Focal chondral defects are common lesions of the articular cartilage. They are predominantly found on the medial femoral condyle and often progress to osteoarthritis of the knee. Various conservative treatment options are available. The conservative treatment might reduce pain and delay the progress of degenerative processes. However, restoration of the articular cartilage cannot be accomplished. If the conservative treatment fails unicompartmental arthroplasty, patellofemoral joint replacement or focal resurfacing are reasonable options to postpone total knee arthroplasty. A careful patient selection before surgery is crucial for all three treatment options. The following overview reports indications and outcomes of medial partial knee replacement, patellofemoral partial knee replacement, and focal resurfacing treatment options for focal chondral defects. Focal chondral defects (FCD) are common disruptions of the continuity of the cartilage layers. They might occur on every articular cartilage surface of the body; however, chondral defects are predominantly found on the medial femoral condyle ,2. FocalDue to low vascular and neural supply of articular cartilage, the regenerative potential of FCD is limited ,9. Most Previous studies have shown that FCD are an important risk factor for an early onset of osteoarthritis (OA) of the knee and, therefore, early detection is crucial ,13,14,15Various treatment options are available for FCD; however, it is unclear which treatment has the best potential to restore a functional articular-cartilage-like tissue . FactorsNon-operative treatment options aim at the reduction of clinical symptoms and the delay of progression of the degenerative processes . They in2) in patients <40 years various surgical treatment options such as local debridement, chondroplasty, marrow stimulation techniques  or osteochondral autograft/allograft transfers are reasonable treatment options [2 autologous chondrocyte transplantation is the preferred treatment option, as promising long-term results were achieved in cases with larger defects [Focal chondral defects International Cartilage Repair Society (ICRS) grade 3 or 4 should be addressed surgically . For sma options ,23. In y defects ,25. Gila defects  showed s defects . Especia defects . Kreuz e defects  showed t defects .In up to 47% of patients over 60 years of age, FCD progresses to diffuse OA of the knee ,32. For The following overview reports indications and outcomes of medial partial knee replacement, patellofemoral partial knee replacement, and focal resurfacing treatment options for focal chondral defects.Indications and contraindications for unicompartmental knee arthroplasty (UKA) are discussed controversially . To achiover 60 years old;weigh less than 82 kg;have isolated medial compartment OA;have no patellofemoral OA;no lateral joint tenderness;no anterior knee pain;low physical demands;a varus deformity of under 10°;a flexion contracture of under 5°;intact ligaments and no inflammatory conditions.In 1989, Kozinn and Scott  presenteUp to today, many surgeons stick to these suggested selection criteria . Over thFull thickness cartilage defects in the weight-bearing zone of the medial compartment of the knee are a requirement for medial UKA ,40 and pIntact cartilage in the lateral compartment is another essential requirement for medial UKA and the progression of lateral OA is a common cause for failure of medial UKA . A previThe current literature provides several studies that evaluated radiographic findings to identify lateral compartment OA. It has been shown that a positive tibial spine sign on AP radiographs of the knee does not indicate cartilage defects in the central area of the lateral compartment .Furthermore, Waldstein et al.  showed tAnother essential requirement for medial UKA is a functional sufficient anterior cruciate ligament (ACL) ,47. HighFor UKA, patient selection is crucial and various radiographs should be taken preoperatively. Hamilton et al.  providedIn uncertain cases, preoperative magnetic resonance imaging (MRI) is recommended. The percentage of full-thickness cartilage posteriorly on the medial tibial plateau should be evaluated on the MRI. Less than 14% intact posterior cartilage indicates wear patterns that are associated with a functionally insufficient ACL .As mentioned earlier, Kozinn and Scott postulated that varus alignment must be <10° to perform UKA surgery. However, medial UKA is still indicated if the intra-articular deformity is correctable after removal of medial osteophytes . The corOne third of patients with focal chondral defects in the medial compartment of the knee need a joint replacement surgery within 10 years . The difPatellofemoral joint replacement (PFJR) is indicated in cases with isolated degeneration or deformity in the patellofemoral joint due to dysplasia or instability or FCD that progressed to OA in the patellofemoral joint . EspeciaIn patients with tibiofemoral OA, PFJR is contraindicated . RestricMost isolated osteochondral defects in the patellofemoral joint are caused by a mechanical mismatch of patellofemoral joint components resulting in increased loads on the patellofemoral cartilage . DysplasIn patients with a pronounced dysplasia of the femoral trochlea, PFJR with combined reconstruction of the medial patellofemoral ligament can be considered to prevent the patella from subsequent luxation . LateralFor PFJR two different types of implants are available: Onlay-designs and Inlay-designs ,68. OnlaThe benefit of PFJR has been debated due to its high failure rates . RevisioCareful patient selection prior to PFJR is crucial. A recent study showed similar patient-reported outcomes after second-generation PFJR and TKA if patients were selected appropriately . Dejour When comparing Inlay-designs with Onlay-designs in a matched-paired cohort, no differences were found between the two designs and both designs led postoperatively to significantly better functional outcome scores . The onlUnnithan et al.  evaluateIn cases of failed Inlay-prosthesis, it is a reasonable option to use an Onlay-prosthesis for revision surgery .A recent retrospective study compared the outcome of patients with asymptomatic patellofemoral FCD undergoing UKA only versus undergoing UKA and concomitant PFJR with an Inlay-design prosthesis . There wThe current literature does not provide long-term outcomes of PFJR and further research is needed to confirm the encouraging short-term results also in the long-term.Symptomatic focal chondral lesions of the femoral condyle occur frequently in patients between 40–60 years ,2. The cFor focal full-thickness cartilage defects of the femoral condyle, a focal prosthetic inlay resurfacing is another possible treatment option when biological treatments have failed and total knee arthroplasty is not yet justified .2 or cartilage damage in another compartment of the knee should be considered as contraindications [The indications for these implants are as follows : Patientications .As patients with focal metallic inlay resurfacing had significantly improved knee function and also significantly less pain, these implants were considered as an effective treatment option . HoweverBecher and Cantiller  observedSimilar to UKA and PFJR, a proper preoperative evaluation and careful patient selection is mandatory. Furthermore, it is important to position implants accurately to avoid step offs or increased pressure on the opposite cartilage surface ,86. In aThe development of newer customized femoral condyle implants with a combined guiding system streamlined the process to position the implant intraoperatively and helped to ensure an accurate position of the implant . As a reFocal chondral defects of the knee are common lesions that often progress to OA of the knee. Conservative treatment options might reduce pain; however, restoration of the articular cartilage cannot be accomplished in most older patients. If biological treatment options fail, unicompartmental knee arthroplasty, patellofemoral joint replacement or focal resurfacing are reasonable options to postpone total knee arthroplasty. Unicompartmental knee arthroplasty is an accepted and well-evaluated treatment option with good long-term results. Patellofemoral joint replacement and focal resurfacing both showed good short-term results, but long-term results might be not as promising. Nevertheless, careful patient selection is crucial for all three treatment options to achieve best possible results.


Delphinus delphis and Delphinus bairdii, to evaluate species differences in whistle contours. Acoustic recordings of single-species groups were obtained from the Southern California Bight. We used an unsupervised neural network to categorize whistles and compared the resulting whistle types between species. Of the whistle types recorded in more than one encounter, 169 were shared between species and 60 were species-specific . Delphinus delphis used 15 whistle types with an oscillatory frequency contour while only one such type was found in D. bairdii. Given the role of vocal learning in delphinid vocalizations, we argue that these differences in whistle production are probably culturally driven and could help facilitate species recognition between Delphinus species.The most flexible communication systems are those of open-ended vocal learners that can acquire new signals throughout their lifetimes. While acoustic signals carry information in general voice features that affect all of an individual's vocalizations, vocal learners can also introduce novel call types to their repertoires. Delphinids are known for using such learned call types in individual recognition, but their role in other contexts is less clear. We investigated the whistles of two closely related, sympatric common dolphin species, This article is part of the theme issue ‘Vocal learning in animals and humans’. An open-ended vocal learner, one that can learn new vocalizations throughout life, can increase communicative complexity by adding new call types to its repertoire , but theTursiops truncatus) [Orcinus orca) [Delphinids have long been recognized as an interesting taxon for the study of how learned signals are used. They have advanced cognitive skills as well as a large vocal repertoire which can be modified by vocal learning through life . They aluncatus)  and killus orca) , but it us orca) –14).Physalaemus pustulosus) [Dascyllus albisella) [Molothrus ater) [The most detailed information on the function of specific call types comes from identity signalling. While relevant behavioural contexts can be challenging to parse, the identity of an individual animal provides an opportunity to study call function in a clear and unchanging context. Bottlenose dolphins develop individually distinctive signature whistles that convey identity of the caller , and othtulosus) , damselfbisella)  and cowbus ater) . Previouus ater) ,23). HowDelphinus delphis, and long-beaked common dolphins, Delphinus bairdii) [Common dolphins off California offer a unique opportunity to study species signalling in a vocal learner. Like bottlenose dolphins they develop signature whistles ,25, but bairdii) , suggestbairdii) , and so . 