Concurrent use of opioids and benzodiazepines (COB) can lead to additive respiratory and central nervous system effects, putting patients at increased risk of fatal overdose. In 2016, the Centers for Disease Control and Prevention released an opioid-prescribing guideline recommending against COB, and the Pharmacy Quality Alliance (PQA) endorsed a COB measure in its core opioid set. From May 1, 2017, to December 4, 2017, a California Medicaid plan launched a COB-focused prescriber outreach intervention for members receiving recent opioid and benzodiazepine claims with the intent of decreasing concurrent use.To assess the effect of a prescriber fax intervention by a Medicaid plan on COB.Two retrospective analyses were conducted using administrative pharmacy claims data: a comparison of the PQA COB rate among selected California Medicaid plans for 2016 and 2017 and a cohort utilization analysis of members identified for the fax intervention compared with controls. Intervention and control members were matched based on 12 pre-index utilization characteristics. Outcomes assessed included proportion of members with resolution of COB in the post-index period, change in mean number of COB days before and after the index date, and proportion of members with decreased benzodiazepine daily dose after the index date. Analyses were also performed for the subgroups of members with < 30 days of COB and ≥ 30 days of COB in the pre-index period.P < 0.01), which was also statistically significant for the 2 subgroups. The intervention cohort had a decrease in the mean number of COB days from pre- to post-index periods, but this was only statistically significant for the subgroup with < 30 COB days . No statistically significant differences were detected between cohorts in proportion of members with decreased benzodiazepine dose.All California Medicaid plans in the study saw an improvement in the PQA COB rate between 2016 and 2017. In the utilization analysis, 4,182 intervention members were eligible according to study criteria and matched to similar control members. Many differences in medication use existed between the subgroups with < 30 days and ≥ 30 days of COB in the pre-index period, with the latter group consisting of much more chronic, complex users. The intervention cohort had a statistically significant higher proportion of members with complete resolution of COB compared with the control cohort (43.8% vs. 40.0%; Our analyses demonstrated that this low-touch prescriber fax intervention produced statistically significant improvements in COB outcomes, despite the overall trend of declining COB among the other California Medicaid plans. Low-touch, targeted prescriber outreach can be an inexpensive yet effective tool to affect prescriber behavior, particularly before COB becomes chronic. What is already known about this subjectThe Centers for Disease Control and Prevention has cautioned against the concurrent use of opioids and benzodiazepines (COB), and the Pharmacy Quality Alliance (PQA) has endorsed a COB quality measure.Pre-post outcomes studies have found that low-touch interventions may be effective in changing prescriber behavior.Opioid prescribing has declined over the past several years, which may be attributed to shifting prescribing practices, changing regulatory requirements, and increased public awareness of opioids.What this study addsThe PQA COB rate among 7 California managed Medicaid plans improved from 2016 to 2017, with decreases in the prevalence of COB among opioid users ranging from 0.5% to 1.9%.The California Medicaid population that received the prescriber fax intervention had a greater improvement in COB resolution compared with a matched control cohort (43.8% vs. 40.0%), providing evidence that a low-touch, prescriber fax notification may contribute to the resolution of this dangerous drug combination.There was a greater difference in COB resolution between intervention and control cohorts in members with fewer than 30 days of COB compared with members with 30 or more days of COB, suggesting that the prescriber fax intervention may be less effective in members with more chronic COB.2 Patients with COB have an estimated 5-fold increase in overdose risk compared with patients prescribed opioids alone.3 The prevalence of this dangerous drug combination increased from the mid-1990s through 2014.5 One study of U.S. veterans from the Veterans Affairs Administration database found COB to be present in approximately 30% of opioid users.6 Another study of outpatient prescriptions in Pennsylvania found that almost half of patients taking opioids were also prescribed benzodiazepines.7 In March 2016, the Centers for Disease Control and Prevention (CDC) released a guideline on the appropriate prescribing of opioids for chronic pain that advised against COB whenever possible and recommended that prescribers carefully weigh the risks and benefits before prescribing this combination.1 In December 2016, the Pharmacy Quality Alliance (PQA) endorsed a COB measure in its Opioid Core Measure Set8; this measure was also adopted by the National Quality Forum (NQF) in October 2018.9The use of concurrent opioids and benzodiazepines (COB) creates an additive risk of respiratory and central nervous system depression for patients, which could lead to potentially fatal overdose.10 conducting retrospective drug utilization reviews,13 and creating “lock-in” programs that limit high-risk patients to a single prescriber and pharmacy for controlled substance prescriptions.14 Interventions focused on changing behavior can be low touch, such as automated provider mailings, or high touch, such as one-on-one case management with the member. In 2017, a California Medicaid plan conducted a low-touch fax intervention, notifying opioid prescribers of members’ recent benzodiazepine fills and the CDC recommendations regarding COB. The purpose of this study was to assess the effect of this fax intervention on COB use.Because inappropriate opioid use has gained attention in recent years, various stakeholders have adopted strategies to combat misuse. Federal agencies, many state health departments, and public and private managed care organizations have implemented initiatives, such as limiting quantity for initial opioid fills,Between May 1, 2017, and December 4, 2017, an automated daily claims sweep identified members of a large California Medicaid plan who had filled an opioid prescription with at least 1 benzodiazepine claim in a 30-day lookback from the date of the opioid claim. The member’s opioid prescriber was automatically faxed a letter notifying the prescriber of the recent benzodiazepine fill and providing information about the CDC opioid prescribing guideline’s precautions regarding COB. The prescriber was asked to fax the form back with a response that indicated the following: “action will be taken” or “no action needed – patient will be monitored.” Prescribers who did not return a response were sent a second fax 3 weeks later. No additional faxes were sent following this second fax.8Two retrospective analyses were conducted: a plan-level quality measure calculation and a member-level COB utilization analysis. The data sources were pharmacy claims and eligibility information from the MedImpact database. MedImpact is a pharmacy benefits manager (PBM) that provides pharmacy benefits for 28 million lives globally and services all plans included in this study. The opioid and benzodiazepine drug lists used for this analysis mirrored those used by PQA in the COB reporting measure, which included all opioids with morphine milligram equivalents.8The PQA COB rates for calendar years 2016 and 2017 were calculated for the plan that conducted the COB intervention (“intervention plan”) and each of the 6 other California Medicaid plans that did not implement this intervention (“other plans”). The PQA COB rate is reported based on calendar year and defined as the number of adults from the denominator with at least 2 benzodiazepine claims on at least 2 different days with a total cumulative days supply greater than or equal to 30 (numerator), divided by number of adults with at least 2 opioid claims on at least 2 different days and a total cumulative days supply of at least 15 (denominator).Members who had been identified for the prescriber fax intervention and had at least 1 day of overlap between an opioid and a benzodiazepine in a 30-day look-back were included in the intervention cohort. Members from the other California Medicaid plans who had filled an opioid between May 1, 2017, and December 4, 2017, with at least 1 day of benzodiazepine overlap in a 30-day look-back were candidates for the control cohort. The target opioid claim for both cohorts was the first opioid claim filled between May 1, 2017, and December 4, 2017, which was the claim that triggered the prescriber letter for the intervention cohort. If multiple opioid claims were filled on the same day, the claim with the longest days supply was used as the target opioid claim. The measurement period consisted of a 90-day pre-index period followed by a 90-day post-index period, with the index date falling on the last day supply of the target opioid claim. Thus, day 1 of the post-index period immediately followed the last remaining day supply of the target opioid claim. The reason for this placement of the index date and post-index period is to observe whether the fax intervention affected the occurrence of subsequent claims after the days supply of the target opioid claim had expired. All members were required to be continuously eligible during the 180-day measurement period. Members were excluded if they had claims for cancer medications or claims filled at long-term care pharmacies during the measurement period.23 Use of long-acting opioids and use of opioids with opioid potentiators have been found to be associated with a lower likelihood of opioid discontinuation.21 Other indicators of more chronic use, such as greater days supply of opioids and benzodiazepines, were included in the propensity score. The number of pharmacies and prescribers has been used as a risk measure in identifying potential opioid misuse.23Intervention and control members in the cohort analysis were matched 1:1 based on 12 characteristics in the pre-index period as shown in 24 Age and presence or absence of long-acting opioids were matched exactly. The 10 other characteristics were included in a propensity score calculated using PROC PS Match, SAS version 9.4  and paired using optimal propensity score matching. Members who could not be matched were removed from further analysis.The total number of prescription drugs dispensed was used as a proxy of disease burden in the absence of diagnosis data.The primary outcome for this analysis was the percentage of members with complete COB resolution, defined as having no days of COB in the post-index period. Secondary outcomes included the percentage of members with decreased benzodiazepine dose and change in mean number of COB days from pre- to post-index. A decrease in benzodiazepine dose was defined as a decrease in average dose per day of the last benzodiazepine claim in the pre-index period. Average dose per day was calculated as the drug strength multiplied by the quantity divided by days supply. Members with no benzodiazepine use in the post-index period were not included in the dose decrease outcome.Two subgroups of the intervention and control cohorts were also compared for each outcome: matched members with fewer than 30 days of COB (< 30 COB) in the pre-index period and matched members with 30 or more days of COB (≥ 30 COB) in the pre-index period. Descriptive statistics were expressed as means with standard deviations for continuous variables and frequencies with percentages for binary data. Pre-post outcomes were compared with repeated measures analysis of variance using the interaction of case and time to estimate the difference-in-difference of means. The a priori alpha was set at 0.05 to determine statistical significance. Number needed to treat (NNT) was calculated by taking the inverse of the absolute risk reduction. Data management and analyses were conducted using SAS version 9.4.The PQA COB rates were calculated for the intervention plan and 6 comparison plans as shown in A total of 5,444 members were identified in the fax intervention. A prescriber response was received for 1,492 (27.4%) of the 5,444 