analysis was estimated using the NOS, which scores of 1–3, 4–6 and 7–9 meaning low‐, intermediate‐, and high quality studies respectively in this meta‐analysis. Two authors independently evaluated the quality of selected articles. Differences were resolved by the third author or by discussion, until subsequent consensus was reached.2.5ADIPOQ SNPs and NAFLD risk under five comparison models: the allele model, dominant model, recessive model, homozygous model, and heterozygous model. HWE in the control group was tested by chi‐square test (χ2‐test) for studies included in the current meta‐analysis. Z‐test was applied to examine the statistical significance of the pooled OR. Among‐studies heterogeneity was assessed using Cochran's Q‐test and I2‐test. When I2 > 50% or p < 0.05, the heterogeneity was deemed as significant, we selected the random‐effect model to calculate pooled ORs, on the contrary, the fixed‐effect mode was performed. Sensitivity analysis was performed by removing each individual studies sequentially or by deleting the outliers to assess the stability of the results. Begg's funnel plots were conducted to assess the significance of publication bias, and Egger's test was further supplemented . Meta‐analysis was conducted using the Cochrane Collaboration RevMan 5.2 and Stata 11.0 software .Summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to quantitatively assess the association between 33.1ADIPOQ +276G>T, the features of these ten articles: nine studies focused on Asian ethnicities and one study was Caucasian populations, besides one study  in five genetic models, and the same result in the nonpolymerase chain reaction restriction fragment length polymorphism subgroup, no association was also detected in five genetic models. When excluded the study by Li et al.  than other four genetic models. As four studies focused on Asian population, further investigation involving diverse population should be studied in future analysis.There were some limitations in this meta‐analysis. First, lack of detailed genotypic information and restrictions on inclusion criteria, so several studies have not been included in this analysis. Second, in some pooled analysis, there was significant heterogeneity, which may have unsatisfactorily explained using subgroup and sensitivity analyses. Third, our study only included relevant articles published in English or Chinese. In addition, gene‐environment interactions in relationship rs1501299 and rs266729 and NAFLD are worthy of consideration.In conclusion, our meta‐analysis suggested that the rs1501299 polymorphism was not associated with NAFLD. The rs266729 polymorphism was found to be associated with a significant increase in NAFLD risk. However, more precise and larger studies will be expected to improve and perfect our findings.The authors declare no conflict of interest.


Preclinical studies suggest enhanced anti-tumor activity with combined radioimmunotherapy. We hypothesized that radiation (RT) + immunotherapy would associate with improved overall survival (OS) compared to immunotherapy or chemotherapy alone for patients with newly diagnosed metastatic non-small-cell lung cancer (NSCLC).The National Cancer Database was queried for patients with stage IV NSCLC receiving chemotherapy or immunotherapy from 2013 to 2014. RT modality was classified as stereotactic radiotherapy (SRT) to intra- and/or extracranial sites or non-SRT external beam RT (EBRT). OS was analyzed using the Kaplan-Meier method and Cox proportional hazards models.p = 0.89). For immunotherapy patients, the median OS for no RT, EBRT, and SRT was 14.5, 10.9, and 18.2 months, respectively (p < 0.0001), and EBRT  and SRT  associated with OS on multivariate analysis. In the SRT subset, median OS for immunotherapy and chemotherapy was 18.2 and 14.3 months, respectively (p = 0.004), with immunotherapy  associating with OS on multivariate analysis. Furthermore, for patients receiving SRT, biologically effective dose (BED) > 60 Gy was independently associated with improved OS  on multivariate analysis with a significant interaction between BED and systemic treatment (p = 0.008).In total, 44,498 patients were included . On multivariate analysis, immunotherapy  and SRT  independently associated with improved OS; however, the interaction term for SRT + immunotherapy was insignificant (Treatment with SRT associated with improved OS for patients with metastatic NSCLC irrespective of systemic treatment. The high survival for patients receiving SRT + immunotherapy strongly argues for evaluation in randomized trials. In the United States, lung cancer is the most common cause of cancer-related mortality with 234,000 new cases and 154,000 deaths from this disease expected in 2018 : 10–15) while the median dose for patients receiving SRT was 22 Gy in a median of a single fraction (IQR: 1–4). The median BED for the SRT group was 60 Gy (IQR: 43.2–70.4) and was significantly higher than the median BED of 39 Gy (IQR: 39.0–50.7) for the EBRT group (p < 0.0001). Of patients in the SRT group with known dose/fractionation information, 34.5% received a BED > 60 Gy with this subset prescribed a median RT dose of 24 Gy in a median of a single fraction. The most common RT dose/fractionation prescriptions for patients receiving SRT to a BED ≤60 Gy vs. > 60 Gy are displayed in Table Regarding RT, p = 0.03). Kaplan-Meier plots investigating the relationship between combined systemic and RT modalities for the immunotherapy (n = 5807) and SRT (n = 2084) subpopulations are displayed in panels A and B of Fig. p < 0.0001) for patients receiving no RT, EBRT, and SRT, respectively. Meanwhile, within the SRT cohort, median OS was 18.2 months and 14.3 months (p = 0.004) for patients treated systemically with immunotherapy or chemotherapy, respectively. A Kaplan-Meier plot displaying OS as a function of systemic therapy with or without SRT is also displayed in panel A of Fig. p < 0.0001). A similar plot displaying OS as a function of systemic therapy with or without extracranial SRT is displayed in panel A of Fig. p < 0.0001) with patients receiving extracranial SRT and immunotherapy having the best prognosis.The median