2 (a)Continuous passive acoustic recordings were obtained from schools of short- and long-beaked common dolphins in the Southern California Bight, off the northern end of Catalina Island from 2017 to 2020. Three surface drifting acoustic instruments were placed in close proximity to schools of dolphins . We selectively focused on single-species schools, as opposed to mixed-species groups. For every recording event (or ‘encounter’), species identity (based on differences in morphology and pigmentation ) was detEach acoustic recording instrument consisted of a surface buoy with a submersible recording package  that recorded via a single omni-directional calibrated hydrophone  suspended by a shock-mounted cable at a depth of 10 m. Five-minute files were continuously recorded throughout an encounter . Recordings were collected before, during and after mid-frequency active sonar signals in the context of a behavioural response study. To avoid bias, recording efforts for both species were balanced across these conditions. (b)aven 1.5 software (ravensoundsoftware.com) and whistles were selected for analysis from the buoy with the highest signal-to-noise ratio (SNR) relative to the other simultaneously deployed buoys. To avoid over-sampling smaller groups of animals or specific individuals, a maximum of 100 whistles were extracted from schools with fewer than 100 animals. For larger schools, the maximum number of whistles extracted was equal to the estimated group size for that school, up to a ceiling of 200 whistles. A random number generator was used to randomly select indexed times within each recording and the first whistle beginning after this time was chosen for analysis. If the chosen whistle did not meet the criteria for analysis, the following whistle was selected. Fundamental frequency contours were manually traced from whistles using the Real-time Odontocete Call Classification Algorithm  module ard.org, ). When aOnly contours with limited overlap with other whistles and SNR greater than approximately 6 dB were extracted and measured. Groups of common dolphins frequently whistle concurrently, resulting in multiple, overlapping whistles that appear as a loud band of indistinguishable contours in a central frequency range (5–15 kHz) on a spectrogram. The number of whistles selected from these time periods was limited to a maximum of three so as not to over-select whistles at atypically low- or high-frequency ranges.Delphinus whistle characteristics, no more than two repeated stereotyped whistles of the same type were selected per 5 min recording file.The recordings also contained repeated stereotyped whistles, possibly representing individually distinctive signature whistles . As sets (c)Whistle contours were organized into types using ARTwarp, which employs an unsupervised neural network to group contours with similar frequency modulation patterns into categories and uses dynamic time warping to allow for differences in the duration of whistles . To be pshared whistle types. Whistle types that were recorded from only one school were considered single-encounter whistle types, and those that were recorded from more than one school were considered multiple encounter whistle types. Whistle types that contained two or more whistles produced by only one species and were recorded from at least two schools were considered species-specific whistle types. ARTwarp whistle types were further labelled as oscillatory whistles if the contour shape (i) consisted of at least two cycles of similar magnitude with two or more maxima, (ii) the maximum and minimum of each cycle was separated by at least 1 kHz, and (iii) at least 50% of the contour exhibited this pattern  that contained whistles recorded from both short- and long-beaked common dolphins were considered n et al. ). Oscill (d) (i)p-value for a two-tailed significance test was calculated as the proportion of permutations with a higher or lower number of species-specific contour types than the true dataset.Sub-sampling whistles from two species with identical vocal repertoires should result in the appearance of some species-specific signals simply by chance. A permutation test was used to evaluate whether the observed number of species-specific whistle types was an artefact of sub-sampling. In the permutation test, the species identity of whistles belonging to types recorded from two or more schools was randomly assigned over 1000 iterations. The resulting proportion of species-specific whistle types was calculated for each dataset and the  (ii)U-tests were used to compare the 50 continuous ROCCA-generated whistle variables across species . The six categorical variables were compared with Pearson's χ2-tests. Statistical significance for these tests was evaluated using a Bonferroni-adjusted alpha value calculated as the standard alpha value divided by the number of tests . Univariate comparisons of species-specific whistle types and single-encounter whistle types were conducted using one whistle from each type to avoid pseudoreplication.Mann–Whitney  (iii)randomForest package in R v. 4.0.2 [Random forest analysis was used to classify whistles to species using the v. 4.0.2 . A randov. 4.0.2 .mtry parameter: the square root of the total number of variables). The number of trees was initially set to 10 000 but was increased by an order of magnitude (×10) until the rate of misclassifications stabilized. Unlike linear discriminant analysis, random forest classification does not make strict assumptions regarding the variance and distributions of the predictor variables. Accordingly, all whistle measurements extracted by ROCCA were included as predictive variables.In this analysis, each tree was grown using a bootstrapped subset of whistles. This allowed the quantification of predictive accuracy of the forest using ‘out-of-bag’ data. The default number of candidate predictor variables was used at each node , only species-specific whistle types that occurred in more than one encounter (RF2), only shared whistle types (RF3), and only single-encounter whistle types (RF4). The classification success of RF2 was compared to that of RF4 to determine whether performance was related to the presence of signature whistles. If the classification success of RF2 was owing to signature whistles of animals accidentally recorded from more than one encounter rather than to species-specific whistle types, then the performance of RF2 should not differ from performance when using whistles only recorded in single encounters (RF4) which would have signature whistles in them as well. For each random forest, sample sizes were matched between species by taking a random subset of the larger class equal to the size of the smaller class, to ensure that imbalances in number of whistles did not affect classification results.. 3We analysed recordings made during 14 short-beaked common dolphin encounters and 10 long-beaked common dolphin encounters. In total, we included 1774 whistles: 872 from long-beaked common dolphins and 902 from short-beaked common dolphins . In the 96 kHz sampling rate dataset, 15 whistles had maximum frequency values exceeding the Nyquist frequency (22 kHz) of the 44.1 kHz sampling rate dataset. These whistles were omitted from our analyses.p = 0.001). Post-hoc visual assessment of whistle types revealed that a large proportion of short-beaked common dolphin species-specific types were oscillatory , in stark contrast to long-beaked common dolphins, where only 1 out of 28 whistle types (representing four whistles) were oscillatory. Some of the single-encounter types that may represent signature whistles were also oscillatory . Oscillatory whistles also made up a very small proportion of shared whistle types .ARTwarp grouped the 1774 traced whistles into 447 types. Most of these types  were exclusively detected during encounters of either short- or long-beaked common dolphins. Of these, 68.3% (190 of 278) represented just one whistle , and 10.1% (28 of 278) represented more than one whistle but were recorded from only one encounter. We expected these ‘singular’ types to include signature whistles of animals encountered once, as well as aberrant or rare vocalizations. After excluding whistle types recorded during a single encounter, we identified 169 shared whistle types  and 60 sComparing all whistles recorded from each species, we found significant differences in 23 parameters, mostly relating to whistle duration, frequency and number of inflections . Fewer, though broadly similar, parameters were significantly different between species when only including whistles belonging to species-specific types: species-specific whistles produced by short-beaked common dolphins were longer, had larger frequency spreads, more frequency modulation and higher standard deviations of durations between inflections than those produced by long-beaked common dolphins . By contrast, single-encounter whistle types were not differentiable by the same parameters, but showed significant differences in the mean of negative slopes, the shortest time between inflections, the number of inflections per unit time and the number of frequency steps per unit time .n = 1744 whistles). Overall classification accuracy increased significantly  to 87.5% (n = 202 whistles) when only including species-specific types detected during multiple encounters (RF2). This model (RF2) also had a significantly higher correct classification score than the model that included only shared whistle types (RF3) . As expected, the classifier using whistles belonging to shared types classified species with the lowest accuracy. Despite being produced by only a single species, single-encounter types (RF4) provided a significantly lower species classification accuracy than species-specific types  and was not significantly greater than RF1 . The electronic supplementary material, table A9 shows the 15 most important predictor variables for each random forest classifier, based on the Gini Variable Importance Index.The random forest models explored species-specificity of whistles further . Each ra. 4The results presented here demonstrate a clear difference in the use of oscillatory whistles between short- and long-beaked common dolphins, suggesting a role for frequency modulation patterns in species identification. A large number of oscillatory whistles is characteristic of short-beaked common dolphins, and long-beaked common dolphins appear to regularly use much simpler frequency modulation patterns. Many whistling delphinids, including common dolphins, encode individual identity information in the modulation patterns of their learned signature whistles  but all The use of specific modulation patterns or acoustic features to encode species identity has also been observed in other taxa. For example, three sympatric species of mouse lemurs in Madagascar produce tonal advertisement calls that do not differ significantly in frequency range or bandwidth but do have very different contour shapes. In playback experiments, individuals responded significantly more to conspecific advertisement calls than to heterospecific advertisement calls but did not exhibit a significant difference in response strength to other whistle types in their repertoires . SimilarWhile oscillatory whistles were diagnostic of short-beaked common dolphins, the results of the random forest models showed that collectively, the species-specific whistle types identified by ARTwarp carry species information for both short- and long-beaked common dolphins. The random forest that included only multiple encounter, species-specific whistle types (RF2) had a significantly higher correct classification score than both the random forest that included all whistle types (RF1) and the random forest that included only shared whistle types (RF3) . HoweverDelphinus delphis and D. bairdii have only recently been recognized as two distinct species in the eastern North Pacific [These results shed light on the possible functions of non-signature whistles and provide a new tool for the development of species classifiers for use in passive acoustic monitoring, which is particularly important for these species.  Pacific  and diff Pacific . Additio Pacific . The ARTSimilarities and differences in the whistle repertoires of these two species are likely to have been caused by a variety of interacting factors such as behaviour, group size and social structure, and environment. Little is known about the behaviour and social interactions of these species and data on their distribution is limited. Short- and long-beaked common dolphins overlap in substantial areas of their ranges, however short-beaked common dolphins appear to range further offshore than long-beaked common dolphins . These dLearning influences vocal development in delphinids, increasing the potential for geographical variation and cultural specialization in how whistles are used. The species distinction between short- and long-beaked common dolphins is relatively clear in our study area  but not Oscillatory whistles have also been described for other dolphin species including bottlenose dolphins , spinner