unique prescriber letters sent. Of the 1,492 responses returned, there were 427 (28.6%) responses of “action will be taken” and 1,065 (71.4%) responses of “no action is necessary – patient will be monitored.”P values > 0.2. The cohorts consisting of all matched members had a mean of 33 days of COB in the pre-index period. The < 30 COB subgroup had a mean of 9 days of COB in the pre-index period, whereas the ≥ 30 COB subgroup had a mean of 58 days. The ≥ 30 COB subgroup also had a much higher rate of members on long-acting opioids (45% vs. 28%) and opioid potentiators (40% vs. 30%). The number of unique prescribers and number of unique pharmacies were similar between the < 30 COB and ≥ 30 COB subgroups.In the cohort analysis, 4,182 intervention members were eligible according to study criteria and matched to control members. P = 0.0004). The NNT for the intervention was 26.1 (95% CI = 11.7-40.6) in a 90-day follow-up period. For every 27 members with COB targeted by the fax intervention, we could achieve 1 additional member who had COB resolution compared with no fax intervention. The intervention cohort also had a higher rate of no post-index COB days when looking at the < 30 and ≥ 30 COB subgroups. In the < 30 COB subgroup, there were 3.5% more members in the intervention cohort who discontinued COB in the post-index period compared with the matched control cohort (P = 0.0123), with an NNT of 28.6 (95% CI = 6.2-51.0). In the ≥ 30 COB subgroup, 2.5% more intervention members had discontinued COB compared with control members (P = 0.0222), with an NNT = 41.5 (95% CI = 6.0-77.1).For the primary outcome of percentage of members with complete COB resolution in the post-index period, the intervention group had a statistically significant higher rate of members with no COB days in the post-index period  compared with the control group . The percentage of members with decreased benzodiazepine dose in the post-index period was greater in the intervention cohort compared with the control group but did not meet statistical significance .The average number of COB days from the pre- to post-index periods decreased more in the intervention group (−2.5 days) than in the control group but was only statistically significant for the < 30 COB subgroup, with a change of −2.5  days for the intervention and −1.5  days for the control group  and up to 5 refills on benzodiazepine prescriptions.Third, members were identified for the intervention regardless of days supply of the claims or type of prescriber. For instance, a member filling a benzodiazepine for pre-procedure anxiety and a short course of opioids intended for after the procedure may not have true concomitant use. The percentage of members with resolution of COB must be interpreted with caution, as it may have included members who would not have used COB chronically. In addition, we did not have diagnosis data for which to evaluate the clinical indication for opioid and benzodiazepine use. We also did not assess for prescriber specialty or type of practice.Finally, we performed our analysis based on the days supply information submitted in the opioid and benzodiazepine claims; however, we could not account for members taking the medication differently than prescribed, which could have changed the true days supply for the claim.The prescriber fax intervention was associated with a decrease in COB in a California Medicaid population compared with a similar control cohort. Our retrospective matched cohort analysis demonstrated that the intervention was able to increase the proportion of members who discontinued any COB by 3.8% over the control group, despite the fact that the plans to which these control group members belonged also had decreasing COB rates.2 Such low-touch prescriber fax interventions are relatively inexpensive and easy to implement in a managed care setting.Discontinuation of COB can help patients reduce their risk of profound sedation, respiratory depression, and/or death from the additive effects of opioids and benzodiazepines.Our analysis reinforces the idea that low-touch interventions are able to affect prescribing practices and use, particularly before COB becomes chronic. Future research in this area should focus on characteristics of members, prescribers, and claims that are most predictive of positive response and improved outcomes to further increase the effectiveness of the intervention.


The authors describe aesthetic refinements to the approach for male chest lifting in male patients with grade 3 gynecomastia and/or significant chest skin excess. An inferior pedicle is used to transpose the nipple–areolar complex allowing preservation of pigment and sensation, liposuction and direct excision are used to reduce volume and excess skin, and the resulting curvilinear scar along the inferior and lateral border of the chest provide a more masculine appearance. Early experience with this technique has shown it to be safe and effective. Perioperative management and the detailed steps of the procedure are outlined. There has been a 66% increase in the number of total annual surgeries performed from 2020 to 2021 .3 Simon et al developed a surgical classification of gynecomastia based on the degree of breast enlargement and the skin redundancy.4 We previously described our experience in treating grades 1, 2A, and 2B cases of gynecomastia using power-assisted liposuction and the pull-through technique, which continues to be our approach for these cases.5 However, grade 3 cases of gynecomastia exhibiting marked breast enlargement and significant chest skin excess present additional anatomical challenges that must be addressed including excess skin, malpositioned nipple–areolar complex (NAC), and poor chest shape, which necessitates the removal of skin from the chest and the repositioning of the NAC.4The incidence of gynecomastia—a condition characterized by the benign proliferation of glandular breast tissue in males6-16 Removal of excess skin results in different scar patterns and locations, and the repositioning of the NAC can be done using a pedicle or free nipple graft. Previous surgical techniques to remove excess skin involve a horizontal incision that extends from the central chest to its lateral border.13 Another technique employs a boomerang incision coupled with J-torsoplasty to minimize vertical and horizontal skin laxity.14 While these techniques afford substantial skin removal from the chest and upper abdomen, the disadvantage is a more conspicuous scar. In these grade 3 cases, free nipple grafting is also commonly used but this increases risks including hypopigmentation and loss of sensation of the NAC.16 Alternatively, the use of an inferior pedicle to transpose the NAC reduces these postoperative risks and has been described by Kornstein and Cinelli, in combination with a skin excision pattern resulting in a scar that extends laterally from the inframammary fold to the lateral mammary fold.12A variety of surgical techniques have been described to manage cases of grade 3 gynecomastia and/or significant chest skin excess after massive weight loss.Over the past few years, our approach to these treating grade 3 cases of gynecomastia has evolved to use an inferior pedicle to transpose the NAC, and liposuction and direct excision to reduce volume resulting in a curvilinear scar along the inferior and lateral border of the chest providing a more masculine appearance. In addition to contouring the anterior chest, this approach allows for contouring the lateral chest with a resulting scar that is placed in a natural transition zone along the inferolateral border of the pectoralis major muscle. In this study, we review our early experience and outcomes using this approach for grade 3 cases of gynecomastia. The guiding principles outlined in the Declaration of Helsinki were strictly adhered to throughout the study. Written consent was provided, by which the patients agreed to the use and analysis of their data.2.Patients should be evaluated to rule out pathological causes of gynecomastia and/or the presence of breast masses. Patients who have grade 3 gynecomastia or those after massive weight loss with significant chest skin excess and inferior malposition of the NAC are ideal candidates for this approach. Patients must be nonsmokers or must have quit smoking for 4 weeks prior to surgery. Prior to surgery, patients should have a stable weight with a body mass index of <35 kg/m17-19 One hour prior to surgery, patients are premedicated to minimize opioid requirements and reduce postoperative nausea and vomiting . Chemoprophylaxis for VTE is utilized in very high-risk patients (Caprini/Davison risk assessment model score >7), or if male chest lift is performed in combination with abdominoplasty.18-20In the preoperative area, patients are started on our perioperative warming protocol, which is continued intra- and postoperatively.vomiting .18,19 CoThe operative sequence male chest lift surgery is outlined in 21 Specifically, the simultaneous separation and tumescence is performed using a 4-mm basket tip cannula,22 followed by power-assisted liposuction  with a 4-mm three hole tip cannula in the planned areas for resection, the upper and lateral chest wall, the upper abdomen, and deep to the pedicle. Following aspiration, fat equalization is performed using a 4-mm basket tip cannula off-suction with an emphasis placed on discontinuously undermining and releasing the zones of adherence of the central and lateral chest and inframammary fold, which facilitates redraping of the chest skin.With the patient in the standing position, a curvilinear skin excision pattern is marked, so the resulting curvilinear scar will be along the inferior and lateral border of the chest , 2. The Intraoperatively, the inferior pedicle is designed to maintain at least a 1:1 length-to-base ratio. An inferior pedicle is de-epithelialized, and the NAC is transposed to lay at the inferolateral border of the pectoralis major muscle. The superior skin is elevated in the subglandular plane without disrupting the pectoralis fascia, and advanced over the pedicle, while the inferior skin is advanced superiorly and medially. Progressive tension sutures with #1 Vicryl  are performed when there is significant dead space between the flap and the pectoralis fascia, and drains are not used.The new position of the NACs is marked at the junction of the breast meridian and a line at the level previously marked on the sternum. The skin at the new position of the NACs is excised in a circular pattern with a 20-mm diameter and the NAC is inset. The wounds are closed in layers.19 All patients are seen for routine postoperative follow-up on postoperative day 1, then at day 5 or 6 for removal of skin staples, and they are seen at 2 weeks and 1 month postoperatively. Patients are instructed to wear their postsurgical compression garment for 1 month postoperation19 and Lipo foam  is used underneath this compression garment for the first 2 weeks postoperatively. Patients begin daily chest massage with arnica gel after removal of staples. Once the incision is healed, scar care with silicone sheeting is started and continues for 6 months postoperatively. After 1 month, patients return for routine checks at 3, 6, and 12 months postoperatively.Patients continue a multimodal postoperative oral analgesia protocol.2 . The mean operative time was 123 min , the mean total tissue excised per side was 197 g  and the mean total liposuction volume per side was 356 mL . Three cases (33.3%) were performed in combination with other body contouring procedures. Eight patients (88.9%) had primary surgery, while 1 patient had secondary surgery (11.1%). The average length of follow-up was 18.7 months  and 1 patient (11.1%) had scar revision. All patients reported that NAC sensitivity was preserved. The aesthetic outcomes were good, and patients reported being satisfied with the results. While these results are encouraging, the results of this study are limited by its small sample size.Based on our early experience, this novel male chest lifting approach for grade 3 cases of gynecomastia and/or significant skin excess after massive weight loss has been safe and effective. This approach allows preservation of pigment and sensation of the NAC and results in a curvilinear scar that is creates a more masculine appearance of the chest.ojad021_Supplementary_DataClick here for additional data file.