survival of patients receiving immunotherapy was 17.3 months vs. 14.4 months in the chemotherapy group ( SRT n = 084 subpop < 0.0001), systemic therapy , and RT modality . This same multivariate analysis performed while adjusting for intra- vs. extracranial RT continued to identify systemic therapy  and RT modality  as independently associated with OS. Since RT site was also significantly associated with OS , results of the multivariate analysis were separately reported for the intra- and extracranial RT subgroups as displayed in Table p < 0.0001 comparing no RT, EBRT, and SRT). Furthermore, for patients undergoing SRT, immunotherapy  associated with higher OS compared to chemotherapy. Despite the prolonged OS for patients receiving combined immunotherapy and SRT compared to patients receiving alternative combinations of systemic and RT modalities, the interaction term for SRT and immunotherapy did not reach significance (p = 0.89).The results of a multivariate analysis for OS for the entire cohort are displayed in Table n = 1739) is displayed in panel B of Fig. p < 0.0001 when comparing all groups). A similar Kaplan-Meier plot showing OS using the same stratification for patients receiving specifically extracranial SRT is displayed in panel B of Fig. p < 0.0001). On multivariate analysis including all SRT patients with available dose/fractionation data as displayed in Table p < 0.0001), and systemic therapy was no longer significantly associated with OS after including BED in the regression (p = 0.51). Moreover, a significant interaction was observed between BED and systemic therapy (p = 0.008) as shown in the forest plot displayed in Fig. p < 0.0001) and systemic therapy  as independently associated with OS for patients receiving extracranial RT.The influence of BED (“low BED” ≤60 Gy vs. “high BED” > 60 Gy)  and syst p = 0.00 as shownWithin the NCDB, patients with stage IV NSCLC receiving immunotherapy experienced improved OS compared to patients receiving chemotherapy. These findings are the first to demonstrate population-wide benefits with the use of immunotherapy in this setting. The median survival of 17.3 months and HR of 0.8 associated with immunotherapy in this NCDB cohort compares favorably to the HR of 0.81 and 16.7-month median survival in the PD-L1 ≥ 1% cohort receiving immunotherapy on the ongoing and recently presented phase III KEYNOTE-042 trial . This siOn subset analysis, patients undergoing predominantly intracranial SRT had improved OS compared to those who did not regardless of systemic therapy choice. Interestingly, among patients receiving immunotherapy, SRT associated with improved OS while non-SRT EBRT associated with reduced OS. BED significantly correlated with OS for patients undergoing SRT with individuals receiving a BED > 60 Gy in combination with immunotherapy having an impressive median OS of 32.1 months compared to just 13.7 months for individuals treated with low-BED SRT and chemotherapy. Although a synergistic interaction between SRT and immunotherapy was not identified among all patients receiving immunotherapy, a synergistic interaction between high BED and systemic therapy was identified among patients receiving SRT.These data add to a growing body of literature attempting to clarify the potential role of SRT in the setting of metastatic NSCLC , 21, 22.Preclinical studies have suggested enhanced anti-tumor activity for combined radioimmunotherapy including intracranial RT in mouse glioblastoma models , 12. Thin = 49/70, 70%) followed by pembrolizumab, they offer a potential mechanistic explanation for several observations in our data including (1) reduced OS for EBRT+immunotherapy, (2) an impressive median OS of 32.1 months for high-BED SRT + immunotherapy, and (3) a significant interaction for BED and systemic therapy among patients receiving SRT. Of note, it is possible that the relative influence of dose and fractionation on the biological interactions between RT and immunotherapy may differ as a function of treatment setting since conventionally fractionated EBRT followed by durvalumab has been associated with improved OS for patients with locally advanced rather than metastatic NSCLC [RT dose and fractionation may influence the complex relationship between RT-induced immunomodulation and anti-tumor response , 19. Staic NSCLC .Areas for future investigation include elucidation of RT’s immunomodulatory effects on the tumor microenvironment, determination of clinically optimal radioimmunotherapy combinations/sequencing for metastatic NSCLC, and investigation of the toxicity of combined radioimmunotherapy. To this end, inclusion of molecular correlative studies on future prospective trials of combined radioimmunotherapy for metastatic NSCLC is imperative. A growing number of early-phase protocols –36 incluLimitations to this study include the lack of information on biomarkers including PD-L1 status, possibility for coding errors in NCDB data, the inability to examine alternative endpoints of interest including toxicity or PFS, heterogeneity of agents coded as immunotherapy in the NCDB, and selection bias regarding treatment received. It is likely that patient selection factors influenced some associations between aggressive local therapy and improved OS as patients with a lower disease burden including oligometastases may have preferentially received SRT and/or higher-BED SRT regimens. Furthermore, the inclusion of patients receiving heterogeneous RT doses within the EBRT subset may limit generalizations for this group. Despite these caveats, our data demonstrate that SRT associates with improved OS for patients with stage IV NSCLC in the NCDB regardless of systemic treatment.Overall, the hypothesis-generating observation of superior OS for patients receiving high-BED SRT and immunotherapy, the reduction in OS for patients receiving EBRT and immunotherapy, and the significant interaction between BED and systemic therapy suggest that RT technique may influence the efficacy of immunotherapy in this setting. These findings strongly support efforts to evaluate optimal multimodality radiation and immunotherapy strategies in prospective randomized trials.