Most Americans with opioid use disorder (OUD) do not receive indicated medical care. A clinical decision support (CDS) tool for primary care providers (PCPs) could address this treatment gap. Our primary objective was to build OUD-CDS tool and demonstrate its functionality and accuracy. Secondary objectives were to achieve high use and approval rates and improve PCP confidence in diagnosing and treating OUD.A convenience sample of 55 PCPs participated. Buprenorphine-waivered PCPs (n = 8) were assigned to the intervention. Non-waivered PCPs (n = 47) were randomized to intervention (n = 24) or control (n = 23). Intervention PCPs received access to the OUD-CDS, which alerted them to patients at potentially increased risk for OUD or overdose and guided diagnosis and treatment. Control PCPs provided care as usual.The OUD-CDS was functional and accurate following extensive multi-phased testing. PCPs used the OUD-CDS in 5% of encounters with at-risk patients, far less than the goal of 60%. OUD screening confidence increased for all intervention PCPs and OUD diagnosis increased for non-waivered intervention PCPs. Most PCPs (65%) would recommend the OUD-CDS and found it helpful with screening for OUD and discussing and prescribing OUD medications.PCPs generally liked the OUD-CDS, but use rates were low, suggesting the need to modify CDS design, implementation strategies and integration with existing primary care workflows.The OUD-CDS tool was functional and accurate, but PCP use rates were low. Despite low use, the OUD-CDS improved confidence in OUD screening, diagnosis and use of buprenorphine.NIH Trial registration NCT03559179. Date of registration: 06/18/2018. URL: https://clinicaltrials.gov/ct2/show/NCT03559179The online version contains supplementary material available at 10.1186/s13722-021-00245-7. The United States is in the midst of an opioid crisis . ApproxiPrimary care is the most common contact point for healthcare, and thus improving identification and treatment of OUD in primary care could help reduce this treatment gap. Buprenorphine  is an effective treatment for OUD in primary care –11, but In the last decade, electronic health record (EHR)-linked web-based point-of-care clinical decision support (CDS) systems designed to improve primary care quality have become increasingly sophisticated and successful –20. CDS In this pilot study, we sought to take the first step towards an EHR-linked OUD-CDS tool based on the National Institute on Drug Abuse (NIDA) National Drug Abuse Treatment Clinical Trials Network (CTN) Dissemination Initiative’s white paper , which iThe study was conducted at HealthPartners, an integrated healthcare system that provides comprehensive medical care for over 1.2 million patients. At the time of this study, there were no systematic efforts to screen for OUD, and the primary process for treating OUD, if identified, was referral to specialty addiction clinics.The study protocol was approved by the HealthPartners Institutional Review Board, which approved a waiver of written consent for patients. The study was approved and monitored by the NIDA CTN Data and Safety Monitoring Board.Phase 1 (February 2017 to May 2018) aimed to develop a functional and accurate OUD-CDS tool and did not involve study participants. Phase 2 (June to December 2018) pilot tested the clinical content, interface format, and usability of the OUD-CDS with a convenience sample of volunteer PCPs recruited via emailed invitations. Eligible PCPs (1) were primary care physicians or advanced practice providers (APPs) engaged in independent primary care of adults, (2) had at least schedule 3 Drug and Enforcement Agency prescribing privileges, (3) had at least half-time clinical primary care responsibilities, and (4) provided informed consent. PCPs were offered gift cards to participate in the study and complete baseline and 6-month surveys.Recruited PCPs who were buprenorphine-waivered (“waivered”) were given OUD-CDS access. PCPs who were not buprenorphine-waivered (“non-waivered”) were randomized equally to receive or not receive OUD-CDS access within strata defined by provider type  and proportion of patient panel with three or more opioid prescriptions . All PCPs were assigned a random number using a random number generator and seed based on the randomization date (20180529).Phase 1 employed a highly iterative process to develop the OUD-CDS. In Phase 1a, the NIDA CTN Dissemination Initiative’s white paper [te paper  was decoPhase 1b, multiple iterations of the user interface were developed—first in wireframes, then on a web platform, and finally as a web platform integrated with the EHR. Detailed feedback was solicited from study team members and physicians throughout this process.In Phase 1c, two primary and three addiction medicine physician investigators tested the OUD-CDS in the EHR testing environment using a library of test patients developed to represent various relevant clinical scenarios.In Phase 1d, the CDS was programmed to function silently in the EHR production environment for all real office encounters in without displaying to the end user. For patients meeting eligibility criteria, the CDS that would have displayed at each encounter was validated by testing clinicians using chart audit abstraction to confirm the accuracy and appropriateness of the CDS. Where indicated, this was followed by programming changes and iterative testing to ensure resolution.Finally, in Phase 2, a convenience sample of PCPs was recruited. PCPs assigned (waivered) or randomized (non-waivered) to receive the intervention that identified people at risk for OUD at office encounters and recommended use of the OUD-CDS. These clinicians were emailed a link to an online training session prior to the intervention’s start. The training provided step-by-step instructions for the OUD-CDS and reinforced the importance of OUD diagnosis and treatment in primary care; all intervention clinicians completed the training. Intervention PCPs were asked to provide feedback on the OUD-CDS via a “Suggestions” tab on the CDS display. Additionally, four intervention PCPs were informally interviewed to gather information to improve the design of the OUD-CDS.In primary outcome was to demonstrate that the OUD-CDS tool was functional and accurate. In the second phase, the CDS output was provided to PCPs to assess secondary outcomes of OUD-CDS use rates, PCP confidence in diagnosing and treating OUD, and likelihood of PCPs to recommend the OUD-CDS to colleagues. Exploratory outcomes included rates of OUD diagnosis, prescriptions of medications for OUD and referrals for OUD treatment.The Use rates of the CDS tool were captured via the web service. At baseline, PCPs completed 15-item surveys assessing confidence recognizing and treating patients with OUD. At the end of the intervention, all PCPs completed questions re-assessing confidence, and intervention PCPs completed questions about their experience with the OUD-CDS  at increased risk for OUD due to having 3 or more opioid prescriptions in the last year or an opioid prescription and a diagnosis of substance use disorder other than OUD or nicotine, (2) with an OUD diagnosis, or (3) with a prescription or documented use of buprenorphine or methadone . These criteria resulted in the banner displaying at 14% of all adult primary care encounters. This was deemed too high of a burden on PCPs by the study team, as the prevalence rate of OUD in primary care clinics was likely a fraction of that based on national data , so the The OUD-CDS included the following modules:The Screening and Diagnosis Module Fig.  providedThe Treatment Selection Module Fig.  includedThe Buprenorphine Initiation Module Fig.  providedThe Buprenorphine Maintenance Module guided PCPs in assessing effectiveness and adherence, adjusting the buprenorphine dose if indicated, and obtaining a urine toxicology screen.The Naltrexone Initiation module was limited to oral naltrexone because PCPs did not prescribe intramuscular naltrexone due to billing complexities. However, it should be noted that oral naltrexone is not indicated for the treatment of OUD . The modThe Naltrexone Maintenance Module helped PCPs assess effectiveness and adherence, adjust the naltrexone dose or consider other OUD medications if indicated, and obtain a urine toxicology screen.The Methadone Module provided medication information, offered a printable list of community clinics offering methadone treatment, and guided PCPs in assessing methadone adherence.The OUD-CDS included several Treatment Initiation and Maintenance Modules:The Other Recommended Care Module Fig.  guided PAverage use rates across all intervention PCPs were calculated for each month of the intervention period. A goal use rate of 60% was chosen because this would reflect use in the majority of visits in which it was indicated while allowing for some visits where another clinical concern would take priority over OUD screening. Changes in PCP survey ratings were assessed via linear mixed models in which repeated survey ratings were predicted from survey timing (post- vs. pre-intervention), PCP group  and the timing by PCP group interaction. Post- versus pre-intervention contrasts within each PCP group tested whether PCP ratings changed significantly over time (p < 0.05). Rate ratios for each exploratory outcome were calculated separately by PCP group as the post-intervention relative to pre-intervention rates per patient-year to describe the extent to which PCPs changed the frequency with which they diagnosed OUD, ordered OUD medications or referred patients for OUD treatment.Fifty-five PCPs participated in the study, including 32 physicians, 17 physician assistants, and 6 nurse practitioners  Incorporate the OUD-CDS into an integrated platform with other CDS tools that are being utilized successfully at high rates at office visits, (b) Have rooming staff trigger and support interaction with the OUD-CDS, (c) Provide clinic leaders and clinical teams with feedback about CDS use rates, and (d) Deploy problem-solving strategies to improve CDS use rates for specific clinics or care teams when necessary. These changes will be incorporated in a clinic-randomized trial across three healthcare systems .We have discussed several potential limitations to this pilot study, including low use of the tool by PCPs, leading to a more limited ability to understand usability and generalizability. We did not survey PCPs as to why they did not frequently use the tool, and only have this information from informal PCP interviews, an additional limitation. Another limitation may have been providing training only to intervention PCPs, potentially making PCPs more comfortable with OUD care regardless of their level of interaction with the OUD-CDS; however passive didactic training alone does not tend to impact clinical outcomes . An addiThe OUD-CDS was functional and accurate and effected changes in PCP confidence in screening and diagnosing OUD despite low use rates. Most PCPs recommended the tool and found it helpful with key aspects of OUD care. A large multi-site study is in progress that will incorporate PCP feedback to make the OUD-CDS more intuitive and simple and will include implementation strategies to achieve higher CDS use, including tapping into established rooming staff workflows.Additional file 1: Appendix A. Baseline Primary Care Clinician Survey.