Oral treatment alternatives for febrile urinary tract infections are limited in the era of increasing antimicrobial resistance. We aim to evaluate if the combination of pivmecillinam and amoxicillin/clavulanic acid is non-inferior to current alternatives for step-down therapy in adult patients with febrile urinary tract infection.We plan to perform an investigator-initiated non-inferiority trial. Adult hospitalised patients treated with 1–5 days of intravenous antibiotics for acute febrile urinary tract infection caused by extended spectrum beta-lactamase (ESBL) producing Enterobacterales will be randomised 1:1 to either control  or intervention (10 days of pivmecillinam 400 mg three times daily and amoxicillin/clavulanic acid 500/125 mg three times daily). The primary outcome will be clinical cure 10 days (+/− 2 days) after antibiotic treatment completion. Clinical cure is defined as being alive with absence of fever and return to non-infected baseline of urinary tract symptoms without additional antibiotic treatment or re-hospitalisation (for urinary tract infection) based on a centralised allocation-blinded structured telephone interview. We plan to recruit 330 patients to achieve 90% power based on a sample size simulation analysis using a two-group comparison, one-sided alpha of 2.5%, an absolute non-inferiority margin of 10% and expecting 93% clinical cure rate and 10% loss to follow-up. The primary endpoint will be analysed using generalised estimated equations and reported as risk difference for both intention-to-treat and per protocol populations. Patients are planned to be recruited from at least 10 centres in Sweden from 2023 to 2026.If the combination of pivmecillinam and amoxicillin/clavulanic acid is found to be non-inferior to the control drugs there are potential benefits in terms of tolerability, frequency of interactions, outpatient treatment, side effects, nosocomial infections and drive for further antimicrobial resistance compared to existing drugs.NCT05224401. Registered on February 4, 2022 Enterobacterales (EPE) is of increasing concern, often colonising the gut and intestines, and causing urinary tract infections (UTI) and bloodstream infections (BSI). ESBL-producing bacteria often carry resistance to other antibiotic classes than beta-lactam antibiotics, for instance quinolones and trimethoprim-sulfamethoxazole (TMX), which are the mainstay oral treatment for febrile UTI [Antimicrobial resistance (AMR) is increasing. An estimated 4.95 million deaths were associated with AMR worldwide in 2019 and the total cost of health care and loss of productivity exceeds € 1.5 billion every year in the European Union [rile UTI . This caEnterobacteriaceae [E. coli bacteraemia [Pivmecillinam is the oral prodrug of mecillinam, a beta-lactam discovered in the 1970s with activity against eriaceae . There aeriaceae –8 and oneriaceae , showingeriaceae , 11, higeriaceae , with lieriaceae  and a loeriaceae . Treatineriaceae . A recenteraemia  while a teraemia . We beliteraemia  but pivmteraemia . When piteraemia . There mteraemia . The pivteraemia . ClinicaWe hypothesise that PAC is non-inferior to ciprofloxacin, TMX or ertapenem as step-down therapy for acute febrile UTI caused by EPE, based on the assumption that pivmecillinam is an effective treatment for febrile UTI and that the addition of clavulanic acid ensures efficacy in patients with ESBL-producing Enterobacterales.To evaluate if the combination PAC (intervention) is non-inferior to ciprofloxacin, TMX or ertapenem (as one composite control group) as step-down therapy in patients with acute febrile UTI caused by extended spectrum beta-lactamase (ESBL) producing Enterobacterales (EPE).To compare participants’ perception of treatment tolerability on a 1–10 scale.To compare the incidence of early study drug discontinuation between groups.To compare the incidence of additional antibiotic subscriptions (for UTI) within 28 days between groups.To compare re-admission to hospital (due to UTI-related symptoms) within 28 days between groups.To compare the incidence of drug-related serious adverse events (SAE) within 28 days between groups.To compare the all-cause mortality within 28 days between groups.To compare the recurrence prevalence of EPE  in urine cultures 10 +/− 2 days after antibiotic treatment between groups .To compare the prevalence of EPE or carbapenemase-producing bacteria in faecal cultures 10 +/− 2 days after antibiotic treatment between groups.Investigator-initiated, randomised, controlled, investigator-blinded, outcome-assessor-blinded, non-inferiority, multicentre, phase IV trial with parallel group design, 1:1 concealed allocation ratio and a 28-day follow-up period.https://classic.clinicaltrials.gov/ct2/show/NCT05224401 and on the trial homepage: https://pacuti.se/.We will recruit patients from up to 29 infectious disease (ID) clinics in secondary and tertiary, emergency and teaching hospitals in Sweden. Participant recruitment 2023 in the following five Swedish ID clinics: Helsingborg, Malmö, Lund, Kristianstad and Västerås. A full list of currently recruiting centres will be updated on Patients will be screened for eligibility by the attending ward physician using the following criteria:Age ≥ 18 yearsFever (≥ 38.3 °C) or shaking chills at least once at home or in hospitalaDysuria, urinary urgency, difficulty urinating, new or worsened urinary incontinence, macroscopic haematuria or increased urinary frequencybLow abdominal pain or flank pain with percussion or palpation tenderness over kidneys and/or bladder.Clinical suspicion of UTI including at least one of the following symptoms:3 CFU/mL) and/or blood culture positive for EPEUrine ≥ 1003 CFU/mLIn-patient who has received 1–5 days of EPE-activeDiscontinuing parenteral treatment and starting treatment with oral antibiotics is considered safe according to the treating physician.Known or suspected pregnancy.Known or suspected life-threatening allergy towards beta-lactam antibiotics.Clinical isolate of EPE is resistant to ciprofloxacin, TMX and ertapenem.Severe renal insufficiency with estimated glomerular filtration rate (eGFR) <10 mL/min or requiring any form of dialysis.Severe decompensated liver failure (i.e. child Pugh class B or C).Genetic metabolic diseases associated with severe carnitine deficiency.Megaloblastic haematopoiesis.Co-treatment with valproate or valproic acid Other reason to which patient is unfit to be included in the study according to treating physician, e.g. cognitive impairment preventing informed consent and follow-up, inability to speak and/or read Swedish, missing national personal identification number or missing telephone number preventing follow-up or planned duration of antibiotics >10 days due to complicating factors.A limited number of infectious disease physicians at each site will be responsible for obtaining informed consent from trial participants prior to treatment allocation. These physicians will receive specific training and instructions on how to follow protocol and how to collect and record data in the trial. The physicians will provide oral and written information about the study, any risks or benefits involved with participation and inform potential participants that termination from the study can be done at any time without explanation in accordance with the ethical approval. Written information will be provided after all eligibility criteria is fulfilled on days 1–5 from the initiation of EPE-active intravenous antibiotic. Recruiting physicians are asked to provide at least a few hours for each participant to contemplate their participation.No additional participant data or biological specimens will be collected other than what is specified in this protocol. The data collected for this study may be used in ancillary studies after approval of an amendment to the Swedish ethical review authority.Fluoroquinolones and trimethoprim–sulfamethoxazole are considered international standard oral treatment for febrile UTI  and haveA 7-day course of ciprofloxacin has been shown to be non-inferior to a 14-day course in women in an RCT . There i5 (1 g once daily5) for men and 7 days of ciprofloxacin (500 mg twice daily) or6 10 days oral TMX (800 mg/160 mg twice daily) or6 intravenous ertapenem (1 g once daily) for women (Table After 1–5 days of EPE-active intravenous antibiotics switchover to treatmenten Table .Table 1P5) and oral amoxicillin/clavulanic acid (500/125 mg three times daily5) for both men and women.After 1–5 days of EPE-active intravenous antibiotics switch-over to treatment totalling 10 days of oral pivmecillinam . After patients are dismissed, the allocation-blinded outcome-assessor (the research nurse) will ask the participant whether he or she has taken all the medicines as prescribed, if not why, and how the participant perceived the treatment tolerability, and if any he or she have received any further antibiotic prescriptions for UTI since recruitment to the trial. Even though this pragmatic monitoring cannot guarantee adherence with certainty, it is similar to the how the medications would be used in the clinic. The recruiting physician will further validate that the participants have collected their study drug prescription, and that they have not received any further prescriptions, during the retrospective medical journal review.We make no restrictions on concomitant care or interventions during the trial.We have no plan for ancillary or post-trial care or compensation for the participants. This is a pragmatic trial comparing widely used medications.Clinical cure 10 days  after antibiotic treatment completion defined as being alive with absence of fever (≥ 38.3 °C) and resolution of, or return to non-infected baseline of, urinary tract symptoms (as defined in inclusion criteria) without hospital readmission (for UTI symptoms) or additional antibiotic treatment (for UTI symptoms) based on a structured telephone interview performed by a centralised allocation-blinded study nurse.Participants’ perception of treatment tolerability on a 1–10 scale.Early study drug discontinuation.Additional antibiotic subscriptions (for UTI) within 28 days from randomisation.Proportion of patients re-admitted to hospital (due to UTI symptoms) within 28 days from randomisation.Drug-related serious adverse events within 28 days from randomisation.All-cause mortality within 28 days from randomisation.3 CFU/mL) 10 +/− 2 days after antibiotic treatment.Growth of EPE  in urine culture . If preliminarily eligible, the microbiologist will inform the locally recruitment responsible infectious disease physician who will then screen the remaining inclusion and exclusion criteria. Participants can also be recruited directly by an infectious disease physician at each site if they find a patient that is eligible and was not detected by the surveillance system.We estimate that recruitment of 330 participants will take 3 to 4 years based on the following unpublished data. There were 190 EPE-positive cultures from 130 adults in Region Västmanland , Sweden, in year 2020. This corresponds to 46 persons per 100,000 inhabitants per year. The catchment area for the eight sites that have so far agreed to recruit patients adds up to just above 2 million persons. If we assume that one in five persons with a positive EPE-culture is eligible for the study and one in two eligible persons can be recruited, it will take 3.6 years to complete recruitment for the trial.We will use a computer-generated blocked random number sequence with stratification for sex and site. We have chosen to stratify by sex because of diverging results in some previous trials for males  and femaThe allocation sequence will be implemented into, and concealed within, REDCap’s internet-based randomisation application .An independent statistician from Clinical Studies Sweden—Forum South  will genTrial participants and in-patient care providers will not be blinded to interventions in this pragmatic trial. Neither will the treating physician who assesses secondary endpoints 2-8. However, the central outcome assessor of the primary outcome will be blinded to interventions, as will the trial investigators, data analysts and author group. When data is extracted from the REDCap database, the allocation will be coded as “1” and “2” and the Code Key will only be revealed