To analyze trends in otolaryngology consultations and provide algorithms toguide management during the COVID-19 pandemic.A retrospective cohort study at a single institution tertiary care hospital.A total of 95 otolaryngology consultations were performed from March 1, 2020to April 26, 2020 (COVID-era) and 363 were performed from September 1, 2019to February 29, 2020 (pre-COVID-era) at the UPMC Oakland campus. Datacollected included patient demographics, COVID-19 status, reason forconsult, location of consult, type of consult, procedures performed, needfor surgical intervention, length of hospital stay and recommended followup.Patient populations in the pre-COVID-era and COVID-era were similar in termsof their distribution of demographics and chief complaints. Craniofacialtrauma was the most common reason for consultation in both periods, followedby vocal fold and airway-related consults. We saw a 21.5% decrease in therate of consults seen per month during the COVID-era compared to the6 months prior. Review of trends in the consult workflow allowed fordevelopment of several algorithms to safely approach otolaryngology consultsduring the COVID-19 pandemic.Otolaryngology consultations provide valuable services to inpatients andpatients in the emergency department ranging from evaluation of routinesymptoms to critical airways. Systematic otolaryngology consult servicemodifications are required in order to reduce risk of exposure to healthcareproviders while providing comprehensive patient care. As coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2), continues to spread across the globe, healthcare systemshave now gathered significant amounts of data to assess the far-reachingconsequences of this pandemic. Across medical specialties, healthcare professionalshave radically modified daily routines and procedures to protect the health andsafety of all patients as well as healthcare workers. Furthermore, viral loads detected in an asymptomatic patient may be similarto those of symptomatic patients. An additional cohort study of 23 patientsdiagnosed with COVID-19 in Hong Kong demonstrated posterior oropharyngeal salivaryviral load to peak in the first week after symptom onset and subsequently declineover time; however, viral RNA was still detected in posterior oropharyngeal salivaat least 20 days after symptom onset in one-third of patients. These findings support the need for the otolaryngology community to modifypatient care delivery during the COVID-19 pandemic.High viral loads of SARS-CoV-2 have been detected in the upper respiratory tracts ofinfected patients. Patients diagnosed with COVID-19 infection demonstrated a higherviral load soon after symptom onset, with higher viral loads detected in the nosethan the throat. This results in risk not only to otolaryngology providers but to members ofadditional care teams. Many groups have published safety guidelines andrecommendations for high-risk procedures in a galvanizing effort to share helpfulinformation.412Due to the nature of the head and neck examination and procedures, otolaryngologistshave been vigilant in their response to the pandemic. Endoscopy in particular isconsidered to be a high-risk procedure due to potential for aerosolization. It isunclear how long aerosolized particles remain airborne post-endoscopy, though somereports suggest particles may remain airborne for up to 3 hours. Similar management algorithms for adult otolaryngology consults have yet tobe established. The purpose of this study is 2-fold: first, to compareotolaryngology consult service data during the onset of the COVID-19 pandemic tothose of the previous 6 months at our institution, and second, to establishalgorithms for safely approaching consults during the pandemic.Handling otolaryngology consultations during the COVID-19 pandemic presents a uniquechallenge for providers. The care team encounters a new patient, possibly withunknown COVID-19 status, and must perform all diagnostic and clinicaldecision-making while balancing the risks of exposure. Algorithms for management ofcommon pediatric otolaryngology consults have been proposed previously.We performed a retrospective chart review of patients seen by the consultationservice of the Department of Otolaryngology at the University of Pittsburgh MedicalCenter (UPMC), a tertiary care center. Data collection was approved by ourinstitutional review board (IRB#STUDY20040289). Patients included in the study wereseen as consults between March 1, 2020 and April 26, 2020, either in the emergencydepartment (ED) or inpatient wards. Our consult service maintained an ongoing listof all patients seen in this time period; data was collected via direct chartreview. Collected data included basic demographic and clinical information such asreason for consult, chief complaint, inpatient interventions and duration ofhospitalization. For determination of hospitalization duration, if a patient wasstill admitted at the time of data collection, we considered the date of dataacquisition to be their “discharge” date. For patients who died during admission, weconsidered their date of death to be their “discharge” date. For comparison, we grouped patients under investigation and COVID-positivepatients together, while COVID-negative and unknown status with negative screenpatients formed a second group.The COVID-19 status at the time of initial consultation was recorded; patients wereCOVID-positive, under investigation, COVID-negative, or with an unknown status butnegative screening assessment. At our institution, patients are “underinvestigation” if they present with signs and symptoms suspicious for SARS-CoV-2infection. Patients with “unknown” status do not have symptoms suggestive ofCOVID-19 (screened negative), and thus were treated with similar precautions asthose with known negative status, though approaches remain guarded due toacknowledgement of potential asymptomatic carriers of SARS-CoV-2.We also analyzed consult data in the pre-COVID era from September 1, 2019 throughFebruary 29, 2020 to establish a baseline for the consult service workflow. Datawere obtained via financial billing records. We used International Classification ofDisease, 10th edition (ICD-10) codes and descriptions to group patients into chiefcomplaint categories. We used Common Procedural Technology (CPT) codes to studywhich procedures these patients underwent during their hospitalizations.A Wilcoxon rank sum test was used to determine whether patient ages weresignificantly different in the 2 time periods, as ages were not normallydistributed. Chi-square tests were utilized to determine if there were significantdifferences in the distributions of gender, chief complaints, proportion of patientsrequiring rigid or flexible endoscopy, and proportion of patients requiringoperative interventions.After review of changing consult patterns and forthcoming literature on safe patientcare during the pandemic, we developed several algorithms for approaching the mostcommon consults at our institution. These algorithms were developed by iterativediscussion among attending physicians and house staff with consideration of evolvingliterature on the topic.Between March 1, 2020 and April 26, 2020, the otolaryngology service was consultedfor 95 patients. The clinical characteristics of these patients are displayed inP = .839), gender (P = .553),consult chief complaints (P = .450), proportion of patientsrequiring rigid or flexible endoscopy (P = .465), or proportion ofpatients requiring an operative intervention (P = .090) between thepre-COVID era patient group and the COVID-era group. Of the 74 patients whounderwent rigid or flexible endoscopy, 63 underwent flexible fiberoptic laryngoscopyand 11 underwent rigid nasal endoscopy.In the 6 months prior to March 2020, the consult service evaluated 363 patients. ThedisMonthly rates of consults for epistaxis, vocal fold or airway evaluation,tracheostomy-related care, head and neck mass, head and neck infections, andotologic complaints were similar, but consults related to craniofacial trauma orother chief complaints decreased in the COVID era. While the overall consult ratedropped by 21.5%, the rate of craniofacial trauma consults decreased by 31.1% andthe rate of “other” consults decreased by 47.8%. The monthly rate of consultsrequiring operative procedures decreased by 52.2%, and the monthly number of consultpatients undergoing rigid or flexible endoscopy decreased by 20.8% .Although the city of Pittsburgh and its surrounding communities have had a relativelylow number of confirmed cases of COVID-19 compared to other parts of the UnitedStates, our institution and department enacted significant measures to protecthealthcare workers and prevent the spread of the virus in our hospitals. Decrease in craniofacial trauma consults at our institution is likely areflection of social distancing measures and reduced participation in activitiesthat predispose to traumatic injuries.The UPMC Department of Otolaryngology provides consultation to 7 hospitals. Prior toCOVID-19, resident consultation coverage included multiple hospitals. During theCOVID-19 area, resident coverage was limited to only 1 hospital. Self-containedteams of residents and attendings were formed to minimize cross-contaminationbetween teams in case of potential exposure. Throughout our hospital system, specialprecautions are taken during each patient encounter based on patients’ COVID status.Telehealth and e-consult measures are encouraged if applicable, and increasedattention is given to the disinfection of commonly used otolaryngology instruments.Understanding how otolaryngology consult approaches have changed in the COVID-19 erais vital for strategizing safe and effective means to deliver patient care andcollaborate with other healthcare providers. While the relative proportions of chiefcomplaints for consults have not changed drastically, comparisons of monthly ratessuggest important differences in patient management/exposure in the COVID-19 era.The volume of patients requiring operative intervention decreased by more than 50%,and a narrower range of procedures are being performed in the operating room (OR).Providers in other fields have noted decreased admissions for various conditions; DeFilippo et al. found a significantly lower rate of acute coronary syndrome (ACS)related hospitalizations during the pandemic compared to ACS-relatedhospitalizations in the previous year and earlier in 2020.By assessing trends in consult workflow during the COVID-era, several algorithms weredeveloped for safe, effective approaches to the most commonly encounteredconsults.17 All patients seeneither in the emergency department (ED) or on the inpatient floors aretreated as potentially COVID-19 positive. Full personal protective equipment(PPE) includes an N95 mask and face shield or surgical goggles. Relevanthistory should be obtained either from other providers or with appropriatecontact precautions, and pertinent laboratory values are reviewed.Due to the risk of aerosol transmission during epistaxis management, anupdated set of recommendations has been published. This can be performed by emergency medicine providers, internists, orintensivists prior to otolaryngologist evaluation. Atomized sprays should beavoided; instead, soaked pledgets or cotton should be utilized forhemostasis and topical anesthesia. Anterior rhinoscopy using a headlight andnasal speculum is performed while wearing full PPE as described above. Rigidnasal endoscopy is deferred unless there is either a suspicion for an activeposterior source or for evaluation of persistent, recurrent epistaxis,raising suspicion for an underlying sinonasal or nasopharyngeal mass. Ifnon-invasive management fails, nasal packing or cautery should be attempted.Sphenopalatine artery (SPA) ligation is considered for suspected posteriorbleeds only if bedside posterior packing is not sufficient; during theCOVID-era, there has been a higher threshold for operative diagnostic nasalendoscopy and SPA ligation, and there has been a dedicated attempt tocontrol all epistaxis cases at the bedside if feasible.Epistaxis management often requires manipulation of the nasal cavity forexamination and achieving hemostasis. To minimize droplet aerosolization,non-invasive management including bidigital compression for at least15 minutes and administration of antifibrinolytic agents such as tranexamicacid should be attempted first.Absorbable packing is preferred to prevent an additional encounter forpacking removal. Patients discharged from the ED with non-absorbable packingare instructed to return to clinic in approximately 5 days for packingremoval. For inpatients, the primary team is asked to assist with packingremoval in order to reduce patient encounters. After hemostasis is achieved,patients are instructed to complete a 3-day course of oxymetazoline twicedaily and maintain intranasal humidification via saline spray, saline geland home humidifier.Airway evaluations range from routine vocal fold evaluations to emergentendoscopies in patients with acute respiratory distress. Flexible fiberopticlaryngoscopy (FFL) is considered the gold standard for evaluation of thelarynx and pharynx. However, FFL requires instrumentation of both thenasopharynx and oropharynx, resulting in potential aerosolization andtransmission of viral particles. To address this risk of viral transmissionduring FFL, members of the American laryngology community provided a set ofrecommendations for the COVID-19 pandemic.FFL was recommended only to be performed in critical cases where findingshave an immediate impact on patient management. Examples include hemoptysisand airway compromise due to infectious or malignant etiologies. For stablepatients, alternative methods such as ultrasound or computed tomography (CT)imaging may be utilized. Ultrasound provides a quick method to evaluatelymphadenopathy, abscesses, neck masses, and vocal fold motion.Transcervical laryngeal ultrasonography provides a safer, less invasivealterative to evaluation of vocal fold motion.At our institution, the decision of whether FFL is necessary is shared by themost senior members of the consult team. Patients with unknown COVID-19status are screened for symptoms concerning for possible infection. Despiteabsence of symptoms or negative COVID-19 testing, all patients are treatedas potentially COVID-19 positive given the risk of false negative resultsand asymptomatic carriers. Examinations are performed with full PPE withsenior team members present to reduce need for repeat endoscopy. Anestheticgels are preferred instead of atomized anesthetics to reduce viralaerosolization risk. In cases where FFL is not crucial for patientmanagement, alternative methods such as ultrasound and CT are utilized toassist in clinical decisions. and prolonged intubation is associated with higher risk of subglotticand posterior glottic stenosis. However, early tracheostomy has not beendemonstrated to significantly reduce post-intubation laryngotrachealstenosis.20Tracheostomy placement and tracheostomy-related care are services regularlyperformed by otolaryngologists. Tracheostomy has previously demonstratedbenefits including decreased sedation, lower risk of ventilator-associatedpneumonia, shorter ICU stay, and shorter duration of mechanical ventilation,22 a discussionregarding the utility of tracheostomy is warranted. Our institution hasmodified our tracheostomy algorithm based on updated recommendations duringthe COVID-19 pandemic published by the Airway and Swallowing Committee ofthe American Academy of Otolaryngology-Head and Neck Surgery.Additionally, our institution has changed our policy to only performopen tracheostomies. Other institutions have temporarily deferred performingpercutaneous tracheostomies to decrease droplet aerosolization. If possible,tracheostomy placement is deferred until at least 2 weeks of intubation inorder to allow for potential decrease in viral load, decreased risk ofinfection to providers and to provide greater opportunity for extubation. Atleast one COVID-positive patient for which we were consulted fortracheostomy was successfully extubated after delaying the procedure. Basedon institution preference and location availability, tracheostomy may beperformed in the OR or in a negative pressure room. COVID-19 testing isrequired prior to tracheostomy. Open tracheostomy within a negative pressureroom is preferred to reduce risk of contamination during transport to andfrom the OR. A tracheostomy specific timeout is encouraged at the start ofthe case in collaboration with anesthesia and OR staff.Determination of whether to perform a tracheostomy must consider patientprognosis as well as risks and benefits to the patient and providers. Goalsof care discussions with patient family members are important regardless ofCOVID-19 status. Particularly in COVID-positive patients, where earlyreports demonstrated mortality rates exceeding 80% for patients requiringinvasive mechanical ventilation,8 Multiple methods are available to convert openairways to closed systems. Simple measures include partial closure with aPassy-Muir valve or tracheostomy cap, which are often employed for patientswith an established tracheostomy, though these may not be tolerated inpatients in the immediate post-operative setting. Heat moisture exchangerscan also provide a droplet barrier in patients with tracheostomy orlaryngectomy. Additionally, in-line suctioning systems can be employed toreduce risk of aerosolization during tracheostomy suctioning.Once the tracheostomy is performed, further adaptations are made to reducepotential viral transmission. Since the presence of a tracheostomy orlaryngectomy stoma may pose increased risk of droplet and aerosol spread,guidelines have been proposed for tracheostomy management during theCOVID-19 pandemic.In patients who require tracheostomy tube change to an uncuffed tube to allowfor use of Passy-Muir valve or transition toward decannulation, theappropriate PPE including N95 mask and face shield or goggles are utilized.Correct tracheostomy tube positioning is confirmed with visualization usinga flexible fiberoptic endoscope, taking caution not to pass the distal endof the tube and manipulate the tracheal mucosa. Where once we would performroutine tracheostomy care including downsizing, we recommend deferringroutine tracheostomy tube changes unless a different tube size or type isrequired for improving ventilation. Our decannulation protocol remains thesame with the requirement that the provider assess both the upper airway andthe airway distal to the tracheostomy tube to ensure patency beforedecannulation.When approaching a new consult for a head and neck mass, the consult residentshould first obtain airway and COVID-19 status from the referring provider.Evaluation for underlying airway compromise is required, which is especiallypertinent for extensive laryngeal malignancies where airway status may betenuous, requiring an awake tracheostomy. If there is any concern for airwaycompromise, the patient must be evaluated promptly with full PPE inanticipation of performing bedside FFL. A brief history and physical exam incombination with CT imaging should provide a reference point for theexpected level(s) of airway obstruction. FFL is then performed and recordedat the bedside. If proceeding with tracheostomy is necessary, timing of thecase must be considered. If there is significant concern for rapiddecompensation, an emergent awake tracheostomy must be performed. However,if symptoms are gradual and the patient’s airway status is stable, atracheostomy can be done in a non-urgent manner. In either case, the on-callresident should do the following: (1) request a negative pressure OR roomand ensure PPE availability, (2) confirm COVID-19 status and request testingif not yet performed, and (3) discuss the airway plan with theanesthesiologist. Once the tracheostomy is finished, direct laryngoscopy andbiopsy should be performed at the end of the case.If there is no concern for airway compromise on initial evaluation, thehouse-staff must determine first whether FFL is warranted. For malignanciesbased at the skin or oral cavity, this can be deferred unless there aresymptoms suggesting a second primary. Biopsy should be performed at bedsideand a definite plan for outpatient follow-up/intervention should beconfirmed before discharge. A provider may consider fine needle aspirationof a neck mass rather than biopsy of an obvious primary site especially whena direct laryngoscopy is needed regardless: This strategy avoidsmanipulation of the upper aerodigestive tract at the bedside. For those withsuspected oropharyngeal or laryngeal based malignancies, FFL should beperformed and recorded at the bedside. If the patient requires directlaryngoscopy with biopsy for further evaluation, one must determine if itshould be performed as an inpatient or if it may be scheduled as anoutpatient. Given the current financial crisis, socioeconomic status of somepatients, and transportation impediments during the COVID-19 pandemic, theremay be greater risk of loss to follow-up or delay in care. If a patientunder suspicion for new head and neck cancer does not warrant inpatientadmission, there must be careful review of the risks for encouraging closeoutpatient follow-up. We recommend that pre-operative COVID-19 testing becompleted before direct laryngoscopy is performed.As with the approach to a new head and neck mass, one should first evaluatefor any airway compromise. If there is concern for airway involvement, FFLshould be performed at the bedside. Available imaging is reviewed quickly,and the extent of the infection and level(s) of airway obstruction aredefined. After evaluating for airway compromise, one should determine ifthere is an underlying abscess based on exam and imaging. If there is noabscess, the patient should start an empiric trial of antibiotics, commonlyampicillin-sulbactam, unless there is concern for a local infectiouscomplication such as osteomyelitis, in which case an infectious diseaseconsultation and prolonged antibiotic course may be required. If the abscessis accessible, a bedside incision and drainage should be performed with fullPPE, limiting additional exposure to OR personnel. If the abscess iscomplicated  ordifficult to access, operative drainage is required. When this isdetermined, the on-call house-staff should request COVID-19 testing andcarefully assess whether any additional surgery teams are needed in order tolimit OR personnel.Once incision and drainage is performed, the patient will commonly havesurgical drains, either an open system such as a Penrose or closed systemsuch as Jackson-Pratt. In the case of an open drain system, it is advisableto apply gauze loosely at the open end of the drain to prevent contaminationof the immediate surroundings  by wounddrainage. Some patients may have open wounds requiring dressing changes anddebridement, which should be attempted at the bedside if possible withproper pre-procedure analgesia and appropriate PPE. If repeat surgicaldebridement is required, the total number of operative trips should belimited, and the procedure should be coordinated with other scheduled casesif possible. If the surgical drains yield a low output, consideration shouldbe given to removing the drains before discharge, and the patient and anyimmediate caregivers should be instructed on proper wound care. This limitsthe need for home health care services, reducing the risk of additionalexposure to healthcare workers and vice versa.Patients presenting to the emergency room with chief complaints such asotalgia, otorrhea, hearing loss, vertigo, and facial nerve dysfunctiongenerally have an acute course or onset of symptoms. If a patient presentswith chronic symptoms, one must assess for underlying cholesteatoma,malignancy, or chronic infection. Unless there is an acute change insymptomatology warranting inpatient admission, such patients may bedischarged home with close follow-up as long as a definitive outpatient planis established. For uncomplicated infections, patients should first undergo a trialof antibiotics. If there is no improvement on an empiric antibiotic andphysical exam findings are concerning, re-imaging may be warranted.For patients with an acute infection, it is imperative to determine if theinfection is complicated; one should assess for the presence of an abscess,facial palsy, thrombosis, or intracranial involvement. In such cases,operative intervention is generally warranted in the manner of a myringotomy± tube placement, cortical mastoidectomy, or a combination of both. If onlymyringotomy and tube insertion is required, it is recommended to perform abedside procedure with a portable operative microscope or in a dedicatedprocedure room to avoid exposure to additional personnel in the OR. If amastoidectomy is required, pre-operative COVID-19 testing should berequested along with a negative pressure room. The case is performed withfull PPE as described above; a drape may be fashioned to reduce the bonedust droplet and aerosol spread.Patients presenting with an isolated, sudden sensorineural hearing loss aregiven an outpatient oral steroid course, and baseline audiogram is obtained.When arranging follow-up, it is advisable to obtain COVID-19 testing priorto clinic visit in the case that an intratympanic steroid injection isrequired.Craniofacial trauma consultations primarily occur in the ED. As with most EDconsults, COVID-19 status is often unknown, so patients are treated asCOVID-19 positive. For minor trauma in which clinical decisions can be madeprimarily based on imaging and history, an E-consult may be performed, andphysical exam may be deferred to an outpatient follow up visit. This reducesthe number of providers interacting with each patient in the acute setting.The decision for an E-consult is shared between the trauma andotolaryngology consult teams to ensure that patient care is notcompromised. thus appropriate PPE is critical. Pre-procedural COVID-19 testingshould be obtained if possible. Operative interventions range from low riskprocedures that only require transcutaneous incisions to high riskprocedures such as repair of mandible or nasal bone fractures that oftenrequire violation of mucosal surfaces or manipulation of the nasal cavity.The AO Foundation recommends additional strategies such as preference forclosed reduction of fractures, use of scalpel over monopolar cautery formucosal incisions, use of self-drilling screws, use of bipolar overmonopolar cautery for hemostasis, and use of osteotomes over power saws formaxillofacial procedures.Treatment of craniofacial trauma may require procedural intervention.Lacerations involving mucosal surfaces are considered high risk procedures,Otolaryngology consultations provide valuable services ranging from evaluation ofroutine symptoms to critical airways. Increased risk of viral spread during theCOVID-19 pandemic has been addressed by adapting common consult protocols foreffective patient care with appropriate risk mitigation. Systematic otolaryngologyconsult service modifications are required in order to reduce risk of exposure whileproviding comprehensive patient care.