after statistical evaluation of the primary and secondary endpoints.Because care providers and patients are not blinded, there is no reason to unblind for safety of care. The Data Monitoring Committee (DMC) will be able to unblind the database if there are clearly more reports of possibly or probably study drug-related serious adverse events than expected.Baseline data and allocation will be entered into the REDCap database using a short and study-specific electronic case report form (eCRF) directly when assessing eligibility and assigning allocation by the physician who recruited the participant. The trial investigators will instruct a limited number of physicians at participating centre how to access and fill out the eCRF and provide a step-by-step guide and contact information for technical assistance. The primary outcome and the secondary outcomes 2-4 will be assessed using a semi-structured interview with a trial-specific guideline and entered into a separate part of the REDCap eCRF. The first 10 participants’ interview responses will be checked for conformity between at least two study nurses. The remaining secondary outcomes will be assessed retrospectively through medical chart review and from microbiological results by the recruiting physician at 30–60 days after the patient was allocated and then entered into a final separate part of the eCRF. The retrospective chart review will also serve as a sensitivity analysis to the telephone interview for the primary outcome and the secondary outcomes of early drug discontinuation and further antibiotic prescription. A copy of the REDCap eCRF (English) and semi-structured interview guideline (Swedish) can be sent on request.Since the follow-up is via telephone and done centrally, we expect that retention will be high. If the central outcome assessor cannot reach the participant, they will contact the recruiting physician who will check if the participant is deceased through the medical chart. Participants who are not reported dead and still cannot to be reached for the telephone interview follow-up will not qualify for analysis of the primary outcome or bacterial culture-related outcomes but can be assessed retrospectively from medical chart review regarding 28-day mortality, which is important for the evaluation of harm. We suspect that patients who deviate from the prescribed intervention will often be categorised as a negative outcome in the primary outcome assessment (e.g. new antibiotic prescribed), while some will simply be regarded as protocol violations. However, if a participant chooses to discontinue the trial, any collected data will be discarded, and the participant will only appear as a figure in the study flow chart.All data entry will be done electronically, except for code keys and informed consent forms. The eCRF in the REDCap database uses data range checks. The primary outcome and secondary outcomes 2-4 will be double-checked retrospectively against the medical journal by the treating physician 30–60 days after randomisation. Individual patient data will be handled as ordinary chart records and will be kept according to the European General Data Protection Regulation (GDPR). All original records (i.e. code keys and consent forms) will be retained in a locked cabinet at each participating centres infectious disease department for 25 years to allow inspection by relevant authorities. The coded trial database will be maintained for 25 years if requested for revision. Standardised data management procedures can be provided on request from Clinical Trials Sweden—Forum South.At the time of randomisation, participants will be assigned a trial ID number which will be used on all the personal information containing documents . The code key will be kept in a locked cabinet at each participating centre which can only be accessed by the limited number of physicians who can recruit patients. The coded information will be kept in an electronic database which requires two-step verification for login. When data from the study is published in a peer-reviewed medical journal, personal data will not be identifiable.Post-treatment urine and rectal specimens will be financed by the trial but sent to each participating centre’s microbiological laboratory and will be evaluated as per clinical routine and susceptibility testing according to EUCAST guidelines. Only culture positive findings of EPE are noted, and samples will be discarded after 2 weeks from collection without further analysis. Isolates from original urine and blood samples collected from participants at the coordinating microbiology centre (Lund) will be saved in the microbiology department’s freezer storage for preliminary future study of PAC MIC.U test. The remaining secondary outcomes  will also be analysed using GEE and reported as a risk difference with 95% confidence interval. Risk differences will be presented in a forest plot. If the telephone interview and the retrospective review report different parameters for the primary outcome , we will always choose the conservative option and consider this a failure.The primary outcome will be analysed between two groups using generalised estimated equations (GEE) using an identity link and binomial family , with sin = 165). Blinded data will be delivered by an independent statistician to the Data Monitoring Committee (DMC) who will then provide an allocation-blinded recommendation to the trial investigators whether to continue, hold or terminate the trial prematurely. The recommendation is based on safety and futility. Safety is based on three parameters, the number of possibly related serious adverse events, the number of early study drug discontinuations and the number of deaths within 28 days. It is difficult to provide fixed stopping criteria for safety since these events are expected to be very few, and the DMC have to assess frequency, severity and possible relationship to the study drug and give their best advice accordingly. Futility is defined as less than 5% probability of finding non-inferiority in the final analysis based on conditional power simulations as suggested by Bratton et al. [An interim analysis will be performed once half of the patients have been included  for the number of days of intravenous antibiotics (as a continuous variable) prior to allocation in addition to the baseline GEE model with a fixed effect for sex and a random effect for site. Secondly, we will perform an unadjusted analysis without fixed or random effects. Third, we will also analyse and report the primary outcome based on retrospective chart review versus results from the primary telephone interview. Fourth, we will also perform and report the primary outcome analysis results based on subgroups for the three different control drug allocations . Lastly, we will analyse and report results for each sex separately. The last two analyses mentioned are underpowered and cannot provide base for stating individual drug non-inferiority but could provide information of interest for future trial designs.We will analyse the population both as intention-to-treat , modified intention-to-treat  and per protocol . We will only state non-inferiority if all three types of analyses provide concordant results . If resuAll variables will be screened for frequency and type of missingness . Multiple imputation with chained equations will be used if missingness is above 5% in any variable included in the primary or secondary analysis. In the case of missingness, data with multiple imputation will be regarded as the primary analysis and complete case analysis will be performed as a sensitivity analysis.This protocol is planned for publication in an open access journal. We plan to publish the statistical code for the primary and secondary outcome analyses as a supplement to the main manuscript publication. Participant-level data can be accessed from the corresponding author on reasonable request.The trial steering committee (SC) consists of the principal investigator (OL) and the co-principal investigator (JT) who will meet in-person or via video link at least on a monthly basis. They are responsible for overseeing the trial and disseminating any changes. At each site, a small team of physician will be instructed and given access to the protocol, study flow chart and the eCRF so that they can recruit patients. They will receive at least one introductory trial-specific education by a member of the protocol author group on site or via video link. The SC will also be available via e-mail, work phone number or video link for questions from the locally responsible trial physician at any of the sites, on a day-to-day basis if needed. On-site responsible physician will receive study updates at least every 6 months. The primary outcome assessor will have access to the SC on a weekly basis.The Data Monitoring Committee (DMC) will consist of three physician scientists and one biostatistician. Professor Niklas Nielsen will lead the DMC. He has extensive experience with running RCTs and is a professor and consultant in intensive care. Jonas Öberg, specialist in infectious disease, and Erik Senneby, PhD and specialist in clinical microbiology, will also be members of the DMC. The investigators are jointly responsible with the DMC for safeguarding the interests of participating patients and for the conduct of the trial. The DMC will be advisory to the trial investigators regarding the safety and efficacy of the trial. The DMC will be responsible to make a recommendation from blinded data at the interim analysis regarding safety and futility (see above). They will also be informed about serious adverse events (SAE) reported by the trial investigators on a half year basis but can request additional monitoring for SAE at any time. The DMC will meet live at least once for the interim analysis and are recommended to have online meetings at least every half year when SAE reports are delivered. The DMC can request unblinding from the SC if they believe that it is needed to make a valid recommendation.Because the trial evaluates well-known and well-used drugs, we have an agreement with the Swedish Medical Products Agency to primarily focus on severe adverse events  is defined as any adverse medical event in a patient who has received a study drug. Non-serious incidents are further divided into mild, moderate or severe (as defined below). Relationship between incident and study drug are defined unlikely, possible or probable, as defined below. Incidents that are judged to be related to the study drug will be followed up to enable an assessment of reversibility.Clinical Trials Sweden—Forum South will monitor the trial with a risk-based approach in accordance with ICH GCP E6(R2). The monitoring purpose is to safeguard the study participants rights and well-being, the validity and completeness of study data collection and to ensure that the study conduct is in accordance with the protocol and ethical and regulatory demands. Monitors will have a live or web-based start-up meeting with each participating site before the study is initiated and conduct two monitor visits during the 3–4 years of patient recruitment for the trial. The first visit will be after 2–5 participants have been recruited and the second visit after 10 additional participants have been recruited, or after 1 year if less than 10 participants have been recruited. The primary monitoring focus will be on informed consent, adverse events reporting and consistency of data entry into the eCRF. The monitor will remind recruiting physician to do the retrospective review. If the monitor discovers major deviations from the protocol, further monitoring visits will be planned. Clinical Trials Sweden—Forum South is a collaboration between Sweden's six healthcare regions (including the sponsor) and is supported and funded by the Swedish Research Council and is independent from the trial investigators. The study will be performed in compliance with the study protocol, the Declaration of Helsinki, ICH-GCP  guidelines and current national and international regulations governing this clinical trial. In case of an inspection or an audit, the investigator will give direct access to source data in the trial to representatives of the regulatory authority (in case of an inspection) and to the representatives of the sponsor (in case of an audit).The steering committee are responsible for disseminating any important protocol modifications to the ethical board, the Medical Products Agency, the monitoring agent, locally responsible physicians and trial participants in accordance with which party is affected. Extensive changes or safety concerns will be communicated directly by phone and moderate changes by e-mail within 1 week. If there are no changes and the trial runs as planned, we will update site responsible physicians in the least every 6 months. All trial updates will also be posted on the trial-specific homepage www.pacuti.se.We plan to publish the trial results in a peer-reviewed medical journal.Choosing a non-inferiority design always constitutes a compromise in scientific validity compared to a placebo-controlled superiority trial. However, giving patients with serious infections placebo is not ethical, and because EPE-causing febrile UTI is (yet) uncommon in Sweden, we considered a non-inferiority trial to be the best compromise. This enables a high possibility for completing the trial with our available resources and within a reasonable timeframe. The implementation of a surveillance system for EPE in urine and blood cultures in Swedish microbiology departments should be an effective method to ensure consistent recruitment.Preferably, the treating and recruiting physician and other healthcare personnel would be blinded to treatment allocation. With our design, using three oral and one intravenous antimicrobial, with one to three doses daily, it was overwhelming to us, both in complexity and cost, to design a completely blinded intervention. This non-blinding may affect how patients are treated and how the protocol is adhered. Part of this bias may be managed by analysing the primary outcome both as ITT, mITT and PP. We have put efforts into keeping the primary outcome assessor blinded and stringent in their assessment through the use of a few trained centralised assessors using a study-specific structured interview.We have chosen to evaluate microbiological cure as a secondary outcome and not include it in the composite clinical cure outcome in contrast to a recently published comparable trial . This chWe consider there to be a low risk of harm from participating in this trial since all drug-specific medications are well-known and widely used. The major risk from a patient perspective is if the intervention is inferior to control. We try to minimise this potential for harm through an interim analysis once half of the intended population has been randomised.If this trial can show non-inferiority, the potential benefit is the addition of another safe, well-tolerated treatment alternative in the era of antimicrobial resistance. This could, in the best of worlds, improve patient autonomy, lower health-care costs and decrease the drive for further resistance.Protocol version 1.0 (1 December 2020): first protocol draftProtocol version 2.0 (21 January 2021): lightly revised protocol sent for ethical and Swedish Medicine Agency approvalProtocol version 3.0 (10 Sept 2021): major protocol revision to fit Trials journal guidelines and sample size update to 330 participantsProtocol version 4.0 (5 May 2022): references update and changed responsibilities of trial statisticianProtocol version 5.0 (30 Sept 2022): major changes in primary outcome evaluation from live visit to centralised telephone interview and addition of third alternative (ertapenem) in control groupProtocol version 5.1 (7 Oct 2022): updates on funding and microbiological samplingProtocol version 5.2 (27 Oct 2022): updates on DMC responsibilitiesProtocol version 5.3 (15 Nov 2022): update on endpoint definition and outcome assessment if discordanceProtocol version 6.1-6.2 (15 Dec 2022): update on adverse events and interactions by request from the Swedish Medical Products AgencyProtocol version 6.3 (31 Jan 2023): updated background with PAC rationaleProtocol version 6.4 (27 Feb 2023): final revision after comments by co-authorsTrials journal regarding SPIRIT item 32, reference checking and an elaboration regarding the choice not to include microbiological cure in the primary composite outcome and a clarification that the statistical analysis is between two groups even though the control group comprises three different drugs.Protocol version 6.5 : minor revision at The first study participant was recruited on 19 April 2023 and recruitment is expected to be completed in year 2026.


While radiologists can describe a fracture’s morphology and complexity with ease, the translation into classification systems such as the Arbeitsgemeinschaft Osteosynthesefragen (AO) Fracture and Dislocation Classification Compendium is more challenging. We tested the performance of generic chatbots and chatbots aware of specific knowledge of the AO classification provided by a vector-index and compared it to human readers. In the 100 radiological reports we created based on random AO codes, chatbots provided AO codes significantly faster than humans  though not reaching human performance (max. chatbot performance of 86% correct full AO codes vs. 95% in human readers). In general, chatbots based on GPT 4 outperformed the ones based on GPT 3.5-Turbo. Further, we found that providing specific knowledge substantially enhances the chatbot’s performance and consistency as the context-aware chatbot based on GPT 4 provided 71% consistent correct full AO codes for the compared to the 2% consistent correct full AO codes for the generic ChatGPT 4. This provides evidence, that refining and providing specific context to ChatGPT will be the next essential step in harnessing its power. The Arbeitsgemeinschaft Osteosynthese (AO) classification is an established system for fracture evaluation and adherence streamlines workflows and allows for optimized patient care, improved diagnostic accuracy and treatment planning, and ultimately better patient outcomes -based algorithms employing large language models (LLM) can address this by comprehending and interpreting human language. OpenAI introduced ChatGPT to a wide audience in November 2022. This chatbot, specifically trained for conversation, is based on a generative pre-trained transformer and the latest iteration GPT 3.5-Turbo. ChatGPT and especially using GPT 4  were shown to provide substantial medical knowledge being able to pass the United States Medical Licensing Examination (USMLE)5, transferring radiological reports into plain language by simplifying them7, or providing clinical decision support on differential diagnoses, diagnostic procedures, final diagnosis, and treatment8.ChatGPT enables rapid processing of complex information and its potential applications in clinical radiology routines have been extensively explored and published in preprints. These comprise the preparation of radiological reportsHowever, ChatGPT is limited to its training data (GPT 3.5-Turbo and GPT 4 trained on data up to September 2021) and thus may not have access to the latest and most specialized knowledge, or might be biased due to the large number of different sources of training data. Therefore, ChatGPT could provide incorrect or incomplete information.9. For this, data was structured via the LlamaIndex python library. This allows for connecting this specific data to a general LLM in a modular fashion.Recently, the feasibility of enhancing ChatGPT’s performance to produce recommendations according to imaging appropriateness guidelines was demonstrated by providing specialized knowledge to the chatbotWe sought to create an AO classification criteria context-aware chatbot (FraCChat) to provide accurate fracture classification based on the report text. To explore this approach, we benchmarked radiologists and publicly available generic chatbots based on GPT 3.5-Turbo and GPT 4 against the FraCChat chatbot built upon GPT 3.5-Turbo and GPT 4 and enhanced with knowledge of the AO classification criteria using a vectorized knowledge index.A schematic of the study workflow is depicted in Fig. To develop and evaluate the proposed FraCChat chatbots, we relied on the AOOTA Fracture and Dislocation Classification Compendium—2018 as a foundational knowledge base.https://github.com/jerryjliu/llama_index Version 0.5.0). Text information was extracted from the classification compendium and an index was created using the GPTVectorIndex function of LlamaIndex. For this, the document text was divided into smaller chunks of up to 512 tokens (a measure of text content) and converted to data nodes. These nodes were then encoded using an embedding model (text-embedding-ada-002-v2 by OpenAI) and the result was stored in a dictionary-like structure.We employed LlamaIndex as an interface between external data and the GPT 3.5-Turbo or GPT 4  and the five best matching data nodes from the index were retrieved. These nodes were used in the answer creation method using either GPT 3.5-Turbo or GPT 4. As a new input the task based on the given prompt, the case and the references where presented as new input to the language model with an overarching prompt to answer the given task based on the presented information. The final output was then captured.The chatbots’ accuracy in comparison to human performance was tested in a scenario resembling clinical routine. For this, 100 radiological reports describing fractures were created. From the more than 500 options of the AO classification , we randomly chose 100. This resulted in 14 cases for humerus, 1 for scapula, 4 for clavicle, 9 for radius, 4 for ulna, 9 for femur, 3 for patella, 14 for tibia, 7 for tibia/fibula, 3 for fibula, 12 for pelvis, 12 for hand/carpus and 8 for the foot. Groundtruth AO codes for the case files comprised information on bone, segment and type of fracture in all cases while information on group was available in 73% and on subgroup in 56%.The reports were then created by an experienced resident describing the fracture in a manner sufficient for classification.The 100 case files were presented to two radiologists and classified independently according to the AO classification. During this assessment consultation of guidelines was allowed.We utilized a script-based approach on the 100 case files to perform a fivefold repetition testing for all four chatbots. From this, the median of the performance of the five runs was calculated.The performance of humans and chatbots was assessed through qualitative analysis of the different levels of the AO classification extracted from the full AO code: (I) full AO code, (II) bone location, (III) part of the bone, (IV) type of fracture, (V) group, and (VI) subgroup. To compare the respective outputs of humans and chatbots, we employed a Generalized Linear Mixed Model (GLMM) with a binomial family (logit link) to investigate the relationship between the dependent variable "rating" and the independent variable "method." The rating method  was included as a fixed factor, while allowing for random intercepts for the „case “ and the „rater “.The consistency of the chatbots was evaluated by comparing the proportion of correct answers that were provided consistently across all five runs versus inconsistently provided correct answers. For this, we calculated the ratios and employed one-sided chi-squared test to assess whether more consistent correct answers were provided than inconsistent ones.To investigate time-effectiveness, we investigated the time to decision per human reader and chatbot and compared this duration via student’s t-test.Both radiologists (with access to the AO classification documents) classified the reports according to the AO with high accuracy as they both provided the correct full AO code in 95% of the cases and even higher proportions of correct classifications were noted for the location, fracture type and group.In contrast, the chatbots generally performed inferiorly as given in Tables Analysis of consistency revealed a higher proportion of consistently correct answers for the context-aware chatbots across all investigated levels of the AO code. Further, we observed that context-aware chatbots did provide significantly more consistently correct answers for the levels type and subgroup, while generic chatbots did not. Details are provided in Table Duration to provide answers on the 100 case files was substantially lower for the generic