Transcatheter closure of patent foramen ovale (PFO) and secundum type atrial septal defect (ASD) are common transcatheter procedures. Although they share many technical details, these procedures are targeting two different clinical indications. PFO closure is usually considered to prevent recurrent embolic stroke/systemic arterial embolization, ASD closure is indicated in patients with large left-to-right shunt, right ventricular volume overload, and normal pulmonary vascular resistance. Multimodality imaging plays a key role for patient selection, periprocedural monitoring, and follow-up surveillance. In addition to routine cardiovascular examinations, advanced neuroimaging studies, transcranial-Doppler, and interventional transesophageal echocardiography/intracardiac echocardiography are now increasingly used to deliver safely and effectively such procedures. Long-standing collaboration between interventional cardiologist, neuroradiologist, and cardiac imager is essential and it requires a standardized approach to image acquisition and interpretation. Periprocedural monitoring should be performed by experienced operators with deep understanding of technical details of transcatheter intervention. This review summarizes the specific role of different imaging modalities for PFO and ASD transcatheter closure, describing important pre-procedural and intra-procedural details and providing examples of procedural pitfall and complications. Transcatheter closure of patent foramen ovale (PFO) and secundum type atrial septal defect (ASD) are nowadays performed in many centers throughout the world even in non-pediatric/congenital interventional laboratories. ASD closure is justified in the presence of significant left-to-right shunt across the atrial communication with evidence of right ventricular volume overload and normal pulmonary vascular resistance  1]. PFO. PFO1]. Although ASD and PFO echocardiographic imaging has been extensively discussed and reported, proper patient selection, procedural guidance, and follow-up monitoring are strongly influenced by different cardiac and non-cardiac imaging modalities that include transthoracic (TTE)/transesophageal (TEE)/intracardiac echocardiography (ICE), vascular Doppler studies, neuroimaging studies, transcranial Doppler study (TCD) .Familiarity with these imaging techniques is of pivotal importance for practioners and interventionalists involved in this field. This article reviews clinical indication to appropriate imaging studies, proper interpretation of imaging findings, and it exemplifies possible pitfalls in imaging interpretation along with possible procedural complications.Anatomy of atrial septum and PFO is presented in Secundum type ASD is related to embryonic deficiency of septum primum, accordingly the defect is usually located or at least involving the central portion of atrial septum . Wide anStandard views for transesophageal echocardiographic evaluation of atrial septum are reported in PFO transcatheter closure should be reserved to young patients with a diagnosis of embolic stroke/event of unknown source (ESUS/systemic embolization), tailoring down those with a high probability for a PFO-related embolic event, where PFO closure proved to be superior to medical therapy in reducing the risk of recurrence ,6. The cHowever, ischemic stroke can result from a variety of causes, such as large artery atherosclerosis, small vessel occlusion, and cardioembolism. Although no truly specific neuroradiological pattern of PFO-related stroke has been demonstrated, reviewing neuroimaging studies is pivotal to correctly identify potentially treatable patients . The maiAn ischemic lesion is defined as superficial when it involves the cerebral or cerebellar cortex. Other locations, including the noncortical gray matter  and deep white matter in the cerebrum or cerebellum are considered deep .Diffusion-weighted magnetic resonance imaging (DWI) is superior to computed tomography for the detection of ischemic lesions in the first hours after the onset of clinical symptoms as well as in differentiating between chronic and acute lesions  7]. Fur. Fur7]. In the vast majority of cardioembolic strokes, one or more cortical or corticosubcortical lesions are present. The identification of multiple acute infarctions involving both right and left anterior or both anterior and posterior circulations is highly suggestive for a cardiac source of emboli . ConversWhen a single corticosubcortical lesion is present, potential etiologies include both cardiac pathology and large artery atherosclerosis. In these instances, head and neck arteries imaging is needed to assess for the presence of atherosclerotic plaque in a vessel supplying the infarcted area .Furthermore, in the posterior circulation cardioembolic lesions show a preferential involvement of the superior cerebellar artery territory compared to other etiologies .Lesion size may offer further clues, since emboli from a cardiac source have been found to result in larger corticosubcortical lesions in respect to those secondary to atherothrombosis.The finding of small deep infarcts, called lacunar strokes (and less than 15–20mm in size) is a challenging quest for differential diagnosis . These aPatients with PFO-related stroke show a higher frequency of ischemic lesions > 15mm, with cortical involvement and without coexisting older ischemic lesions .Among the cardioembolic stroke patterns, PFO-related events are more often limited to the cortex or may present scattered pattern with multiple and small (<15 mm) lesions, while atrial-fibrillation related lesions are usually larger with corticosubcortical distribution . AdditioFurthermore, a higher frequency of multiple cortical lesions in patients with PFO-related stroke was associated with greater amount of right-to-left shunt as well as the presence of atrial septum aneurysm.A key decision element for proper PFO closure indication is to provide evidence of important right-to-left shunt occurring at the level of PFO tunnel . TCD proTEE is required before final decision to PFO closure . It is rA subgroup of patient is referred to PFO closure for platypnea orthodeoxia ,16. ThesPerioperative monitoring is usually accomplished via TEE or ICE  ICE has Procedural monitoring is usually carried using three main TEE views: (1) mid-esophageal long axis  of the atrial septum; (2) mid-esophageal short axis (45°–60° aortic view) of the atrial septum; (3) mid-esophageal 0° that is particularly useful to scan the posterior border of atrial septum . Imager If the interventionalists chose to use a Gore© CardioForm , a post-deployment contrast study may be performed having the device still attached to the securing lines. We strongly suggest performing such a study, because the presence of large shunt may be associated with undetected device malposition and increased risk of post-closure recurrent event. We perform a saline injection from the large femoral sheath. After complete device release, a final contrast study should be performed along with reassessment of device position and spatial interference with cardiac structure. Final release is usually associated to subtle device repositioning . AccordiAlthough there are slight differences between children and adult patients, current indication for ASD closure requires large left-to-right shunt with evidence of right ventricular volume overload and normal pulmonary vascular resistance  1,18,19,1918,19.We recommend to routinely check for sign of anomalous pulmonary venous return, that should be suspected if there is discrepancy between ASD size and degree of right volume overload, or in case of enlargement/abnormal flow in the innominate vein, superior vena cava, inferior vena cava or coronary sinus. Similarly sinus venosus defect must be always ruled out and in case of concern, cardiac magnetic resonance imaging should be performed to reassess pulmonary vein and defect anatomy  19]..19].As discussed for PFO closure, the echocaradiographer needs to be perfectly aware of the technical aspects of the procedure and the planned device . If ICE Periprocedural monitoring must confirm pre-closure findings , guide device deployment and confirm absence of residual shunt and abnormal interference between closing device and surrounding structure . Three-dWe routinely use a combination of bidimensional imaging, color-Doppler imaging, and balloon sizing to guide device choice . The larRoutine high risk anatomies include diminutive posterior and SVC rim (<5 mm), very large defect (>30 mm), thin and flimsy rim tissue; the absence of aortic rim is not considered an absolute contraindication but it has been associated to increased risk of erosion and embolization in particular if SVC border is also diminutive or absent  23]..23].As described for PFO closure, intraprocedural imaging needs to tailor details that help the interventionalist during deployment and device release . Again fAlthough, some intradevice shunt is frequently seen and it is often due to tension from the delivery cable or securing lines, there are some subtle echo markers of suboptimal position that should be always identified: (1) incomplete grasp on the superior or postero-inferior border; (2) residual shunt viewed at 45°–60° between the device and torus aorticus at baseline and under gentle device traction; (3) shifting device position during pull and push maneuver; (4) interference with mitral valve/superior vena cava/inferior vena cava/coronary sinus; (5) severe device wedging (device not moving throughout the cardiac cycle but entangled between the anterior/aortic and the posterior rim) with direct contact between device and surrounding atrial wall or structures . In all Training for proper acquisition and interpretation of each imaging modality has been presented in multiple documents. The specific setting of periprocedural multimodality imaging requires a dedicated collaboration between interventionalists, cardiac imagers, and neuro-radiologists. Although data regarding training in this specific setting are lacking, it may anticipated that a minimum of 10 supervised TCD, 50 supervised pre-closure TEE, and 30 supervised periprocedural TEE are required to become independent operator.A number of quality measures parameters have been discussed both for imaging and procedural performance . We beliTranscatetheter closures of ASD and PFO are established cardiovascular interventions that are now being performed often by adult interventional cardiologist with limited experience to congenital and structural heart intervention. Multimodality imaging is required for proper patient screening, procedure indication and to deliver these transcatheter therapeutics safely and effective. Although dedicated and formal training in high volume centers by expert operators is of primary importance to master these imaging techniques, we believe this document may be useful to review current practice, identify potential gaps in knowledge, and promote clinical improvement in the future.