chatbots than for human readers . In addition, generic chatbots were significantly faster than context-aware chatbots  and chatbots based on GPT 3.5 were both faster than the respective GPT 4 based one (both p < 0.001).In this study, we assessed the feasibility of generic and context-aware chatbots to provide AO fracture classification codes from radiological reports. Though the time needed to provide AO classification was significantly lower for chatbots than humans, we observed an inferior performance compared to human radiologists. However, we found that providing specific knowledge substantially enhances the chatbot’s performance and consistency and not being inferior to human rating in terms of location, part of bone, fracture type and group.10. AI based methods are also available for image-based fracture classification, but mostly are limited to a particular region of the body. For example, for the ankle11, the distal radius12, the hip13 and the knee14, convincing results were obtained by deep learning and the respective AO classifications derived directly from the image dataset.Various AI approaches have been proposed for fracture detection based on the image dataset, reaching to whole-body approaches as commercially available toolsOur approach follows a different track—human radiologists are easily capable of adequately describing a fracture in terms of its morphology and complexity. The translation of this description into the respective AO code classification was performed by an AI approach in this proof-of-concept work. Although we did not reach the performance of a human classifier on all levels of the AO system but only for location, part of bone, fracture type and group, we were able to show that chatbots based on LLM are very well suited for this purpose and might improve workflows as they are more time efficient than human radiologists. In addition, the provision of specialized knowledge showed a clear superiority over generic chatbots; not only the performance but also the consistency were substantially improved.15 or fracture site16. Deep learning-based NLP methods using Convolutional Neural Networks have shown improved performance compared to classical NLP approaches. However, these approaches require rather large datasets as the performance scales with the amount of training data as shown for classification of hip fractures or smoking status17. In contrast to those specifically trained models, the method of providing specific knowledge via a vector index to a pretrained generic LLM comes with several advantages. The LlamaIndex interface offers a flexible data connector between an existing data source and LLM, structuring and optimizing data. Through this, the specific knowledge base can be exchanged swiftly and independently of the original LLM, removing the need of a task specific trained or fine-tuned model. Furthermore, the generated index is editable and individual references can be added or deleted . In return, an existing index can be provided to a new LLM as content, avoiding the need for resource-consuming re-training of the AI algorithm itself.Previous studies employed natural language processing (NLP) to extract data from radiology reports. Good performance was found in NLP algorithms that were specifically trained to extract fracture presence7 or passing United States Medical Licensing Examination questions4. Further improvement in performance is expected with newer GPT models and better vector indices as we noted a significant increase in performance and consistency for GPT 4 based generic and context-aware chatbots over the GPT 3.5-Turbo based variants. This might also address the limitation we encountered with all chatbots in the case of the complex hindfoot fracture (AO 89A). Here, the chatbots mostly correctly classified the individual fractures of the talus and the calcaneus, but did not manage the translation to AO 89A. An interesting pattern was observed in the case file for AO 2U3A3. Despite the description of "multiple bone fragments", the chatbots incorrectly classified 2U2 whereas the human raters assigned the correct AO code.The significantly higher performance of chatbots based on GPT version 4 compared with 3.5-Turbo is corroborated by recent studies on the simplification of radiological reportsPotential applications of the presented approach go beyond just supporting AO classification in clinical routine, but extent to retrospective analyses of existing reports and comparison with further procedures of the patients for quality control. In addition, the extension to other classification systems is also conceivable as well as providing information on evidence-based therapies with provision of the respective evidence in clinical routine. Nevertheless, this approach requires validation with real-world case files to test the generalizability.In conclusion, we found that a context-aware chatbot can derive structured information on fracture classification from radiological reports. Though not reaching human performance, the time consumption was significantly lower.We nevertheless provide evidence that refining and providing specific context to ChatGPT will be the next essential step in harnessing its power.


Visceral crisis is a life-threatening clinical condition requiring urgent treatment and accounts for 10–15% of new advanced breast cancer diagnoses, mainly hormone receptor-positive/human epidermal growth factor 2 negative. As its clinical definition is an open topic with nebulous criteria and much room for subjective interpretation, it poses a challenge for daily clinical practice. International guidelines recommend combined chemotherapy as first-line treatment for patients with visceral crisis, but with modest results and a very poor prognosis. Visceral crisis has always been a common exclusion criterion in breast cancer trials, and the available evidence mainly comes from limited retrospective studies which are not sufficient to draw solid conclusions. The outstanding efficacy of innovative drugs, such as CDK4/6 inhibitors, questions the role of chemotherapy in this setting. In the lack of clinical reviews, we aim to critically discuss the management of visceral crisis, advocating future treatment perspectives for this challenging condition. Breast cancer (BC) is the most common malignancy and the leading cause of cancer death in women worldwide . Thanks Actually, the clinical presentation of advanced breast cancer (ABC) includes a wide spectrum of signs and symptoms. They may be related to the primary tumour  or to the secondary site of disease: skeletal pain in bone metastases, respiratory symptoms in lung or pleural disease, abdominal pain in peritoneal involvement and neurological symptoms in brain lesions. Sometimes the onset of the disease or its progression is dramatically sudden, leading to a rapid deterioration of general conditions and/or organ functions that can be life-threatening. This critical clinical presentation, which occurs in about 10–15% of all ABC diagnoses, is commonly referred to as visceral crisis (VC) .The clinical definition of VC is a rather open topic. The term “visceral crisis” was first adopted in the second ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 2) to indicate a condition of severe organ dysfunction that does not mean “the mere presence of visceral metastases, but implies important visceral compromise leading to a clinical indication for more rapidly efficacious therapy” . BecauseThe incidence of VC reflects both the general epidemiological distribution of each BC subtype and their unique aggressive behaviour, eventually deriving the hormone receptor-positive (HR+) ABC as the most common subtype in the VC series. Actually, this is the only case for which current guidelines explicitly recommend a therapeutic indication other than the standard one: CT over endocrine therapy (ET) ,6,7. ThiUntil recently, there was no prospective evidence on the treatment of ABC patients with VC, as this has always been a common exclusion criterion for most BC trials. Consequently, all data on patient characteristics, prognosis and treatment in this unique clinical condition come from a few retrospective series Two case reports demonstrated the efficacy of tailored management for patients with lymphangitic carcinomatosis treated with eribulin (HR+/HER2- ABC) or paclitaxel, trastuzumab and pertuzumab in personalised doses (HER2+ ABC), achieving both positive symptom control and a partial radiological response ,14.biomp = 0.23). Of note, all treated patients received at least one dose of CT in the last 5 weeks before death [In a retrospective query of a Moroccan database, Sbitti et al. reported a median overall survival (mOS) of only 4.7 weeks in 35 patients with HR+/human epidermal growth factor 2 (HER2) negative ABC who met criteria for VC. 35% of these patients were not eligible for CT and directly addressed to best supportive care, while the remaining 65% received different CT regimens: epirubicin plus cyclophosphamide (25%), paclitaxel plus bevacizumab (20%) and docetaxel (20%). Apart from the very poor prognosis of all these patients, CT did not result in any significant survival benefit compared to best supportive care . Resolution of VC proved to be an important prognostic factor with a large difference in mOS compared to no resolution , and a prognosis similar to patients without VC at baseline. Indeed, 42.6% of patients with VC received at least one dose of CT in the last 30 days of their life. Poor PS, hyperbilirubinaemia and a higher number of previous lines of treatment (>3) were independent prognostic factors for OS .A Japanese retrospective study investigated the feasibility and efficacy of combining paclitaxel and bevacizumab in a cohort of 44 ABC women diagnosed with VC. A total of 80% and 20% of them were HR+ and triple-negative (TNBC), respectively. The proportion of patients still on treatment after 3 months was 68% and mOS was about 1 year (323 days). Weekly administration and paclitaxel dose adjustment resulted in a safety profile comparable to that previously reported with this combination; nonetheless, 30% of patients permanently discontinued treatment due to adverse events .Dawood et al. examined a US real-world database (TriNetX Platform) and identified 336 patients (17.8%) with VC at diagnosis among 5966 patients with HR+/HER2- ABC between 2015 and 2020. They showed that VC was a strong negative prognostic factor: the mOS in VC and in non-VC patients was 8.1 and 21 months, respectively. Interestingly, 61 VC patients (18%) were treated with a CDK4/6 inhibitor, resulting in a 5-month benefit in mOS compared to patients who received CT  [A retrospective analysis of medical records of consecutive breast cancer patients treated in a Chinese hospital from 2018 to 2022 identified 133 patients who met the criteria for VC . All HER2-positive patients received anti-HER2 therapy (trastuzumab and pertuzumab for the vast majority and an antibody-drug conjugate (ADC) for the remainder). In the HR+ population, patients received endocrine therapy in about one-third of the cases . The remaining part of the HR+ and all TNBC patients received CT . Overall, the mOS was 11.2 months. According to the different VC types, the best prognosis was observed in patients with bone marrow VC (mOS 18 months), while liver and meningeal carcinomatosis VC were associated with significantly worse outcomes . Interestingly, patients in the luminal-like subgroup treated with ET had significantly longer mOS compared to the CT group . In multivariate analysis, ECOG PS and the type of VC were found to be independently associated with survival. A lower rate of adverse events (AEs), grade ≥ 3 AEs and dose reductions due to AEs were observed with ET and anti-HER2 therapy than with CT .Finally, the phase II RIGHT Choice trial presented at the 2022 San Antonio Breast Cancer Symposium was the first prospective study to evaluate a CDK4/6 inhibitor versus CT in a study population that included patients with VC. Previously untreated peri- and premenopausal patients with symptomatic visceral metastases or rapid disease progression or impending visceral compromise or marked symptomatic non-visceral disease were included. Patients were randomised to receive ribociclib plus an aromatase inhibitor and goserelin or a combination