Silver diamine fluoride (SDF) is an effective non-surgical treatment for dental caries which may also impact oral health-related quality of life (OHRQoL). The objective of this study was to conduct a network meta-analysis of SDF versus other standard of care therapies on OHRQoL.Studies published in PubMed/MEDLINE, Scopus, or Web of Science through July 2021 with no date or language restrictions.Any randomized controlled trial, cohort, or case-control study that included silver diamine fluoride as either a single or combinative treatment for dental caries and a quantitatively measured outcome for oral health-related quality of life was included.Potentially eligible studies were screened by two independent reviewers trained in conducting systematic reviews. Studies meeting inclusion criteria underwent a full-text review with data being extracted using a standardized form, including publication details, study methodology, outcomes, assessors, and sample information. Studies underwent a risk of bias assessment. Quantitative synthesis was performed using fixed effects meta-analysis and individual comparisons were assessed via network meta-analysis.Oral health-related quality of life.19 articles were returned following search strategies. Following screening, ten studies were evaluated for full-text eligibility and five were retained for meta-analyses. Results across all treatments indicate no differences in OHRQoL when compared to SDF . Direct and indirect estimates from network meta-analysis indicated that OHRQoL in children was not significantly different when treated with SDF versus atraumatic restorations  or placebo .Evidence from the literature consistently shows no discernible impact on OHRQoL across various non-surgical treatments for dental caries. Overall oral health-related quality of life may increase regardless of treatment protocol due to treatment of the underlying disease. Concerns over the staining of dental decay and oral mucosa resulting from treatment with silver diamine fluoride do not seem to affect OHRQoL. Silver diamine fluoride (SDF) is a novel therapy for the non-surgical treatment and prevention of dental caries, primarily delivered as a 38% concentration solution consisting of 24-27% silver, 7.5-11% ammonia, and 5-6% fluoride [Oral health-related quality of life (OHRQoL) is a multidimensional construct consisting of subjective evaluations of oral health, functional well-being, emotional well-being, satisfaction with care, and sense of self . Prior rResearch on the secondary effects of treating dental caries with silver diamine fluoride on quality of life yields mixed results, with SDF treatment demonstrating both improvements and no discernable effect on OHRQoL in children –16. SimiThis study is reported using the PRISMA checklist for network meta-analyses (PRISMA-NMA) . The MEDPotentially eligible studies were first independently screened by two reviewers (TBG and RW) who were previously trained for systematic reviews. Eligible studies were those that met study inclusion criteria: studies must have used silver diamine fluoride for the treatment of dental caries and must use a validated quantitative instrument for oral health-related quality of life. Any study that lacked a control group or comparator was excluded from quantitative synthesis but not from qualitative review. Any comparative intervention was included, such as atraumatic restorative tretments (ART), glass ionomer sealants, traditional amalgam restorations, fluoride varnish (FV), or combinations of therapies . Studies that met inclusion criteria underwent a full-text review with the following data being extracted using a standardized form: publication details , study methodology , outcome measure  and assessor (parent or child), and sample information .Risk of bias of included studies was independently evaluated (RW and TBG) using the Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies  and the 2 statistics. Direct and indirect comparisons across individual treatments across all studies were then evaluated using a frequentist network meta-analysis. Mean differences and standard errors were included for each study. Network geometry was evaluated and it was determined that two subnetwork analyses were required due to node disconnection. Individual network meta-analyses were then performed on each subnetwork and network graphs were computed. Node split analyses were not performed due to the small number of studies included in analysis. Treatment ranking from the network meta-analysis was calculated using the P-Score ranking metric, analogous to the Surface Under Cumulative RAnking (SUCRA) method. Tables for direct and indirect evidence as well as forest plots or subnetworks were computed. No studies included had multiple arms. All treatments included in NMA were performed in similar subject populations, suggesting the networks met the transitivity assumption. Analysis was performed using R v4.0.2.Overall pooled analysis of direct evidence was computed using a fixed effects meta-analysis, which also produced consistent treatment effects and standard errors for each study. Heterogeneity was determined using the Q and INineteen articles were returned after searching. There were no duplicate records. Nine articles were excluded following initial screening yielding ten full-text records assessed for eligibility , 23–26. Bias assessment for randomized studies included in quantitative synthesis  indicate2 = 0.0%, Q = 0.75, p = 0.95, Meta-analysis results indicate that, irrespective of comparator, there was no significant difference in quality of life versus silver diamine fluoride. There was no heterogeneity among the included studies (IResults from treatment ranking indicate that the standard placebo had the highest P-score (0.5689), followed by ART (0.5095) and SDF (0.4216). In this context, P-scores are interpreted as the extent that any treatment is better than any other treatment. Similarity in P-scores in these results indicate comparability of treatment on OHRQoL.The American Association of Pediatric Dentistry supports the use of silver diamine fluoride as part of a caries management plan and provides clinical practice guidelines for its use . Single-Facial aesthetics are a potential significant influence on perceptions of self, such as in children with orofacial anomalies  and in aOur findings indicate that while there is no comparative difference in OHRQoL among children receiving silver diamine fluoride versus other standard of care treatments such as atraumatic restorations, excluded studies suggest that there may be general improvement in OHRQoL over time due to treating underlying disease. Studies that only assessed within-subject change in oral health-related quality of life prior to and after treatment with silver diamine fluoride for dental caries were not quantitatively evaluated in this study due to a lack of an adequate comparator. Of these excluded studies, two found that OHRQoL/caregiver satisfaction improved , 24, twoThe small number of clinical trials of silver diamine fluoride that include measures for subjective quality of life prohibit analyses by severity of disease. We were therefore unable to explore whether the baseline severity of untreated caries treated by SDF had any impact on OHRQoL. Some studies have shown that oral health-related quality of life was negatively impacted by the general increase in severity , 34, theThe diversity of available non-surgical therapies for dental caries  means that numerous studies are necessary for a fully connected network. The disconnected networks presented in this analysis due to inadequate support therefore limits estimates of effects, specifically the disconnection for packaged treatments of SDF plus FV versus ITRs plus sealants. While we considered incorporating nonrandomized studies in analysis to expand upon the network, the lack of a comparator in these studies jeopardized the plausibility of the transitivity assumption . FurtherDespite these limitations, our study suggests that overall oral health-related quality of life is not appreciably affected by silver diamine fluoride treatment for dental caries when compared to other standard of care interventions and results are strengthened by the similarity of effects across alternative treatments. The impact of the baseline severity of disease treated by SDF or the role of anterior versus posterior treatment on OHRQoL is still unknown.S1 Checklist(DOCX)Click here for additional data file.


Anti-vascular endothelial growth factor (anti-VEGF) therapy currently plays a central role in the treatment of numerous retinal diseases, most notably exudative age-related macular degeneration (eAMD), diabetic retinopathy and retinal vein occlusions. While offering significant functional and anatomic benefits in most patients, there exists a subset of 15–40% of eyes that fail to respond or only partially respond. For these cases, various treatment options have been explored with a range of outcomes. These options include steroid injections, laser treatment , abbreviated anti-VEGF treatment intervals, switching anti-VEGF agents and topical medications. In this article, we review the effectiveness of these treatment options along with a discussion of the current research into future directions for anti-VEGF-resistant eyes. Vascular endothelial growth factor (VEGF) is now known to play a central role in the vascular changes associated with the leading causes of blindness in developed countries, namely age-related macular degeneration (AMD), diabetic retinopathy and retinal vein occlusions (RVOs) ,2,3. EacFor most causes of vascular leakage, anti-VEGF therapy alone is sufficient to reduce leakage and restore vision. In the case of eAMD, randomized clinical trials of treatment naïve eyes found that treatments are effective at reducing leakage and improving vision in 59–68% of cases for IVB ,12, 61–7While the focus has been on VEGF-mediated leakage and vascular proliferation as the causes of vision loss in eAMD, diabetic retinopathy and RVOs, it is clear that there are other players involved. The literature is confusing, however, with some review articles talking about VEGF as being the corner stone or rate limiting factor causing pathologic vascular leakage and proliferation. Other reviews describe separate pathways where cytokines, for example, directly mediate leakage independent of VEGF  22,23,2,25. TherPatients with anti-VEGF-resistant leakage have a different biological picture than the average person. Given the origins of anti-VEGF therapy are in oncology, resistance in cancers may provide insight into the culprits of anti-VEGF resistance in retinal diseases. These studies have demonstrated the importance of alternative proangiogenic factors in the development of anti-VEGF resistance such as platelet-derived growth factor, fibroblast growth factor, placental growth factor, interleukins and transforming growth factor-β ,31. ManyThe current anti-VEGF treatment strategy involves a loading dose series of three monthly injections followed by a transition to a pro re nata (PRN) or treat-and-extend strategy depending on physician preference. With all of these treatments, the shortest interval between injections is four weeks ,38. SeveTreating at shorter intervals has not been the only alternative dosing strategy attempted in anti-VEGF-resistant eAMD. Some researchers have also attempted larger doses at regular intervals. Routine dosing of IVR and IVA have been with 0.5 mg and 2 mg, respectively. The HARBOR study demonstrated equivalent outcomes between 0.5 and 2 mg IVR dosing in treatment naïve eAMD eyes . AssessmImportant considerations when employing either shorter treatment intervals or higher anti-VEGF doses are the possible systemic side effects. There have been concerns raised about systemic exposure to anti-VEGF following intravitreal injections leading to increased rates of myocardial infarctions, cerebrovascular accidents or thromboembolic events ,51. SuchMany eyes with eAMD initially responsive to a single anti-VEGF agent will develop resistance or tachyphylaxis over repeated treatments. To counteract this resistance, numerous