CT of the physician’s choice . More than half of the patients in both arms , were diagnosed with VC as determined by the investigators. Ribociclib plus ET doubled PFS and halved the risk of progression or death  and achieved similar ORR and time to onset of response compared with the physician’s choice combination CT. No new safety signals were observed with ribociclib; rates of treatment-related adverse events were lower and the need for dose reductions was less than with CT [The Right Choice is the first head-to-head trial demonstrating the superiority of ribociclib over CT in both efficacy and safety in VC. A number of clinical trials with other CDK4/6 inhibitors are currently ongoing on this topic to further investigate this issue. Two single-arm phase II trials are investigating abemaciclib (NCT04681768) and dalpiciclib (NCT05431504) plus ET in HR+/HER2- ABC with clinical features meeting the criteria for VC. Finally, the ABIGAIL trial (NCT04603183) is evaluating the efficacy and safety of abemaciclib in combination with ET compared to upfront CT with paclitaxel followed by endocrine maintenance therapy  in HR+/HER2- ABC with aggressive disease features. VC is a unique and challenging clinical condition associated with an immediate threat to life and the need for urgent and effective intervention. From a clinical practical perspective, it is not so easy to outline what a VC actually is, and the lack of defined clinical criteria has left clinicians much room for interpretation. This is probably one of the main reasons why for years oncologists prescribed more CT than indicated in HR+/HER2- ABC, often in combination rather than in sequential regimens ,22. To pIn the absence of established criteria, the definition of a VC seems to be essentially based on the subjective clinical perception of a potentially fatal condition that urgently requires the most effective treatment available. This is closely related to the idea of a one-shot treatment: the visceral organs are on the cusp of compromise and if the treatment of choice does not work quickly, there is very likely that there is no other therapeutic option for this patient. From this point of view, choosing the right treatment is extremely important. While current guidelines still recommend a combined CT as the preferred option, the fifth edition of ABC questions its role for the first time. In recent years, drugs with unique and innovative mechanisms of action have dramatically changed the therapeutic scenarios of ABC . CDK4/6 inhibitors prevent the G1/S transition of the HR + tumour cell cycle and block the downstream pathway that ultimately leads to the activation of E2F transcription factors, promoting DNA replication and progression through the S phase . Figure Despite the outstanding results, the critical nature and likely poor prognosis of VC have meant that these patients have always been excluded from breast cancer trials, so these drugs have not been properly tested in this setting. The retrospective series reported in the literature are mainly related to CT, and data on CDK4/6 inhibitors or anti-HER2 target therapies are reported only in limited cases. They are also very heterogeneous in terms of definition, population and outcomes.The definition of VC varies widely in this series. The heterogeneity of these studies lies not only in the definition and distribution of VC types but also in the clinicopathological characteristics of the patients . According to real-world epidemiology, HR+/HER2- ABC is the most common BC subtype; when included in the study, TBNC and HER2+ diseases do not represent more than 15–20% of the population each ,17,19. AAll these selection biases led to very different results that were difficult to compare , already prefer CDK4/6 inhibitors over CT even in patients with VC; moreover, their use appears to be feasible and effective, without relevant concerns about the safety profile ,19. The Finally, in terms of potential future prospects, the ADC class could also become extremely interesting for VC, as it has shown unprecedented efficacy with extremely high and fast objective response rates in pre-treated ABC patients with different BC subtypes, including HR+ ,31. TherVC is still a clinical challenge for oncologists with many unresolved questions. In the absence of established criteria, the central pivot of its definition is essentially the immediate threat to the patient’s life from the burden of the disease. Since it has traditionally been an exclusion criterion from most breast cancer trials, this patient group cannot benefit from the innovative and extraordinarily effective drugs that are increasingly enriching the therapeutic scenario of ABC. Therefore, the treatment indication for VC is still CT based on old indirect comparisons with regimens that are now outdated and suboptimal. Recent prospective data clearly highlight that newer drugs such as CDK4/6 inhibitors are likely to replace CT in HR+/HER2- BC cases. Further dedicated trials are advocated, also to explore new classes of drugs such as ADCs, which have all the prerequisites to play a role in this context as well. Finally, in the absence of consolidated prognostic factors, the fine line between the appropriateness of active treatment and the need for palliative care poses a challenge to the proper decision-making process.


The aim of this study was to investigate to what extent PD affects the ability to walk, respond to balance perturbations in a single training session, and produce acute short-term effects to improve compensatory reactions and control of unperturbed walking stability. Understanding the mechanism of compensation and neuroplasticity to unexpected step perturbation training during walking and static stance can inform treatment of PD by helping to design effective training regimens that remediate fall risk. Current rehabilitation therapies are inadequate at reducing falls in people with Parkinson’s disease (PD). While pharmacologic and surgical treatments have proved largely ineffective in treating postural instability and gait dysfunction in people with PD, studies have demonstrated that therapy specifically focusing on posture, gait, and balance may significantly improve these factors and reduce falls. The primary goal of this study was to assess the effectiveness of a novel and promising intervention therapy  to improve balance and reduce falls in people with PD. A secondary goal was to understand the effects of PST on proactive and reactive feedback responses during stance and gait tasks. Multiple-baseline, repeated measures analyses were performed on the multitude of proactive and reactive performance measures to assess the effects of PST on gait and postural stability parameters. In general, the results indicate that participants with PD were able to use experiences with perturbation training to integrate and adapt feedforward and feedback behaviors to reduce falls. The ability of the participants with PD to adapt to changes in task demands suggests that individuals with PD could benefit from the protective step training to facilitate balance control during rehabilitation. Postural Instability and Gait Dysfunction (PIGD), a subset of PD symptoms describing impaired standing posture and balance, bradykinetic gait features, freezing of gait (FOG), and falls, is a disabling condition that, unlike other cardinal features of PD, is often not adequately treated by dopaminergic medications. Fall incidence rates among the PD population are estimated to range as high as 50–70%, with many individuals suffering recurrent falls, and these falls are a major cause of injury and disability. It is estimated that healthcare expenditures related to these falls exceeded $27 billion in 2013 , studiesvia both feedforward (predictive) and feedback (reactive) mechanisms , defined as balance training using repeated, external perturbations, is one such method of therapy that has demonstrated improvements in balance and fall recovery in multiple populations . Severalchanisms . Predictchanisms . Studieschanisms , making Recent literature for PST in populations with PD is represented in The primary goal of this study was to assess the effectiveness of two kinds of PST (anterior translations of a split-belt forceplate during (1) forward gait and (2) static postural stability tasks) to improve balance and stability in people with PD by better understanding the effects of PST on proactive and reactive feedback responses during stance and gait. We hypothesized that PD patients will be able to learn in an explicit, feedforward manner, adjusting base of support prior throughout walking trials to prepare for unexpected perturbation, but may be unable to improve reactive response variables such as reaction time and strategy. This work may enhance the clinician’s ability to treat balance/gait disturbances leading to falls in people with PD utilizing protective step training.2.2.1.Twelve participants diagnosed with PD by a movement disorders neurologist were recruited for this study . Participants were included in the study if they were able to ambulate without assistance, had no known neurologic, cardiovascular, or orthopedic deficit that could significantly impact cognition and functional performance , and had a Hoehn & Yahr (H&Y) score between II-III. Subjects were excluded if they exhibited functionally disabling dyskinesia or dystonia, orthostatic hypotension, neurosurgical intervention (deep brain stimulation), and any significant musculoskeletal or metabolic disorders. All subjects were examined during the “on” dopaminergic medication state, having taken their last dose approximately 1–1.5 h prior to testing. Disease severity and clinical scales of symptoms were tested in the “on” state utilizing the H&Y scale (2.2.1), Timed Up-and-Go Test (TUG1), Short Physical Performance Battery Test (SPPB1), postural stability in both the eyes-open and eyes-closed conditions , and 2-min of treadmill walking (TW1). Following baseline trials, participants in the first group commenced postural perturbation (PP) training during stance while the second group commenced gait perturbation (GP) training during walking. Both groups were instructed to maintain their balance and avoid a fall when introduced to unexpected perturbations. Upon completion of the respective training paradigms, a ‘washout’ period was introduced in which the groups performed a second 2-min treadmill walking trial (TW2) to observe any after-effects from baseline. Following this period, the two groups crossed over and commenced the alternate perturbation training paradigms. Finally, both groups performed a final 2-min treadmill walking trial (TW3) along with the post-training tests performed during baseline testing: OG2, TUG2, SPPB2, PSEO2, and PSEC2. All perturbations occurred on each participant’s dominant leg. A schematic of the study design is presented in Prior to baseline testing, two 3-min walking sessions were given to the participants to familiarize themselves with the treadmill and the laboratory environment. The first session was primarily for familiarizing and adapting to the treadmill. Following this session, the participant was given a rest period and encouraged to ask questions or bring up any concerns with the task. The second session was used to standardize the participant’s preferred walking speed (PWS) that they would be using throughout the trials. In this session, walking speed was increased incrementally until participants indicated that the speed was consistent with their normal walking speed. The walking speed was then increased in 0.1 m/s increments until the participant expressed discomfort or reported the speed to be inconsistent with their normal walking speed. Following the familiarization period, the protocol began with a series of baseline tests: 2-min of overground walking (OG2.3.1-12) of unexpected perturbations. Participants began walking unperturbed for a baseline period of approximately 15 s. The subsequent 10 s following the baseline period are designated as the perturbation window: a 10-s window in which the subject is given an unexpected anterior translation of the right treadmill belt  at the instant of right heel contact, i.e., the perturbed step. This translation resulted in the displacement of the subject’s COM, in which participants were instructed to restore their balance. Following the perturbed step and the subsequent recovery duration, participants walked unperturbed until they were able to match their preferred walking speed again.Perturbation training protocol was based on previous study on young and older adults without PD . The pro1-12). Participants were instructed to stand upright with their arms by their sides and look straight ahead. The training began with participants in quiet stance for approximately 15 s. Following this static period, a simultaneous anterior translation of both treadmill belts was induced with an acceleration of 8 m/s2 and duration of 0.1 s. Akin to the GP training, the resulting platform translation resulted in the displacement of the subject’s COM, in which participants were instructed to restore their balance.The protective step training protocol during stance, i.e., postural perturbation (PP) training, evaluated standing balance maintenance given 12 unexpected perturbation blocks  of stride intervals and the signal regularity (MSE) of center of mass (COM) velocities – were unfiltered during the analysis. All analysis was performed using custom Matlab routines .GRAIL system  was utilized to simulate both types of  perturbations. GRAIL consisted of a dual-belt instrumented treadmill equipped with dual embedded force plates in a speed-matched virtual environment projected on a semi-cylindrical screen  . Subject2.5.hc). Adaptive behavior was determined by comparing responses from GP11 and GP12, with GP1. Regarding PP training, predictive postural adjustments were assessed from the 15 s of quiet standing prior to the perturbation. The whole-body center-of-mass (COM) dynamics, base of support (BOS), and angular kinematics of the trunk, knee, and ankle in the sagittal plane delineated any changes to feedforward control prior to a perturbation. Adaptive behavior was assessed by comparing responses from the last two perturbation blocks (PP11 and PP12)-Post-test-with the initial block (PP1) – Pre-test. Joint angles were measured from perthc, while joint angle range of motion (ROM) was standardized from the minimum and maximum angles within the dominant leg’s normalized gait cycle just prior to perthc. Angles were calculated by the segmental method for determining 2D joint angles by the means of cardan sequences and a 6 degrees of freedom model. Relative angle was determined between the local coordinate systems of each proximal and distal segment. The angles chosen for sagittal plane analysis were trunk flexion/extension , knee flexion/extension (defined by the long axis of the tibia with respect to the long axis of the femur), and ankle plantar and dorsiflexion determined by the shank and foot segments. For knee joint angles, full extension was defined as zero degrees and movement into flexion being positive. Regarding ankle angles, zero was set at 90° to delineate plantarflexion and dorsiflexion. Plantarflexion was set as the negative degrees. In the frontal plane, lateral trunk flexion was measured as the angle between a vertical line bisecting the contralateral ASIS (perpendicular to the ground) and a line from the ASIS to the AC joint marker. Feedforward responses from gait were analyzed from the 15 s of unperturbed walking prior to each perturbation. Spatiotemporal parameters and gait variability were extracted from the 10 steps prior to the perturbation, while dynamic stability was examined at the final heel contact before the perturbation (perthc) immediately following the perturbation (11 and GP12) was compared with the dynamic stability of the initial block (GP1), to evaluate adaptive feedback control. For PP training, reactive modifications from the first recovery step after the perturbation (rechc) was identified as the initial recovery mechanism. The end of the recovery period was identified as the zero-cross point of the COM velocity in the anteroposterior direction , which measures the movement of the COM relative to the base of support . Specifi1 and TW3). Measures of gait variability, complexity, and smoothness were employed to determine the sensitivity of the pre-and post-training effects. Variability was assessed by the RMS of COM accelerations  along with statistical measures of variability from spatiotemporal gait parameters: Standard deviation (SD) and coefficient of variation (CV). CV denotes the variability of a specific gait parameter normalized to its mean value; it is represented as a percentage (CV=SD/mean × 100). Gait complexity was measured by multiscale entropy (MSE). MSE is a regularity measure developed by Costa et al. (1-3) – were excluded from the analysis. The local average and the local SD of each time series were computed for each spatiotemporal parameter. Combined after-effects of the perturbation training were evaluated from continuous gait on the treadmill, both before and after testing  were tested using the normality and Leven’s tests. Correction for multiple follow-up comparisons was done using the Bonferroni correction. All other univariate analyses uses one-way split-plot repeated measures ANOVA with Greenhouse–Geisser correction for sphericity . The Subject effect is nested within the Group effect which was specified as random.The generalizability of two types of training programs (PST during stance and dynamic gait) and Pre-test and Post-test differences on dependent measures in 3.3.1.F1,10 = 5.662, p = 0.0386, effect size 0.259)  on the knee flexion angle or all other feedforward dependent measures in The results of the univariate repeated measures ANOVAs on all dependent measures associated with feedforward variables in e 0.259) . No sign3.2.Latency) showed significant improvement   was observed for the reactive adaptation variables in Compared to the initial unexpected perturbation block, reaction time (Time =0.352) . This su =0.352) . No sign3.3.1) and the 10–15 steps preceding the last perturbation block (GP12). Flexion angles of the trunk, hip, and knee of the perturbed limb (pertbhc) were significantly greater from GP1 to GP12, revealing feedforward adaptations in anticipation of the perturbation. These biomechanical modifications are characterized by the varying trunk     –11 and h = 0.05) , 13 and, = 0.33) , 15. Gro3.4.No significant differences were observed in any of the reactive parameters associated with recovery from a slip.4.The primary goal of this study was to assess how PD affects the ability to respond to slip specific perturbations and if one session of protective step training can produce short-term adaptations to improve walking and static balance control. A secondary goal was to determine the generalizability of two types of training programs (PST during stance and dynamic gait) and to what extent the perturbation-based balance training are specific and transferable to the nature of the perturbations experienced. At present, little is known regarding the effect of PD on the ability to react and adapt to standing and walking perturbations. For example, previous studies have shown improved adaptive capacity with perturbation responses in the mediolateral direction , 32. How1) and the final perturbation block (GP12). Particpants demonstrated significant feedforward adaptations in anticipation of the unexpected perturbation by significantly increasing trunk and hip flexions during walking along with higher heel contact velocity to veer away from untimely balance perturbations and adopting a more cautious gait to increase stability. However, this proactive effort may not have been fully realized in the current study as we found no significant differences in any of the reactive measures for these patients.The results in this study are consistent with previous studies regarding early PD, which reported proactive adjustments during postural stability and locomotor perturbation tasks , 7, 20. Predictive control is associated with supraspinal structures  involvinStudies have closely linked the striatal system to motor learning, , 35, 36,4.1.hc) were significantly greater compared to baseline, revealing feedforward adaptations in anticipation of the perturbation. Furthermore, heel contact velocity was increased in an effort to regain balance given a perturbation. The gait modification demonstrates the adoption of a more considered and vigilant gait to increase stability.Learning integration for both proactive (feedforward) and reactive (feedback) adaptations were analyzed from the gait and postural PST paradigm, 4.2.1stStep) – the time elapsed between perturbation onset and the first recovery step of the contralateral foot – showed no significant difference between baseline and the last perturbation trial. Similarly, the recovery period (TimeRec) – time elapsed from perturbation onset until the zero-cross of the anteroposterior COM velocity – also did not show improvement in their reactive recovery time.However, even after a significant effort of the feedforward system, the reactive responses to gait PST were not robustly impacted through a single session of 12 perturbations. Regarding walking slips, recovery step time  and may affect the strength of our conclusions. Given the heterogeneity of PD, further studies involving a larger number and a wider range of PD participants is warranted. Further, the present finding only looked at acute after-effects of compensatory and adaptive behavior modifications, directly after the intervention. The authors did not perform repeated measurements over a period of time to determine the efficacy of the adaptive responses and do not expect the after-effects to imprint over a longitudinal period. Further, observed feedback and feedforward behavior may be dependent on the specific type of the perturbations experienced and may not show transfer to other forms of perturbations. Future studies will investigate the longevity of the acute after-effects produced in the present study. Finally, these effects were associated with PD patients’ average H&Y score of 2.7, and further study linking these two assessments to create a personalized treatment program is highly recommended.Several limitation to this study should be considered when interpreting the findings. First, this was a preliminary study to elucidate the optimal dose and frequency, as well as the therapeutic index, to determine maximal efficacy for a PST dose–response relationship in PD populations. The present study applies only a single perturbation acceleration of 10 m/s6.PST is an efficient and effective way to discern reactive and proactive responses to therapeutic intervention. It has been suggested that this task-specific training approach may present a paradigm shift in fall prevention. While PD patients are still able to improve performance with practice, particularly in feedforward aspects of postural responses, reactive aspects of postural responses were not uniformly improved through practice. Because of this, patients with PD may require more training to achieve and retain motor learning and may require additional sensory information or motor guidance in order to facilitate this learning. These shortcomings in motor learning in PD could contribute to the degeneration in gait and balance often seen in the disease, as patients are unable to adapt to the gradual sensory and motor degradation. Research has shown that physical and exercise therapy can help PD patients to adapt new feedforward strategies to partially counteract these symptoms. In particular, balance, treadmill, resistance, and repeated perturbation training (PST) therapies have been shown to improve motor patterns in PD. However, much research is still needed to determine which of these therapies best alleviates which symptoms of PIGD, the needed dose and intensity of these therapies, the long-term retention effects, and the benefits of such technologies as augmented feedback, motorized perturbations, virtual reality, and weight-bearing assistance.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by Arizona State University Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.TL was responsible for compiling the sources used within this study and writing the drafted manuscript. TL, MO, and AL provided additional articles, discussed possible implications, and revised the manuscript. All authors contributed to the article and approved the submitted version.