researchers have proposed switching agents to a different anti-VEGF which may offer improved responsiveness. Similarly, some eyes will be unresponsive to one anti-VEGF medication but when challenged with a different agent show a substantial response. In a study of 63 treatment naïve eyes with eAMD initiating anti-VEGF therapy, 14 eyes (22.2%) were unresponsive to initial anti-VEGF medication and 8 eyes (12.7%) developed tachyphylaxis in the one year of follow-up . This raThe U.S. Food and Drug Administration (FDA) approval of IVA for the treatment of eAMD offered a novel anti-VEGF medication option after years of only having IVR and IVB available. This was especially important for the treatment of anti-VEGF unresponsive eyes and those with tachyphylaxis. Numerous investigators have evaluated its efficacy in these circumstances and all demonstrated some benefit ,60,61,62When eyes with eAMD develop tachyphylaxis or are unresponsive to IVA, some have theorized a switch back to IVR (or even IVB) may be beneficial. The SAFARI study prospectively evaluated switching to IVR for a series of three monthly doses followed by PRN dosing for the six-month trial. A total of 100 eyes were included and nonsignificant improvements in mean macular thickness (−35.38 µm) and visual acuity (+1.9 letters) were noted at six months. In total, 34% of eyes were noted to have an increase of 5 or more letters after the switch in therapy . Other sThe development of tachyphylaxis offers a treatment challenge, but numerous studies have demonstrated that switching anti-VEGF medication can be beneficial for many such eyes. Both IVA and IVBr appear to play a key role in the initial therapeutic approach when treating eyes that develop tachyphylaxis to other therapeutic agents. These agents have significantly different molecular structures and sizes when compared to the ranibizumab and bevacizumab compounds which may play a role when the retina becomes sensitized to these anti-VEGF treatments.Photodynamic therapy (PDT) as a treatment option for eAMD precedes the current anti-VEGF therapies but has fallen out of favor as a primary treatment. The therapy relies on an intravenous injection of verteporfin  which is then activated when in the retinal and choroidal circulation by a low-energy laser at 689 nm wavelength. Activation of verteporfin results in the creation of free radicals which cause vascular endothelial cell damage. When applied to the choroidal neovascular membrane in eAMD, it results in regression of the membrane but recurrence is common and repeat treatment is required. In eyes with anti-VEGF resistance, PDT may offer an alternative treatment option.Multiple studies have evaluated various PDT protocols in the treatment of anti-VEGF-resistant eAMD. Park et al. retrospectively evaluated 78 eyes with anti-VEGF-resistant eAMD treated with reduced fluence PDT (laser delivered for a shorter period of time resulting in a 20% reduction in energy density delivered from standard therapy) . All enrIntravitreal steroids have been a mainstay of therapy for numerous retinal vascular disorders for many years but have overall not found favor in the treatment of eAMD. In the case of anti-VEGF-resistant eAMD, some have proposed that an inflammatory component is partially to blame for this resistance . This haIn a number of smaller studies, alternative treatment approaches have been evaluated including the use of oral medications or surgical interventions . AnotherPerceived to be a variant of eAMD, PCV is most commonly seen in Asian patients ,88 with Intravitreal steroids have served an important role in the treatment of diabetic macular edema (DME) for many years, preceding the use of intravitreal anti-VEGF injections by a number of years ,105,106.Multiple investigators have evaluated both IVTA and DEX in the treatment of anti-VEGF-resistant DME. Kim et al. retrospectively evaluated 20 eyes with anti-VEGF-resistant DME treated with a single IVTA injection. These eyes experienced a significant improvement in both macular thickness and visual acuity at three months after treatment . Jeon anThe FDA approval of DEX for the treatment of DME offered another intravitreal steroid alternative to IVTA with the benefit of an extended therapeutic window. Multiple studies have investigated the use of DEX in the treatment of anti-VEGF-resistant DME. In several retrospective studies of anti-VEGF-resistant eyes, a single DEX implant was noted to improve both macular thickness and visual acuity for three months following treatment ,115,116.There are two other extended-release steroid implants available that utilize fluocinolone acetonide (FA). The 0.59 mg intravitreal FA implant  requires surgical implantation but can provided years of therapy, whereas the more recently developed 0.19 mg intravitreal FA implant  is an injectable implant that can be performed in clinic which can also last for a year or longer. Multiple studies have investigated the intravitreal FA implant in the treatment of anti-VEGF-resistant DME with beneficial, sustained visual acuity and macular thickness results ,127,128.As an alternative to intravitreal steroid therapy, posterior subtenon triamcinolone has also been utilized in the treatment of DME with mixed results ,130. EriThe use of thermal laser photocoagulation has been around for decades in the treatment of retinal diseases, especially vascular disorders such as diabetic retinopathy. Various forms of thermal laser photocoagulation have been utilized to treat different aspects of these diseases. Panretinal photocoagulation (PRP) applies equally spaced laser burns to the retinal periphery in eyes with proliferative diabetic retinopathy (PDR). These are applied to ischemic areas of the retina which effectively destroys those areas and halts the eyes’ drive to produce VEGF. Focal laser photocoagulation applies gentler, lower energy laser to leaking macular microaneurysms which are key to the development of DME. Grid laser photocoagulation similarly applies gentler, lower energy laser to diffuse areas of macular leakage instead of specifically targeting leaking microaneurysms. Finally, the more recently developed subthreshold or micropulse laser provides short, repeated bursts of laser energy which allows the tissue to cool prior to the application of further laser energy. This is different to traditional laser photocoagulation which provides a continuous wave of laser energy without requiring a cooling period between applications and thus limits the spread of laser damage to the surrounding structures. Micropulse laser has been utilized similarly to grid laser photocoagulation in the treatment of DME.In eyes with PDR, multiple studies have shown better visual acuity benefits from the use of intravitreal anti-VEGF therapy over PRP treatment ,134. As The initial Early Treatment Diabetic Retinopathy Study demonstrated the benefit of laser photocoagulation in the treatment of clinically significant macular edema . As has As previously noted, micropulse laser offers an approach to the treatment of DME similar to grid laser photocoagulation with less collateral damage to the precious macular tissue. Multiple studies have demonstrated a significant decrease in the number of intravitreal anti-VEGF injections when combined with micropulse therapy to treat DME ,142. In Overall, laser photocoagulation, in all of its forms, has an important role in the treatment of diabetic retinopathy and DME especially as an alternative to intravitreal anti-VEGF in eyes that are resistant.As discussed with anti-VEGF-resistant eAMD, some cases will have improved responses to a switch in anti-VEGF agent. This possibility has also been evaluated in anti-VEGF-resistant DME. Multiple studies have investigated switching from IVR and/or IVB to IVA in eyes with anti-VEGF-resistant DME. These studies have demonstrated significant improvements in visual acuity and macular thickness with this switch while utilizing either a standard every eight week or PRN dosing regimen ,145,146.The topical application of medication provides an additional therapeutic route in these anti-VEGF-resistant eyes. Various studies have evaluated the efficacy of topical anti-glaucoma medications as an adjuvant therapy to intravitreal anti-VEGF injections with mixed results. In a randomized controlled trial, the carbonic anhydrase inhibitor (CAI), dorzolamide , was applied to one eye of 16 patients receiving monthly IVB in both eyes for DME. Comparison of the eyes treated with and without dorzolamide at three months did not demonstrate a difference in visual acuity or macular thickness results . On the Another commonly used topical medication in the treatment of retinal diseases are nonsteroidal anti-inflammatory drugs (NSAIDs). We have previously reported of a single case of DME responsive to combination topical NSAID, steroid and CAI and subsequently maintained on the topical NSAID alone for a year . In a coSome investigators have evaluated other therapeutic options not traditionally applied to retinal diseases as well, including methotrexate and interferon alpha. Methotrexate is an antimetabolite that is commonly used systemically as an immunosuppressive agent. Previously, intravitreal methotrexate has been applied as the treatment of intraocular lymphoma and proliferative vitreoretinopathy ,158. IntSimilar to the case with DME, the use of intravitreal steroid therapy in the treatment of RVOs has a long history. The initial SCORE studies  demonstrated the benefit of IVTA in the treatment of central RVOs (CRVOs) but did not report significant benefit in branch RVOs (BRVOs) ,164. OncThere has been a number of studies exploring the use of the DEX implants in the treatment of anti-VEGF-resistant RVOs demonstrating an overall benefit for such therapy. Yong et al. reported on one eye with anti-VEGF-resistant CRVO with a significant improvement noted in both visual acuity and macular thickness six months after a single DEX implant . Ip et aThe development of anti-VEGF resistance in many eyes may in part be due to diminishing levels of anti-VEGF which naturally occurs between treatments. As discussed above, some have counteracted this by decreasing treatment intervals or increasing treatment doses. On the horizon is another alternative solution to this troubling scenario, the ranibizumab port delivery system (RPDS). The RPDS is a surgically implanted refillable reservoir that continuously delivers ranibizumab to the vitreous cavity. A phase 3 clinical study is ongoing , but earlier studies have demonstrated its safety with comparable visual acuity and macular thickness results to IVR therapy in the treatment of eAMD ,171. ThiAlthough targeting VEGF continues to be the mainstay of therapy, as discussed above, there are numerous pathways and targets involved in the development of macular edema in retinal diseases. Research is ongoing into investigational drugs that can utilize these alternative pathways including angiopoietin and CCR3 ,173,174.Treatment resistance to intravitreal anti-VEGF injections represents a clinical dilemma for eAMD, diabetic retinopathy and RVOs. Various alternative treatment options exist with varying degrees of success and selection of the best treatment approach must largely be determined based on the clinical scenario. An important consideration before initiating one of these alternative approaches is the patient’s adherence to scheduled injection appointments. Certain patients cannot tolerate even being a few days late for their scheduled injection so it may be necessary to first introduce a strict injection schedule, with one injection every four weeks. Following this, many patients may respond to a simple switch of anti-VEGF agents while others may require more regular injections or even injections of larger doses than utilized in standard protocols. Beyond that, the addition of supplemental intravitreal steroids either in the form of IVTA, DEX implant or FA implant appears to be of benefit most often in the retinal vascular diseases. Laser therapy  is useful when steroid therapy fails or is contraindicated by other patient characteristics such as poorly controlled glaucoma . Finally